Engineered polynucleotides for cell selective expression

Abstract

The disclosure features compositions or systems and uses thereof, comprising a first polynucleotide encoding a target molecule, optionally a second polynucleotide encoding an effector, repressor, or endonuclease molecule; optionally a recognition or cleavage site in the first or second polynucleotide, and optionally a repressor / effector binding site in the first polynucleotide. The disclosure also features compositions or systems and uses thereof, comprising a messenger RNA (mRNA) comprising (i) an open reading frame encoding a polypeptide, and (ii) at least six miR142 target sites.

Description

[0001] ENGINEERED POLYNUCLEOTIDES FOR CELL SELECTIVE EXPRESSION   CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application No.63 / 391,863, filed on July 25, 2022, the entire contents of which are hereby incorporated by reference. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on July 24, 2023, is named 45817-0112WO1.xml and is 263,327^bytes in size.   BACKGROUND Off-target effects are common and limit the utility of many drug candidates (Chartier, M., et al. BMC Pharmacol Toxicol 18, 18 (2017). While target-cell specificity is desirable in general for enhancing the safety of therapeutics, limiting off-target expression is especially important for some applications, e.g., gene editing where the genetic material of cells is permanently altered and / or the expression of toxic cargo in certain cell types, e.g., myeloid cells that release perforin (Dufait I. et al., Cancers (Basel).2019 Jun 11;11(6):808) or cancer cells that make the p53 upregulated modulator of apoptosis (PUMA) (Yu J, Zhang L. Oncogene.2008;27 Suppl 1(Suppl 1):S71-S83). This is particularly relevant in the case of gene therapy and mRNA therapeutics which have the potential to revolutionize vaccination, protein replacement therapies, and the treatment of genetic diseases (Kowalski P.S. et al., Mol Ther.2019 Apr 10; 27(4): 710– 728). Further, there is a need to better utilize the body’s own cells, such as hematopoietic stem cells and other immune cells, to treat a wide range of conditions such as cancers and hematological malignancies, autoimmune disorders, allergies, inherited and acquired disorders, etc. For instance, treatments such as allogeneic hematopoietic   stem cell transplantation are limited by the poor availability of matched donors and the mortality associated with the allogenic procedure due to graft vs host disease (GvHD) (Jalapothu D, et al. Front Immunol.2016;7:361). As an alternative to allogeneic HCT, an inherited genetic defect can be corrected in the patient's own hematopoietic cells by gene therapy. The isolated hematopoietic stem cell can be genetically modified and returned to the patient as an autologous transplant. However, it is challenging to deliver a relevant gene into all or a fraction of the affected cells of the body and sustain its therapeutic effect. Thus, there is a need to enable selective expression of therapeutic proteins in specific cells and tissues, as well as tuning that expression to achieve a desired expression profile and to limit off-target effects and enhance safety of treatments, with wide-ranging applications in immunotherapy and immune-oncology therapeutics, in vivo gene editing, stem cell transplantation, and gene therapies for various diseases. SUMMARY The present disclosure provides, inter alia, compositions or systems comprising a polynucleotide (e.g., a messenger RNA or DNA) encoding a polypeptide (e.g., a target molecule) with selective expression in cell types (e.g., hematopoietic stem and progenitor cells or mature immune cells), wherein the expression is dependent on the microRNA composition of the cells. In one aspect, the disclosure features a composition comprising a messenger RNA (mRNA) comprising (i) an open reading frame encoding a polypeptide, and (ii) one or more microRNA target sites present in hematopoietic stem and progenitor cells (HSPC miRts). In some embodiments, the one or more HSPC miRts comprise miR-126-3p, miR- 130a-3p, miR-10a-5p, miR-29a-3p, miR125a-5p, miR125b-5p, or miR196b-5p. In some embodiments, the polypeptide is a gene editor, a cytokine, an apoptotic protein, a transcription factor, a DNA-binding protein, a receptor, an enzyme, or a chimeric antigen receptor.   In some embodiments, the composition comprises one or more delivery agents selected from a group consisting of a lipid nanoparticle, a liposome, a lipoplex, a polyplex, a lipidoid, a polymer, a microvesicle, an exosome, a peptide, a protein, cells transfected with polynucleotides, hyaluronidase, nanoparticle mimics, nanotubes, and conjugates. In some embodiments, the composition comprises a lipid nanoparticle. In some embodiments, the lipid nanoparticle comprises an ionizable amino lipid of Formula (I): (I) or a salt thereof, wherein R’ais R’branched; wherein R’branchedis: ; wherein denotes a point of attachment; wherein Raα, Raβ, Raγ, and Raδare each independently selected from the group consisting of H, C2-12alkyl, and C2-12alkenyl; R2and R3are each independently selected from the group consisting of C1-14 alkyl and C2-14alkenyl; R4is selected from the group consisting of -(CH2)nOH, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, and , wherein denotes a point of attachment; wherein   R10is N(R)2; each R is independently selected from the group consisting of C1-6 alkyl, C2- 3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R5is independently selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H; each R6is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H; M and M’ are each independently selected from the group consisting of -C(O)O- and -OC(O)-; R’ is a C1-12alkyl or C2-12alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13. In some embodiments, the ionizable amino lipid has the formula: (Compound II) or a salt thereof. In some embodiments, the lipid nanoparticle further comprises a PEG-lipid. In some embodiments, the PEG-lipid has the formula: (Compound I). In some embodiments, the one or more HSPC miRts comprise at least one microRNA target site specific for miR126.   In some embodiments, the one or more HSPC miRts comprise at least two microRNA target sites specific for miR126. In some embodiments, the one or more HSPC miRts comprise at least one microRNA target site specific for miR130a. In some embodiments, the one or more HSPC miRts comprise at least two microRNA target sites specific for miR130a. In some embodiments, the one or more HSPC miRts comprise at least two microRNA target sites specific for miR126 and at least two microRNA target sites specific for miR130a. In some embodiments, the one or more HSPC miRts are in a non-coding region of the mRNA. In some embodiments, the 3’ untranslated region (UTR) of the mRNA comprises at least one HSPC miRts. In some embodiments, the 3’ UTR of the mRNA comprises at least two repeats of one HSPC miRts. In some embodiments, the 3’ UTR of the mRNA comprises six repeats of one HSPC miRts. In some embodiments, the 5’ UTR of the mRNA comprises at least one HSPC miRts. In some embodiments, the 5’ UTR of the mRNA comprises at least two repeats of one HSPC miRts. In some embodiments, the 5’ UTR of the mRNA comprises three repeats of one HSPC miRts. In some embodiments, the mRNA has one or more HSPC miRts in the 3’ UTR and the 5’ UTR.   In some embodiments, the mRNA has one or more of the following features: (1) an AU-rich element; (2) the one or more HSPC miRts comprise at least one mismatch to the microRNA that binds the one or more HSPC miRts; (3) structurally accessible UTRs; (4) a short polyA tail; and (5) the ability to form microRNA bridges when a microRNA binds to the one or more HSPC miRts. In some embodiments, the 5’ UTR and / or the 3’ UTR comprises an AU-rich element. In some embodiments, the 3’ UTR is 60%-90% AU-rich. In some embodiments, the 3’ UTR is about 70% AU-rich. In some embodiments, the one or more HSPC miRts comprise one to three mismatches to the microRNA that binds the one or more HSPC miRts. In some embodiments, the polyA tail is 20-100 nucleotides in length. In some embodiments, the microRNA bridge is formed by one or more miRts in the 5’ UTR and the 3’ UTR of the mRNA. In another aspect, the disclosure features a method of preferentially expressing a polypeptide in hematopoietic cell types other than hematopoietic stem and progenitor cells (HSPCs), the method comprising contacting a population of hematopoietic cells with a composition described herein, wherein the population of hematopoietic cells comprises HSPCs and hematopoietic cell types other than HSPCs. In some embodiments, the contacting of the population of hematopoietic cells occurs ex vivo. In some embodiments, the contacting of the population of hematopoietic cells occurs in vivo. In another aspect, the disclosure features a composition comprising:   (a) a first polynucleotide comprising (i) a repressor binding element, (ii) an open reading frame encoding a polypeptide, and (iii) optionally one or more microRNA target sites present in non-hematopoietic stem and progenitor cells (non-HSPC miRts); and (b) a second polynucleotide comprising (i) a sequence encoding a repressor that binds to the repressor binding element and (ii) one or more microRNA target sites present in hematopoietic stem and progenitor cells (HSPC miRts), wherein binding of the repressor to the repressor binding element reduces translation of the polypeptide from the first polynucleotide. In some embodiments, the one or more HSPC miRts comprise miR-126-3p, miR- 130a-3p, miR-10a-5p, miR-29a-3p, miR125a-5p, miR125b-5p, or miR196b-5p. In some embodiments, the one or more non-HSPC miRts comprise miR142-3p, miR150-5p, miR223-3p, or miR122-5p. In some embodiments, the polypeptide is toxic to HSPCs. In some embodiments, the polypeptide is a gene editor, a cytokine, an apoptotic protein, a transcription factor, a DNA-binding protein, a receptor, an enzyme, or a chimeric antigen receptor. In some embodiments, the one or more HSPC miRts comprise at least one microRNA target site specific for miR126. In some embodiments, the one or more HSPC miRts comprise at least two microRNA target sites specific for miR126. In some embodiments, the one or more HSPC miRts comprise at least one microRNA target site specific for miR130a. In some embodiments, the one or more HSPC miRts comprise at least two microRNA target sites specific for miR130a.   In some embodiments, the one or more HSPC miRts comprise at least two microRNA target sites specific for miR126 and at least two microRNA target sites specific for miR130a. In some embodiments, the one or more microRNA target sites are in the non- coding region of each of the first and second polynucleotides, wherein each of the first and second polynucleotides is an mRNA. In some embodiments, the 3’ UTR of the first and second polynucleotides each comprises one microRNA target site. In some embodiments, the 3’ UTR of the first and second polynucleotides each comprises at least two repeats of one microRNA target site. In some embodiments, the 3’ UTR of the first and second polynucleotides each comprises six repeats of one microRNA target site. In some embodiments, the 5’ UTR of the first and second polynucleotides each comprises one microRNA target site. In some embodiments, the 5’ UTR of the first and second polynucleotides each comprises at least two repeats of one microRNA target site. In some embodiments, the 5’ UTR of the first and second polynucleotides each comprises three repeats of one microRNA target site. In some embodiments, the mRNA has one or more HSPC miRts in the 3’ UTR and the 5’ UTR. In some embodiments, the mRNA has one or more of the following features: (1) an AU-rich element; (2) the one or more HSPC miRts comprise at least one mismatch to the microRNA that binds the one or more HSPC miRts; (3) structurally accessible UTRs; (4) a short polyA tail; and (5) the ability to form microRNA bridges when a microRNA binds to the one or more HSPC miRts.   In some embodiments, the 5’ UTR and / or the 3’ UTR comprises an AU-rich element. In some embodiments, the 3’ UTR is 60%-90% AU-rich. In some embodiments, the 3’ UTR is about 70% AU-rich. In some embodiments, the one or more HSPC miRts comprise one to eight mismatches to the microRNA that binds the one or more HSPC miRts. In some embodiments, the polyA tail is 40-100 nucleotides in length. In some embodiments, the microRNA bridge is formed by one or more miRts in the 5’ UTR and the 3’ UTR of the mRNA. In some embodiments, the first and the second polynucleotide each is an mRNA and comprises a polyA tail or is a DNA. In some embodiments, the one or more HSPC miRts in the second polynucleotide are in the non-coding portion of the second polynucleotide. In some embodiments, the one or more HSPC miRts in the second polynucleotide are (a) positioned between the sequence encoding the repressor and a polyA tail; or (b) positioned between a 5’ cap and a start codon, wherein the second polynucleotide is an mRNA. In some embodiments, the repressor binding element comprises a kink-turn forming sequence. In some embodiments, the repressor binding element is selected from the group consisting of PRE, PRE2, MS2, PP7, BoxB, U1A hairpin, and 7SK. In some embodiments, the repressor is selected from the group consisting of Snu13, 50S ribosomal L7Ae protein, Pumilio and FBF (PUF) protein, PUF2 protein, MBP-LacZ, MBP, PCP, Lambda N, U1A, 15.5kd, LARP7, L30e, and other RNA-binding proteins.   In some embodiments, the composition comprises one or more delivery agents selected from a group consisting of a lipid nanoparticle, a liposome, a lipoplex, a polyplex, a lipidoid, a polymer, a microvesicle, an exosome, a peptide, a protein, cells transfected with polynucleotides, hyaluronidase, nanoparticle mimics, nanotubes, and conjugates. In some embodiments, the composition comprises a lipid nanoparticle. In some embodiments, the lipid nanoparticle comprises an ionizable amino lipid of Formula (I): (I) or a salt thereof, wherein R’ais R’branched; wherein R’branchedis: ; wherein denotes a point of attachment; wherein Raα, Raβ, Raγ, and Raδare each independently selected from the group consisting of H, C2-12alkyl, and C2-12alkenyl; R2and R3are each independently selected from the group consisting of C1-14 alkyl and C2-14alkenyl; R4is selected from the group consisting of -(CH2)nOH, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, and , wherein denotes a point of attachment; wherein   R10is N(R)2; each R is independently selected from the group consisting of C1-6 alkyl, C2-3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R5is independently selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H; each R6is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H; M and M’ are each independently selected from the group consisting of -C(O)O- and -OC(O)-; R’ is a C1-12 alkyl or C2-12 alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13. In some embodiments, the ionizable amino lipid has the formula: (Compound II) or a salt thereof. In some embodiments, the lipid nanoparticle further comprises a PEG-lipid. In some embodiments, the PEG-lipid has the formula: (Compound I). In another aspect, the disclosure features a method of preferentially expressing a polypeptide in hematopoietic stem and progenitor cells (HSPCs), the method comprising   contacting a population of hematopoietic cells with a composition described herein, wherein the population of hematopoietic cells comprises HSPCs. In some embodiments, the contacting of the population of hematopoietic cells occurs ex vivo. In some embodiments, the contacting of the population of hematopoietic cells occurs in vivo. In another aspect, the disclosure features a method of expressing a polypeptide in a hematopoietic stem and progenitor cell (HSPC), the method comprising contacting the cell with: (a) a first polynucleotide comprising (i) a repressor binding element, (ii) an open reading frame encoding a polypeptide, and (iii) optionally one or more non-hematopoietic stem cell- microRNA target sites present in non-hematopoietic stem and progenitor cells (non-HSPC miRts), wherein modification of the one or more non-HSPC miRts reduces translation of the polypeptide from the first polynucleotide; and (b) a second polynucleotide comprising (i) a sequence encoding a repressor that binds to the repressor binding element and (ii) one or more microRNA target sites present in hematopoietic stem and progenitors (HSPC miRts), wherein the HSPC expresses one or more microRNAs that bind to the one or more HSPC miRts and reduces translation of the repressor from the second polynucleotide. In another aspect, the disclosure features a method of expressing a polypeptide in a hematopoietic stem and progenitor cell in a subject, the method comprising administering to the subject: (a) a first polynucleotide comprising (i) a repressor binding element, (ii) an open reading frame encoding a polypeptide, and (iii) optionally one or more microRNA target sites present in non-hematopoietic stem and progenitor cells (non-HSPC miRts), wherein   modification of the one or more non-HSPC miRts reduces translation of the polypeptide from the first polynucleotide; and (b) a second polynucleotide comprising (i) a sequence encoding a repressor that binds to the repressor binding element and (ii) one or more microRNA target sites present in hematopoietic stem and progenitor cells (HSPC miRts), wherein the HSPC expresses one or more microRNAs that bind to the one or more HSPC miRts and reduces translation of the repressor from the second polynucleotide. In another aspect, the disclosure features a composition comprising: (a) a first polynucleotide comprising (i) a repressor binding element, (ii) an open reading frame encoding a polypeptide, and (iii) optionally one or more microRNA target sites present in hematopoietic stem and progenitor cells (HSPC miRts); and (b) a second polynucleotide comprising (i) a sequence encoding a repressor that binds to the repressor binding element and (ii) one or more microRNA target sites present in non-hematopoietic stem and progenitor cells (non-HSPC miRts), wherein binding of the repressor to the repressor binding element reduces translation of the polypeptide from the first polynucleotide. In some embodiments, the one or more HSPC miRts comprise miR-126-3p, miR- 130a-3p, miR-10a-5p, miR-29a-3p, miR125a-5p, miR125b-5p, or miR196b-5p. In some embodiments, the one or more non-HSPC miRts comprise a microRNA target site present in an immune cell or in a hepatocyte. In some embodiments, the microRNA target site present in an immune cell is miR142-3p, miR150-5p, or miR223-3p. In some embodiments, the microRNA target site present in a hepatocyte is miR- 122-5p.   In some embodiments, the polypeptide is a gene editor, a cytokine, an apoptotic protein, a transcription factor, a DNA-binding protein, a receptor, an enzyme, or a chimeric antigen receptor. In some embodiments, the one or more microRNA target sites are in the non- coding region of each of the first and second polynucleotides, wherein each of the first and second polynucleotides is an mRNA. In some embodiments, the 3’ UTR of the first and second polynucleotides each comprises one microRNA target site. In some embodiments, the 3’ UTR of the first and second polynucleotides each comprises at least two repeats of one microRNA target site. In some embodiments, the 3’ UTR of the first and second polynucleotides each comprises six repeats of one microRNA target site. In some embodiments, the 5’ UTR of the first and second polynucleotides each comprises one microRNA target site. In some embodiments, the 5’ UTR of the first and second polynucleotides each comprises at least two repeats of one microRNA target site. In some embodiments, the 5’ UTR of the first and second polynucleotides each comprises three repeats of one microRNA target site. In some embodiments, the mRNA has one or more HSPC miRts in the 3’ UTR and the 5’ UTR. In some embodiments, the mRNA has one or more of the following features: (1) an AU-rich element; (2) the one or more HSPC miRts comprise at least one mismatch to the microRNA that binds the one or more HSPC miRts; (3) structurally accessible UTRs; (4) a short polyA tail; and (5) the ability to form microRNA bridges when a microRNA binds to the one or more HSPC miRts. In some embodiments, the 3’ UTR comprises an AU-rich element.   In some embodiments, the 3’ UTR is 60%-90% AU-rich. In some embodiments, the 3’ UTR is about 70% AU-rich. In some embodiments, the one or more HSPC miRts comprise one to three mismatches to the microRNA that binds the one or more HSPC miRts. In some embodiments, the microRNA bridge is formed by one or more miRts in the 5’ UTR and the 3’ UTR of the mRNA. In some embodiments, the first and second polynucleotide each is an mRNA and comprises a polyA tail or is a DNA. In some embodiments, the one or more microRNA target sites in the second polynucleotide are (a) positioned between the sequence encoding the repressor and a polyA tail; or (b) positioned between a 5’ cap and a start codon, wherein the second polynucleotide is an mRNA. In some embodiments, the repressor binding element comprises a kink-turn forming sequence. In some embodiments, the repressor binding element is selected from the group consisting of PRE, PRE2, MS2, PP7, BoxB, U1A hairpin, and 7SK. In some embodiments, the repressor is selected from the group consisting of Snu13, 50S ribosomal L7Ae protein, Pumilio and FBF (PUF) protein, PUF2 protein, MBP-LacZ, MBP, PCP, Lambda N, U1A, 15.5kd, LARP7, L30e, and other RNA-binding proteins. In some embodiments, the composition comprises one or more delivery agents selected from a group consisting of a lipid nanoparticle, a liposome, a lipoplex, a polyplex, a lipidoid, a polymer, a microvesicle, an exosome, a peptide, a protein, cells transfected with polynucleotides, hyaluronidase, nanoparticle mimics, nanotubes, and conjugates. In some embodiments, the composition comprises a lipid nanoparticle.   In some embodiments, the lipid nanoparticle comprises an ionizable amino lipid of Formula (I): (I) or a salt thereof, wherein R’ais R’branched; wherein R’branchedis: ; wherein denotes a point of attachment; wherein Raα, Raβ, Raγ, and Raδare each independently selected from the group consisting of H, C2-12 alkyl, and C2-12 alkenyl; R2and R3are each independently selected from the group consisting of C1-14 alkyl and C2-14alkenyl; R4is selected from the group consisting of -(CH2)nOH, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, and , wherein denotes a point of attachment; wherein R10is N(R)2; each R is independently selected from the group consisting of C1-6 alkyl, C2-3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R5is independently selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H; each R6is independently selected from the group consisting of C1-3alkyl, C2-3 alkenyl, and H;   M and M’ are each independently selected from the group consisting of -C(O)O- and -OC(O)-; R’ is a C1-12 alkyl or C2-12 alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13. In some embodiments, the ionizable amino lipid has the formula: (Compound II) or a salt thereof. In some embodiments, the lipid nanoparticle further comprises a PEG-lipid. In some embodiments, the PEG-lipid has the formula: (Compound I). In another aspect, the disclosure features a method of preferentially expressing a polypeptide in hematopoietic cell types other than hematopoietic stem and progenitor cells (HSPCs), the method comprising contacting a population of hematopoietic cells with a composition described herein, wherein the population of hematopoietic cells comprises HSPCs and hematopoietic cell types other than HSPCs. In some embodiments, the contacting of the population of hematopoietic cells occurs ex vivo. In some embodiments, the contacting of the population of hematopoietic cells occurs in vivo.   In another aspect, the disclosure features a method of expressing a polypeptide in a hematopoietic cell other than a hematopoietic stem and progenitor cell (HSPC), the method comprising contacting the cell with (a) a first polynucleotide comprising (i) a repressor binding element, (ii) an open reading frame encoding a polypeptide, and (iii) optionally one or more microRNA target sites present in hematopoietic stem and progenitor cells (HSPC miRts), wherein modification of the one or more HSPC miRts reduces translation of the polypeptide from the polynucleotide; and (b) an second polynucleotide comprising (i) a sequence encoding a repressor that binds to the repressor binding element and (ii) one or more non-HSPC miRts, wherein the hematopoietic cell expresses one or more microRNAs that bind to the one or more non-HSPC miRts and reduces translation of the repressor from the second polynucleotide. In another aspect, the disclosure features a method of expressing a polypeptide in a hematopoietic cell other than a hematopoietic stem and progenitor cell (HSPC) in a subject, the method comprising administering to the subject: (a) a first polynucleotide comprising (i) a repressor binding element, (ii) an open reading frame encoding a polypeptide, and (iii) optionally one or more microRNA target sites present in hematopoietic stem and progenitor cell (HSPC miRts), wherein modification of the one or more HSPC miRts reduces translation of the polypeptide from the first polynucleotide; and (b) a second polynucleotide comprising (i) a sequence encoding a repressor that binds to the repressor binding element and (ii) one or more non-HSPC miRts, wherein the hematopoietic cell expresses one or more microRNAs that bind to the one or more non- HSPC miRts and reduces translation of the repressor from the second polynucleotide.   In another aspect, the disclosure features a composition a first messenger RNA (mRNA) comprising (i) a first open reading frame encoding a first polypeptide, and (ii) at least six miR142 target sites. In some embodiments, the polypeptide is a secreted protein. In some embodiments, the at least six miR142 target sites are in the 3’ UTR of the first mRNA. In some embodiments, the at least six miR142 target sites each comprise the sequence UCCAUAAAGUAGGAAACACUACA (SEQ ID NO:191). In some embodiments, the at least six miR142 target sites each comprise the sequence UUACAAAAGUAGGAAACACUACA (SEQ ID NO:197). In some embodiments, the composition further comprises a second mRNA comprising (i) a second open reading frame encoding a second polypeptide, and (ii) at least one miR target site. In some embodiments, the second mRNA comprises at least two miR target sites. In some embodiments, the second mRNA comprises at least three miR target sites. In some embodiments, the second mRNA comprises at least four miR target sites. In some embodiments, the second mRNA comprises at least five miR target sites. In some embodiments, the second mRNA comprises at least six miR target sites. In some embodiments, the at least one, at least two, at least three, at least four, at least five, or at least six miR target sites of the second mRNA are miR142 target sites. In some embodiments, the at least one, at least two, at least three, at least four, at least five, or at least six miR target sites of the second mRNA each comprise the sequence UCCAUAAAGUAGGAAACACUACA (SEQ ID NO:191).   In some embodiments, the at least one, at least two, at least three, at least four, at least five, or at least six miR target sites of the second mRNA each comprise the sequence UUACAAAAGUAGGAAACACUACA (SEQ ID NO:197). In some embodiments, the at least one, at least two, at least three, at least four, at least five, or at least six miR target sites sites of the second mRNA are selected from the group consisting of miR-126-3p, miR-130a-3p, miR-10a-5p, miR-29a-3p, miR125a-5p, miR125b-5p, miR196b-5p, miR150-5p, miR223-3p, and miR-122-5p target sites. In some embodiments, the second mRNA does not comprise a miR142 target site. In some embodiments, the first and / or second mRNA comprise a 3’ UTR comprising the sequence UGAUAAUAGGCUGGAGCCUCAUUAAUCCAUAAAGUAGGAAACACUACAUA UAAAGUAAAAUUUCCAUAAAGUAGGAAACACUACACACCAUUUUAAUUAU CCAUAAAGUAGGAAACACUACAUAAUAAAAAUAAAGUCCAUAAAGUAGGA AACACUACAUAUAUAAUUCAUAGUCCAUAAAGUAGGAAACACUACAUACC CCCGUGGUCUUCCAUAAAGUAGGAAACACUACAUUAAAUAAAGUCUAAGU GGGCGGC (SEQ ID NO:154). In some embodiments, the first and / or second mRNA comprise a 3’ UTR comprising the sequence UGAUAAUAGGCUGGAGCCUCAUUAAUUACAAAAGUAGGAAACACUACAUA UAAAGUAAAAUUUUACAAAAGUAGGAAACACUACACACCAUUUUAAUUAU UACAAAAGUAGGAAACACUACAUAAUAAAAAUAAAGUUACAAAAGUAGGA AACACUACAUAUAUAAUUCAUAGUUACAAAAGUAGGAAACACUACAUACC CCCGUGGUCUUUACAAAAGUAGGAAACACUACAUUAAAUAAAGUCUAAGU GGGCGGC (SEQ ID NO:155). In some embodiments, the first and / or second mRNA comprise a 3’ UTR comprising the sequence UAAAGCUCCCCGGGGGCUGGAGCCUCAUUAAUUACAAAAGUAGGAAACAC UACAUAUAAAGUAAAAUUUUACAAAAGUAGGAAACACUACACACCAUUUU   AAUUAUUACAAAAGUAGGAAACACUACAUAAUAAAAAUAAAGUUACAAAA GUAGGAAACACUACAUAUAUAAUUCAUAGUUACAAAAGUAGGAAACACUA CAUACCCCCGUGGUCUUUACAAAAGUAGGAAACACUACAUUAAAUAAAGU CUAAGUGGGCGGC (SEQ ID NO:170). In some embodiments, the first and / or second mRNA comprise a 3’ UTR comprising the sequence UAAAGCUCCCCGGGGGCCUCAUUAAUUACAAAAGUAGGAAACACUACAUA UAAAGUAAAAUUUUACAAAAGUAGGAAACACUACACACCAUUUUAAUUAU UACAAAAGUAGGAAACACUACAUAAUAAAAAUAAAGUUACAAAAGUAGGA AACACUACAUAUAUAAUUCAUAGUUACAAAAGUAGGAAACACUACAUACC CCCGUGGUCUUUACAAAAGUAGGAAACACUACAUUAAAUAAAGUCUAAGU GGGCGGC (SEQ ID NO:171). In some embodiments, the composition comprises one or more delivery agents selected from a group consisting of a lipid nanoparticle, a liposome, a lipoplex, a polyplex, a lipidoid, a polymer, a microvesicle, an exosome, a peptide, a protein, cells transfected with polynucleotides, hyaluronidase, nanoparticle mimics, nanotubes, and conjugates. In some embodiments, the composition comprises a lipid nanoparticle. In another aspect, the disclosure features a method of expressing a polypeptide in a subject, the method comprising administering to the subject a composition comprising a messenger RNA (mRNA) comprising (i) an open reading frame encoding a polypeptide, and (ii) at least six miR142 target sites, as described above. In some embodiments, the method comprises multiple administrations of the composition to the subject. In some embodiments, the method comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten administrations of the composition to the subject.   Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.   BRIEF DESCRIPTION OF THE DRAWINGS FIGs.1A-E provide schematics of systems that provide cell-specific expression of target sequences. FIG.1A shows a system in which cell-specific microRNA binds to microRNA target sites (miRts) on polynucleotide (mRNA), leading to mRNA degradation and suppressing (turning OFF) target protein translation. FIG.1B shows a schematic of a polynucleotide encoding a target sequence, and having multiple microRNA target sites in the 3’ untranslated region (3’ UTR). FIG.1C shows a system in which microRNA binding to the miRts of a repressor encoding RNA turns ON expression of target RNA, by reducing expression of the repressor and thereby preventing the repressor from binding to the repressor binding site on the target RNA. FIG.1D shows a system in which microRNA binding to the microRNA target sites (e.g., miR150- ts or miR142-ts miRts) of a repressor encoding RNA turns ON expression of target RNA in mature immune cells, by reducing expression of the repressor and thereby preventing the repressor from binding to the repressor binding site on the target RNA. FIG.1E shows a system in which microRNA binding to a microRNA target site of a repressor encoding RNA turns ON expression of target RNA in HSPC, by reducing expression of the repressor and thereby preventing the repressor from binding to the repressor binding site on the target RNA. Alternatively, a pan-immune cell-specific microRNA binding to the microRNA target sites of a repressor encoding RNA, combined with a target that has miR-target sites to turn off expression in mature immune cells, turns ON expression of target RNA in HSC, by i) reducing expression of the repressor in all immune cells and thereby preventing the repressor from binding to the repressor binding site on the target RNA and ii) by further reducing the target RNA in mature immune cells FIG.2 depicts OX40L expression in various cell types in the presence of mOX40L reporter mRNA OFF system. C57BL / 6 mice were injected intravenously with 0.5 mg / kg mOX40L reporter mRNAs containing three miR-target-sites for the potential   HSC specific miR candidates, PBS (control), or mOX40L reporter mRNA with no miR target sites (miRless mOX40L group). mOX40L expression was analyzed in the bone marrow and spleen 24h post dose. The graphs show the % frequency of OX40L+ cells and geometric MFI of OX40L in LSK: Lin-Sca1+c-Kit+ progenitor cells, hematopoietic stem and progenitor cells (HSPCs) and in mature immune cells (macrophages) in the bone marrow. FIG.3 depicts the percentage suppression of mOX40L depicted in FIG.2 in a tabular form. % suppression is calculated as percentage frequency of mOX40L+ cells in a given cell type for a given miRts vs miRless for the same cell-type. HSCs: hematopoietic stem cells; HSPCs: hematopoietic stem and progenitor cells; Macs: macrophages; cDC1: Conventional type 1 dendritic cells; cDC2: Conventional type 2 dendritic cells; Ly6C-hi mono: monocytes expressing high level of Ly6C; Ly6C-lo mono: monocytes expressing low level of Ly6C; NK: Natural killer cells; CD8 T: CD8+ T cells; Neut: neutrophils; Eos: Eosinophils FIGs.4A-B depicts the percentage suppression of mOX40L in various cell types as indicated (HSC, HSPC, Mature BM, Multipotent progenitors (MPP), Common lymphoid progenitors (CLP), Granulocyte Monocyte Progenitors (GMP), Common Myeloid Progenitors (CMP), and Megakaryocyte-Erythrocyte Progenitors (MEP)) in the presence of mOX40L reporter mRNA OFF system. Lonza human bone marrow mononuclear cells were transfected with 500 ng of mOX40L reporter mRNAs containing the indicated miR-target-sites, mOX40L reporter mRNA with no miR target sites (miRless mOX40L group) or PBS (control). mOX40L expression was analyzed 24h post transfection. Each graph in FIG.4A shows the geometric MFI of mOX40L+ cells. FIG. 4B shows a summary table of the percentage suppression of OX40L in various cell types as indicated 24h post transfection. FIGs.5A-C depict the percentage suppression of OX40L in various cell types as indicated (Lin+, Lin- CD34+, HSC, MPP, CLP, GMP, and MEP) in the presence of mOX40L reporter mRNA OFF system. Lonza human bone marrow mononuclear cells were transfected with 500 ng of mOX40L reporter mRNAs containing the indicated miR-target-sites, mOX40L reporter mRNA with no miR target sites (miRless mOX40L   group) or PBS (control). mOX40L expression was analyzed 24h post transfection. The graph in FIG.5A shows the normalized % frequency of OX40L+ cells in the indicated cell types. The graph in FIG.5B shows the normalized geometric MFI of the mOX40L in the cell types. FIG.5C shows a summary table of the mOX40L percentage suppression for each cell type. FIGs.6A-B depict the percentage frequency of OX40L+ cells (FIG.6A), MFI of OX40L (FIG.6A), and the percentage suppression of OX40L (FIG.6B) in various cell types as indicated in the presence of mOX40L reporter mRNA OFF system.3M HSPC cells maintained ex vivo were plated in a 24 well plate and transfected with 100 or 500 ng mOX40L reporter mRNAs containing the indicated miR-target-sites, mOX40L reporter mRNA with no miR target sites (miRless mOX40L group) or PBS (control). mOX40L expression and MFI was measured by flow cytometry over a 6h-48h timecourse. The graphs in FIG.6A show the % frequency of OX40L+ cells and MFI of OX40L in the various cell types (HSC, Lin+, Lin- CD34+) at various timepoints as indicated. FIG.6B shows a summary table of the mOX40L percentage suppression for each cell type at various timepoints as indicated. One-way ANOVA comparisons were made to the miRless mOX40L group. Mature BM: Mature bone marrow cells; HSCs: hematopoietic stem cells; HSPCs: hematopoietic stem and progenitor cells; MPP: multipotential progenitor cells; CLP: common lymphoid progenitor cells; CMP: common myeloid progenitor cells; GMP: granulocyte / monocyte progenitor cells; MEP: megakaryocyte– erythroid progenitor cell FIGs.7A-B depicts the % frequency of OX40L+ cells (FIG.7A) and geometric MFI (FIG.7B) of mOX40L in stem / progenitor cells in the presence of the mOX40L reporter mRNA OFF system (top panel) or ON system (bottom panel). In the OFF system, human bone marrow mononuclear cells were transfected with 100 ng or 500 ng of mOX40L reporter mRNAs containing the indicated target-sites miR126ts, miR142ts, and miR150ts (Target_3XmiRts), mOX40L reporter mRNA with no miR target sites (control) or PBS. mOX40L expression was analyzed 24h post transfection. In the ON system, human bone marrow mononuclear cells were transfected with 100 ng or 500 ng of the mOX40L_D99K target with miRless repressor RNA (Repressor) or repressor RNA   containing target sites miR126ts, miR142ts, and miR150ts (Repressor_3XmiRts). mOX40L expression was analyzed 24h post transfection. FIGs.8A-B depict the % frequency of mOX40L+ cells and geometric MFI of mOX40L (total cells in FIG.8A, and OX40L+ cells in FIG.8B) in HSCs, HSPCs, and mature bone marrow cells in the presence of the mOX40L reporter mRNA OFF system. Human bone marrow mononuclear cells were transfected with 100 ng of mOX40L_D99K reporter mRNAs containing the indicated target-sites miR126ts, miR142ts, and miR150ts, mOX40L reporter mRNA with no miR target sites (miRless) or PBS. mOX40L expression was analyzed 24h post transfection. The experiment was run in triplicate. FIGs.9A-B depict the % frequency of OX40L+ cells and geometric MFI of OX40L in various cells as indicated (HSCs, HSPCs, and mature bone marrow cells Lin+ cells in FIG.9A; MPP, CLP, GMP, and MEP in FIG.9B) in the presence of the mOX40L reporter mRNA OFF system. Lonza bone marrow mononuclear cells were transfected with 100 ng of mOX40L_D99K reporter mRNAs containing the indicated target-sites miR10ats, miR126ats, miR130ats, and miR1542ats, mOX40L reporter mRNA with no miR target sites (miRless) or PBS. mOX40L expression was analyzed 24h post transfection. FIG.10 shows the various design modifications that can be employed for increasing efficacy of the miR target sites in ON / OFF systems in a polynucleotide construct. Ts#: number of target sites; AU = AU-rich element. FIG.11 shows the various design modifications that can be employed for increasing efficacy of the miR ON / OFF system in an exemplary polynucleotide construct. FIG.12 depicts the % frequency of OX40L+ cells and geometric MFI of OX40L in HSCs and monocytes in the presence of an mOX40L reporter mRNA OFF system. Human bone marrow mononuclear cells were transfected with 1 µg of the mOX40L_D99K target RNA without miR target sites(miRless), or containing 3XmiR126ts, or 2XmiR126ts+2XmiR130ats (AU, mm). mOX40L expression was analyzed 24h post transfection. AU=70% AU rich UTR; acc = predicted structurally accessible UTRs; mm=mismatch 18-21   FIG.13 depicts the % frequency of OX40L+ cells and geometric MFI of OX40L in HSCs and monocytes in the presence of an mOX40L reporter mRNA ON system. Human bone marrow mononuclear cells were transfected with 100 ng of the mOX40L_D99K target RNA with non-relevant filler RNA (hEPO control) or with various L7Ae repressor RNA constructs (each 0.5X molar) as follows: L7Ae repressor RNA alone (R_miRless); L7Ae repressor RNA containing miR126ts (R_3XmiR126); L7Ae repressor RNA containing miR130a (R_6XmiR130a (AU, mm)); and L7Ae repressor RNA containing 2XmiR126ts+2XmiR130ats (bridge, AU, mm). AU=70% AU rich UTR; mm=mismatch 18-21. mOX40L expression was analyzed 24h post transfection. FIG.14 depicts the % frequency of OX40L+ cells and geometric MFI of OX40L in HSCs and monocytes in the presence of an mOX40L reporter mRNA ON system. Human bone marrow mononuclear cells were transfected with 100 ng of the mOX40L_D99K target RNA with non-relevant filler RNA (control) or with various L7Ae repressor RNA constructs (each 0.5X molar) as follows: L7Ae repressor RNA without miR target sites (R_miRless); L7Ae repressor RNA containing miR142ts (R_3XmiR142); L7Ae repressor RNA containing miR150a (R_3XmiR150a (AU, mm)); and L7Ae repressor RNA containing 3XmiR150 ((R_3XmiR150). mOX40L expression was analyzed 24h post transfection. FIG.15 depicts the % frequency of OX40L+ cells and geometric MFI of OX40L in CD8+ T cells and HSCs in the presence of an mOX40L reporter mRNA ON system. Human bone marrow mononuclear cells and PBMCs were transfected with 100 ng of the mOX40L_D99K target RNA with non-relevant filler RNA (control) or with various L7Ae repressor RNA constructs (each 0.5X molar) as follows: L7Ae repressor RNA without miR target sites (R_miRless); L7Ae repressor RNA containing miR150ts (R_3XmiR150 (AU, mm)); L7Ae repressor RNA containing miR150 (R_3XmiR150 (structure prediction)); and L7Ae repressor RNA containing miR142 (R_3XmiR142). mOX40L expression was analyzed 24h post transfection. FIG.16A-D depicts the % frequency of OX40L+ cells and geometric MFI of OX40L in HSCs and monocytes total cells (FIG.16A), HSCs and monocytes OX40L+   cells (FIG.16B), in CD34+ HSPCs (FIG.16C), and in CD4+ T cells (FIG.16D) in the presence of an mOX40L reporter mRNA dual ON / OFF system. Human bone marrow mononuclear cells (in triplicate) were transfected with 1 µg of the mOX40L_D99K target RNA with non-relevant filler RNA (control) or with various L7Ae repressor RNA constructs (each 0.5X molar) as follows: L7Ae repressor RNA without miR target sites (R_miRless); L7Ae repressor RNA containing miR126ts (R_3XmiR126ts); L7Ae repressor RNA containing L7Ae repressor RNA containing both miR126ts and miR130ats (R_2XmiR126ts+2XmiR130a (bridge, AU, mm)); or L7Ae repressor RNA containing miR142ts (R_3XmiR142ts). R_2XmiR126ts+2XmiR130a (bridge, AU, mm) represents an L7Ae repressor RNA construct with further modifications - AU=70% AU rich UTR; mm=mismatch 18-21. Some combinations further included 0.5X molar L7Ae repressor RNA R_3XmiR150-OFF as indicated in the graphs. mOX40L expression was analyzed 24h post transfection. FIG.17 depicts the % frequency of OX40L+ cells and geometric MFI of OX40L in monocytes and HSCs in the presence of an mOX40L reporter mRNA ON system. Human bone marrow mononuclear cells were transfected with 100 ng or 500 ng of the mOX40L_D99K target RNA with non-relevant filler RNA (control) or with various L7Ae repressor RNA constructs (each 0.5X molar) as follows: L7Ae repressor RNA without miR target sites (R_miRless); L7Ae repressor; L7Ae repressor RNA containing miR150ts (R_3XmiR150ts (AU, mm)); L7Ae repressor RNA containing miR150ts (R_3XmiR150 (structure prediction)); and L7Ae repressor RNA containing miR142ts (R_3XmiR142). R_3XmiR150ts (AU, mm) and R_3XmiR150 (structure prediction) represent L7Ae repressor RNA constructs with further modifications - AU=70% AU rich UTR; mm=mismatch 18-21. mOX40L expression was analyzed 24h post transfection. FIG.18 depict the % frequency of OX40L+ cells in CD8+ T cells and HSCs in the presence of an mOX40L reporter mRNA ON system. Human bone marrow mononuclear cells and PBMCs were transfected with 1 µg or 500 ng of the mOX40L_D99K target RNA with non-relevant filler RNA (control) or with various L7Ae repressor RNA constructs (each 0.5X molar) as follows: L7Ae repressor RNA without miR target sites (R_miRless); L7Ae repressor RNA containing miR150ts   (R_3XmiR150ts (AU, mm)); L7Ae repressor RNA containing miR150ts (R_3XmiR150 (structure prediction)); and L7Ae repressor RNA containing miR142ts (R_3XmiR142). R_3XmiR150ts (AU, mm) and R_3XmiR150 (structure prediction) represent L7Ae repressor RNA constructs with further modifications AU=70% AU rich UTR; mm=mismatch 18-21. mOX40L expression was analyzed 24h post transfection. FIG.19 shows the trends of repression and rescue with miR-OFF and ON systems. FIG.20A is a graph depicting GFP protein AUC with mimic as a percentage of expression without mimic. mirVana miR mimic was transfected using lipofectamine 2000 at concentrations listed, along with eGFP reporter mRNAs containing 3XmiR150ts, 3XmiR150ts (AU, mm), or no miRts (miRless and miRless-AU), in HeLa cells. eGFP reporter expression was analyzed over 48h using Incucyte live cell imaging. FIG.20B is a table depicting representative data from the same experiment. FIG 20C is a graph depicting GFP protein AUC with mimic as a percentage of expression without mimic. mirVana miR mimic was transfected using lipofectamine 2000 at concentrations listed, along with eGFP reporter mRNAs containing 3XmiR150ts, 3XmiR150ts (AU, mm), 3xmiR150ts (accV2), 3xmiR150ts (accV1), or no miRts (miRless) in HEP3B cells. eGFP reporter expression was analyzed over 48h using Incucyte live cell imaging. In FIG.20D, human PBMCs (n=3 donors) were transfected at 100 ng with lipid nanoparticles containing mOX40L reporter mRNAs with the indicated target sites 3xmiR150ts, 3xmiR150ts_AU, 3xmiR150ts_mm_AU, or mOX40L reporter with no target sites (miRless) or with no target sites in the AU rich UTR (miRless_AU). mOX40L expression was analyzed 24h post transfection by flow cytometry. AU=70% AU rich UTR; mm=mismatch 18-21. Acc = predicted structurally accessible UTRs. FIGs.21A-B depict the AUC of total green fluorescence as a percentage of no mimic (FIG.21A) and AUC (FIG.21B). For FIG.21A, 20 ng eGFP reporter mRNAs containing indicated target sites 1XmiR122ts, 3XmiR122ts, 1XmiR122ts (AU, mm, bridge), 3XmiR122ts (AU, mm, bridge), or eGFP reporter with no target sites (miRless), and 10nM miR122 mimic were administered to HeLa cells using lipofectamine 2000. eGFP expression was analyzed over 48h using Incucyte live cell imaging. For FIG.21B,   HUH7 cells were transfected with 10 ng eGFP target RNA with non-relevant filler RNA (control), or with various L7Ae repressor RNA constructs (each 0.0625X molar) as follows: L7Ae repressor RNA without miR target sites (R_miRless); L7Ae repressor RNA containing 3XmiR122ts; L7Ae repressor RNA containing 3XmiR122ts (mm); L7Ae repressor RNA containing 3XmiR122ts (AU, mm); L7Ae repressor RNA containing 6XmiR122ts (AU, mm, bridge). eGFP expression was analyzed over 48h using Incucyte live cell imaging. AU=70% AU rich UTR; mm=mismatch 18-21, bridge = miRts in the 5’ and 3’UTR. FIGs.22A-C are graphs depicting the AUC of total green fluorescence. In FIG. 22A, RAW264.7 cells were transfected with10ng eGFP reporter mRNAs containing indicated target sites 1XmiR142ts, 3XmiR142ts, 3XmiR122ts (AU, mm, bridge) using lipofectamine 2000. eGFP expression was analyzed over 48h using Incucyte live cell imaging. In FIG.22B, RAW264.7 cells were transfected with 10 ng eGFP target RNA with non-relevant filler RNA (control), or with various L7Ae repressor RNA constructs (each 0.0625X molar) as follows: L7Ae repressor RNA without miR target sites (R_miRless); L7Ae repressor RNA containing 3XmiR142ts; L7Ae repressor RNA containing 6XmiR142ts (AU, mm, bridge). eGFP expression was analyzed over 48h using Incucyte live cell imaging. In FIG.22C, RAW264.7 cells were transfected with 10 ng eGFP target RNA with non-relevant filler RNA (control), or with various Puf repressor RNA constructs (each 0.2X molar) as follows: Puf repressor RNA with no miR target sites (R_miRless); Puf repressor RNA containing 3XmiR142ts (R_3X142ts); Puf repressor RNA containing 6XmiR142ts (R_6XmiR142ts (AU, mm, bridge)). eGFP expression was analyzed over 48h using Incucyte live cell imaging. AU=70% AU rich UTR; mm=mismatch 18-21, bridge = miRts in the 5’ and 3’UTR. FIGs.23A-B depict % V5 positive cells in mouse spleen (FIG.23A) and liver (FIG.23B). CD-1 mice, at 5 mice / group, were administered lipid nanoparticles IV containing 1 mg / kg NPI-Luciferase target mRNA with non-relevant filler mRNA or with various L7Ae repressor RNA constructs (each 0.5X molar) as follows: L7Ae repressor RNA without miR target sites (R_miRless); L7Ae repressor RNA containing 3XmiR142ts, (R_3XmiR142ts); L7Ae repressor RNA containing 3XmiR122ts,   (R_3XmiR122ts), L7Ae repressor RNA containing 6XmiR142ts, (R_6XmiR142ts (AU, mm, bridge); L7Ae repressor RNA containing 6XmiR122ts, (R_6XmiR122ts (AU, mm, bridge). Spleen and liver were collected at 6h post dose for IHC analysis. %V5 positive Kupffer cells in liver in FIG.23B were determined by brightfield colocalization.

[0002] FIGs.24A-B depict expression of FVIII. FIG.24A is a schematic showing the first dosing regimen. FIG.24B shows that FVIII mRNAs with mir142 targeting sequences show lower FVIII expression. FIG.25 shows that FVIII mRNAs with mir142 targeting sequences show low or no FVIII inhibitor formation. FIGs.26A-B depict expression of FVIII. FIG.26A is a schematic showing the second dosing regimen. FIG.26B shows that FVIII expression was maintained in HemA mice after repeated dosing of hFVIII mRNAs containing 6 mir142 targeting sequences in the 3’UTR. FIGs.27A-B depict expression of FVIII. FIG.27A is a schematic showing the second dosing regimen. FIG.27B shows FVIII mRNAs with mir142 targeting sequences show low or no FVIII inhibitor formation. FIG.28A are graphs showing expression of eGFP in THP-1 non-activated (left) and THP-1 activated (right) monocytes. Cells were transfected with eGFP reporter mRNAs containing indicated miR target sites. eGFP expression was analyzed. FIG.28B is a graph depicting the % frequency of OX40L+ cells. Molm-13 cells were transfected with mOX40L reporter mRNA with the indicated target sites. mOX40L expression was analyzed. FIG.28C are graphs showing expression of eGFP in HEL cells. Cells were transfected with eGFP reporter mRNAs containing indicated miR target sites. eGFP expression was analyzed. FIG.28D is a graph showing expression of eGFP in HeLa cells. Cells were transfected with eGFP reporter mRNAs containing indicated miR target sites. eGFP expression was analyzed. FIGs.29A-C are graphs depicting the % frequency of OX40L+ / eGFP+ cells in monocytes (FIG.29A), T cells (FIG.29B), and dendtrictic cells (FIG.29C). Human PBMCs, as noted, were transfected with eGFP and mOX40L reporter mRNAs containing indicated miR target sites. eGFP and mOX40L expression was analyzed.   FIG.29D is a graph showing expression of eGFP in CD11c+DC cells. Cells were transfected with eGFP reporter mRNAs containing containing indicated miR target sites. eGFP expression was analyzed. FIG.30 depicts the eGFP reporter expression from several mRNAs. A mimic experiment was done in which HeLa cells were transfected with a mirVana miR223 mimic across a dose range, along with eGFP reporter mRNAs containing the indicated miR target sites. eGFP reporter expression was analyzed. FIG.31 are graphs showing mOX40L expression. Spleens of Sprague Dawley rats were injected with 0.5mg / kg of mOX40L reporter mRNAs containing the indicated miR-target-sites. mOX40L expression in macrophages (left), T cells (middle), and B cells (right). FIG.32 are graphs showing the total green intensity. HeLa cells were transfected using with 10 nM, 1nM, or 0.2nM mirVana miR126 mimic or miR150 mimic along with mGreenLantern reporter mRNAs with the indicated miR target sites. Reporter expression was analyzed. FIG.33 are graphs showing total green intensity. HeLa cells were transfected using with 10 nM, 1nM, or 0.2nM mirVana miR126 mimic along with mGreenLantern reporter mRNAs with the indicated miR target sites. Reporter expression was analyzed. FIGs.34A-C show that 6xmm and ‘bridge’ designs perform comparably. The findings of FIG.34A are depicted in tabular form in FIG.34B. Similar studies were done in THP1 and Hep3b cells. Degree of knockdown achieved for the noted constructs are shown in FIG.34C. DETAILED DESCRIPTION Efforts to limit off-target effects of RNA-based therapeutics have focused on turning off expression of the therapeutic RNA in undesired cells and locations. The present disclosure is based on the discovery that RNA expression can be turned on or off in specific cells (ON and / or OFF systems), thereby permitting targeted and precise therapeutic and / or prophylactic action and preventing off-target effects. Further, the present disclosure is based on the discovery that various design modifications can be   employed for increasing efficacy of micro RNA target sites in polynucleotide constructs for delivery. Accordingly, disclosed herein are compositions or systems comprising polynucleotide constructs that are dependent on endogenous microRNAs in specific cells to express the polypeptide of interest, and minimize off-target expression Definitions Administering: As used herein, “administering” refers to a method of delivering a composition to a subject or patient. A method of administration may be selected to target delivery (e.g., to specifically deliver) to a specific region or system of a body. For example, an administration may be parenteral (e.g., subcutaneous, intracutaneous, intravenous, intraperitoneal, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection, as well as any suitable infusion technique), oral, trans- or intra-dermal, interdermal, rectal, intravaginal, topical (e.g., by powders, ointments, creams, gels, lotions, and / or drops), mucosal, nasal, buccal, enteral, vitreal, intratumoral, sublingual, intranasal; by intratracheal instillation, bronchial instillation, and / or inhalation; as an oral spray and / or powder, nasal spray, and / or aerosol, and / or through a portal vein catheter. Preferred means of administration are intravenous or subcutaneous. Approximately, about: As used herein, the terms “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value). For example, when used in the context of an amount of a given compound in a lipid component of an LNP, “about” may mean + / - 5% of the recited value. For instance, an LNP including a lipid component having about 40% of a given compound may include 30-50% of the compound.   Contacting: As used herein, the term “contacting” means establishing a physical connection between two or more entities. For example, contacting a cell with an mRNA or a lipid nanoparticle composition means that the cell and mRNA or lipid nanoparticle are made to share a physical connection. Methods of contacting cells with external entities both in vivo, in vitro, and ex vivo are well known in the biological arts. In exemplary embodiments of the disclosure, the step of contacting a mammalian cell with a composition (e.g., a nanoparticle, or pharmaceutical composition of the disclosure) is performed in vivo. For example, contacting a lipid nanoparticle composition and a cell (for example, a mammalian cell) which may be disposed within an organism (e.g., a mammal) may be performed by any suitable administration route (e.g., parenteral administration to the organism, including intravenous, intramuscular, intradermal, and subcutaneous administration). For a cell present in vitro, a composition (e.g., a lipid nanoparticle) and a cell may be contacted, for example, by adding the composition to the culture medium of the cell and may involve or result in transfection. Moreover, more than one cell may be contacted by a nanoparticle composition. Delivering: As used herein, the term “delivering” means providing an entity to a destination. For example, delivering one or more polynucleotides of this disclosure to a subject may involve administering a composition (e.g., an LNP including the one or more polynucleotides) to the subject (e.g., by an intravenous, intramuscular, intradermal, pulmonary or subcutaneous route). Administration of a composition (e.g., an LNP) to a mammal or mammalian cell may involve contacting one or more cells with the composition. Effective amount: As used herein, the term “effective amount” of an agent is that amount sufficient to effect beneficial or desired results, for example, clinical results, and, as such, an “effective amount” depends upon the context in which it is being applied. For example, in the context of the amount of a target cell delivery potentiating lipid in a lipid composition (e.g., LNP) of the disclosure, an effective amount of a target cell delivery potentiating lipid is an amount sufficient to effect a beneficial or desired result as compared to a lipid composition (e.g., LNP) lacking the target cell delivery potentiating lipid. Non-limiting examples of beneficial or desired results effected by the lipid   composition (e.g., LNP) include increasing the percentage of cells transfected and / or increasing the level of expression of a protein encoded by a nucleic acid associated with / encapsulated by the lipid composition (e.g., LNP). In the context of administering a target cell delivery potentiating lipid-containing lipid nanoparticle such that an effective amount of lipid nanoparticles are taken up by target cells in a subject, an effective amount of target cell delivery potentiating lipid-containing LNP is an amount sufficient to effect a beneficial or desired result as compared to an LNP lacking the target cell delivery potentiating lipid. Non-limiting examples of beneficial or desired results in the subject include increasing the percentage of cells transfected, increasing the level of expression of a protein encoded by a nucleic acid associated with / encapsulated by the target cell delivery potentiating lipid-containing LNP and / or increasing a prophylactic or therapeutic effect in vivo of a nucleic acid, or its encoded protein, associated with / encapsulated by the target cell delivery potentiating lipid-containing LNP, as compared to an LNP lacking the target cell delivery potentiating lipid. In some embodiments, a therapeutically effective amount of target cell delivery potentiating lipid-containing LNP is sufficient, when administered to a subject suffering from or susceptible to an infection, disease, disorder, and / or condition, to treat, improve symptoms of, diagnose, prevent, and / or delay the onset of the infection, disease, disorder, and / or condition. In another embodiment, an effective amount of a lipid nanoparticle is sufficient to result in expression of a desired protein in at least about 5%, 10%, 15%, 20%, 25% or more of target cells. For example, an effective amount of target cell delivery potentiating lipid-containing LNP can be an amount that results in transfection of at least 5%, 10%, 15%, 20%, 25%, 30%, or 35% of target cells after a single intravenous injection. Expression: As used herein, “expression” of a nucleic acid sequence refers to one or more of the following events: (1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by 5′ cap formation, and / or 3′ end processing); (3) translation of an RNA into a polypeptide or protein; and (4) post-translational modification of a polypeptide or protein.   Ex vivo: As used herein, the term “ex vivo” refers to events that occur outside of an organism (e.g., animal, plant, or microbe or cell or tissue thereof). Ex vivo events may take place in an environment minimally altered from a natural (e.g., in vivo) environment. Modified: As used herein “modified” refers to a changed state or structure of a molecule of the disclosure, e.g., a change in a composition or structure of a polynucleotide (e.g., mRNA). Molecules, e.g., polynucleotides, may be modified in various ways including chemically, structurally, and / or functionally. For example, molecules, e.g., polynucleotides, may be structurally modified by the incorporation of one or more RNA elements, wherein the RNA element comprises a sequence and / or an RNA secondary structure(s) that provides one or more functions (e.g., translational regulatory activity). Accordingly, molecules, e.g., polynucleotides, of the disclosure may be comprised of one or more modifications (e.g., may include one or more chemical, structural, or functional modifications, including any combination thereof). In one embodiment, polynucleotides, e.g., mRNA molecules, of the present disclosure are modified by the introduction of non-natural nucleosides and / or nucleotides, e.g., as it relates to the natural ribonucleotides A, U, G, and C. Noncanonical nucleotides such as the cap structures are not considered “modified” although they differ from the chemical structure of the A, C, G, U ribonucleotides. mRNA: As used herein, an “mRNA” refers to a messenger ribonucleic acid. An mRNA may be naturally or non-naturally occurring. For example, an mRNA may include modified and / or non-naturally occurring components such as one or more nucleobases, nucleosides, nucleotides, or linkers. An mRNA may include a cap structure, a chain terminating nucleoside, a stem loop, a polyA sequence, and / or a polyadenylation signal. An mRNA may have a nucleotide sequence encoding a polypeptide. Translation of an mRNA, for example, in vivo translation of an mRNA inside a mammalian cell, may produce a polypeptide. Traditionally, the basic components of an mRNA molecule include at least a coding region, a 5’-untranslated region (5’-UTR), a 3’UTR, a 5’ cap and a polyA sequence. However, in some embodiments the mRNA does not have a polyA tail. In some embodiments, the mRNA is a circular mRNA.   Nucleic acid: As used herein, the term “nucleic acid” is used in its broadest sense and encompasses any compound and / or substance that includes a polymer of nucleotides. These polymers are often referred to as polynucleotides. Exemplary nucleic acids or polynucleotides of the disclosure include, but are not limited to, ribonucleic acids (RNAs), deoxyribonucleic acids (DNAs), DNA-RNA hybrids, RNAi-inducing agents, RNAi agents, siRNAs, shRNAs, miRNAs, antisense RNAs, ribozymes, catalytic DNA, RNAs that induce triple helix formation, threose nucleic acids (TNAs), glycol nucleic acids (GNAs), peptide nucleic acids (PNAs), locked nucleic acids (LNAs, including LNA having a β-D-ribo configuration, α-LNA having an α-L-ribo configuration (a diastereomer of LNA), 2’-amino-LNA having a 2’-amino functionalization, and 2’- amino-α-LNA having a 2’-amino functionalization) or hybrids thereof. Open Reading Frame: As used herein, the term “open reading frame”, abbreviated as “ORF”, refers to a segment or region of an mRNA molecule that encodes a polypeptide. The ORF comprises a continuous stretch of non-overlapping, in-frame codons, beginning with the initiation codon and ending with a stop codon, and is translated by the ribosome. Patient: As used herein, “patient” refers to a subject who may seek or be in need of treatment, requires treatment, is receiving treatment, will receive treatment, or a subject who is under care by a trained professional for a particular disease or condition. In particular embodiments, a patient is a human patient. In some embodiments, a patient is a patient suffering from an autoimmune disease, e.g., as described herein. Pharmaceutically acceptable: The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable excipient: The phrase “pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound)   and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Pharmaceutically acceptable salts: As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form (e.g., by reacting the free base group with a suitable organic acid). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Representative acid addition salts include acetate, acetic acid, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzene sulfonic acid, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,   tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418, Pharmaceutical Salts: Properties, Selection, and Use, P.H. Stahl and C.G. Wermuth (eds.), Wiley-VCH, 2008, and Berge et al., Journal of Pharmaceutical Science, 66, 1-19 (1977), each of which is incorporated herein by reference in its entirety. Polypeptide: As used herein, the term “polypeptide” or “polypeptide of interest” refers to a polymer of amino acid residues typically joined by peptide bonds that can be produced naturally (e.g., isolated or purified) or synthetically. RNA: As used herein, an “RNA” refers to a ribonucleic acid that may be naturally or non-naturally occurring. For example, an RNA may include modified and / or non- naturally occurring components such as one or more nucleobases, nucleosides, nucleotides, or linkers. An RNA may include a cap structure, a chain terminating nucleoside, a stem loop, a polyA sequence, and / or a polyadenylation signal. An RNA may have a nucleotide sequence encoding a polypeptide of interest. For example, an RNA may be a messenger RNA (mRNA). Translation of an mRNA encoding a particular polypeptide, for example, in vivo translation of an mRNA inside a mammalian   cell, may produce the encoded polypeptide. RNAs may be selected from the non-liming group consisting of small interfering RNA (siRNA), asymmetrical interfering RNA (aiRNA), microRNA (miRNA), Dicer-substrate RNA (dsRNA), small hairpin RNA (shRNA), mRNA, long non-coding RNA (lncRNA) and mixtures thereof. RNA element: As used herein, the term “RNA element” refers to a portion, fragment, or segment of an RNA molecule that provides a biological function and / or has biological activity (e.g., translational regulatory activity). Modification of a polynucleotide by the incorporation of one or more RNA elements, such as those described herein, provides one or more desirable functional properties to the modified polynucleotide. RNA elements, as described herein, can be naturally-occurring, non- naturally occurring, synthetic, engineered, or any combination thereof. For example, naturally-occurring RNA elements that provide a regulatory activity include elements found throughout the transcriptomes of viruses, prokaryotic and eukaryotic organisms (e.g., humans). RNA elements in particular eukaryotic mRNAs and translated viral RNAs have been shown to be involved in mediating many functions in cells. Exemplary natural RNA elements include, but are not limited to, translation initiation elements (e.g., internal ribosome entry site (IRES), see Kieft et al., (2001) RNA 7(2):194-206), translation enhancer elements (e.g., the APP mRNA translation enhancer element, see Rogers et al., (1999) J Biol Chem 274(10):6421-6431), mRNA stability elements (e.g., AU-rich elements (AREs), see Garneau et al., (2007) Nat Rev Mol Cell Biol 8(2):113-126), translational repression element (see e.g., Blumer et al., (2002) Mech Dev 110(1-2):97- 112), protein-binding RNA elements (e.g., iron-responsive element, see Selezneva et al., (2013) J Mol Biol 425(18):3301-3310), cytoplasmic polyadenylation elements (Villalba et al., (2011) Curr Opin Genet Dev 21(4):452-457), and catalytic RNA elements (e.g., ribozymes, see Scott et al., (2009) Biochim Biophys Acta 1789(9-10):634-641). Specific delivery: As used herein, the term “specific delivery,” “specifically deliver,” or “specifically delivering” means delivery of more (e.g., at least 10% more, at least 20% more, at least 30% more, at least 40% more, at least 50% more, at least 1.5 fold more, at least 2-fold more, at least 3-fold more, at least 4-fold more, at least 5-fold more, at least 6-fold more, at least 7-fold more, at least 8-fold more, at least 9-fold more, at   least 10-fold more) of a polynucleotide of the disclosure by a delivery agent (e.g., a nanoparticle) to a target cell of interest (e.g., mammalian target cell) compared to an off- target cell (e.g., non-target cells). The level of delivery of a nanoparticle to a particular cell may be measured by comparing the amount of protein produced in target cells versus non-target cells (e.g., by mean fluorescence intensity using flow cytometry, comparing the % of target cells versus non-target cells expressing the protein (e.g., by quantitative flow cytometry), comparing the amount of protein produced in a target cell versus non- target cell to the amount of total protein in said target cells versus non-target cell, or comparing the amount of a first and / or second polypeptide in a target cell versus non- target cell to the amount of total first and / or second polypeptide in said target cell versus non-target cell. It will be understood that the ability of a nanoparticle to specifically deliver to a target cell need not be determined in a subject being treated, it may be determined in a surrogate such as an animal model (e.g., a mouse or NHP model). Substantially: As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena. Suffering from: An individual who is “suffering from” a disease, disorder, and / or condition has been diagnosed with or displays one or more symptoms of a disease, disorder, and / or condition. Targeting moiety: As used herein, a “targeting moiety” is a compound or agent that may target a nanoparticle to a particular cell, tissue, and / or organ type. Repressor binding element: As used herein, the term “repressor binding element” or “binding element” refers to a nucleic acid sequence, e.g., a DNA or RNA sequence, which is recognized by a repressor molecule. In an embodiment, the binding element forms a structure, e.g., a three-dimensional structure, e.g., a kink-turn, a loop, a stem or other known structure. Exemplary binding elements are provided in Table 4.   Repressor Molecule: As used herein, the term “repressor molecule” or “repressor” refers to a molecule which binds to, e.g., recognizes, a binding element or a fragment thereof. In an embodiment, the repressor binds to, e.g., recognizes, a sequence, e.g., a DNA or RNA sequence, comprising the binding element, or fragment thereof. In an embodiment, the repressor binds to, e.g., recognizes, a structure comprising a sequence, e.g., a DNA or RNA sequence, comprising the binding element, or fragment thereof. In an embodiment, the repressor comprises an RNA-binding protein or a fragment thereof. Exemplary repressors are provided in Table 1. Therapeutic Agent: The term “therapeutic agent” refers to any agent that, when administered to a subject, has a therapeutic, diagnostic, and / or prophylactic effect and / or elicits a desired biological and / or pharmacological effect. In some embodiments, the therapeutic agent comprises or is a therapeutic payload. In some embodiments, the therapeutic agent comprises or is a small molecule or a biologic (e.g., an antibody molecule). First polypeptide: As used herein, the term “first polypeptide” refers to an agent which elicits a desired biological and / or pharmacological effect. In an embodiment, the first polypeptide has a therapeutic and / or prophylactic effect. In an embodiment, the first polypeptide comprises a protein, a polypeptide, a peptide or a fragment (e.g., a biologically active fragment) thereof. In an embodiment, the first polypeptide includes a sequence encoding a protein, e.g., a therapeutic protein. Some examples of first polypeptides include, but are not limited to a secreted protein, a membrane-bound protein, or an intracellular protein. In an embodiment, the first polypeptide includes a cytokine, an antibody, a vaccine (e.g., an antigen, or an immunogenic epitope), a receptor, an enzyme, a hormone, a transcription factor, a ligand, a membrane transporter, a structural protein, a nuclease, or a component, a variant or a fragment (e.g., a biologically active fragment) thereof. The terms protein, polypeptide and peptide are used interchangeably herein. Transfection: As used herein, the term “transfection” refers to methods to introduce a species (e.g., a polynucleotide, such as a mRNA) into a cell.   Translational Regulatory Activity: As used herein, the term “translational regulatory activity” (used interchangeably with “translational regulatory function”) refers to a biological function, mechanism, or process that modulates (e.g., regulates, influences, controls, varies) the activity of the translational apparatus, including the activity of the PIC and / or ribosome. In some aspects, the desired translation regulatory activity promotes and / or enhances the translational fidelity of mRNA translation. In some aspects, the desired translational regulatory activity reduces and / or inhibits leaky scanning. Subject: As used herein, the term “subject” refers to any organism to which a composition in accordance with the disclosure may be administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans) and / or plants. In some embodiments, a subject may be a patient. Treating: As used herein, the term “treating” refers to partially or completely alleviating, ameliorating, improving, relieving, delaying onset of, inhibiting progression of, reducing severity of, and / or reducing incidence of one or more symptoms or features of a particular infection, disease, disorder, and / or condition. For example, “treating” cancer may refer to inhibiting survival, growth, and / or spread of a tumor. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition and / or to a subject who exhibits only early signs of a disease, disorder, and / or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition. Preventing: As used herein, the term “preventing” refers to partially or completely inhibiting the onset of one or more symptoms or features of a particular infection, disease, disorder, and / or condition. Unmodified: As used herein, “unmodified” refers to any substance, compound or molecule prior to being changed in any way. Unmodified may, but does not always, refer to the wild type or native form of a biomolecule. Molecules may undergo a series of modifications whereby each modified molecule may serve as the “unmodified” starting molecule for a subsequent modification.   Uridine Content: The terms "uridine content" or "uracil content" are interchangeable and refer to the amount of uracil or uridine present in a certain nucleic acid sequence. Uridine content or uracil content can be expressed as an absolute value (total number of uridine or uracil in the sequence) or relative (uridine or uracil percentage respect to the total number of nucleobases in the nucleic acid sequence). Uridine-Modified Sequence: The terms "uridine-modified sequence" refers to a sequence optimized nucleic acid (e.g., a synthetic mRNA sequence) with a different overall or local uridine content (higher or lower uridine content) or with different uridine patterns (e.g., gradient distribution or clustering) with respect to the uridine content and / or uridine patterns of a candidate nucleic acid sequence. In the content of the present disclosure, the terms "uridine-modified sequence" and "uracil-modified sequence" are considered equivalent and interchangeable. Variant: As used herein, the term “variant” refers to a molecule having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity of the wild type molecule, e.g., as measured by an art-recognized assay. Target Site: As used herein, the term “target site”, “cleavage site”, and binding site are used interchangeably and refer to the recognition sequence within a polynucleotide molecule. A target site in the context of this disclosure can be a microRNA target site, or an endonuclease cleavage site. A target site can be engineered to be in the 5’ UTR or the 3’ UTR of the polynucleotide molecule. Turning ON expression: As used herein, the term “turning ON expression” or “turning ON translation” refers to refers to increasing the degree of transcription or translation from a particular polynucleotide when the polynucleotide comes into contact with a particular microRNA) in a particular cell / microenvironment and that miRNA binds to and cleaves one or more microRNA target sites (miRts) on the second and optionally the first polynucleotide in a dual polynucleotide system. In some embodiments, binding of the miRNA (e.g., HSPC-specific miRNA) to the corresponding miRts on the second polynucleotide leads to degradation of the second polynucleotide encoding the repressor, thereby allowing expression of the target protein from the first polynucleotide (turning ON expression) in the desired cells (e.g., HSPC   cells). In other embodiments, binding of the miRNA (e.g., non-HSPC-specific miRNA) to the corresponding miRts on the first polynucleotide leads to degradation of the first polynucleotide encoding the target protein, thereby reducing expression of the target protein in undesired cells (e.g., non-HSPC cells). In some embodiments, the second polynucleotide has one or more microRNA target sites that are capable of binding to miRNA present in hematopoietic stem and progenitor cells (HSPC miRts). In other embodiments, the first polynucleotide has one or more microRNA target sites that are capable of binding to miRNA present in non-hematopoietic stem and progenitor cells (non-HSPC miRts). In some embodiments, binding of the miRNA (e.g., non-HSPC-specific miRNA, such as a mature-immune cell specific miRNA) to the corresponding miRts on the second polynucleotide leads to degradation of the second polynucleotide encoding the repressor, thereby allowing expression of the target protein from the first polypeptide (turning ON expression) in the desired cells (e.g., non-HSPC cells). In other embodiments, binding of the miRNA (e.g., HSPC-specific miRNA) to the corresponding miRts on the first polynucleotide leads to degradation of the first polynucleotide encoding the target protein, thereby reducing expression of the target protein in undesired cells (e.g., HSPC cells), but keeping expression ON in non-HSPC cells. In some embodiments, the second polynucleotide has one or more microRNA target sites that are capable of binding to miRNA present in non-hematopoietic stem and progenitor cells (non-HSPC miRts). In other embodiments, the first polynucleotide has one or more microRNA target sites that are capable of binding to miRNA present in hematopoietic stem and progenitor cells (HSPC miRts). Binding of the miRNA to the miRts can cause partial or full cleavage of the second polynucleotide, leading to turning ON expression or translation of the first polynucleotide. When the transcription or translation of the first polypeptide is turned ON due to miRNA-miRts binding and cleavage in a specific cell / tissue, it can increase the level of transcription or translation of the first polypeptide in that specific cell / tissue by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%,   99% or 100% when compared to the level of transcription or translation in the absence of miRNA-miRts binding and cleavage. Turning OFF expression: As used herein, the term “turning OFF expression” or “turning OFF translation” refers to refers to decreasing the degree of transcription or translation from a particular polynucleotide (e.g., an mRNA) when the polynucleotide comes into contact with a particular microRNA) in a particular cell / microenvironment and that miRNA binds to and cleaves one or more microRNA target sites (miRts) on the mRNA in a single polynucleotide system. In some embodiments, binding of the miRNA (e.g., HSPC-specific miRNA) to the corresponding miRts on an mRNA encoding a target protein leads to degradation of the mRNA encoding the target, thereby turning OFF expression of the target protein from the mRNA in the cells that express the miRNA specific to the miRts on the mRNA (e.g., HSPC cells). Binding of the miRNA to the miRts can cause partial or full cleavage of the mRNA, leading to turning OFF expression or translation of the mRNA. When the transcription or translation of the first polypeptide is turned OFF due to miRNA-miRts binding and cleavage in a specific cell / tissue, it can decrease the level of transcription or translation of the target protein in that specific cell / tissue by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% when compared to the level of transcription or translation in the absence of miRNA-miRts binding and cleavage. Unsuitable for canonical translation: A polynucleotide (e.g., RNA) that is “unsuitable for canonical translation” is a polynucleotide with a nucleotide modification, sequence modification, and / or a structure that is not suitable for translation. In some embodiments, the modification(s) are at the 5’ end, and / or the 3’ end. In some embodiments, the modification(s) stabilize the polynucleotide. In some embodiments, a polynucleotide that is unsuitable for canonical translation (a) does not have a polyA tail; (b) is circular; (c) has no cap; and / or (d) has no cap and no tail.   Polynucleotides of ON and / or OFF systems Disclosed herein, inter alia, are compositions and systems that are ON and / or OFF compositions and systems that encode for a polypeptide and optionally, a repressor. In a single polynucleotide system, the compositions and systems encode for a polypeptide, that is a target protein. In a single polynucleotide system, the single polynucleotide is an mRNA of the composition. In a dual polynucleotide system, the first polynucleotide of the composition encodes for a polypeptide, that is a target protein. Additionally, the first polynucleotide also has a repressor binding element. In a dual polynucleotide system, the second polynucleotide of the composition encodes for repressor protein. The single and dual polynucleotide systems and its features are discussed below in greater detail. Single polynucleotide OFF system Disclosed herein, inter alia, are compositions and systems comprising a single polynucleotide, i.e., a messenger RNA (mRNA). In one aspect, the composition comprises a messenger RNA (mRNA) comprising (i) an open reading frame encoding a polypeptide, and (ii) one or more microRNA target sites present in hematopoietic stem and progenitor cells (HSPC miRts). An example of such a system (a single RNA system) is depicted in FIG.1A. In this example, the mRNA encodes a target polypeptide and contains microRNA target sites. FIG.1A shows that in the presence of microRNA binding to the microRNA target sites (miRts), the mRNA is degraded, thereby suppressing (turning OFF) target protein translation. Target expression is turned OFF only in HSPCs that express the particular microRNA which is capable of binding to the miRts on the mRNA. FIG.1B shows an exemplary mRNA with a 5’ Cap, a 5’ untranslated region (UTR), a target polypeptide encoding region followed by 3 miRts in the 3’ UTR and a poly A tail. In some embodiments, the methods of this disclosure can be used to turn OFF expression of target polypeptide in particular cell lineages, e.g., hematopoietic progenitor cells in which gene editing is desired, thereby increasing safety of gene-editing technologies, or mature immune cells (e.g., macrophages, T cells, B cells, etc) in which   gene expression is not desired. In some embodiments, the single polynucleotide OFF system disclosed herein has immune-oncology applications. For example, the OFF system can be used to turn OFF and reduce expression of mRNAs in HSPCs (HSPC-OFF system) that induce differentiation and polarization in HSPCs to mitigate risk of reprograming bone marrow development. In some embodiments, the HSPC-OFF system can be coupled with a mature immune cell ON system, such that target mRNA expression is turned OFF in HSPCs but turned ON in mature immune cells, thereby providing additional safety and selectivity for target RNA expression in mature (differentiated) immune cells. Dual polynucleotide ON / OFF system Disclosed herein, inter alia, are compositions and systems comprising two polynucleotides, i.e., (a) a first polynucleotide comprising (i) a repressor binding element, (ii) an open reading frame encoding a polypeptide, and (iii) optionally one or more microRNA target sites present in non-HSPCs; and (b) a second polynucleotide comprising (i) a sequence encoding a repressor that binds to the repressor binding element and (ii) one or more microRNA target sites present in HSPCs, wherein binding of the repressor to the repressor binding element reduces translation of the polypeptide from the first polynucleotide. In some embodiments, both the polynucleotides are RNA molecules (e.g., mRNAs). In some embodiments, both the polynucleotides are DNA molecules. In some embodiments, one polynucleotide is an RNA molecule (e.g., mRNA) and the other polynucleotides is a DNA molecule. An example of such a dual polynucleotide OFF system is depicted in FIG.1C in which microRNA binding to the miRts of a repressor encoding RNA turns ON expression of target RNA, by reducing expression of the repressor and thereby preventing the repressor from binding to the repressor binding site on the target RNA. FIG.1D shows a mature immune cell ON system in which microRNA binding to the microRNA target sites (e.g., miR150-ts or miR142-ts miRts) of a repressor encoding RNA turns ON expression of target RNA in mature immune cells, by reducing expression of the repressor and thereby preventing the repressor from binding to the repressor binding site on the target RNA. FIG.1E shows   an HSPC ON system in which microRNA binding to a microRNA target site of a repressor encoding RNA turns ON expression of target RNA in HSPCs, by reducing expression of the repressor and thereby preventing the repressor from binding to the repressor binding site on the target RNA. In some embodiments, the dual ON system comprises different miRts in each polypeptide of the dual ON system to fine-tune expression of the target polypeptide in desired cells. For instance, as shown in FIG.1E, the repressor encoding RNA contains microRNA target sites that are specific for a pan- immune cell microRNA (e.g., miR142). Binding of the microRNA (e.g., miR142) to the microRNA target sites (e.g., miR142ts) of the repressor encoding RNA turns ON expression of target RNA in all immune cells, by reducing expression of the repressor and thereby preventing the repressor from binding to the repressor binding site on the target RNA. Meanwhile, the target encoding RNA contains microRNA target sites that are specific for another non-HSPC-specific microRNA (e.g., miR150). Binding of the microRNA (e.g., miR150) to the microRNA target sites (e.g., miR150ts) of the target encoding RNA turns OFF expression of target RNA in mature immune cells, by degrading target RNA in those cells. Polypeptides of ON and / or OFF systems In some embodiments of the ON and / or OFF systems disclosed herein, the polypeptide of the ON and / or OFF compositions and systems encodes: a secreted protein; a membrane-bound protein; or an intercellular protein, or peptides, polypeptides or biologically active fragments thereof.  In some embodiments, the polypeptide is a secreted protein, or a peptide, a polypeptide or a biologically active fragment thereof. In some embodiments, the secreted protein comprises a cytokine, or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the secreted protein comprises an antibody or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the secreted protein comprises an enzyme or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the secreted protein comprises a hormone or a variant or fragment (e.g., a biologically active fragment) thereof. In some   embodiments, the secreted protein comprises a ligand, or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the secreted protein comprises a vaccine (e.g., an antigen, an immunogenic epitope), or a component, variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the vaccine is a prophylactic vaccine. In some embodiments, the vaccine is a therapeutic vaccine, e.g., a cancer vaccine. In some embodiments, the secreted protein comprises a growth factor or a component, variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the secreted protein comprises an immune modulator, e.g., an immune checkpoint agonist or antagonist. In some embodiments, the polypeptide is a membrane-bound protein, or a peptide, a polypeptide or a biologically active fragment thereof. In some embodiments, the membrane-bound protein comprises a vaccine (e.g., an antigen, an immunogenic epitope), or a component, variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the vaccine is a prophylactic vaccine. In some embodiments, the vaccine is a therapeutic vaccine, e.g., a cancer vaccine. In some embodiments, the membrane-bound protein comprises a ligand, a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the membrane- bound protein comprises a membrane transporter, a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the membrane-bound protein comprises a structural protein, a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the membrane-bound protein comprises an immune modulator, e.g., an immune checkpoint agonist or antagonist. In some embodiments, the polypeptide is an intracellular protein, or a peptide, a polypeptide or a biologically active fragment thereof. In some embodiments, the intracellular protein comprises an enzyme, or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the intracellular protein comprises a hormone, or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the intracellular protein comprises a cytokine, or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the intracellular protein comprises a transcription factor, or a variant or fragment (e.g., a biologically   active fragment) thereof. In some embodiments, the intracellular protein comprises a nuclease, or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the intracellular protein comprises comprises a vaccine (e.g., an antigen, an immunogenic epitope), or a component, variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the vaccine is a prophylactic vaccine. In some embodiments, the vaccine is a therapeutic vaccine, e.g., a cancer vaccine. In some embodiments, the intracellular protein comprises a structural protein, or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the polypeptide is chosen from a cytokine, an antibody, a vaccine (e.g., an antigen, an immunogenic epitope), a receptor, an enzyme, a hormone, a transcription factor, a ligand, a membrane transporter, a structural protein, a nuclease, a growth factor, an immune modulator, or a component, variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the polypeptide comprises a cytokine, or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the polypeptide comprises an antibody or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the polypeptide comprises a vaccine (e.g., an antigen, an immunogenic epitope), or a component, variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the vaccine is a prophylactic vaccine. In some embodiments, the vaccine is a therapeutic vaccine, e.g., a cancer vaccine. In some embodiments, the polypeptide comprises a receptor, or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the polypeptide comprises an enzyme, or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the polypeptide comprises a hormone, or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the polypeptide comprises a growth factor, or a variant or fragment (e.g., a biologically active fragment) thereof.   In some embodiments, the polypeptide comprises a nuclease, or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the polypeptide comprises a transcription factor, or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the polypeptide comprises a ligand, or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the polypeptide comprises a membrane transporter, or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the polypeptide comprises a structural protein, or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the polypeptide comprises an immune modulator, or a variant or fragment (e.g., a biologically active fragment) thereof. In some embodiments, the immune modulator comprises an immune checkpoint agonist or antagonist. In some embodiments, the polypeptide comprises a protein or peptide. In some embodiments, the polypeptide comprises a protein associated with gene editing in a cell (an editor protein). For instance, the protein is a Cas nuclease, a zinc finger nuclease, or a homing endonuclease. In some embodiments, the polypeptide comprises a self-splicing intein, wherein the editor protein is fused to a degron domain that leads to rapid protein degradation. Repressors of the ON and / or OFF system   In some embodiments of the ON and / or OFF systems disclosed herein, the single polynucleotide of the OFF system, or the second polynucleotide of the ON and / or OFF system encodes an RNA binding protein or a fragment thereof, e.g., a repressor or a biologically active fragment thereof. In some embodiments, the repressor is chosen from the molecules provided in Table 2, e.g., Snu13, 50S ribosomal L7Ae protein, Pumilio and FBF (PUF) protein, PUF2 protein, MBP-LacZ, MBP, PCP, Lambda N, U1A, 15.5kd, LARP7, L30e, or a variant or fragment thereof.   Snu13 is a human spliceosomal protein which binds U4 snRNA during spliceosomal assembly. ( EMBO J.1999 Nov 1;18(21):6119-33.) L7Ae is an archaeal ribosomal protein which regulates the translation of a designed mRNA in vitro and in human cells (see, e.g., Saito H, et al.. Nat Chem Biol. 2010 Jan;6(1):71-8); and Wroblewska L, et al. Nat Biotechnol.2015;33(8):839-841. In some embodiments, when the repressor is 50S ribosomal L7Ae protein (e.g., wildtype 50S ribosomal L7Ae protein, a variant or fragment thereof) the binding element is a kink-turn forming sequence (e.g., SEQ ID NO: 7, or a variant or fragment thereof). PUF is a family of proteins that bind RNA sequence stretches defined by their amino acid identities at specific positions. Some amino acids in the protein can be engineered to change binding to any other RNA sequence. PUF2 is such an engineered protein. Filipovska A, et al. Nat Chem Biol.2011 May 15;7(7):425-7. In some embodiments, when the repressor is PUF (e.g., wildtype PUF, or a variant or fragment thereof) the repressor binding element is PRE (e.g., wildtype PRE, or a variant or fragment thereof). In some embodiments, when the repressor is PUF2 (e.g., wildtype PUF2, or a variant or fragment thereof) the repressor binding element is PRE2 (e.g., wildtype PRE2, or a variant or fragment thereof). In some embodiments, when the repressor is MBP (e.g., wildtype MBP, a variant or fragment thereof) the repressor binding element is MS2 (e.g., wildtype MS2, or a variant or fragment thereof). In some instances, MBP predimerizes prior to binding to MS2 hairpins. In some embodiments, when the repressor is MBP-LacZ or a variant or fragment thereof, the repressor binding element is MS2 (e.g., wildtype MS2, or a variant or fragment thereof). In some embodiments, when the repressor is PCP (e.g., wildtype PCP, or a variant or fragment thereof) the repressor binding element is PP7 (e.g., wildtype PP7, or a variant or fragment thereof).   In some embodiments, when the repressor is Lambda N (e.g., wildtype Lambda N, or a variant or fragment thereof) the repressor binding element is BoxB (e.g., wildtype BoxB, or a variant or fragment thereof). In some embodiments, when the repressor is U1A (e.g., wildtype U1A, or a variant or fragment thereof) the repressor binding element is U1A hairpin (e.g., wildtype U1A hairpin, or a variant or fragment thereof). In some embodiments, when the repressor is 15.5kd (e.g., wildtype 15.5kd, or a variant or fragment thereof) the repressor binding element is a kink-turn forming sequence (e.g., wildtype U1A hairpin, or a variant or fragment thereof). In some embodiments, when the repressor is LARP7 (e.g., wildtype LARP7, or a variant or fragment thereof) the repressor binding element is 7SK (e.g., wildtype 7SK, or a variant or fragment thereof). In some embodiments, a repressor comprises an RNA-binding protein or a variant or a fragment thereof. Exemplary RNA-binding proteins are provided in Tables 1 and 2. Table 1: Exemplary repressors and repressor binding elements RNA binding protein (RBP) RNA element Recognition basis PUF PRE sequence PUF2 PRE2 sequence MBP MS2 structure MBP-LacZ MS2 structure PCP PP7 structure Lambda N BoxB structure U1A U1A hairpin structure 15.5kd Kink-turn forming sequence structure 50S ribosomal L7Ae protein Kink-turn forming sequence structure LARP7 7SK structure Additional exemplary RNA-binding proteins or RNA-binding domains which can be used as repressors are disclosed in Corley et al, Molecular Cell 78:1 pp.9-29, the   entire contents of which are hereby incorporated by reference. For example, Table 2 provides additional exemplary RNA-binding proteins or domains which can be used as repressors. In an embodiment, a repressor disclosed herein comprises a domain (or a variant, or a fragment thereof) or a protein (or a variant or a fragment thereof) listed in Table 2. Table 2: Exemplary RNA-binding proteins and domains Domain name Protein family containing domain Cold shock domain Cold shock proteins, Y-box proteins Double stranded RNA binding domain RNAses, ADARs, DICER Helicase DExH / D-box, Ski2-like, RIGI-like, NS3, UPF1-like RNA binding helicases Intrinsically disordered regions (IDR) Most RBPs K homology hnRNPs, translation regulation proteins, La motif (LAM) La proteins, La-related proteins (LARPs) Piwi-Argonaute-Zwille Argonaute proteins, Dicer (PAZ) P-element Induced Wimpy Testis Argonaute proteins, (PIWI) Pentatricopeptide repeat (PPR) RNA editing proteins Pseudouridine synthase and RNA modifying enzymes, metabolic archaeosine enzymes transglycoslyase (PUA) Pumillo-like repeat (PUM) PUF proteins Ribosomal S1-like Ribosomal proteins, Translation initiation factors, RNase II, PNPase RNA recognition motif (RRM) hnRNPs, splicing factors Sm and Like-Sm (Sm / Lsm) U1 spliceosomal proteins, Hfq   thiouridine synthases, RNA tRNA modifying enzyme methylases and pseudouridine synthases (THUMP) YT521-B homology (YTH) YTH family m6A readers Zn finger Transcription factors, METTL enzymes, In some embodiments, the repressor comprises MBP. In some embodiments, the repressor comprises an amino acid sequence provided in Table 3 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity thereof. In some embodiments, the repressor comprises the amino acid sequence of SEQ ID NO: 21, or an amino acid sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity thereof. In some embodiments, the repressor is encoded by a nucleotide sequence provided in Table 3 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity thereof. In some embodiments, the repressor is encoded by the nucleotide sequence of SEQ ID NO: 22, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity thereof.

[0003] S QCT AGG S QTA RLI LS P ATKCMACCAGC CMKPKED LGF STTVATGG CCACTGTATAT TAN D AGAEKRTRARRG LGL ETPAPKK YVGIC TAGA TC AGCV C KKRVKPADF ECI NELDRQTLRNVRALGCGC CTACCQ ETYI DL TAL L E RA VT LCEEVKNSA QARS CGCGGAGACAG AAQECVGKLV VGSQRSD TELDDKSQSDI QD S A ACA A G TST TGCRDSDPSTGPVPEKLE LG KS LGALR NSNACCCCSST CA AAGCGCNNSTIKQRDMAP SD HG E GHFKF GIAGCCTA CAA TTCASS A PRPWK AMTTRENRIMLTI RNRWFIEPGGCA ITCGGCAAGGC IGWFIL PPGGKE L PVEKRQ ALSQKTLD TG AI TL GTG GTAACACAGGEI ECAI TLP RQ A KTKQFKLSLTAKTVL SKKR TGR GETCCA GEQSNMAAVKISAENMCA  AFNACAGAA ACGCNMLMT LM KQ LEVDC EH ETDPSIRR 75NLGTTGG AAGA AGATAFNLSTARI PTCKMDII R PAELSYGCGA CTAC TCACTNSYFI GDLLE RKC EH MKH ERSA ERPSARTTGCACCCCAG TAPSRS TK GNMNMQI E EAMMGSD KAGseVWTCGC CGlTACGCCA CCGVWGAF LLIN S AK KETQE SIARDD u VGA CGCCAGGG GTGTAG VGGSPVT RYELNFAE PVSG c DKCPYICGCACGCTC AC DK YITFAIV RAFVVMYKT PKA eloGTVGCGTA AGG AT CGTmGE SATGP ITV GDKRSEKLQ DHINAKEr GVNCGCA TCGGACTTGA GE SNPGRFFD PLNDKQW F MDGGSG osNKATCA A C AG AA C GV KAC EDPEDL RPITGGREsDIeTAI CAC C C TCC CN DITAINIKQRTSIKEGKKDGS RSrVYA pLSA AGTGAGAGT CGTGVYASGPKAD KIFAPD KGVSLeV KrF RPICGCAGCTACCLVKRPQ ILGSGK EEKIEQLG KSSf NPGCATAGo ecQ TQN ATG AACCGFNP RQ TQDFFIENFDDPGLGRQ GCGGGGCCGCTQ TQN GPSA DLK QGL L RGRWV se nce FA nu NSDCAGSSe qQK GGT CGGL GTAGAFA GASDDRLR E DIC SD KRSPSILV GGAGTACCNS SQKPP EGVR RRGVPRRR ueA qS RL T CARLL RGL RGNI PG M V G ACCA GCG G A GGTGC M V GLPG DKLLRLATW T NGPGN P D esy neral e oitcn ))p cna emem uaqat(n(N-de G xuq roE efesPBPBPB4F)a:SniroM MI a3ssMe (eelrbQ aESDIOpe1 2 5T N R2 2 2

[0004] PGISHEGEEL YLQACCT CAAG GCGAGTCTTACT AGCACAG AGGT TTTC VP RMLIG LTNAQTGGCCPVTGTAT TACCGCA CT AGCGATTCCGAATAA AGG LF DIE ELT SQECA AF ALL A GTGATA AGCCA GACTTGTATG GG TGCTGTAGGL YEVI E P CATCCTCCG ACGTCCGCTGGAT TA CGGCTC CTA ATA ALLLESVQ QKD G QK GCGCGGAACGTAG AGTCCT CAAACC TCACGGGA E RSPLIA AK QE E SSCGACA GAA TGC C TCCCAA AACGGAA GA TCT CCAA SESDEACAATGCGT T C CG GGC TGG KYKE LAAC T C TACA GCCGA GGACA VA LLGLA VNCLWS CAAGCCGCCGC CACG TGCA C A ACAG ACATGC GTTTA A DEG RQQPFA EGVYRLAIY KYA GCCTA CAATCAGCA CGTAGCGG CCCC CA ACA GGGG GFWQAGGCATCAACGTACG AATCCGTCC C CCTAGTTCA GARCYPDQQKIDD LLDTGCTGGG GA GGGC TAC TGC CAGGA CGCCA GGTAACA RVATIQFVKEK GTA AC CAGGCGGTCTTC TCAG G A ACGCAGGTATCAA DATSEGERARVTCCACCA AGAAGCC C CCG A ACAAACTCTT CACA GA 8  EETKLRFPQ V ACG NAGAGGGAGAT CGCCGG G ATGCCGTCCLHTAG AAG A5MGLE LF S KDENTTGCAA GAATCGCA G G GAAAGCATAAGACCACCA SE S LDHTAC TCA AACT CAGAA GG G ADAGKGV DCGC CC TGCA AGC C TG GA ANL CLMPWEAYLS TTTC AC CAG TAA GCCGAT C C TCG GAGAG CCA GTGGK RHLK VS LV DAEE GC CGGCGCCCCGTAC CL LACCAC CGAAYQC CACAATCGCT HGLGLVDFEACCCAGGG GTGCCA CTAACC TGGAGT GGCCCACTGGKRFAGCAGCC A CCACCCC TCCCEELEAE LECACTC CGA GC CCTGCATPEII LQQERL PMRRL CGTAGG ATGTACTA CAA AGAAG G AGTGAGCAAG QSAGLIQWRTELA LWCGCAACTA TGAGGCGAACGTT CAACA GTGAG TG P RKSMPTLNFI EKHVT INKTTCCGG AATCAGAAGG GACGGACCGGC TGGCCCA G GLEAPPFF CAC C C TA CCC C CAGGAGGCACG TGGAACGCG AGTCRK E L ESAAGGAG GTAGCAAAAGTA SE R EVSRL AEE IAKP YQCE TVATCGAG CT CAGCTGCGCAGG GCCTGACCACACGGTGCTGTGGAGTGTTGG GTCEE ALKLVE SYPAVLT SGCES RLGRATVKL AATG AGTAACG GGGT C CCCGGA GGTAACACA GCGGGGCCCGCTATCACACTGCCTCCCGG TAAAA G ACKL ELWMQVVSG MLA A VCGCGTAGAGCCGGAGAACGA GGCT ATG TAA S A FTHKP LS ASEPI CAAA GG RQLGTG G KGTGAGG TA ACCGTA CACGTGCG C GCGAAAACCTATG G RKLV DLLESV A G ACCA GCGCG A GGTGCG CTTGCTAGCGA GTCGCAGA A A GCGGCG G A A GCCA A )tn(N -dPG B4FMIe62

[0005] GA T TA ACAGGCGGCG GGGGGGG CCTAGCT AGACTACGGT GGCTGCTATAGCTA CG ACCA CTGA ACC T CCACCA CC CCCGTGGCGGCCCA AT CGGTTA GA CCCAGATGCCGCGCGC CTCTCGG GATAATC CGAGT CAAA TTTG ACG A A GAGA GGA CAG TT TGCG TATGGA TAAGT CA GGTAGCG GGCGGGATA TT AC GAG ACA A A ATGCGGCCCGCAACAC CGGGGCGATAAAAACAACCA GGCCACA GCTAAA AGGAGCA GGCCGAAGTGGGCAAGGCAGGAGCAGGGT TGA GG GGCCCGCACGAGC CA GCCAAA CGACAGACGATCAACGTGG GCGCGT CG AG AT AA CCTGAGATAG AGG CGGGG TCGA GGAGTGG CCTACTG ACCGG GGTAC CTC TAACAG TTGACCGC TAAC T CACAGC TAGCGGCCA CCAC C AC TTCCATG GAACAGTAAAAGGTACATCG TGGTGG CGC TGCCACGTGGGC TACTAT GA TGCAAC GA CCGAA CGG GCCGT CATGGGCAG AGAA TTGCAACG AGA GTGAACGCACGCAAT CTGATGGCG AGACG ACA AGGGCTACCTTCGCGG C CCGACGCAGGGC C CT T TGTC TCGA GAGATG A ACGGA TC TGAC GGAAGCG C T T A  G ATGAGG ATAGGTA GG CTCCG TTC CA GGGC CTAAT GC T CAGT C T95GCACTAGCAAACATACGACACATCCTTG AACATG CGAT CGG AGGA GGT CCG CAGT C TG GC TTGGGAAT C CG T CTGCAAC CGTGGCGAC TAATTGGCCAAGCTTACA ACAGCGGC CACTGGT C CCA ACACG AGACGCAC CATCGCTGCTCCAACACAG GGTAGGGAC TGCGACGCACTCTAAAGACGGC CGGGAAG AGATTGCTAG TATGCGCGCGGTGGCAGCGGCACG ACAC CTCATAAGCGC T GTAAG AAAAGACG GAGACACGA GGGCCGG AACAAAA ACGTCTGTCCAT T C TAGGG AAGAA CTA GGACAGGTTCGA A GGGC CA GGCA GC TTCA GAG GT GT CCCG GACCGTA AT CTCGCC GAC TGT CGGTCAAGACGA CGCGCGC CCACGGGGGTGAA GATGA CCACACCATGAAC TAAGCCACAGCGT CACA CGGCC A CGAAG AACCGCGTAACGTACCAC TGGGAGCG AGC C TGGCGACGATCGGAATG TGA GAAGACCATCTAAGCGA AGGAACGAACGG ACTTCTATCATA CCGC TAGCGGCAGAGGT CGCCGCAAAATAGA GGGCGT CTCGAGCCAG CCGAG GAGATGCGTAGTTAC GCCGGGCTTAC AAAGCGC C CGTTCCT TCA GGACCCGCAG GACGCAGAAG G AATG CGTGTGAACC GCAA ATCC C CG GTA AATAG CGTTA CGTG GATTCTCCC CACAGAAGA GA GGACA GGCTG ACCATGGCAG GCATGGGA AGG GAAGTCG ACGTTGCAGCACCACTT TC GG AT AGC TAAGTACG GTATTAGG A AATGGCCCC TTCGAG AAGCGACGG GCGT CG ATG G A A AGTG ACC AAC G ACTTC G AGTCC AAC G ATGACG A GCG GCC A A G GCC

[0006] TG TGGATT AGAATTTCGG GG S QGGP P QAIEP EES LS VKS EVDAFGD ETC AAGAA CAC CGTGACG TTGACTM APPRVG P QNL IPE EKS AEWIF LNT LKRC AA GCGTC TCCAGTAG V AT AA KKFA PAPYPAV PEV EAEAKTEQFA MLN LM GA CCT CATCVIAQQQSAPQEKFVIN G ACGC TGCAGCGYP PPLEENDG S SA ACACTTGG CTACGCGCALEQP ASQ TN MELSPPT LEG PA LA ELLPTTARY ACAC C CAAGGQC LQP TP DE E E F IVA GAGGG GGG C GGGATSVLGE EE K EF IRV TCGA GCC CA GTCTCCCACAACGRSDSGPV RVVPGPSP SSPVG AIPKR RDPKRRSGTATTC TAACGTGAG NNTSP SYTT GTPS SLVPSE RPPDG P FL FN CG T CGCAGGA TGGTGTG TCGGCGAT SA GSIA AASPAQP SP RMLG ERRVYRCNEKDPETG TACTCCAC F PAAI P SRSGVPQYPGD NVEEKGSKIGRPQTSICGCGCTC TGG ACAA GAAWE PIPTGPPQGTTP SEEGPPEAEVGKEQGKSA A ATACAGCGTAGCTACA GTTGCTAIL TQGP PFTS SP THPPEE SESELLRQGK E GCGACATTCCGCGGTCTGE SQAIYQAS EIRESPEV EAEQ P NT SDFI 0 TCGCTT CATGACCTTGCT N AM NP RSYQTRH ESI VTAMVG LPPDRA DL 6CGCCTA GG AACGGCCGCTCTCF LA KPYAV GAPGPTHGEQPTNKL RPPE DIG AT CTCT CNYNFGQGPS SNESWGEV AGAGT CGAT C CS SSQSEAL EARLGG AGA CGCGACAAACCAAGAG CAPARGH QSAPMLIGEL LEQAG AQ DLPGRKG GTGAGGCGACGG GGACACVWGAY ARPE PRVPST EPAPA APP S TADLKPKRGACA GCA TGTGGG AGAGG AAATGPYYEVGGQSATDMPQSTEQK YNGDEAAA GCAC ACAAGCCGAATCDKPYI SPIQGIDAIQA I QA TALNNE EARPAETGGGGCTTCATGCGSAIT L SQ YKLA TGGATACTGT GG ATV GTKAP P PVDET DIAGGAAACACAC CAAGG GE SNPNIYTGTGGMSSAI A STLEK PQLGRAG TC TGA CTA ACTCGT C TGC TCAG C GV MM KAQ GFQQSTSPVANVEV VGKLP SQCGCCA CGCG TT A GTG AAA CG TTG TGATN G DITAI TM VE NRDFEP PA YAAT PDGS S TPIAPGPQDSGSGP TKV CGCGTAAAV SQQ P DDPIE EAPNI IQ AGACACGCGC CG ACTGTGAAAGCCGAGLKSGTAVF R PI PPTGSARIRPRSL P SVP SCP TIS AEENEHPRLPW P AK GG AGAGGTGCNS A G I VVP TP KAGK MGT TGCGCCGGGCCCTGGCGCG CGGAT TA CCQ GTQN F AGF PVYPYTKIAVALKS PPPP P FGLAN AL HIEREPTAQ TCAG GTTG GGSDVVF RANLP LDSKQGCTG TTG AA ACA GGTCG TC A TTANS SQK LPHGPEVP TAMSEELLKK QL NFGCT CGTCGCGTA C GTCC TCGTCCAGG AR LATAARQESVE LGDDE T LM ACGCTC M V G QAPGKPPTG VEPATG G KMSTRKIQPG4FIe_ )PaaB()Mlf(72

[0007] IMEHIP AE KHRALTK KM LHLELF SSKENA CCT CAAG CGCTAGC AAC TTGC CCT G IEEE SGES RDSMG DAGEGLVDH DTGGCCG GTATA AC CTCAGGCA AC CGCQAM A KEQMKAGANCMKEKAYLSKT NE EG CTA GTATA AGCCG GTGA CCG AAGGCCG G ASIARKLHLL PW V VS LDA DECATCCG EL F PDDC CT CAT GTAT C CCTACGATCF MYEKVTSPGRAL LQ YHGL LGGKV FEG ER FA GCG CGGAACCAGTAACGCG GCG CC CCCAGGGAGTTCCA VKQHK GELEALL MEGAGATC TG GCATELDINKED DKMQWA GE PEIGQI LQQELI RQP RRRT LLA ACCAACAT TGCGTGGAGGCCCGATCCCA CCACGACGTCGCFRDIGS SAG WE LW AACGC TCCGCAGCDLP TGGREP K PS MTLN LFIINKA GCCTA CAATAGCCCCGACTCG AGC CTTKEK GAKPDG DS RREKH EVTGEP F TCAE AP FGGCACACGC CCAGCGGGTTTG DIS S RK LSQATCGGGGGC TACCGGAKFKG EV LF KE R EVSYE T TGAGGCGCCIEFQLGTGCENDDPKSS SRL AIALKPL CL VG G GTAACACAGGGT CCCTCG CC CA GG GLGREE EEA KSYPAV AT SVK TCACAGACAGCACACCT TTCACTC C AKGLQRGQE LGR C CAACGC TGAC C C C1 LDRWVV RQTVLGAGGGAA C G A AAG6CSKRPSI SLVESKL ELWMVSGMLA VTTG CAA GAATCA CCCACATACATTTRRGVPRRA NTKP LAGAC TC C TCGG GCG RIP RSLR TSH AA QGCTGCTWGG GNFSA KEPI CLECATAAAG T ACC SR LKTTCTC AC CAG TACG CGGT CCT CAAC CG LALI LNSPP PDT RLPVDILEV LA YG QGC CGCG CCC CGC TACCCGGTG AGG AG KDRLRGGAF S KT SG HEGLIEGT LQ A CGCCAGGGGTGGCGCGGT TCGC CA ARFA C RLG RL EQT APVP RM DEL NSA QEACCGCAGCC ACC T ACACGCGG CCC CT NEELCDLRNPT PV LFELL TYVILP CGTA ACGGTT CGTC CCC AAACGGAC CVL EK LVD NV ARAAIF ALLEQEDA A KK CGCAA CTATGAC C CAC CGCCGTCGG TEDS SQ ALESVQTCGGTG GTGTG GAV TE SD P KELEQDLGIRE LLAKEQS CA C AATCA GCTCKSQGLD ALR SIAQSEKPLS T ADE CAC C C TACCA CGCCCGTCGAA CC GT CCES EKEAGGAG C GAC C CCTKRMAP S RYGANC WTGT C TGGGCG GTA TGH TRNFRIMLKFDVA ALL LVALYSYACGA CAGCTACCCT TCACCTGG AGTA TCPEKRQTI RGNRDEG QPRFEAIKFG ACATGGACGCCCTATGCCA GTCAVELKAL SQKTLDRQ VYLPGWQ LDA A CGGTA GGCCCGCCTCGCCCTACGC C T TT LTKSTV KLTGGYIDRSGR CQKATDF L E CAGCGAGACA CC T G TCG TATTT CAAV VKISTRDQAIQVME CKEHTAE RVT EGRKK QAGG RVTGTG VGTGAGG TACG CACGTACCACATGCCCC CCGGGCLE D P S D A S R E CACGG GC C CAACATG D D KR I R R E E L F PN A D ACG G A GT CA G G G GTAC CG G4FIe_ )tPnB()Mlf(82

[0008] AGTAGCGCGAACCGGG ATT TCA TG TGGGCCTGGTTA GGCGAGTCCG ATA C CCACCCCCCCCGTCAGCCAG A AGGAAT CGA AAAGTGTG ACGTGCTG ACG CGACGAT CAGGCG AGTAGTTG AC CTGC CAACGGT CGCGAC CGCA CTGA CG GGAGGGACATATACACC CGGCTGCAGACGG CCCGAACTGTCGTCC TCG CAAG TCCCAACCCCGT TCG GA GCGTTCA TGG GA TTG G GTT G AA AGTCT CCACATCG TCAAACTC TTGGCCCAGT CG GCAC T CGGC CACGTCTCCC CG AAAC C CCCTAGG ACAATCA GCAGCAGGCGAGCGCAGC TGA AGT CGCG GA GAGGCT T TGCT GGAGGA A GGT TGCG A CTACACCGAT TGC CGGGCGGTAACTTCCA GG CCCC CC CCTAAA AGCC CCAC GTGA TGAA CTAGG AAG G GCTG AGTCC T CAG GCG CTAG G AAGCCA CTGGCCACGA A GCAGCCGGCA ACCGGTACCC CATGT CTGCCTCG A GACGT TCT TCTA GAGT CACACCGCAAC ACAA A CGGCGCT C CG CCGAAAGAACCCATTA CCAGG GCCG TACAAAGCGCGCA GAC CCCGCGT CGCTACCAGAAA GAG ATC CACCCTAACAA AGAGACAA CTA G  CGCAC GC C CGAGT TGAAAAAAA2ACAGG A CCGC T CCCACAG G GCT CGC C 6T TA AGGGGTATCG CGGTAGCG GGCCGTATACCGTGCGAAAAAGGTAG CCTGTCCAACACAGCG AGGG CGGAAT CGAGAAT GACGT CTGGAC A AAGCAAA GCGCCGACCC ACC TCTC C GGATA AACCCTCG AGGGC TGG ATAATAAGTATGC CCGC CACAGAGCTCCAC CGA ACGTCGGCA TGACCAATGACACG G ACTA GCGTGCACA CCCCTTGTGG GAA GAAGAAAC CGCG AGA ACG GGTTG TAAAGCT TGGCATCCCGCG GTCCCAGGGGCGA CATTGCCAAGG AAGCCCCCCGA AAAAT GCTA A AAATAT CCCGCCGT T TGGCC C C CCACAGTCA GA G TAG ACACCTGCTGA CGACC ACAGTA AAAGAGTAC TCCCGATGCAGGAA AGGGA CAAGTG GACCCGCG CGACC CTC CAGCGC GCCGC C TGGAC TGCCCTA CA CCCCCACACCCAGT T CCGACGCAC CAAGAGGCGA AAGGAA ACGAGTTGAGC CG GC C CAAAGGCCGTGAC TG AGCGGGC CCCG GCGGGA GATGTCTCCGCCT C CATGC CCC T CGACAAGCCGAGAATGCGGTTAGCAATCAACCTTAGA CCGGGCTACACCCC TCA AC CCCACG GACGCAT CAGAGCGACA GC CTA CCAA AA CGC AAGCGAGCCCAG AG ACTC TATGC GACA ACGCTATG GCC TGACGAG TTT CA GTTTGTCATAGCG ACCGG CCTGTACCA GGACGCTGGG CCCGGCCGC CCGG GACGGTTGGC GACTG AA ACT CGAGGAGCCAA CCTCCT GCA GA TCGCG G AACA GTCAC CGTGGT CGC TA GAGTAGGA AGCGAGC T T CG ACA A G GATGTG A GTCACCTCTGCTCACTC A A A A G A G GACATTTACCCAC

[0009] CAAGCCCCACT CC GGGGAT T CCTG AACGATGGCCTG AGGGC TG ATGGA GCG TCT C CCCTG AATTCAA TT C CA AC CGA AGACGAACA AC CGC TAGACG CGC CCAGGACC GGCGAC T TAG TACAATGTGGTAC CACAGTA AGAACG GTAACGA CCGCGATCCG TGCG ATG TCTGA GT AAACCACGCGATTGCGTG GCGGACA GACAA T GGAC C C T CCAA G TCACGGGCG GGAACGACGATGGCCCAA GGGA GGTAGGCG GC CAGG CATCG TA TA GC TA AAG ATGAA AC TATTTGCACGAAGCA ATAGCA ACAGCAA TCTAAGTGA AGGC CCCCT CGTT CGA GGCA CGCAGAACAGT CGGCGG AGGCA CATCGG GCACAAA ATCTAGCTG GAT CG GA TGAG GACGCCATGAAGCA ACCTTAAC C CTCGGATA GCAG GCAGATCCCGACCAC CAAG TCG GCA TACAGCCACGGCCACA G GTGAT C CCAGAACCT CTA ACA GGGT GGCCCTGGCA A AGG G GTAGCCCGCCACTCAGAAA GC CCG AGC ACCC TCT CA GCCACG TC TAT TG AAGCGA GGGGA ACGGTAC CG AAGC ACAAGCCTG GAGCAGGAG TT CA GG AAATAGACGTAACACGA GGGCCG   G AA G AGCA AGTTA GAGGACCACGT CA CGAAGA GCTAGGTTCGA A GGGG36GC T TCACTA GCGCCCGGGGTGTG GT CCCG GG GA C CTCGA ACCAGATCG GGA AGCG G GAACGCG GGCCAAGAA GGCCATGATACGAAACGC ACAGCG C GCTG CCAAA A AG GG GG CTTCA GTGGGCAATGCCGT GATGGA TGAAGGA CATCC CTGC CGGCAAGGAAGCA CC CCGA ATTCCGCAGCGAC T C CAGGAACCTTGG A GTAC CCCGGAGTA GACAACGGAAG GG AAGGTGAG CAG G ATAG GAGGCTTACGCAAA CGCGGGATGG TGCCTCC GG GCCCGT CGC T CGACAC AAAG CCTGACTCATG TA AACAAGGCA GTTG AGAGA C C CCCG C CC CGCA GAA G G GCGTC C TGAT T C C T CAGACG TGCGG AT TGGGTG CAG GAT C AA A AGGA ACGAA AACGCA GAACG AAGC CA GTGGT CAGC C CTTTTGGTG CGGAG GTGAG GCCTAAGGGAGC ACAAAGGT TGCG GAAAGATAAATATGTAGG CAAAA G GACTT GCCCC TGC TCCGA AA ACGCATTACTCACACGGCGATACG GCA AGCAACG GTCGCATGG GCGTAA CGCAG G AC GC CGG TCGGGGG TAGACTTGTG TGTGTCCGATATGAG ATAACCAGCA CTGACACCCC CA CCCACCC C CGG GCATGCTAAG GAGA GGTC CAAGA ATAGC GTGGCT CTTCGGATG ATTTA CTCAC TAGGA GT CGTA GAGCA CCA CCA AC CA ACTGGAA ACCA AGC CGTATGG AAGACGCAGGCGGAACTGTCGGCCGAACACACGGGG CGGAGG GTCG TCA GCGACAGTAG ACG AACCGCGCACAAAG AGC A GGAG A GG GACA GGC A ACC ACTG AGC GTTA AGTA AGCATGACCC AGC A GAC G AAC A GCAAC

[0010] GTCGG CC C TAATCCGAACGCT GCG AATAG TTGS QT GTGAGCMKA RP KEL G ATT CATG AC TGGGGCCGCA N DEK GC AC CCT CGCGCGGGAGTAATA GTRGCAGTGCCA GGTGGGCAGATCCGCTT TTGACCCA V AAACKKA KRA P ADI FN CAAAA TCTGCATA CGG GAATTAC CAGCTA TCAGG GTV T YILD L TRA VAGGTGG AC TCGAGTTCC CGCT AG AA GCGA GCATGTTCCGCGC CAL E LTEVGKQTV TAA AGCGC TGC T CTT CGG ATCGTCTCGGC CCCATT CATGACACCTTTGQTTCS CRDVGSDPSTPVTPG CCGTCCAGTC TGACGTGT GGC GC C C S SSG QK GC TTGGTGCCCTAG GAA GTACT CCTCGCCTGANNT IHGK WKETATCA GATTA AT GG G GCA A GCGCGGA CC CA AAGACCASCSIA PRLPAMTGCACGG ACAGCGC TGCGCGGTGTAAA AGAGGCGACGGAAWFIPPGG KLQPV AT GTGCAT AT CGT CCGCA GCATGG AAGGAG AGAGTCCEITEEP RAQKGCTC TATAGCAATGG AACAACAAATCTAAG GGGACGGACCAG TTCAGCA GAAILKTSKALA ACAT CG GEQL NM CCAA GATGCCGGCCT T GG NMT LQM4  AGAGCCG TCTCCGC TGTGAGATA GGAAACGC CAGG AC ANMST KIPTL6ACGT CG T AC ACT C T GAA ATGT F LAR CCCGCAGCATTTGAACGC T C C TCNGDARACA AACCGTAGAT CCGCCAACCG GGG AGTAG YFAASPS IS LETKCTGGGGA GCT AA ACGGTAAC TG GRN NM AC CA TC CG GC TT AGCGT TAA A GMAN AGAGTGC TCA GTGCAAACAACGCCC TGCGAGTA CAVWGAAL IGFVSA CGG CCTCTTA TCTACTGGGA TAGTG AG CGTA GCT CGTSGGTG VGGP T RY CGC C CGT T TAGGTCACG DK Y T AVA GAG GCATCG GGCGCGCTGP I F IIRV A CG AAATGA AGAAGGGCTGCACA CAC GTT CGCACTGGGCTGGG ACAGTG TACA GGTTGGTTVEGSDPKRRF SFGAGCGGCGT TACGGCC A GGVNG PLN G AG TTCAA GATGGACGAACGCCACC TTA GCTAGTCTCT C C CG G NKAC EDPEAGAGC CGCTG AG ATATG TGCGC GTTTA GCGCTG GG DITAINIKQRTSIACCGAGTGGGT C C TGCCTG GATAAAG AACATATT CGA YAG GV SQPKSA GCAGGAGAGTG AA ACG A TTALKPG K CG C GCC C TTGTAG CATCGCGAVRI LQGEGTACACACATCGA TAGG GACGTCCCCAGTT AAC CGFNP RD NTQFITCA GGC GTGCATAATT C CCCACACGTCTATCGCAGGCQQ GTAGPSA DRDLD AAATG GGGAGG AGACGAGTAACTTCGGTACCGCG AFAT NSSDLREEIAACGAC CGGA GGACCCAGC SKPPV GGGGCCAA GGGG GGCAGGAGQ L GGG GATC TGTGC TGT CGA G AT T C T CA ACACAR L R L RA ACGGTG GCG G G GGT C CC C GT TAGTM V GLPG DKLG4FI- e3)_ 2A P6(3,BN9 )d95aM- 1a(92

[0011] I DLS RLGP A E RRS EKHVTL INCT AGTGE IP ACCAGCGAGCTTACT AGC ARRGFECGL S RK ERLEVESAS PQTGGCCTGTAT TACACGCA CT AGCGA G EL LLC D RQL SENS RL AIALKPKLYCEGCTA GATA AGCCGACTTGTATCG EL RKN SREE EEASYPAVLT CGACTCGC CTCCG ACG GTC GCC TGGA E V ELDDSSD QVES RLGRW QATVK GGGAACAGTAAAGT CTCCA AAAACKSEQLGISV VEKL ELVMSG VPML L CAGCACAGATG GCTCTTCCCGGAA L REK GDM GPRSATFASHKPCALAAAQVAAC T TCGCCCTA CACGGG ACG C RHFA MKRNS KE IVDLLESARLGCA AAG TACGCG GC CAACTGCC A AACENRI LTEKRQIDRKLPGIEG EEVAKCATA YG GCCATCACCGTA CGGCCGG CALSQKTTST SVHMLIGLT LQGTGCA GGCACGTAT TGC TAACGC CT LSAKTVLETAP P RVDELLTNSA QQEGCT G GAAGCG GAC TGCCCTAGG CAVKKI RSPT PVRLFI EALYVIL AGTTCACAGCGG C TGA GT T CAGGACEV KEH ETD AAAFL LLES E E PCAGAA VQKDCACAAC CC CCCCGACA A5  DCDKI RIPQRA ELS LIAKQEQK GA TGG G GAGATGCCGG GAGATAAG6MEHIKMQIKHQD EE RLE SLRPEA KQE S TA ESDS GCAACGTA CATCGCAGGAGCA G GARKSYDVALGALNCE CTTTGC CCA GTACT CAAGGC CAA TGA KAM KEETQMNEKSASFI GALLEGP VLFAYWS TC ACCGCA PRC TCGAT CCCCGAC NRDRQQ YREFL F EDLAIKYGCFACGCGCC CGGTCACCAACTCTA GG MYKV LGG VCYPGIWQ DLANC CAG CAGGGC TG ACAACCCAGC AVQT TGRQKDF LD CGCT CCGACGC CEK HNS DQT EHCGA GCTACTAAAAG DLDIDKQWT RDFM AERVATIEQ GVK RAKDSATAG RDIGPS CAATCGTACACAGAG ATRDAEESLRF EPQRVECG TCGGAT TG GAGG GA A GGAGC TCKLEP TGG DGRAE TKHLE LNSAVEKDETCA ACC ATAC ACAGCGGA AGCDGKKKIFAPDSGVSALERLSMGFDADAGE S L EACA KGVDEAGC CTGAG CCT CGCGGTAGG CAGCGCCTG CA E K GSNCMEY R AAGCTC AACGGCGA FKIEFQLDPKAGA RKLLL PVW A S KVL L CGCCTAG GTA CC CGG TTC TTG END GLGAR H LDAW GGA GGGCC CGGKGDLQGL LAAATACCCATC CC GCTQGCL LDRWD RR SSGLGYH LGEG VDK GG AKRFFF C GCGCGTGCAAT C CCCRSRKPSILRPAEEELQE ELL F CA GGGTGGTAGA ACCGGAG T AA AA G CG NR GIVPPK GAKEPQIIQ GLI RQ PTMRATGGGAGG TACGCGCC TG ACG LRLATW T NGPGPGSGA RSPK MPTWRLNEFLTLVSACCA GCGCG A GGTGCTTGCTAGCG GTCGCA A G4FI-3)e2A _6 3P( ,BN99) Md-5t1n(03

[0012] ACATCG TGAGGT TTT ACGA A GAATACTACAGGCGGCG GGGGGGG TAGACTACGGT G AGGTCTAGCACCA CTGA ACC T CCACCA CC CCCGGC TGGCGGCCCTGGCTGC GATAGGGA CCCAGATGCCGCGCGC CTCTCGG AATGATC CGAGTGCCT TC CTA ATA A AGA GGA CAG TT TGCGTATGGA TAAGT CA AG GGT CG ACACG GGAGAG ACA A A ATGCGGCCCGCACAC CGGGGCGATAAAAAA GGCATG CT CCAAACA GGTGC CAAAAAAGGAG AGGCAGGAGCCAGGGGCG GACGTAGCGG AGGCCCGCA CGAGC CAGCAAAACGACAGACGATCACGTACCTAGG GC GTTTAAG TAA CCTGAGAT CAG GGCGGGG TCGA GGA AGTGG CC CA CCACGGAAC CTC TAACAGAACCGC TAA ACGC T T CAAGCGGCCACCACTGGTTAG AA TTCCAC CG AGTAAAACGGTACATCG TGGTGG CGCATG G GCA ACAGCG TAAC TT GA TGC CAAC GA CCGAACGG GCCGT CATGG G GCAA A AGCGTATAAATAGGAACGCACGCAAT CTGATGGCG G GACG ACA AGGG A CCGCTT CCCAACCGA GCGTGCAGGGC CA GACGGA TC TGCT TAC GTG GAA  CG TGT CA AGG AGCGA A A G ATGAGTAGGTA ACCTCCG TTC CA GGGC CTAA66GTA AGACACAGCACTAA GCAAACAT C TGCTG GAT CGG GACCG CAGAAC CGATACGACACC TAAACAGTTGA GGGGCTGCAAC CGTGGCGAC TAAGCACGTGCATAGG AAGCTTACGGC CACTGGT C CCA ACACG AGACGCACCAACCCAG TCGGAGCCGAGGTGAC CGCACAACACCATCGAAAAC CGGGA G GGCAACCC TTACAGCAGGGTCGA GCGGGCACGTACGG CAAGCATCTTCC CGGTG CCA CCCG GC T GTAAG AAAAGACG GAGACACGA GGGCCGG AACA A GCCTGTG A GCATGAT T C TAGGGAAGAA AGACTA GGACAGGTTCGAGAC CAGA GTAGGG ACT GT T CGCT C CGGGTCGA ACCGG AGATG CGAGA ACGTACGTGATA ACGAATGACCACAGGCCGC CCC CGGTGAG AAC TAGC AC C TACGAGGACGCGGCGG CAACCATTGG GGAGACGC CGGCC AAGC CCG TGA GAAA GGAGAG TGCT CACGGTG TCGA GAAGACCATCTAAGCGACAGGAACGAAGGAGGTGGGCAA CCGC TAGCGGCAGAGGT CGCCGCAAAATGAG CGATA GGTAATCG ATCAC CGAG GAGATGCGTAGTAC GCCGGGG CAAAGCGGCCCC TGGAAAAGGATCGGAGT CGCTGCGAGTAACGA CCA GCCG TATCC CGCAGA G GATTGAACCAAACGTTA CGTG GATTCTCCC CACAGACGAACGA A G GGGCAAA C TTAATGGGCGGGTTCCAAAGCC AATGGTGAG AGG G A A ACGTGGGTCTAGGC CTTC GGTGACGGCAAAGAG ATA AATGGCCCC TTGAGGCG C G A A ATG ACC AAC G ATTC G ATCCCAACAA G ATGACG A G G A A GCA GG C GA

[0013] GCTGCTATAGCTA GTG TGGATT AGAATTTCGG GG S QTL QM E LECKEDIAAT CGGT CTTAAA AA AGCAC CGTGACGTTGACTMT KARIDP CDDII RHPCAATGAACC TC TAG VKG T R MHKE RGATACGA GGT CAGAT AALEL C EME SGCCGGGATTT ACG GAACCCGTCCTATCKV GCAGCGYINTK NMKI EG AMMKCAACCA GGCTGAGCTACACTTCGG CTA CG ACG GCALGE AFMLLINQ Q KE E SIGTGAA A GGGGAGGA GCGCC CAQAGGGATS CSPVTSA YKTLNFAE PGCGC CG GGACC CTAACR DRAEYKVCGCTGTGG CGCGTCGS ST AIVFMQTTA TACCGGTGGTCCCA GTATTC TAACGTGGAG NNFTDIKRV SV KLDHIN T CCCTGCATACACGAATAC CG TGCAGGA TGGGGGTG CTTCGAT SCACGSIAPFI GR RPFF EQW LNDKM DFRDIG CTGGTG ACGC C CT TAGCAAWC EDP LP TG CCTATAGATCGCGTC TGCACCAA APAGAEITNIKQESDEIKGKKD TACGCGGTACAGATGC AGRTIAPD TCCGAA AAGCT TGT GT ILPADFKGVGCGCCTTCCT T AGTCGACATCCGCG CTCTC GEQ N GKMLSKKEKIEQLP 7 TCGTGAGTGCATG GTCG CCTT CATGCACT TGT A NRQGEQDFFNFDDL 6G TCTTTGGAT C CTCGCTA GGAA TGGCCGCTCTCFNLTPSAIL EKGLLGRGRCAT GGGCCCTG AGA AATGC T CTCGACT CY CS S DRSRDDIQSD KRPSIAGCGC TGGCGCAG CGCGACAAACCAAG G CGACAPARGPEEVCRRRGIVPCAACGCGGTG GGCGA GAWGG GGT PTATTGTGAATGGAGC CVAL RK NRWG A CATAAAG CGT CGACA GCTGGGG AAGAGAA GATG VGGGDL LLAITLNSPPCGATTTAC CAGAAACACT CAAGCACAAT TCC DKPYIAPKRE LDRLRGG CG GT CCTCG GCC GG GGGGCATATCCTGT GGGCAGTVGGD AEK TR A C RLG R ACAGCG AC CGTTGG AGGAAACACACAAGG GE SRVNPADI FNEELCDL RGACC CGTGAGACACG TCTA CCG TATTTCGA TCAAACTCGT CGC T TCAG C GKALETRA VL EVK GC DGCGGGAA CG TTGTNI AGL TE LCCGAG DT IKQVE SDSTCTC TGTA GTAGCACACCGC TTCATTC CCTAGGACGT TAAAVYAS GP SSTTKEEQLG K AAGAG ACACGTGCG AC ACGA TGLVKRPIGPV KPLKRDMA GTAGC TAATCTGCGG ATTGAAG CGTGTGG A GCAFNPGQ R H WKE GFRMAGAAGG CTG GACAG CATGTGCGCACGGGC CGCG GGCGCTGAT TCCQ G GTQN F AGPPA KMTLTRN PEEKI LLRQ AT CCAC T CGGA TGGGNSSDGEQL SQ AGGACG GCGTTGCTG TTA CAACCGGTCTCTATTASQK LRV AQ A SKTKTV CCGTAA GTG ACG ARL TKF LAVKKIG G GCC A G GCC ACC GTC GTC GGTCC GTCCAGCTC M V GSLN M A A V K H G4- FI4)e5aa_6P(()B 2N99Md-5113

[0014] RREEE TKLFPNACT AG HLLS D ACCAGCGCC TTGT ATCGGTACT TC CTAA ALEFSKENTGCCTAATC GATGG GA A ERLSMG DAGEGLVDH GCATGTATCGCCC TG CAG AACCTCACCTGG CAA S DANCKEYDGTGAAGCTCACACT GG AGARA KLL MPWKA VLSAE CGATCCCTCCG ATCCGGA AAAGAGACGT CACA TA DDR HL LVS LQGL LDDECG EGGGAACAGTACACGG ACG CGCAGG CGTA S GLPAGYEH LGGK EAE VLRFLFACEAGCACAG AA GA TGTCG CGCA TGCA GCACATGA GCCCCTAC TGGGG TAAKK E ELE MR AAC TCCCTTA GC CGTGCAE PI Q QIQLI RQPRTRLL CAAGCGCGCGTCTAACGC C CCAA ACC G GCAAA GSG RSA KGPW LNEFLW A GCCTA CAA TTCAGCGC CAGG CGAC T TATAA AA GEPM RR SHTVTLEIINPKF GGCACAACGTCC TGGA GCAG TGCTT CCCGG GSSEK KE LGAVES P FATGCTGGG GA GGGAACCG A ACA AACCT CA AGA CA SLGS RSE RAEAKSP Y QE TGTA AC CAGGCGCGGA G GTAGCGC TA A AGACACG KSRELE IALKLACVLTVSTCCACAGAAGA A CGGAGCATAAA GCGGGTA   GRQEEE SYP CLA GRAVK GAGGACG GAGACT CCAAG AGC C TGCCAGG 8C6WSVVLVES REWMQ GTVLLATTGCAA GAATG CTCCC TCG GAGA CAC CAG TCGTRRKLALTVSMKP LAVCTAC TTGC C CCAT C C CTCACGACTAA GCCCCTC GRSFASHPI CA EA QLGTTC AC CAG TAA C A ACC TGG CAGCGTCCA GCATGN PD SRKELVDLL S RK VAG GC CGGCGCCCCGCCA AGC CCCCGTAGCAG GG ATK P IS GEGEELTYLQACCCAGGGGTGTAA AAG AGA AGTAG AGTA ATA FSLE TAVHLRMIEGQL NAECGCACGCTC ACCGACGT T CCAC C TGGCCCGGC QTP P PPVDELT SVQACGA GCATAGATGTTG GAG GGACGG AG ACGCGTA NVTNR LFIALLYE ILPQEDCGCAA CTGAGCGCACG TGG AAAGACGCTGGCSA AFLQAALESVQKKTTCCGG AATCAG AAAGG GCCA AGG AGTGTG GTA DI QRDE LS LIA AK QEQSE SSCAC C C TCCC C CGGCTC T GTGGGAATCACAGSL RGPA LSRKPS EKE LDEA AGTGAGAGT CGTGTCCC CCGGTA GTAAACGGG AA DVAYLGLANC WAL S CG CAGCTACCACATGCCCCCATCT ATG TATG KFTI RGALKNRDEGP VFEIYYFGCATAGTG AACCGGAG GAACG GGGGCACCTGG A DRQQRYLA K A WCQACGGGGCGCTA TL C ACTG ACCGAA AACGGACCCALTRSGGRVPGCYKIDFLLDECAGTCGGTAGACGG AG A GTGA GGGAGT TA STGRDD GG RQQTVAIQVKKGGA GGAGTACCATCTACCCTGACAACAGGTAT TG TAPESD ATSERRGEQAVTRV ACCA GCGCG A GGTGCCCTGCTA GACAACG GTTCTG GCTAAG G A A G4- FI4)e5tn_6P(()B 2N99Md-5123

[0015] GA AGGCACATAGC CGCTA CAT AA GG AGCAC TCGAGTCAAATT TACGG AA G ACAAATCTGCGG A ACGACATCACGTGG GGGCAG GCGCTGGGGGATTT AC GGG CGGCAA GGCA ACACAGCAAAGGAGCAA A GAAAACCAACA CGGCGCGG AGC CG ACTGCGCAAG TCAGCGGACG AACGAACGGGGGCTGATGAAGTG AT ACCTGACAGAG GGCCTG A AGGGCA GGAATCAACGTGG GCGCGGT CG ACTT TCAA A TC CC CGACT CAAACACTCGT TACAGGTGC CTCGC TAACCGG GGTGAC CA CGAGACGGTCAACG GCATGGGTGG A GC AC TTCCATG CGAAATT TGAA CGC CCGA AAT CG TGCCGTT CATCGCGC TGCGTGCA GGC TACCG CGAA AGCA GATGCGG GAGGA T AA G CCGACGGCAGGGGCGGACA ATGC TAGA GAGATAAGGACGGA CA GTATGCTGCT TA CCAGA GGCTACCTCGCGG GGATCG TAATA C G A AC C CTTCCTC CAATGGCGGAG ATCGCG C TCCG TTA GCACGGA AT CGTGGCGCTAC T T CAGATA ACACC TAGCTATAG GAT GAGTGGCTAAGCG TCTAAC ACAC CGATACG CAGGCAT C CAGT C TG GC TGGGCACG T   A AGCCGGCGACTGG GG AG GGTGAT C CCGAAC CATAATT TATGGCC96ACCAAACA GGCAGGGTGACCGCC C CA AAGACCGCCG AC CAT GGC C TGCGTC GC T GAAGCAGGGCA AAGCATA GGTACGGCAGGGGAA GCAGA GCCGCGAT T T CAA G ATAACGATAACGACA GGCCGATGC TTC TATT TAAGG GAGGG A TTCACT GT CC GCCGGA GCAACGGTG TCGACGAA ACAAA ACGATCTGC CCAC TGTGTACAGGTTGA C CCGACCGG GATG GC CA GAGCGA CTTCA GAG GGGGGA CAACCATGGAAC TAAA CCA CA ACAGCGA CGTCCGTCCGCCGCCGCCGGTGCTGATGGGAGACG G GAACGACCATCCTGCGCGCGAAGCCAT CAAG CCGACAAAGC CGTAACGTACAAC TG GGCAA GAACTGGCAGACGATCCCG CGAGA GAG TAGG GTAGGCCAG ACGCAAAATGAACGGCTTCTATCATA GGA GA A G GCGCACGTTTGAC GCGGGGGAGA A GCGT CTCTGAG CCCAG CGT CAGTTAGTGAAT CCC CC CCA CCCAC A GCACGGCCCCGTTTCT TACA CAAT CG GAT C CGTGACGGA GA ATG GGC CCAAATC AC CA G AA ATGAGTAGGGTTGT CGGT CG AC AGGC CT TTA GGTGAGG GA AGA GAGCA GGGTACCATAA G GAG ATAGTGTCCAAAATCGG C C GCC TTCGAG G GATAATCCG AGCACTCGA GAAATTACA AG AACC G ACGA TCGGGTTGC CGAGTCC A AAGAGCGCATAGA GCGC CGCGGGCT CG AAATC G GCCTCGACA CGACACCCG TCG AGGG GA AT A C CT G ACA GGTGGTC CGTGCTG AACCAGA G A G ATG A GCTGT CGC C CGCTCCCTCCCGCGCGGG ATTG ACG GGCCTGCCGAGATAATTC G GCTCT

[0016] AAGGGCCAC TGGCGTTTGA S QTL M E AGKQ LECK EDIRREEE TKLFPHLLGAGTACAC CCC CGTCCAG TATAT CMTCACAATCGVARIKGDPTCDDIRMHI RKHPA ERSALERLSMGEFDAGEAAC TGCCG GGGCKLEL C EME E SDA K GATGGGCGAGCTACCCACAGG YVILNTK MNMKIM GGANCMW QA MKARKLLPS LTCGAGG CCCGCAGG CG ACT CTGTCTGATC AE AF LLIN AKEQ TNE SIA DDR HL LV QGL LK ACAAACGQS CDSPVTSRYKTEL FAE PVSGLTPAGYHGG AECG CTT CGA GA GGT CGAGTGAG RGTGT S STGFAIVAFMY QKTKKEEELL E LQE QGGTCT CCGCGAG ACNSNTDIKRV RS VEKLDHINAE PI Q GQIQLI R RAC CTGCTTCTTA GGCCAAAA ASIAPGRFFNDKM W DGGSRSA KGPW LN L GTA ACA AG GCCA TACAGA GTTGCTWFIEPICPNE LKDPEDFR IGEPDLE PKTG KDGRR SMTSEKH EVT ELGEGCGTTGCGG TT IQ SIKGPDSRKEVSTCCGGACCTACCCGA CTTCTGCATILGRP TKADIA F KGVSLGSSE RPL A AKLGCCTATGATAC CC GTTGEQ N G MLSKKEKIEFQLSPKR IREEALKPA 0  AGAGAAT CT GG CTC C CCCCANRQGETQDFI FD END GLGQEEE SYLGRQ7AG GCACGGTACCG AA GTGC FA NLYPSRALKGLLGDRRWSVVVES RLEWMGGTGAAA G GCCA GAGACGA GCCA SPS DSRD CAACAGT CGE DIQSKRPSIL RKSALTVSKPA GGGAAGACARGPGEVCRGRRGIVPP RGRFASH EPI CLEA GAGTCGG AC AAGGAGCAGA CVWG AGLGRK NR TTWGGN DSRKLVDIL SEGGACAGGGCTTCACTAAT TGC TVGGGDL LLAI LNSPP PATS K PSGEGL ETATACTGGCAK YAKRLD LGGTHMIG GAG AAC C CG G DP I P EKR RFEA VR ELT CGG T A GAA T GACACAATG AGGTV GGD AETRA C RLG RLQTP P PPVDELTC T CAC C T TCE SRP F E LDRVTLFI LYCG A GAGCGTGVN ADINE CLNRF ALECGCCGCTTG AGTG AACTTTGAG G NKALETRA VL EVK DNSA QAA AL LESV AGC CGTAAAI AGL TE LDSDRE LLAK CAAGCCGCGAA DT IK QE SI QDSIAQGGCAATGTGA AGG CT CGTG AVYAS GP SSTV TKEEQLG KS LALRKPS EKEGTCTG CAG CTGCGGGCCGTALVKRPIGPV KPL GQKRDMAP S RDVAYLGLA G TCG ACG GC CGGCGGATCCG GFNPGH NRWKE GNFRMKFRGA DLEGP VRFGCG TGTGGTTAAAGCG G QQ CGTATAGPPAMTTREKIRLTQINRDRQQ YLA G AC TTCA TGCCGTTCTATGFNSSDGKELQP ELLSQKTLTGGRVPGCYKIC CGTAGCGTCGTSKRVA SVL S GQTD ATGC GT C CAC CQ LTAQ KTKT TDQIQ GTGGAT TA AR LKF LAVKKI R R RVA A A A G A A AGCATATTTCGG G G M V GSLN M A A V K HSTAPESD ATSERGEG4- FI4)e5aa_6P(()B 3N15Md-4133

[0017] ACTCT CAAG GCGCC GT ATT ATCGGTACT TC CTAAGA AGGCACTATAGC C GGCCTGTATGTCCGTGGATCGTG CACGGAG AACAAACTG ACGG AAACGCCTA GA GATA TC AGCCCCGCTCCA CAAAAC CACTG CT CA GGGGG GC GGCG ACA CAGGCGC CT CAT CGGAAAGAGACGT CACA T G A GC CG ACTGCGCAAT CCGGAACAGACAGTACACGG GAA TG ACG CGCAGG CGTA AATCACCTGAG ACAGAG GCGCA GCAACATGA AC CC CAC TGGG A AT TCA AC CGACT CAA CAAACAT TGAAGCCC C T TTAGCGG CCC TGGTTGACTT CTCGAC CA CG GACG A GCCGCGTCTAACGC C CCAACA A ACC GG AAT TGAA ACGC CCCGA GCCTA CAATCAGCGC CAGG CGAC T TATAAG AC GA CGACGA GGA CAGGGTG CCATGGCAAGGCGTGGC C TGA AG GGACAG AA T GCTT CCA CACGGCGAGATGAAGGATG GAA AGTACAGG GTG ACCACAC CTA GCACTAGCAAA GTTCAACACAGGCGCGGA G GTGCGC TACA AGACACGGATA TCG GCACACACCACCA AGAAGA A AC CG AGAGCATAA AGCGGGTAGGCGCTTAA GCCACA1 GAGG G GAGACT CCAAG AGC C TCCAGGAA CACAGCCG ACAGAGGC7TTGCAAGAATG CTCCC TCG GAGAGCAC CAG TCGTACAA AGGGTCGA G G CTA GCCTCCCAT C C CTCACGACAA GCCCCTCGGCGC T G AAG G CAAAAGATT CGAAAC TG GT GCAAT T T T TAACTC ACATCACGAC TCGCA GGGAAGG GC CGGCGCCCCGCCACAGC CCGCCTGTAGCAG GGGACT GT CCT CCCGG A CCCCAGGG GGCATGTAA AA AGA AG AG AGTA ATAACAC TGG A GGTGA AGTG A CGACGCGT C ACCGACGT T CCAC C TGGCCCGGCGG AACCCATG TGGA GGA ATAGAT CGTTG GAG GGACGG AG ACGCGTACCGGTG TGA GAAGACCGCA TACTGAGCGCACG TGG AAAAGA GCT CGGCAAGC TGCGGCGAAGA G TCCGG AATCAG AAAGG GCCAGG AGTGTG TGTACCCCGA GAGATGGCGCA AC CAC TCCC C CGGCTC T GTGG ACAGAACAAGCGGAGCGCAGTGT C TG AAGTGGCGAG GCCT CGTAGCTGT CCGGTACACC CCCGGTGTGGGAAAACCAAA GTTCA GA GTGATT ACATGGCCACCCCGATGCT AG GC TCT ATTGGGCGGGTCTGTCCA GG ATCAG ACG AATACGGAGAGG ACA GAAA G ATTG A CGG CAG GCGCGCGCAGTA AC ACTG GACCGAA AGAACG AGC CGA AGC ATGCGA GAAGTG TACACACAAGGACG GGTGT CGGTGAAGGGTATA ACCT CG GA TGG CAACG GTCACCAGTCTACGC CCTG ACA AAC CAGGGATTT A GGCCAAG GTA CGACA CGACAC G GT TGTG A ATAC CAGA G A G ATG ACG G A GGT CCCTTA GACT C C G AA GCTGTG4- FI4)e5tn_6P(()B 3N15Md-4143

[0018] GCTA CAT AA GG AGCAC TCGAGTCA AATT TACGGAAAGS QGR GGCC ADKL G GACATCACGTGG GGGCAG GCGCTGGGGGATA TT AGAGTCCTM APKLRLLC CA AAAGGAGCAA A GAAAACCAACA CGGC CACA GCACCT V GD KKRAEK A GGCG GGAGACACAGAACGGG AGCGCTGATGAAGTA GGAT CYVIPAETRFCCTG AGGGCAGGATAACGTGGG GCG TCGGT CGGGG C G G ALLEETRDIN AACA GTACTCGT TACGACGGTCGCCTACACCGG GGTA TCCGAQS CGKA VLTATCACG CG ATTGCCGGGTGG A CGC AC TTCCCATG CGAACGCG TT CAT CGRSDSGP SS QV T GCGCGTG GTGCA TGGC TACCT GA GC TGG NNTG GPKT PGA GTGC CGGG GAGAAGCAAT GC SVK G TAAGG G TGC CTAA CCAAC TTTAGAC CS ARWQEGCT TA ACAGTGG ACGT CC CGCGGCGTI FPG ATACWIPAKTC TC CTTCCGTCA TCGG GCGGAATGCGCTTCCTTA AGTCAAE PI G KEMTPCCTAGCTG GAT CGCGAGTA CGAT GCTGAGT CATG TCG GACAI TLRTALQV CCGAACAG GCAGCGGGGCGGE SKQ KTGTTGGCCAGAT CAC C TATCAGC TTT TAT C CGC TCGCCTA G NML NF LA2 TGAC CGACACG AT G GAGAANT LM7CGCCACGATCA AAAGACCGCAC CAAGC C TGGCCG TCAGAACF LTRKIQM L GACTGGTACGCG AAGCGG AT GTGCAG TAT CGCGGCT G GTA NSYS GSDPTCCAACGAGCC TATAGGAGAP RELRA AACG G GT CGACGG AACATCAACAAATCTGTCCCG A ACGCT A G WTG KCG ATCGTGGGGC CAA GATAAG AVAMNM CCT CGA AAACC TCAGA CAG CGAGAGCGA CGTCCG GT CTCCCGCGCCGCGG CGGACTGGGTGLVG KGVLIN TSA GA CGC AGC T CAC AGA TAGA DPYI RY ATC TCTGCCAAGCGC AGAAGC CCGACAAAGC CGTACG G ACT CGG GGTV G AIIVA AGGCCAGGAACT TG G G GA AC CA T CCG TATT C TTGCA GE SVNKRRVSTTACGCCGAC GCAAAA A GGGGGAGAGTGCCCT TA GCACACCGCCGTGKARP FFCCC CAC AAAGCCGG C TTG TA TC CTAG AAG NICAAG DTAI E LN KDPTCCCGCTCC CG GACA G CGGACGCACG GAT C TAACTGGGCAVYAS RQESCCAA TCTACGA GAGGAAG GATAGAATGTCAGGTAG CTCLVKRPIP T IGKA ACAT TGTCC GTG TAGCAGGG AGATAGTCGA GCATGCG ACT C C FNPQSK GACGGTG TGCC C CAGTCCCG AAAG CGAGCA TAG GACGCCGACGTCGTAATGCAG Q GTG TTCTQN F AGQG S DEFIC G G G G GG ACGGC ACACTT NSSDRALCG TCCAGC G A AT AC CT G ACA GGGTG GTCGCGTGCACTGC SQK LRPD EDIC CCC C CGGGCC T C CAGATG AT CG GT TATGG AR L EV G GCT CCTCC G G ATTG A GG C G AT C CA A G M V GGLG G G4- FI4)e7_6(aaP1()Bdi97Mm-0153

[0019] RII WPCT AG C GCGGCTGATACGGTC ATACCACGGA TG AGGCCCAC GTTA DTLNG SPTGGCCG TGTATG GCGCCCAG AAACGCGGCGG AAGCCGA ATG RLGPCATA ACCGA GAGAG T CGGC TG R GGTGA E EC RLGCAG GC TGGGGT CAC TGGAAGATCCG CCT CACCTCGGGA AGTGCTGGGCAA LLC CGTCTGA AGCCDLRRGCG GGAACGTAC G CCTCGTAATGTGCACAC CG G AAAGAG TEE ELVKCGACA AGTAGAT GGCAAC CG A GATGAAAGCGG CGTGCGCA TGCK LSDDSA DACAACT TCGCC TGGCCG GGGCGTCATGA TAACAACA GTTAGTREEQLGIKS CAAGCGTA ACGCGGTGAAA AAACT TGGG GTT CGCCG AG AGD RHMFAGPA GCCTCAATCACGCCTAG AGCGCG GACGCGGCAAAGTGGT CTEENRKIMKGGCATCAACGACGGCAG ACAA CAGAGC AGGAA G AGTA GTA ARLTI TGCTGGG GA GCGAAGCTGA GT CAG AGTTTTACAAA AT CTACAG TLL SQ S QKTGTACA AGGCGTCGATCGT CGTG GCATAGGCGTAGCACCA AKTVL TCCACCA AGAAGCCGTG AGAT TGATCGTAGGTAACCCAGACT3 AEVK KKI RSGAGGACG GATGACCAA AACCCTGTC CA TAAGAGA GGAA7DVCEH ET TTA DGCA GAAT CCCGGAAAACA GCTCGGAG AACG ACA ACATG MDKEHII RIHP CTA GCCTCCCAT CGGG ACGG ACGAACG TCAA A GGGGGGCT AKMIKEEERSTTTCCACCGCAG GC T ACCGCACAACA CCGCGGC TAG GT CGACTAGGCAAGC CGCAGACTG Q KAG G EM GC C CGCT C C CGAC GTAAT A C C AQMEK ACCCAGGG GTGG ATCGC C C CCCTAC TGGGACTCTC TG AACK ETSF LNAIPCGCAGCACT C ACCC CTAGG CACAGGATTATGAT C CAC CG A VMFYEEVCGKTAGG ATGTCGA G TAGGACAACCG GC CTAAAATTGA GC CACDLQK HI TA NCGCACG GATACGACTA GTAA T GT ATAAGTA CGAACGCA DKDQWTTCCG AATCAG AAGGA AGCAAGCC CTT CCCAA GCGA GCG GCGTG DFM KL RDIGCAC CAC TCCCCGAGCA ATG AACCTA AGAAG A A A GGATGAA DE P TG A AGTGGAGT CGTGTCCCA G G TG A AGA A CA ACCAGC CAAATCAG KG EIKKD F APDCGCAGCTACCC CCGAGCACGT CGGGG AGTAGCTG GCA A FEKIKG EVGC TAAAGTG AACCGCACTCTAC CAA GCCCCATGGAAGCGTCTCG NFQ DLP CGGGGCCGCTCCCGG CG AGCTAAAG TCGCTACCA AAACA KGDLGL CAGCGTAGA AG AAC CCCGGCCCTGGCAGGG Q G GTG AC T CG AG CLRSG DRRRKRP SGTGG CAACGG GTA CACC GAAA AGGG AG CTGCT CA GCACTACTTTGTACAA GCGTAC CGACAGG G NRG VIPACG G A GGTGC ATAAC A GGTA G G AACGTGGTACAC G4- FI4)e7_6(tnP1()Bdi97Mm-0163

[0020] CCGGGT AC CC S Q C TL M E MT K QLECK EDIRACCT CAAG GCGCC TTG AGGT I P CDDII RPATGCCTAAC GGT CAATARDTH HRA G ATGTGT C TGAA AG GGCATCCTV KKGA VILELRCMEKMEENTK KIME SEGSGCTGATA ACATC AGCGCTC CCGCT CTC CACCCYLMNMQA MKGCGC CCACCG AGGTAGG A A GG QE AF LLIN AKEQ TNEASIA DGGGAA AGTAAACG GCACGGTTTCGAS CCC RD SSPVTTSARYK VAEL F E PFMYKVSCT PAGCACAA GATG TTGCG CTTGCTAG GA CGAT T C C S F IIV QHKAACCCCGCGTAT C AANSNTDK RRSFVEKLDINACA QWAG G ACTACG TCGAACAC C CT S AP RFDKMSCAA ACGC CAG AT I FGPLNFRDIG GCTCA TC TCGGAC IAAGATWPIC EDPED DLE P TGG GGTG CCA GGCA GGCG GCAG CCGGGENIKQSK KKDSGTGACCG GAGATRT IGIAPDSTGAACGCGG TCGCCILG AA C TCGEQPAD GKKKFKGVG ACLGTCCAAG GACG GGAG G   GC C C CGCGCTNMLSRQGEEKTTGTGCG T AFNLTQFIEFQ DPK GCACA A ACGCGCGA TC 47CAGCC CSDFIEN GDLGLGGAGG WTTAAGA AGATGC CGANPALK S YDRDDQLDRRRSSGCGA TAC TCACTTCCCCC AGGCAAAGGC PSRSRPEISVCRK GPVILPR CTTGCCCAGCA A GACCCCAGAAATC AGVWGGELGGRNRRITWPGTCGC CG G C TCCACGCCA GCACATAGRKLT NGG CGC C CGTAA ATGG CG GDLAI LPPACAGGGTG G AGACGC TV G AACDK YAPKRELLD LSGPGAFCCGCAGCC ACACA GA GCGTAA GGTAGPVIGGDEK CACAA CGTRRARCRLGLQCGTA ACGGTCG G ATGT AGTCTGE SRPA ATDF E LDRR A NVCGCAA CTG TGAGCGCGCG C A AGGATGVN KALETIANE CVL E LVKNSATCCGG ATCAGAAGG CAGGGANI ARLE L DQT ATACCGG GCTGAGTAT T IGKT SDSDQCAC C C C CGCCAGAC C CD TVYAGP SS QTVETKE QGIS LAGGAG CTT CGGT CCCAA AT CTALK SPGPVPLEDLK AGPASATCGAG CAGCTTACC CCTAA CCACCCCGVF RNIPGKQKRMR KE GHFMKFR GC TGGACCAA GGAG G GC CA GTTAGC TGG Q CGA QNPW AMT RNRI LTIN AAA GGTA GGCCGC TFAG SCGCTAAGT DPGKLTPEEK LRSQ QKTL CTCAGCGAGACCCGG CGAG ACACNS EQVALSGGTGTACG TGG AGAG GSKRA CGAQTTKTVL SG GG A AQRLL TS KFKLAVKKI RSTGTG CAACGTCA GCA CA GTCTTG G A A G ACA M V GLN M A A V K HTAPACG G A GT C C TA G4- - FI4 Ge56) 445 )(aaFI6(tn_()e_(P20 P2 )Bdi 3dMm-1B i031Mm-117383

[0021] TTTACT A AGACA GCG TAT A S QP T ACGGTC CA GAGC TTACC CAGGCKV GGA ATCGTG CAC TGGAG AAGCGG AAACACT AAAACGACATCACTM AWQ AACACTGCGGGGCGGCAA G VKAK ACGACTAAAGACGGGGC ACA CAGCAAGG KK MGGACGTACA T G A GC CG ACTG ACGCAAT CAGCGGAV ACYIE LGCAGGGTAT A CTG GG CGG G ALAQ ACGCACAAC CACAGAGC TA G T EKQAA ACATG CC CAC TGGG A AT TCA CAC CGACCAGTAAAACA ACQGC S CNFC G CGC CC TGGTTGACTT CTGAC CGGTA AC GACAA CGCATCRSDS LKM GTCC CCAA ACC GGCTAAAAT TGA ACGC CCCG AAT CTG GCCG NNT IQDPAGG GACGAC TATAAG AAC GA CGACGA GGCAGGGA GGTAGGC SCSIAE TLGACAG TGCTT CCCGGCGAGATTGAAGG T ACA GTATG TCFC TWITPK A ACA TAACCT CA CGC TAGA ACAG AGGCA ACTAA G ACGGCCA AAACCATCCCTT CAGG TCT EI MT AT LN VLIAAGTAGACACGGAT TGCACCC IL SGCA GAA A GCGGGTAGGCA GCTTAA GCCACACTCGAA G G GTGGE TAR5  AA T AGC C TCGG CCAGA GCCG GGCACA ACAGAGGCTGATCC CN AM NIIV R7GA GA CAC CATCGTACAA CAGGGTCGACG G GCACC CCATAF LKRRCAC CAACCTGGGAAG GAG GTNYP FT GATGCCCGC TCAAAAGAG AS SS LGG CAGGCC TCCA GCATAT T T TGGG AAGAACG GATCAACACG TPARGD G AC CGCCTGTGAGCAG GGGAACT GTGCGCT CCCG GGGTA CGGTVWGQATAAA GACGT T CA GTA GATACAC TA GGTGAGATG AACCT CGACTG AACVGGKSCACGC TGCCCGGCGG CAACCCATTGGA A GGAGA CGC ADKPYIG G AA GCGAG ACGCAG TCACGGTG TGA GAACGACCATCTGCGCGGTVGD C CTGG AAAAG GCTGGCAA CCAGGC CGC TGAG GGCAGAGGT CAA GCCA GE SA VND AGTGTG TGTCAC CGA GAG CATCGCGTAGTTACGCGCG NKAET GCTGG A GAGAACAAGCGGACGT CG GTG AG GAC I AAGGACCC CA DT I EGGG CTGTGG TGA AA GAACAA ACTTCGTA GATTCTCCCGCTCCVYASRCACCAC CGA GCTGC TCT ATTGGGCCA GGGTTGT CGGATCAG TACCGGCAA CTCTTTA GGLTV KFRPNID P K G GGA ACA GAAAGAGGATC AAACND ACTCGAAG A ACAGC CCAA TGGAAA ATGACACGACTG TGCCQ GTQ A F AGA CG G AAGGGAG GTTACGA ATTCAG AACC GTCGGCGGCGA G GTNSSDTC CCTG AACAACACAG GAT TGGCCAAG GTACCGA AGCA ACGACACCG TCCAGC G ATSKRAQLK A G ATG A GT T CGCGTCCTCC RLGCG GTTCTGCTG A AGTACGC G C CCG M V GSSG4- FI2e1 )_7(aa3(P)Bdi03Mm-1193

[0022] TPK KL E QLGISLA CCT CAAG ER EGCGAAGCC CACT CC GGGGAT T CCTG AAC DMK TGAGPAS TGGCC GTAT CG CT C CCCCTG AATTCAA TT CTCA AC CG TP RHFRMKFENI RG CTA GTATA AGCC C CGACC G GTAG ACAATGTAC CA ACKRLTINCATCCTCCGG AACGA AGC TGT ATG CAAC GCAGA ACGCVELSSQ QKTLG TGCGCGGAACGTAACAA TC T CAA G ACGGCGAACGTA KAL TL SC CA AGCAC CT CG GGAGA G LTK VTGAGATTGC TAAAAGCTGAA AA K AVKKI RSA A ACAACAT TGCCGTAGCA ATAGCGCACCAGAA TCTAA MVEHTPCGC CGCAA AG GGGCACGG LE CEDRAACGCAGGC C TG GATGCA CDDKII RIPA A GCCTA CAATCAGCGAGAGCCCA GTAAG GGACACTTA R CMEHKH ERSA EGGCATCAACGGAAC CACCAATCGCTACAGCCG AACA MKMI EMEGS TGCTGGG GA GGG AGGA A GT GGCCC CACCTGG GCCTAGGG NQ KAEQMEKA S A GTA AC CAGGCGC ACCCCCTGTGCACTAT TGTAA CAG AT N I TCCAGA GGC TAGCAGGAG A YKFAPDCACACAGGGTACTGGAA6  AEF LMYEV SPGA A GGACG GAGA GAT CACATGAG TG AACACGTGCGC7VS VFEKQK HTNKTTGCAAGAAT TCACACGGGGCCGCCCGGGGTAAGTGTA NDLD KIA MQWGCTA GCCTCCPDF CATGCGGA GCCAAGAGTACGGCCCA ATERDIGSTTTC AC CAG TACTCAA AG GGG CT TGCGAATGTCGT GGA S DLKE PKTGG DG GC CGGCGCCCCGGA GGATG G ATGTCCAC CGC TGAG I GK S A CGGGTAGAACACGGAAAGA ADIAPDS C CAGGTAGGTG AGTG CA KKEE FK FF KIEGVF QLGCGCAGCACT CCCCTCGCGTG AA TAGACCG ACAACG GTG DPKCGG ATAGATGTCA TACGGCGC TCTTAGGGCTACTTCA I LEN KG DLGLG GW CGCA GA CTGACGG ATGAAAGCAGGGG AATG CCAG GDIQLSDRRR S TTCCG AATCAG AACCGAGA GCAG AC CA G AGGTG AAGGTVCKPSILGCAC C C TAAGG GCCG ATA RRGPRCC CCKNRT CAAAGGT TATAAA G RIV TPG A AGTGAGAGT CGTG G AAACCGATTTA GGCCT TCAACA LLRL AITWG ELDLNP GP CGCAGCTACCCLS PA GC T TGGTT CTGCTA GAGGTG AA CGACC AAAGTG AACCGATCG AGT TA GCT TAAAGC CAG AGAGA EKR RGGFGG GCGCGGC G C CTAAG A TR A C RGLC GC TAAC TCACGAGGACDF LINE LRQVCA GGGTCGGTAGA A AACAACATCGG AA CAGGCACAACTALV ETLCEDL RN VKNSA QGTGGAGG TA ACCAA G GGG ACGTTCGGG CAGGC GGTC Q VEELSDDSD Q ACCA GCGCG A GGTGCG ACACCG ACTAG G AGCA GTTAA A AGT CACAGCATG4- FI2e1 )_7(tn3(P)Bdi03Mm-1104

[0023] GATGGCCTG AGGG T S QA GEPIGQIQ R GLIQRP TRRLACCT CAAG GCGC AGAGAAACCMS SAPWELTGCCTAG AC T CAGC TARP KMTLNFLW GTGTAGCGTAA ACGG A AA CCGCGATCCV KKG VGESRRSESH KEVTLI LGEEIN APKCA PFFGCTAGATA TC AGCCCG CCGTATGCGYIS RKREVS SGC CT CA G CCAA AGGG CGGTAAGGCTGC CALTQECGLSSKSR EEL AIAK ALK PLYQCEALTGCG GGAACVCACAGTAA G GTGATC TC SDRE E SYPAVT SG GAT GCAGG ACT CCT CG TTRS SG CAWQEVVERLGRQAACA ATTVK AAC TC GCCCTAAACACCTCAGCTGAACNNT SVEKSELLWMSG MVL LACAAG G ACGCGGCCACCATTG GGTATG CGSCSIALFIRRSGRFATV ASHKPEPCALAA A QV GCGGC TCAA GCAT TCCA AACG G TAGGCGC C CWPNS KIL ES RLK GCG CGACGCACCA GTAGG GAGTAEIAATGPDRTKLVD GILGEVAGTGCTG G GAAGCG GA TAGAGTAACGILEAF STPSHEMLIELGTYLQ GTTCACAGCG G AACGACAACGTG NML ETAPVRPVDELL NSAQECACCA AGAA ACGC7 GCCGGG ACATCCG GATCANQ NPTRP FI E L TYVQ IL APGTA TGGGAGA7TGAGTG AC T CAAA CC FNLYNV AALAFLALLS EVQEDGCA AACGTA CACGGAAGAAGG ATCGATGC CSPS SRSQRDAL ELAKQK EQ KS CTA TTGC CCGTA CGACGGCC CTCAAGGCCG A GQ ESIA AVWGLLAR RPKS EYKQ SESGE LDE TCGCACCGCA GCGCC TCC CG G G TA AGCGCTAGSDVAL LANC W AC GG CGGCGTA GAGTTGAC GTGAACCC CC C CVG A DKGF GALEGP VFA ELYS C CAGGGGCAGC TCACGC C GPYI RRGNDDRQQRYLAIKYFCCGACTGGT C CTATCGATTTAGCCCAAC TAC TVE SLTGG VCYPKGIW DQ LA ATGACAA G ACGTTAGGC CTAATTTGGGTG GVN ASTGRRDQQ ATID QF LDECTCGGT TA AGA AAGAC T GCCC NKI AIAERVT EG VRK AKTCCAACACCCTACCACGCACGTGGGCGAGTD VTYAPSRRDAS REE L F EPQRV V AGGAG CCT CGG AGT CACG G CT CGGG A ATLKSPAELTKHLE LNSAD ATCGAG CAGCTACCTGACC C C CCC CCCCVF RNIPA ERLSMG DAGFE SKLEDNGC TGGTACCG AGCTGTGG GT CATTCG N D KGV HAAA AQQSGANCMP EYD GGTA GCCGCAG TAGCCCTCAGG TA TFAG S A DRA KLLLVWSKA VLAS CCAG GCGCAGTA G ACGGCGACAC CNSADHGLLEGTGTCA AG GAA CCCAGSKDGRLQLDD CAF EG G GGACAG GCCA G A A GACGG G AAAQRLLSPALCM V G K KGY EEHGEGKVF EGTG ELLQAEELRLMAEACCAAGCGTCACG A GGTGC G4F -I0 )Ga4F -0 )te 8a I8n_ 0P1(()e_ 01 ()B 199P(95B 1 9MC- 1MC-511424

[0024] GACAGAC CGTG CGCTG T GATCTAC GCAATGCGCTGGCCCGTTGTGAAT AGG CT GATGCG AAG G GCAC TA TACCGGTTG GAAC CAA A GGGTCGTGACG A CGC TAG GCC TCAACT G G GGAT CG A TGCGGCAGCC CAC GC T CGTGC CAAA GAGGTGCCTCATCGGTGGTG TGGCAT CG AGAT GCGCTTCTGCACAAACTGCGTCGGGGCGACAAAACTG CCTTAGGCA ATACAGCTA TCA GT GTG GTGGCAG CAT CCT TCTAAGTGG GTTA CC CG TCCG TAGTA CGA GTCACCGCGC CTT GCCAACCGCGA AAGCGCCT CTCATG TCG CCTC TGCACCTTTG TTCGTGG GGTAT GGTAGGATAAG GCCG GAT CGCGC TGAGC C C TGGATGCC CACATCGAGGA TCCCTAGATGC TTGGTCC TCGGAAT C T CCTC CCGATGA T GCAGAA TTAGGCTAGACGGACC ATGC CACGCAT GT CA G AACCAAGAC CCCCCCAGAA AGACCGCAC CG AAGGCG GCGCGGCTGA AGGCG GACGG GAA AACGG CAACGGTGAACATG GGAG CGTACGGGATTGTTTCG GAAGAGAT CATCACAA GAGCCGCTCA AAATAAA CGTCTGG GC CAAACACCAAGCAGA C G G GA AC C T TGG GGTTCACAT CG8  A GGTTCGACA GGC CAA GA GCGC TTCAA GCGC GGGGATACTCGT GGGG7GACGTGAGAC C C C TGGAAAAC CAACAACCAGA G GCACGA CCGTCGTCCAG GCG AGTGA CTGAATCGT CACATCGTG GCACGC TA CGGCC ACGACA GACGTACACTTCT CCAACGTGGG AGTAA AGGAAGC C TGGACC CAG TACGA TATCG GCGTCTATAA CG CTTGA TAAG CCCAGGA GCAAAACGAA ATAGAG GC GC C TCTA GC CA GCAGACGC CGTGCGAGTA A CGGGGGCGGTCT CTG TAC CTA CACAAACGG GTAGA TG CCGCTG CCAC ACAAG ACG GAC C CGTTCTAATG GGGTACTGG GTGC GCGCGCTCG G CCTTCCG CAGACG CGAGAATGAG AGAAGTCA ATGCACG GCGCGGACG TA G TA GGTGAG CGGA GAGCA G GGG ATAAGTCTCGA GCCACT T CGCTGG TTG CGAAACCATTGG GGTCTC ATGTC GC TTAGGCGA GCGTGCTTTAGT C CG TGCCCC GAGTCCCG AAAA GTAGAG CGACGCGCGGCTAAA GGCCA ACG TGCG GGC GTT TCGC CAGTCA TGG GA GGGGGCAGAC CGAGT C C TAT TA AAAC TATCG CTA GTGGCCGA GACG ATTG ACAT CGCG GCATAGTA AGA GCGTAA CCCC CGGCGTG GA GCCCT CAT CGGTTGAAG GCCTC TCC CCAGTTCACGATTCA AAG TCACT G A A GGTCACATA ATCGA TAGACGCGTCTATA AGGCA CGG ATCACA GTGG GCGACAATGGGGGATG AGT C CCA A ACCTGG CTG ACCGCG GTG G CA AACCAA GCCAGGTAA GT CACCC CAAACAA GAG GG GA G GG AGTGC GCTGTG A GGC G GGC G AGCGCCGTGCTG AACG A G G A G ACA GA A GG

[0025] S QAEPIIQ RQ CT AG CG CAGAC C TG CC GGQGLI RACCAGCG GACAA GGCGCTM ASRSPA KMPW TLNTGGCCTGTATG AAGG CT G ATGCG AAGTCG AC TA TA VKGE R SHTL CATACAC TAG GGCC TCK GREVGEGTGAAGCGTGCGGCA CC CYVI SS S RKEKRLEVES CGATCCGCC CT CAGG AGTCCTCATCGGTG GGTG TG ALQEGLSSRES CL AIAK KPCG LGGGAACAGTAGCGTCGGGGCGACAAAACTG CRDKSGREEEALSYPACGACAGGG GACSSAGAT GGC CACT TAAGTGG GTTA CCNWQV EERLGRACATGCQAAC TCCCTTC TTGCCAACCGCGA TAAGCGCSNT SV VEKSELLWMSGCAAG GCGACGCGGC TG TGAGTGCGGCGATGCGTG SIA LRRSATV S HKPACTATA A GCCATCACAACG CAGGA TCCCTA ATGC TTWFIEPGRFI NSAEPI CLE GGCACACGTGG AGA GT C CCGAACACGACTTCATC AI TGGLPDRKV EAKLD GILGSETGCTGGG GAAGCGAC C CAAGACCGCA GG AAGG FTSTPSHE LIEG GTCACAGGCGA GTTAACGCGCAGAT GTGCCTA ATTNML ETAPVRM VDEL TCACCA AGACAGCACA GAGACGCGGCATCAAAA9 ANQ NPTPP FI ELL TYGAGGA G A GAGACGGTG TCGACGAACCAACCGA GC7FNLVR LS YNAAAF ALLS E TTGCA AAGAATCGACCGG G GATGAG CAGGT CTCPS SSQRALLELAV KCTC TTGC C CCA GTAA CCA C AACAGCGT CACG CACAAARGQD VWGLL ERSP IEATKQTC ACCGCAT ACG GC CGG ACGC ACCG TGAA GC CG TAGARKSAYGEGCG CCACGC C CGGAGCGACAGGAACGAG AC CGACTTVGGSFD GV ALLGLP V ACCAG CAGGCTGCACGCAAA GGATGAG CGAGTCCG DKGPYI RTVNRDEQQR FACG G CCGACGTC CCCGCCG CAAG AGCGGCCCTCTGTTEGD SLGRYLG VYPGIATAG CAATCGTT A GC CC CG AGAG G G GCGAGAA G GVNTS GR CQQKTDCG TCGGAT TG GACTTACA A GGAGCATAGA GACAGGGG CNKIA AT RAE DRVATIEQ GTCA ACC AA CTACTGTC GTGAGGA AGTCAAT CD VT IPSAS RCACCC CGG CCTGGGAGG A LYRDE F EAGGAG G TC CG CCAATAGC CG VK SRPAEEFRNIPALTKLHL PRLE LATAGT CGCTG CCGAT CGAACG QSMGGFE CG CAG CCAGGGTGCCTA GGTA ACCG AGGG GA A GGTAT A CTGCG GG ATQNESD DAF AGAGANCMNSRALLPK AAA GTACCG CC CCCCC CGGCGTG GAGCCCT C CATLVWCG CAG GCG GCG AGTTAAT CA GAAGTCACT G A A GC GTCACS SDA KDDKH S LAQRLLSPGRLQGL LGGTGTGAC AALYHGEGKGTGG CCGTCACATGGCGA G ATGG GG A AACG GTCACA GG G G A AA AAGGAGCAGGACCG M V G K KGEEELLQAEELACG G A GGT CA G G A G ACA G AGTGC GCTG G4F -I08)Ga4- aFI 08)te0( e0 n_P 1( ) _1 ()B 215P(14B 2 5MC- 1MC-413444

[0026] GC TGTGGT GA CCCS QFQH GRS THAQP T I TLE EE FL S ACCT CAAG GCGG CCGGTATG GAAC CACTM AEFSFY DGKEGPVGLDERPCTGGCCTGTATA G AC G ACTCGTGCGV C KKLECSLQASKLRA K VMQL LGCTA GATA AGCCCGCCAT CG AGAT GCGTYVIEISK DEWGPD GES E EELCTM KCGATCG CCT CA TTAGGCA ATACAL EAEQL PA QPQPPAD KSM NYID GCG GGAACAGTAA CG CT CCG TA TCT AGTCGA QS CDSRPE L LH VDHVP EN TL PCRACGACG AGAT GTC TG TCG CCRAS SSSSCDKGKAK LS LACANL VSAAC T TCGCCCTAG GG G ACG TCGCTGNSNTGDWTEIHMLS LAA QNT RQRVL TCAAG G ACGCGAT CCCG AGA AA SIA AATAD NQGDP RRA EFRLELA GCCTCAA TTCA ACGGCTG GCTGCAG CGC FAWIEPSWGS L PH KHSLEKT FPTK QGGCACACG G AGC CGGTGAEIT SAQFSNINRRWPDMF GE I TCGGG GMTGTGAAGCGA TCGGTG AAACAGT CGCGTILESSIDGG AEDREKTVT ME RGTCACAGGCG A TCGC CAAACG AH F GNMAS TGP RLSSTLMSS PN YTCACCA AGACAGC0 TTCAAGG CG GGGG GGAANS QNDPN RQSSQK FL R LQYGAGGA G GAGA8TGCG GC C TAGGFNL S TAEGCTAGTG YNRALQSHLTYLDAMT EQTTTGCAAGAATC ACT CTTCGS S ES ES WKQGGTTIVMG ELIP CTAC TTGC C CCATGACTCAP R E IGRHDKDKFL P TCGAA GA CC TGC GA GDKRPSDVR TC ACATCTAT AGC CACGCGCAGATVWGG CGTAGDTGGRHCDTG PARSCEGTL GCT ENLC TPACCGGCGGCCCCGGG G A TC CA A A VGGGLGNG NKL SNC CAGTC T TCACATGGGATG DKPYIETME RRGD EIRRAFTQWCGCAGCACGT CCCAAATAGGTTGCATG CGCCACGTVEGSKDRDL DRIR SRP LKEP MSA TIFFLGE S CGNATGAG CAATGTA CGTACTGG GVNASH F HP LI NLMACGTA G AGCCG CA GTGCTT TC G NKALNP L PANS LI AFSWCHTTCCG AATCAG TAA CCT CAATCGCTI ALDLK GTDT IGKPKS EIDETK I SLRR C EI CAC C CCC CCA GGCAC CTATGGVYASQSQTG GLMRKDE LA VVAGTGAGAGT CGTG GCTATAGCCGTA A GLVKRPIVGKH QNPAQTKSV ETDVDAELCG CAGCTACCCGGTT TA A GAAGGCCFNPYQTI YSKEMAQDELGCATAGTG AACCG ATA ATCG TA TAG CGACGTACQ CTQN F AGEQHELPP RVKAV EQNEK P NKQLA QQK VS CGG CAG GCGCGCGCAGTATASDV V QYLRA GGCAT NSHR TGTACAGGCAC TAACTC SQK LY ARKRHPDHG GQITEEDTL GG G GA GGAGTACCTGA GG GGAR L SG A GGC G GGC G A M V GDIGRHFMP RAS PN G QTRRQSTV V QMTSACCA GCGCG A GGTGCFIFTICT-CP )-B aP) aB tM(Mn(5464

[0027] T CG GTGC AC CG GGCATCTGCCACGG GCCAGA GAACCCA ACAGTAC CGAC GCCCGTGAAGGGC CAGA AACGGCGG CG GC TT CGACCT TTAAGGCAAGAC CGTGGTGC AC TCGGTGC CCCGCGCAAC AGC A TG ACGGCCCA CCTCCCGCGGACGCG GAAAACGGG GAGAGGATCACGAC CACCAG GCAAG ACAGACGGTCAGA GTGCT CCACAGACTAA CGACAC A CCGCGGGGTGCG TGCTG GC TG GTA G ACGGGCTTCCCG AGGGGCGCCACAG AGGGCA CGCGCTGT TG ACCTC GGCT TCCA GT CC CA GGAGCGG CAGGC GTTCG GCGA GTCA ACGCACGCG GGACGGCAAAGAT CG GCCCACGCGTATGGTG GACCCTGGGGGGG ATCTG GCCAGCCACT GAC T C TCCAAGGA TCCCGCA CGGGT ATC CAACTTG GTGCCCGACGTT CAGACA GC C CAG GCAC C CAGCATAAGCGCT GAG AGGGCCACCG ATACA CACACGCCTGCAGCATACACCACGACCGCG CCAA AG TCTG CGG TC ACCTTGCCGGTAG ACGGTAT CA AAA GTTCATCTCGGCCCCGCCACGCCAA ACGAGCTG ACGA GCTCAACG G  CTTC AG GGC CGCAGG GT AGGCAAATG GGCTG ATG G AACT TG CAA GCC TGCG GC CAC CGGCAT CC TGCGT GCAA18AGGCCACAGC CAGGT TGAAAGAGC GCGCCGCCCAT CTCGTGACCCG CCG TCGAAG ACAAAATA GCGGCACG CACCCA AGAGATGAA GCCT CGCG A GGCGTGC GCAGAGGACG GCCGAGGATGC CATAGCGA AA ACGCAGGCA G GCCGGTGCGC AT ACCGCCCCG T AGG GAG C AGAT CG CAACACGGCATAGGGG AGAGTTGTGC CAC CGAG AGTAATGCC CGCC C TG CTCGCAC C A CACCCG AGGCGTGGGCCGAGG A GA AGAC CA ATGAT CGCGGCCTA CGTA GTGTGCA GGGCGAAGAGC CAG GAC CAA AC AG GTCT CT ATG GAC CGCGCAGAGG GTG AAG TGAGTAGGACCGCTGAACCAGCG AGCTACCGTG TACACACCTGACG CG GCGCCG AGCC ATCTTCG TG GCACACACCACGA GCGGC CAG ATGGCTAG CAGGCA GCG GAGACAACGGCTA CCTGC C CC CGGC C CAAAGAAGTGGGCCG GCTGAGGAGGAACA GA GG TAT CGCCCACGGGCGCC CTGAAACTCG CCGCGAGCATCGCACTCGGCTTGG CGGA CC CGGC CGAC TG ACTACAATGGT CG GGCGGCAG CGG TG A GAGT CAAACCG GGCAACCACGA GACCG TAAC C AACAC CAGCACCCGAGGGC CGGC T CTA GGC C GAGACC GTCA GTAG AGT TG GGATAACTACCAA GTCCCAACGGCCG GTCG ATATACGACTG G ACAT CCTAG CAG AGCGCTCA G CGCGGC CGCCACG CGG GCAGCGACG C GACGG ACCGCACA GGGCAAACATA CTTGC C CAG ACGGC C CGCGA GGACA A G GGCG AATATC G G A GGTGC ACTACACCTA ACC G A AGTAGCCTGAC A ACC G AGCCTGTG

[0028] C GTC TCGA S QNLCQSLA LACCT CAAG GCGG CC GGTGC AGTTA TGGCA T CGTGCTM AARFV RLETGGCCTGTAT TCCAT CTCCGGCGACC CCACGCGT TVKEAAGA KEKT FCGAPTGCTA GATA AGCCCA GGA GCTAG GCAGGA G G GCV C YILMGEMCAMGC TCGC CTG CCATCAC CAGG G TGCGC T TCCTGA AA G CA CTQE FT EG VTEGGGAA AGTAAGGG AT G GCGCG GAG AT TCTCS C CA T GD TLMSS PL CAGCACAA GA TGTA CGAAGTA AGCGGTGAC C TGAT CC RSKFRQT TC GTGTGGGGAGGTC S T L EAACCCCGCGCAGTAACA GGCCCGNSNTDAMTECA AC AG TACG ATC CG AG A CA AGCG GACG AGGG A GGCGTACGCSIAFVMLKG LGCCATCAC CACCGCTCA G GTCCACCCG T CC C TAWIPDFISDVRGGCACA GTCGGGGCGA GGAGA GGCGCGGGGAA GC CTGGCCG TEAT SNCL ETGTGAG ACGAGA CA AC TCTTA GATCGTGCC CAC C IGLENKCL SNGTA QTCCCAAG ACG GTGCGGT C CGGG TAAGAG GGG GCTG ANMRAFTL WS CACAG A ACGC CACA G CGAAC CT CAGA GTT 2  GA TCAAAFNLMSA TIF EMNGTA TGGGAGATA GGCTCAGCTTG TGAC 8C CCCCAG N G NYFGA LS H GCA AACGTA CAAACC CATGGGTATCC TGCC GGGCAGACSPS L ARS FWCCL CTTTGC CCGTAGACAAACGCCCGAA TCG GT TCCGTGTCCCA GSWEGRRL I TC ACCGCA GC TCACATAC TTAAG ACGT TG GTAVTAGDEVVGCVAE ACGC C C CGGGG ACCG GACTGG AACCCTAT G ACGGS L CAGGGTGACGACGCC C TV VDDC CAGCC AC CAC GAGGGGGGACACDKAYGP IAQEL CG KL CGACGTC CCTACACA CTGCTGATCTCTAACV GKQSTAGATGAGGCT CG GA G AGT E SQQVRACACT CGC CCCAGG AGG CACCG C G GVNYILDT CG TCGGAT TG GAAGA AGCACCAGA GTAGCA C GCGGCNKIAEQAT ES LMTCAATA CGACC AA CTACA AGTACGCTGC TG GC T ACTGCAA AD VT I RYAVRQSCA I VL EAGCTGA GG CCT CGCTGGGG AC TG G TTGTCTCAC CCGGA TGA G AC C C LK SP ET L S AA A GC CGCAATG AGGAR F E P CG CATACGACGG GAA AG V IPGDRCGC TGCTGG GGGAC CG GTATCCTCFN QQNLMKLCLAAAGTAA CCG CATG AAC GTGTACACG GA G TA AGCGATTFAGEQLTMCGG CAGGCGCG GT CGCGTAA TG G AGCGCT CCCACCA GGNSSD KEMYGG CSQS IK PDGGTGGTA A GA GGAGTACCA TCT CCGCGGTG ACA GG ATTACGG TGC GT TAARLLNNC RGTG ACGCA AACG ACC G ACC M V GTSLLVASACC G G A GGTGC ACAGTACT CA G GACTG A ACA A -9- 7)a97)t-3P(a 3BF(-(nI) P F(T9 B I)T9MC75MC757484

[0029] S Q KFL P CT AGC ATCTG TTAGGC A D ACMSDVE RTLATCCA GCCGCG TAC C TG CGGA AG AACTGG TCA TC GTASCGPGTGTAA AC CCAGCGCCG V T KKNLV KCI NLTSNG CTA AFQGATA WCATC AGCCCACG GGATA CCGTTGG TGCA TA TCGAAGGCC CA C YR TLS C CT CAT G AGC CCGACGA G ALEMA TIF EG NGCG GGAACAGT C C CTAACATACG GG TC CA ACGCG AQCS CDSNFAGLMSACGACG AGAT GTGA GGC AAGCGTGGGA GTGG T ARS S LIFHACAWC LAAC T TCGCCCTATGCAC CGGCG GTTGTTCCTCA CNNES C ECAAGCG G GGGAGCGCG CSSTIRRL IACGA GATAAGGCAT G AGIAF LDESVVV ACEGC TCAA TTCA ACGA AAGTAGC TGGGAC C T CCWIK A P DVDDLGTGCA GCACGCGTC GGGTCAGTCG GGGAA AACA AEICAI TMAQ LKKQELKLSGCTG G G GTAACAGCG AC CGGA GGACGCA ACAGCA CTGG GTA CGGG ACACC G T GENQQVRTCACGTGCACGC C CGGNMQYILEDTL CACCA AGAACACGA AC CGGAG GT CGGTAGGAAC3 CGA NQP TRE QSMGTA TGG G GAGATAGAA ACC T GGA AGTCGTGCA8AFNLYTVRVQS GCA AACGTA CAC ATCG CCGGTCGC TGC CTAGAGCG GSCPS TSIETL EFL SCTT ARGTTGC CCA GTAACAA CGAACTCAGA GGTT TC WGLDE PRCTC ACCGCA GC TCGA GCTGC CAGTTA GTC T GCG AVG GTAG TMK VGGEQL LGCCMA CGC C C CGGGGT CA ATG G AACCC CGTGCAACA G G DK YIELSMTYKCCCAG GCAGGCGC TTC AAG CGACCACA TACCTGAG TACATCCG GGT TCTGGP IDCGA GT CTA AA GTGGACGA ATVEGSN TN LPRCAATGAG CAACGTAG AG ACCGCCGAAAGAC CTCGG G G GVNSNLLVSCTATCGGAT TGACAGAAC CACAGTCTGG AGG TT GTG T NK DIA TAIQS LA VL T TCCA ACCCTA CAA ACCACGCCGT CCGC C TGAG YAARFRLELACKAGGAGCCCGCG G GACGAC A CCCGAAGTAGA G TVCLAV K S EPEKFTPTQIATAGTGCTCCAGC CGCGAGAGA GTGCAG G TF RNIPMGEMTCGGCCTA GGTA ACCG A AGTGCGCTG TA CCTG AACTCQ TQNFGT EG TVTSME RNAAA CGGTA GGCCG CGCA TCGG TAAC TTTGTCAC C C CACGGGTGTG GGG CFALMS PYCAGCGAG A GAGACATCTNSSSD QKKFLT L RLMQY QGG GTA GTGA GGAGTAC CCCGCTG AGTGCAG GTGTA GGGCG ACA CGGCACA AR LDAT E T TACGC C C CGAGA GTGCM V G V M GELIPACC G G A GGTGC A GACGCTTG A A GCAGCTCCCCC - -56)5a63()t-3(a-nP F( FI(B I) PT89B T)8MC 5MC_959405

[0030] G T S QF L KCT AG CCMM QAA AV VKEATCCA GCCGCGCC TACCTCTGTGCCAGGAAGGGCCTT CGTGCCTGTGTAPME CG ATGTGGTA TACAGGGA A V A KK YVT LIL CDDKIIG CTGATA AGCCCACA GTTGCCGGGA AGCCCACTLKRMEHKCGACTCGC CT CG AGCGGCGCG GTCACG CGCT GA TGA G A A CQ ENCMSCLIMKI EQAMGGGAACAGTAAA AACGAT CAG QCGACATGGAGCGGGCA CCGCAG AG AGA CD SNKEACA A G G GTGTAC CC GGCA TRAS S RA YKTLNFAAC T TCGCCCTA GGTG ATCCAGGGGTGACGTG TA CNSNTV RAEFMYCA AC AG TACG TCGTA GGAAACCGAACACACTCTG CSAIAF RFV SV KQ LD GCCAA TCA ACATG TATTA AGGGTGTGA TCGGT AWIPIL F EDKMGTG CCA GGCA GGCG GGCGC CGG G G AC CGAAA AAGA GEAAI TDN QPDFRDLPGTCTGAG ACGAA AAGCGCA CAGGACTG GATGCA GLET ESIKEK G TCA CCAAG GACG GGCGAAG GT C CAAT CTAA GCCA NMK ASADGIA F KCA ACA A ACGCACAG AGCTTCGGCCACGACGGA48CAFNLGKKEKIEFGTTGG AAGA AGATTTCCGGA GAGGTACA AG GA A N T YDEAFI FEND GCGA TAC TCACTGTG TAATAA GAAGAGGA ACA CTCSPSAAR SGLDKGLL CDTTGCACCCC TC CAGAC GGT C TGGG AACA GGCTCT IQS RTC TC C TCAGGA GC GG VWGCKPGC CG GCCACC C GG GC CAGTAGVRA VGGGRNRG RIV TWACCGCCAGC CGATGG GTGGGACGC CGG TAAGTAAG CTG CAGACGGA A GCTDK YKLT CGCAGCCAGGTAC TCAA C CGPTVIGLARLI LNS CGACGGTT C CTAC CCTGAC TG AGG TCGCAC CC A GE S E LKDRLRGATGACAA G ACGTC CCCTAGG CGACCAGTA GCAA C GVNEKATRFAEC R CLL TCGGT TAGA ACGTACAAGCGGA GA G GAACT NIA DAIDINE C DLTCCAACACCCTACCGCACCGTATAA GA AAACGATTVTYAALVT LEELVAGGAGCCT CGGAGGCATCCA GGCGAAG ATGA C CLK SPQVE SDATCTVF RGAG CAGCTTAC ACTCG TTACGAAGG AGCGTCA G NIP TVTPKE QLE LGC TGGACCGGGCCTA CACCA GATGACTGACC CCQ CTQNQKRDMAAA F AG GGTA GGCCSCGCTACAGACA GGTAAGGCGTCTC DKETGHFRCNRCAGCGAGAGACACGTGCAGGCGA CA AAACCGNSMIGGTGTA AC GAC CGG A AGG CSCAQK RLL LTPEEK LRSGGGAGG TAC CAC CATC C TTGCGCTG AA G QV T A M V G Q KALTKSTTACCA GCGCG A GGTGCA AA GGTG GCCCACG AGTACT TGT CA G G G - G - 4 - FI2 G4- )2e5-7P( aFI 57)tB 4a(e- (di)3PB4n(di)3M m99M m991525

[0031] C S Q ACEQ GTMKQAS S DNGELTG NVPLR ST KIQ QVQQGG LSRFA A CCT CAAG GCVASSKTPYVDA RGGSE VAP EL REIRNW FRDGLPSHD QKLQSA P WLAGDDPQF SDVTSGG CCACTGTTA G A KDHDWVD NPVC YVILAFKIYP GTGAAG LLD TMFIIRLAAVENDSD KSVEVEAS GSWRNEGRS CGACTCGC CTG AE GI RQRT QCGAVRY S GRFQDTI LTWWWLGISHQ REYTQPWWSGGGAACAG CSD GEWTNQMFG KLDAGRVK QDCDRGMR RKPAN R G HAGCACAGA GRTAS S LESSPGV V ADEDLNYLKIW VHLA PEFW QSILGPDAGAAC T TCGC AGNSNTG ANVEQL NFDILIC IMAS F PTKSA WNFG LLYGI CA AAG TACG CATTSIAFVRVL RNREADPEDWG QVHKGRGW D TC DAR P TWNG GCCCAA TTC WIPFIWSVTWSE TG AGAVMNPQ AL TKDNIKNLRGVEMGTGCA GGCA AC EIVADEGEGAIMGAVL FAARH CGGGTNFAVFTA R VVNGTQRFGTGAACAT ILEKPPAED VRHPFALTQHTG HPFP LMP LEA EHE TAGG GTCACAG CGG N N MTHPLNLFDTGEEIGPY QG Q WVICSQ WVCDITCACCA AGAAC5 TG AGA NLAD FTAS GDD SI SANSQ MED RN MHVFV GAQRLNLGA TGGGA8ATFGCNLTA ASYSFS LCRE LS LQDTA VTHVAENE FACLQDGDLRD QF EVMIDHAALG QNWTTGCA CTAACGTA C AP S LYFTCAARGNC PQL L V QNTENTCETGC CCWLWSGESKTEGV HVS RWRDLSTD LTI NSGTP ETC ACCGCA GCVGQA HEVL WAYDSWTL L F EGCGCGTAGTE T PGVPY IIYKNL PACGC C CCAVGGVP P L LV GCNR LQAHLGVMA P HRQLHAVG RAIVARYHC CAG AGGC AGDKGPYIGPAE S SVWRHY SP P FGTDFLG APITDA P LLK QCG GCG ACGTCGTV GSNEPTPDL YEQDS LHRHCIIGGYSAFA QLP TYHC CATAGATCAGEVNEAVFGRF VTNP RDCNRD LS FDES EPHSDTHPMRWCGCA GGACT AGG GA WPY NKIAFPIVIEN VLTDTANGTQARLD ATDHSVTCTLTCA A C ATAGDTAID RWPGGNVSRLA GYRQTGGVP AYE L PP D STTS LTEQCAC C CCATCVYASRAVWMYS RIWVTMIDAATEPLTLCAPQLMYA AGTGAGAGT CGLKPQFT R RDWLLSQLLVDLHGGCACVRIL RIP LLPMAHEVQLEYCCATAAFNPGWRNVWYNML KPHRTGAWPG SILSLKLAVWQ QRGC TAAAGTG AA GGQQVE TAC E PKNGYNLNK DRQG GCGTAGPG DNGPVGERQAVDSACGGGCGTFCNSSDDNV NWQGCENYREECLGFKED AGEATIF YSCAGTCGGTA G AGSTAQK RLRLKLLS T LRYI HD FELMV QNLLLHLS SY QI NEQG FQ LIQACARLGG G G GGAGTLCMLRAPPDF P RWYM R Y Q A W M H QASIQ T NLTEACCA GCGCA G M V GL L PA Y VRVG A G ZcZacLa-LP )-B aP) aB tM(Mn(3545

[0032] G AG GTAACGT TCG TCGTGGGCCCA CTG CGAGGGG T TATGAC CCAGTACGC G CTCCGCT TC ACGGAGA T GAC CGCAT CG GATTAC T CTGAAA AC C CT T CC CCG GCACTC C T C CAAAG A CCCGTGTGC GTGG GAT TGACATCGT TGAGCTGCTATCCACCTCATG CATGGT CCGATGT CCG GCATCAGA GTAC CAA GAGAATCAGAGGTA CCCAGTAT CC CG TTGT TGTTCAG CGCGT CCA GT CAT CA TGAGCGT CACATT GCG GTACGGGTGGC ATCCCCTG GCTTGC CCATAAGAGCTG GGGCA GTT CGGCGTGA C GTTGCG GGG CTG TCTAGAGG AGTCGTACGGCAACACCTTAT TGA AC CGAT CA CGG GC C C CGAAGGCGG AAAC T CGGCAGAC CGAGCGTAA TGA GG TCT CAGGC TGGGCCGATAAC CA GGATG GTCG CGATC TCCACGGGACCGT TG CCTA CGAAGGCGA TGTGCTGC GC AACGGA GGTA TGCACCGCGCCCCTTAGATCACGATGAC CG CT TTCATTA GTAGCGGA CGGCCGCTGACGGAGT TTCTCC GCGCT CA AAGATGCCG ACGT TAAGCCG AG TA TT CCCACGGCCC GCA CGC TGGCT TCGAGG AATGGT GT CGGC CAG   GCGA CCTAAGGACA ATA GA CGTGA TCATAAAGGGT TGGACGCGACA A AGC C CGG CGG GAGAGC CGGCG6CG8ATCAAGTTGCCG CTATTG GCTATCCGCACG GGGT TGTCCT TAAACCACACATCGAGCC CGACGTC AG ACGTGAA AG TATGGCTC CGAGGT A GTGC CGAGTGCA AGG GGTGCCCGG GGC GCG GC CGGTT CG GCAC C TGTCCAG GCTCAAGA GACGTA GCACAGGCACTC CG GCG G TGAGG TGCCTGT C C CACG GGC CA GAAACGTA ATA GCA AAGTA CTGGCG CAA CCGCTTCTCGGAGTAA TA ATCAACC GTAA GTATAA AC ACACATTAG GCGTA TA AGCG A C G ACT CGCA GAT CCGTAGTGGT CCC CAT TTTGATCACGTCTGTGCAAGGAGACCG AGCGTA GCACT TGTGACAGTAAGTGTATGGA GA AACAACG CGCGTGACGCGGGCTAGGCGGTCAG TGCAAT AGCTCAC CAGCCAATGGCTCAGCGG CGACTCCACGCACCG TG CCGTGTACAAT CACCACGCTGGCG AGCGCA AGGCCG TAGGCCTAGG CAC TCC CGGC CATGG GAGAACA CAACATAGGGTC T CA AAC GACGT TGTGGGCCTA GGCAT CGATGCGT CCCCGACGC TCATTCGCA GAGCCG AGCCC GC C CGAC ATCGGCT CTAAGCTTA AAGGCGG A CTGGGACGTT CGCTA GCA GATATG AGTACGC TGTTGGGTG A GTG AG TTGGATCTCTCCTTG TCGT CATGTG GC GTG GAGT ACGA GGATTACCCAT CCCCGGG G ACAGG GAGC GGGCGC CGCGGGACA GAGCCC CAGCG AC CATT TGAGGGCCCA AGGG TGAGCTT CAG GCGCCCGGGTTCTATAACCGTGCTTG A A G G A A A A GCTA G GGCCC AAC GCA GCA A G G G G GACG ATCGCTG

[0033] A GGTTG TTTTGCC TTAAC TGCGCA GAGGTACTAGCTGACAC CGAAACGG C G ATGGCA AGCC CC C C T G CTA GG AG AACATACGT C CTAAC CGAG TGAGCGGATGCAGG GGGAG GACG GATGACAA GTATGTGG GCG AGC CTCG CACGGACACG CC CT TGACG CAGCGACGC C CATGAGACGCGC TGACGC T TGGGGT CGATCGA GC CGGG GCTGCGGATCGG CCGGATGCGTGC T G GTGCATC CT GG AGTTAT CGTGGCCTACAGC TATGCCGCG AGAAC CGCA GT CG AACG GC CATGCGGCTTCTA AT TCAAGTTTG CCGTGT CATGAGAGCA GCAT C TCA TGCAGTAGAG G C TCTCTATG TTCCG GTCC TAT AA CCTGCG AAACGT TA CTTACCCCCA G TTACTCGTG AAAGC CAGG TCCA GAAAGACATGG CTTCGC T CGCCG AG AG GC CAGAT CGAGACCTGGTA TGC TCGCTTGCGC T TGG GCA AGT GGCC CACTAC TG GAC CGCG CAGAG AC TACCCCCT C T T CGGGATAGAGAAGGC AAGCACTGGTCGCATACTT CATA GGCGCAGGGT C T CGC TGCCCGCAT CCTG TTGGTCTGG GCAAAA GTGCAAACACGAG GTACTATGG AGG CGTCCA C  GCGCCACGA GTAAGCAGGCTCACGCC CTG GAAGC CGACT CTC CAACAC78CG CCG TTACTACCAAG GG GAAG ATGGCCAAGAG GTTAA TGT GG CCGTAT CTAGCGC GTGCAGCACAC TAT TC CATGC T TG GGTGGA AACGACGCGG AG GAGGCCAGCA G ACGCC CTTG CG G CT CA ACAG GTA GTGCAATACGT CG G ACCCCTAAT GCC CTGGT CAGATG G AGGCTAC CGAC C CGCGATATGG TGGAA GGGTTGTGAT T C TACAGC GC C TCCG GCCCG ACG GCAC TC GTA A GACGGCGTCCGCGCT CTTTGAGTCG TA GCAAT TGAAGCAACTGCCGAGCCG CG G A CAAGGCGG GGTG CGA TG TACGAATGGTG AGA GCGGG CAC A CAGT TCTT CGAGCGTGGT GTA ACGAC CGACA ACTGCAACAT CG A AC CA GCGCTCGCAC AGAGCAAC CAGC GTTATCCGCGGAGTAGCA T GCGGG A GC GGG GTAAA AGCCGA GC CCATG GGGCCGCCCTACATCGCGAGGTGCA CGAG GATCGCCAGG CAGGC CCGGGCCTGGGA TGGAA TGTGT CATGGGCC TT TGCAC TAGGTATA GGGAGCGTA ACAA CG CCGAGGCCGACAGTGCG GCATTAT TGG ACGCG GGCACATCTCGCCTG TGT CGGT CCG GAGGTAGGCCT C TA GTGG CG A AGC C CG GTA AAT CTGTAGCAT GAGCCTA A GAC GCGCACAGCC CGAG ACGCATTG GGATACGAC CCAG GGATGCAGT GGCT CG ATCAG ATATGG C TC CGGAAA ATGC CT CGTAGC CCGTG GCGCG GCAG G GCAGTTGG G ACTGCGCCGTAA CGCAT CGACATTACGG GCGCT TACGC TGCGACAG G G GGCAC C TGGCAAG ATAATG AGC G A GT T G A GGA AG AACG GCAC CG A GCA ACG G G GTGTA G GCA G

[0034] GCVI LA C TGCTACGAAGTT S ACFI VLKK GG GCCG GTCC ATCCGAAACCG KAAGCTTTT T P RVI GTATAA GGCGS CAATTACVI VNL CG GCGACC TAGCAA GAAGGA KT FQEGC TGTACGCCTLCAACCACYLQCGGC T CT GGC TGC G TRPAG V CEGACG TCACGGTC AETA MFSSDS CG GGAGATACGGCA GTAATG VEI CAG AGT TGTTG GATQASNNA SQN ACAAATCA GTCTA GG GCGCA G ATT CTARLART CACG GGC CGTG A AV AC TAG GSYSVAAT AGTACGGGAC KGGAACAAANSGS FGTAGAGCACCGTAGG GGGS RC IP CTAT TT TAC GTA ATE RAGCA G GAATTTAASG GIWGTI CG TTCCGGCGTAGTACG AGACTCGNLG AGGGAAWAGVLGTGCAC CGGTDT TGC TGEA KEGTAC GAC GGGCAA GCGNAGTGACC CGCGAC AV YPIY GAMTGCKKC C TACA ACAGTGC CA CTCGGGCGKSACGCGGA V GAGTGGTGLE SQNLGACAACTG TCGT TA GGTC  GTVK G V GAGCGGGKCT TATC N N VASRYTGCGG A GAA ATTA AAGGTG CGG88CG G YG I AGAT CAG TGCAG GGFGAI SSNR CTAGCCCACGG A GGG AGTTCTSEY GTGGAA TGGCGGG NS VASTS SWT TG CCCCCAACACAGGGCACT T R PVCG CGCTTA AAP P IA GC CGGCGAAAGGA AQ I WAACGCGGAACATGGV GAKNKTAG G GGGACA TVT PANEVPYI CCCAGGCATAAG GCGAC TTGCCCC EKLEQTTGTATAA GAATATVVGA VL GGCE S CGACGG GAACTG TG TALELSCG GGA G GAGGGCA TG DKD P KGVN A ATTAGG AATTTCATG AGTG GALL KACGAT GV LNGTGCAACT TA C CC AL IKGA TAAAGTAA AATGE LAFGAIT CCGGACAATGC TCGC CACC GC EP T GGCCTG VGVATACC ACGG GG CA TTNL ETQHVTG ACAALAGACG TCG AAA G NK G DIQN TMSTPSACQPI ATTCTGCGGCGGC TCC TAGGCA GG G MSG GGCGCGYAAT P CG CC TG TCATGA TCDVIEG AG TACTTCCAGTGVLKKVAN G TVG AC TGGT TCGCTTACGC GCEPP LEGCAT CGCACAACG TAVF RVIA VKDC GA GTA AGCTGA A G ACCTC TT VPC T EDK GRGTACATCGGTG C N QQLEDPVK LCGTGGCGC ACAC ACT TGFVLCACTA CT CA AGCCTCTFACGTE LGG GTGAGT CGCCC CCC TGA A GCRDET CT VEGTG GCAATGC CCGGTG TATNSAS SDQSGVG NGKTI Q ACCAAGTG GTCC GTTG ATCCAGTACCGYAI E T TTACACAR TNTM A GAGCG A G M YNIAGTGCT CA G G G M V A D Y A GTCTC A AACCCGCTTGC A nile ni ) )ateor latode)aede de )tedemo pmrpzia(rcnnil zin(rcnnilSs0o e ose5bA)ia S oA)t- reemPeBke rnuqed- reemPeBke rnuqedr7La(05bir7Ln(rPidMil(esnurPidMil(esnu55657585

[0035] CCCCGTGS Q C TL M CE MT K QLEKEDIRA CCT CAAG GCGCC TTGT ATCG GCTGGCCCGTAR IDPTCDDIHI RHPA RATGGCCTGTATA GTCCGTGGA A GG TT CV GAKKGLELRCMEMKEEE SESG CTA GATA AGCCCCT CA AACGTGCGTV A YITK LNMNMKIAMMG KACGACTCGC CTCCG ATCCCGGA AA AT TG AA LNQEQE SA AC T C CGGCG GC AAEF L IKT N IDGGGAAGAAA ACGC TACCCQS CDSPVTSA RYKL FAE PVSCAGACAGATG GCGCA TGCAACTGC G RSTAEMYKP CATGC TAGCG GTC TGSAIVFQTKAAC TCCC TCGCGCCTACCNSNFTDIKRV RS VKELDHINACAAG GCGT TACGCGAACGC CAGCAAP R FKMQWGACTATACCAGG AA CCGSIFNDFDGSGCCATCAGCTCTGCCGCFTWI GPCPE LDPDL RPITGGGGCA GCACGTCGA GCAGGACA AGTTAAAEITNIKQESDEGCAT AIKGKKPDGTCG GGG DSGTGAACACCG GACA TAC ILEGRP TKADIA AKGVSG GTCACAGGCGCG A GTAGAAG CC CGGG Q N G MLQSKKEEKIEFQLTPKCACCA AGAAGA A AC CGG GCG9 ATG GGTGCGA NRG TQDFI FENDD GLGGAGG G GAGACGTCCCAA TGA8A TTA GC AFNLYPSGGRALKGLLDRGRWTSTGCA AACGTA CATCT C CCGAC GGT CTAC SPS DSRD EDIQ CSKRPSILCTTGC CCA GT CAC CAT CTAG A AG AGCARGPWGEVRGRRGIVPP RTGTC ACCGCA CT ACACCG AGC AC GTGCTCCTVG TAGLGRK NL R TTW NGGGCPA CGCGCC CGGCT CG AAACG G CCA TCAGA G GDLAIA V GA R LLPLS PAC CAG CAGGCTG AAAG A AA GATAG GCC DKYGP I PK DE LDGGF CG G EKR RRGL CGACGT CCC CGGGCGTCAGT CC VGGRA CL TAGATGT AGACACT T E SRAT F E LRQ ACACTGCAGG GACCG TA G GVNPLA TDINE C DL RNV KNACG TCGGAT TG GAGGCA GCTA AC AT CAAC NKIA AE RALVL ETE LVDSQTCAACC A AGCCC TA CCGGCGA C TCCAAGG DT IG GKSQVE SD EQSD GI QCACLAGGAG CCGCGTCCTCTG GGC CT CG VLYA KSP PSP TVTK PLE LKSGA ATAGT CCTG CTCCCC GG CTC CGAG ACAVRIG PGKQKRD A HMF P SFCGGCCTAG GTA CCAATGC CCC GG GCCGCAFN QQNRWKETGRNR MK LTRAAAGTAA CCG CGA AA AGGCG A CTAG GGATTFAGPPAMI IN LTPEEKRQKL CGGGCGCGTC ACTG GACA GAGTCACATNSSDGKEQVA LLSSQT T CA GGGTGGTAGA ACCGGTCGA AATCCGASKRAQRLL TA KQFKTKTVL SKRTGGGAGG TACATCTAC CTG AAATASLAVKISTCA GCGCG A GTGCCGCC TA GACA ACG ACG M V GLN M A A V K HTAPACG TG -2-d2im-)adi )tPa(mBt-uP n(BtuM m M m 9506

[0036] GTTACT GGTC CAAGA CTGAGAGGACA ACTA GTCAGC GGC GCCTA GCAT A A ACGG TAGE C NT CA CAACGCCTCA GAAACGACT AAAA AC C SGAA CACTGCG GGGCGGCAAGGQN AA G AGACTCGGGC ACA CAGCAAGRA AGGG GACGTACA T GC CG GC CA GAACTAGAAT CAGCGGAACLTSV GGC TGCAGG ATGAC GCT TA A G ATGAC CCTC TG GGCG AACAGAGACCG AC TAAAGGGIA CACT ATTVCA GC CGG CC CA GATCAC CAGTA AGCLDC CAA CCCCTGGAATT ATCGCG AC TAAT GAC CT TGAACCGACGGTA CCGAATCCGCATTGCC RLHA SC TTCA CGACC GTAA G AACGACAA GCGR CCGTGAC TAGG T ATAGCCAACGCGACG GGCGAGATG ACAGGGATGGACGG TAAGGCTGC CGW T VV GTGAC CCCATC TACG ATGATAGGC TCL QAGAA CCCGTCCTAGAAGACAGCACTAA GCAAACTCCT CG TT P TGY G ACGA G TAGACCACGGATCA TCG GCACA ACCACC TCAG ACATC VRR CGATCTAA A GTGGGTAGG AAGCTCTAACGGC CACT G GGTGG KVG KLGGAG A0  GC CGAG CCA GGGCACAG AACAGAGGCTCAC CATCGCGATCC C EE P PVGTACG AG9CTTACACAGGGTCGA G GCC CGGCACATAFILE LGAGAACGTAA GCCGG ACCGC TTG AAG CAAAAGACGAGGTAQRGNCG GC TCCACCGTCCGCATGATGTGGAATGA CA G GATCAACACG T DCV VVACATCCGTGTGAGCA GAAGGACTCGTGCGCT C CG GGGTA CGGTAST LGGGCCCA A GTGATACAGTGTGAA GATG AACCT CGAC T D T C AAAC SSE C C CG ACGGC TGCCCGGCGG AACCCATTGGA A GGAGACGC A QI CDSTG AGCC GAG ACGCGTACCGGTG TGA GAAGACCATCTGCGCGET CTVAGGG GA AAAGA GCT CGGCAA CGC TGCGGCAA GAAGA GT CGCCALVQ VCTATG GG GAGTGTG ATGTCACCCG AA GAGATGGCGAGTACGCTD CRG AVAAGA A AGA GTACAAGCGG GT CGCTGCGAGTTACGAC GCC CATQLSCCG TCCCGGGAAAACC A AA GTTCA GTGA GATCTCCCG CGATGCT AGTC AEDCLKACT CGGC TCT ATTGGGGGGGC CGGTC A TAC CCA GGT CAG ACGCCACT TAGG T VKTLLGATAGCCCG G A AACA GAAA G ATTG AAT TGSNDCGGAACG AGC CAAGCTGGA CGA GAAGTG TACACACAAGG ACGACTG TGCCCC AGLVI VYARLCA GGCG GA AGGGTA CACACAGGATTT A GTA ACCT CGGGG GT T SCA A GCCTA CGACA CGACACCCG TCG CAGG C G YKA AT KSAR GCAGTG A G TA G G G A ATAC CAGAC T SGTTCTGC G AG A G ATG A GCTGT CGCGCTCCCTCC G M K ATAGTG GAC )aa)t(n(PCPPCP1626

[0037] CCGA CT HV C GYNAFVI RHL ICQV G TTG K QQIAM GACAGACACGTTATT GTTGCCACA AISQ EGQV QQV IAHGFD VSPGVRKY E VTIAGCCG K GGGTTGT CGAGT GG GGG TGCTA CA GC CGCTGAFDGVRMDIF CACC C TACT CCGATAG RLVSPI K Y ETVIVFEAGRS RGQTGT CAGGA GCTTC TCCATGCCC GCCCCCTGQD VF F CAGRKRMLDAIIYA Q GCG CTGCCA ATGC CG GC A ACGAA GGLNMELDIYSAQLQKFH PQDT EACACGGGGTGA GT A AGCGCCTCGGTGCTGPYLQAIFQ DHG P YEILQVCA GTGACCG GGGCAGTTGT CACCG A GGC T T RYK NAEIQ LQTVVEAVSVV G CAARSQLPQKEDIACCGGCCG GGTAGA CA CGGCGCAGGT TG GTTTAG CN VSGTGT CRALVQ EVMGGG AGTQ RC CCAASQPQKEDLIIGQ YVTVKL CDGC TCCAG TTTGG CTGATGGCGCCAFCACG DLIGQETVMENMCH CGGEE EQNSQVACGGC C CG AAGTGAATCG A NYV CHV NKFQLIV HAVGCAATAG CAGCAGG GA GTG AACCCCG GCAALMEQS EVCLFYNC C TC TACG AGGLFQIH VLAKEK K GGC CT TC G 1 CAAGCRS VL L CL AFVQLSQEHC CAMACT CACAAT ATGACG ACGCTC9CAGAGRQALKEQEKYSRE LVLVIPQ CGASYYCCCT CGCGCC TAGGCGA TTTTTGA C GRESVLIH QAAV QYCAGA HHLLKAGTC TG GG ACAG ACGTA GG ACM HALVVPLSLYPQTGC TVD GQLKE C GTAA CCCG C A ACGCGATGG A CT CA GGCPPTHHCTVDARRINDVMLKCAAC CG GGCAA AA AGTGCAGC GGACG QAG RRGQ DLK VE REQPLN GMTACCCGG ACA GGAGCGCA AG G CA T CACCCG GFIN LE RQPMLD LN KAKC RLI YI TACATC CAGC GAC TGCA G A GCGAAVLKEDCGMTLLAVH EE LH KC ACGTTG ACCC CGTGA CCGTG AGCGCG TAACGEL LALK VHRIEEY IF L CKLIAASGCACGGGTAGTAGGGTA GCGGGA CTAGCDQI ACELALARKL RVIHY CCCCA GG GQ TCCGTTCGTGACA ATGTT S FRLKK IRVI S SQVEGE IKS P TGYCG GAGT TG CACGGA ACTG ACAGTGHSQLVEIKHPHLHV S GRKDKG AGATGA A GC CGGATCGTG G CGCGGAGTHG HELHVSKGQGDSDNRGELCACA AACACAATC C C C TCCTCG AA GTCH GRDDFLHQS SDNQEE Y PM TTG ACATAGGCTCAC TG ACCC GGT CCTC HDGF DLGEPMSFRP RGCAI CTTGCTCCG AAGTCCTGCAGCG C CGACGAGCHQGSS EFERYP RT FE FKVHTHVEHPGGGCAGACA AG A AC AA A ACAGTSFFVHGCVMQIMES ELDI RIG GTCC CCACTG GCGCCCAG G GCGGGEKTHE IVLVLKT T C TGTCCAATG A G MMIEIMESLELDHPN Y QAFH V H AGTTCG GCTGCTACGT TG G GGT TAGC )a) at(n(FUFPUP3646

[0038] CG T GAGGGATTGTA GGGA GC T CCAGAGGTTA G AAA GACGC HVN G GYQAFAGGGCGAAC ACGCGCTCGCGACAC TCAC C GCAAC CGGCGTGCGAINQV CG ATA CTGGTTCG AACTGGTGATGGG TCC C CAAGA CGAGTAAC EGFDSQ G AT T CGCCAAA GCGAGCAA AGC TCACG TC CCCTGCGAGT TA CARLVPI KGGCTAA GACCGGC CTAGGATG AAGAG CCAGCGCAAC GGAACG GAGCCGC CGGCTTGCGQD AAGT AALVFEFA CGACGCGTGGC T CAGC T C T CANMLDACCAGG ACCG CAT GACG CGCC TGA C TCTTGG CGAGTGACCTGCTG CCCAAAGP LAIKIFAGT C CGGG GTGA TGACCGCACACT TGC CTG AT TYQ GARYQIQ AAGCACGTGAC GGAGTAA A CACGGTAACCCG GACCTAAAGCGGGAACNAV LSGCCTCA GTC CC CC CCCCTGGCCC GTTGGG AAGC T CGAA N TRA QRQTTGTATTTTC CATC ATTTGA ACGACGTCCTC CCAA A CA TCG GC CGC F LNPGQ AGAGA GTAGC TCCTATGCGATGTAATTTCCCCGGCADITEEYV A CGTAA GAG GGCAGA TCGGACC TCGGGCCCAACGAAGTGGAGTG GGTGATCACAG AATCTTGLNALFMCQEI 2  GGACC C CA GATG GCACCGC RVL C 9C CA ACAAGG GCC CGCG AAA GAGTGTACGAGACGCTGG GCA CGSRLQAK GA ATC CGGG AC CAG G AGAGGGCGG G CCAGCGCCG AA AAA C CCAA GRLSQ V GCGAACAGA ACCT CA CAAC CGACGTG GGT AGGCTC CCACCCG G MEALVV GTGCACAT CGGTATCTGTACGGCTGCGA CTT TAGCT CGGGACTGTTAACGCAATGAGT HGGACC PPTHHGCGGA CCAAGGTATAACA AGT TGTG GAG GGC TGA TAAAGCGT ATT CGTGCATAATACCTGGTGA Q AC AAFRREIRN TCA C GTCCCCACCCGC TG CCAGCTATTTGCCACCGGT TGCGCA AL L EQ D CATGCGC CAGTGA AAGCGG AAT CGTG GCGGGTTGG GTCV AG CCE KLAK TGA A CAGTA GGCCGTGA AG ACAAT TCC GT TCGCC TGG CGT TGAGT CCGL LDQA VC GTGG ACTG TGC CG TCCGAGC TAGCC CGAGCTGGIAC CTCQF LKCCCCACTCGCTA GCAT C CG ATA AC T CACAACG AGT CAACAGCGSRK HSQLV GGGAG GGGGGTG ATACCAA CG AGCGGGCA AG AGCG TGCCTG GHGEH T CAGC AC T TGAATCTA GTTG GGGCTC CTG TGAGACGTTACTACTATHHLQSG CCAGCAGCGTGCC CT TACAT TG AATACCCTCCGGAAGACACC HDGF DLGGAAAAACGTACTTTGTAGCGCTAG TAG G AGTG GTTGTH GCAHQS EEAG AGGAG GGACGAG AGCAAGGS FRGT C TACGC TGTAC GCG CTTG ASFFV AGCT AGGTACTCTCTG TGG GAG TG GGT CCCCGG TCGGT CCAACA GT GEK CT CG A ACATGC C TGC T CTT C CACCT CGCA ACG MMIQIME)aa(2FUP56

[0039] V HILI KGFDSQI GVRVT GTTGCTC TAGT GT CG TA CAC AGGAGGCTTACG QIVHVPI KYEIGTGNTKAAAAT T CATTAGC TG GGTGCAACGTAACTTTG T VAYRMD EVIVFEFLAGRYS RA AQ GG AC TGGCGTGTA GGAAG AGC TA GCCAAG TA CA TCGGGACTAA GTTAGTGGG CTMADIGTATTGCGAT T CAGTAAC AGR KRLIQHQKFDTPTCGATGC CTGATCTGATATGA AG GAGGTA CTGATACYSQ Q QQE CGAG GCTCGG TCAAT TATG A YQIL VATAAT T TTCG GC GTCAAAG DHG QTPA VEAVRSVQL CKV A DIGTG TACCGGTTT C CGT GC C CTGAAGTCCCAACGTAC TG CACAACG GAC CA GGG LVCAQNPQQGGTAGTGAC CCAACTC TGA VLIGQETVM VLACCG GGACGGGGT CAGTGC CTCG CTGACG GCGACG QKEEDI EYV TVCH K NQDGGAG GAAGCAAA GTTCCAC C CG CCTGTCTGCTACGC MNFM QEIQ HNVV GCTACTCGG TTTCTG AC CGC CG TACACCTAA GGAGHVKVQNQL L CL AFV YNTA CCACACCGGCATGGCT TAGG GCGG ACATGTTA CTC HSVQALKEQEKNKA CTGAGG AAGTCA GTGAGGACCAGC T CGC CAT C3 LEAEFVRSVLIH QAM A YTAGCACG CC T GAGAATTAAAGTTTCCCTA TGAA9LKYEALVVPLSY QYACC A GC C CI HNAT CTGTTAGCGCACTATGAAG GC CAGA P QAPH THNT LVDK EC T TGCAG TLC T C TGAA CCCG GGCAA AGGACGAAA CTSLY QAG Q RGDLKLAGCG GACCTTAAA AGT CGCT CTACG CCA AA GC CCTG VDREIRNPVMKCN ACGA TAAAG GGGACATCGATCTTGCAACCGCGCG Q QL MDLKL EPVKAD L KCGTLHRYIA CATTCCCCGAAC TA ACAGAAACCAGT TACAG GT CTGG AACAGCATG ACTTA CNML LIHCCG GGAAGATGCATAAC TG GMQIA VCEL E LK AAGAACTAG AGAGCA C GTGGGGACTACCGGTTGGGA H ERITYFLIKKRVSY CTT AT CTGACCTTCG GCGTGACCGGCAC CAAGTAG G IE L R LQIHT CGTATGTAGCT A A C CG L NQVIKPACG GCATRA GGAG ATQV AISGEHHLHVSGY S GRKDKCRCTGG CGCC C CG TAGCTTCA AG TATCCGTAG GCTGGTTCGTGCACAACCGT CG AG IKPQ NDN GCGCCT CGAGGACA CATA VSG G DF DLGEL TPMT CAAGTATAGCTCTGACTAA CTTA GGTAGTGG ATTA RKDQEE Y T AGAAAGA AAT TGGTG AA ND FP R ICTAAGAGGCT TAAAG AC TTGENSFF RVHGCVH ACCACTAATCCTATTCGTG TAGCTCCTCGTCGGTGATYPPMEKTHE PTA GGCCAC TCA AATCA RT MS E RGTAA TCACC C CGCAGGATAHGCMIQIVENL LDIG VILKG GC CAATA ATC TG ACCCGGGT TAGTGCCCCTS HVEH LELDPY R QAFHVHGT TN Q V Q A M ACCACA CTTAAAG CTTACG GGTCTGACAGCATGAA G A ACCACTGCG AGG A ACAAGCA A G GTA )tn(2FUP66

[0040] CTACCT GGGGATATC CT ATTACAG GA AT TGAGA GAC G A KKATC GGC AGT CTG GGTTCGG CA GGCG TTCTCTAACA AG ALSMCGATAATTA ATGCCGTTCCC TCTATCCGCCC CTGAA CATCATTGGT CCACAGTG ARK SAI ACICCGTGCGGCGC G TGCACAATATACG AATGG VTGGACACTGA GAGAGAC CAGCTG GCC CTGGACCAACGGCCA GG TGCGCCLIDDSAA DCGT ATC CT ATC CA TGCACGT T C CGCGCACGGLTAACG AGAA TCGGCGCCATG TATAAAAG ATTG AT CGIAGQKTCA GT TCGG C ATTTAT GCCTCT CACACAG GAACGTGGACGA F YTAACTG AACA TTGCGGCTGAGAACTCAACCCGAGCG G Q AAA AC TC AAG QI CGGGCG AAATGTA GACTAATGA ATGCGC GTCATAAC SFI R CTGTGGTA AGGAC CTC T ACGTGGM ACTCAA CCAAACGTAT T CATA AP CGCT CCCATA TCTG TGC CGAAC CGAGCTT CCAGAG GTA C G AAAGTGAA AGTG Y ALK A S DCA GCTT CCGCAG 4 T CAAG T GAAGGAA GYC CAC C 9T CTTAG CCGAGC TCTTCCATACA AT GCA GTK C A KFPA AAGGA GAT CT GAG ATA AAC GTAAA TTACC CGCAAANA GCALEF TGAG GCAAGTCA CAAA AGATGGGA GGTG ATGACGCA CGTG A G AADQCCACCG TACCC GGAAACTT CA AAAAGA AC GA AATTCA A K GCC KMAAG GCGCC AAAG ACTGAGTGT CGATAT CGGTG AGCCA G WAGKI SR GG ACGCCT CAG CCCGCA CGGAAGG GCGGCGTG ACAAAAA QC C KE LA CATTAGAG ATG GAT TA GGGTTTCA GAACC CCC CG AC CA AGNNCCTGG ACAGG TA CTTGAAAGATAATATC C CTGTT CGTA AAAGA Q TKGGLNTA GAAGAA AGA GT CATA ACT TGA GCC TGAAT EGA C A GCTANISAACACTGAGCAGG TACTGAA ACC TA GA GTAG ATAG A RCGYSGTAGGCAAT TA ACAGAAGAC CGTTTGCTCCC TGACCCA ARECG ITVECGACAC CG AT TCC GTGAG ACA G GTCGT TGGTGACARGCTGHKCATA GCGCGA GC CGCGAC TGGCCR NFIG GT TA CAT C G TAC GGATAG AAP T CCCACAAG AT T CAACA ACA AAT TA AGGG G CGRTACCCRTVFGATCCGACACAACAG TCAAC C CGCAGCTACACGTA GRGCEACCAAAGCGC CAG T TG TGGG CTA TTGCG TGAATGAA A ACGGCCGA NGGPQ V TTT CG GGGT CAGCAGTATG C AG GT TGCG C GATAAGCG G GCCCCTAC GACCTACTATAGGACTATTT MTGARFTGTCAAC M M G ACGACA GCA A AGTATCT)aa)t(na()dabdaba)t(n(mam La AL1AU1U 76869607

[0041] N LRTSGAG TCC ATACTGS F FR VRPT DG TTYERGELIGGGAG ACCACGA A KVCAAC CG CAACCG GACWLAREA EMRDCKKELLK A GAGG CTA GGGCAGTGACGG EA TCGG CAGAGFDR I ENVP EEE KLEQ RD G WD GCT C TCGTGGTGGGRCCCA GCAAA GCA AWG VIS P EPEKLEDNV YY YA E GA ATCAGAAG ACN AGGG AAGCCAATQLHN AAKKNNASS TSMAT L RQSFGGAGTCG TG A GAA GLG A ATGCAGCGCCGAIGVLFQIAIEIW EK VA EERIGAGA GGTC T TCG K RQCLKT ACCGG CAGCDN AADTEINEVDS ENSIH DHGGGSCGA GTATACGCAC CA ACCGT GCCALTK LPADE RRK NSKAG KSAAGGCGTGAAA CGGTQ KRCCACCG CCGCCTGTVKLLK AKDRE LMASVG L LAGG TAA CCAGGACC YVFAG NVTGGC T C CAC QK KEKKKVAMSRT IQ LTDE QGACT CTGCTCG AG TCSYPCTCGAGG GG TGG GAGVM KYQERK KA N EPIQRLKTGGGTAAAAAAGGCQV GGC T CAGACA GRSNF VTKG KKSVPV K QWAAAA CGCAGACG CGGT  QNVGTCAGT CGGTARSRTEKKS AEEEV GKCVLKLDLACA HLGGAAAC CGCGGC59RAACTCCGTACCK CACCT KV LELDFEEK KCQKIIGS RRMDGKIGGGAGKKGGCGTA CTGGG TA DEE TGCCGK VKKDTP E T TGGCG CG LL CISCGGCT CGGCAESGVID KFAKQKK HELPNIAA CGACCAAAT TGC GT KLLQCCTCGACTATAAED VP FKPKEQIIRM EETETKTCGAA TG TCCGKPLQIAGGTTCCA GGCKRG KYEK E TESKKSESI YILAACGGACGC CG ACT LHSA GTG CAGAATG GAKG DGP EVEIKHS IA KNKACGCCCGGG AACATHLAI QII TGAACGGT T CETR LPD VK GVDKKKIVI IEGAGVTAGT CAGGGTDEQ QGCAAG CG GCT GCASSKKTSRSLGSKQSVAG GCGG TCA GGACA AG ALP KAA GAGCCCTAAGT EEEIKRKAERSPHITGSQRKGAC CAAA AGACLE LG GA GGGERYPI AKA AAGG AGCPQACT TT QI T L RKVD KGGTAAGA A YA DSCCATCC TA CG ACCG T M VERHPPKPRS KK LF E ERAAGCCC TA AGAA A KAGEGCGATC TGGG P AK ACRT IGKLGSIGINSE TRAKSQPPT PGAGGGGAGG A AAACGA GCA GC TEFREYK A VKDL GTKQ NCCG AACCA GAG TA CG NMTGG AT C CQDLVE LM FLA GAACA VVVGTGAATAN DTMS SSARGGAC TDIF S CCCAGGTGCG A K V GGH LNKPKSS SAN D AKG AACCA A ACACCA AGC E ACAACAGC STC E ESKV VGISRK Q KHCQGAGGG AE CGCALFIGAA CGGA TSIAGIGT CCA TCCACGTGATCCGGTGAEN AVCKGP TKRLDL EET RDGC T CGTA G GA G G G G M DSG KSK GL TD VTGG A A AT TTCCG MRVPACA N A Q T CACA )a) at)a(n a)t(n(d(d7P7k5. k55. RP151ARLAL17273747

[0042] GTC GG AAC CGAAGCA GACAAT VI TTTATA AA GACGCACTGCAT T LA GC CGGAGGAA CGA GTCGTAA AGATGAC CGGTG G AATGCAGTCAA KASTGCAGCGGT C C CGGCCG ACGC CGTCCTCAGCACGAACG GGGAALA GGTAACAGCACAACGGCAAA GAAC TCAAG AGCATACGGCGAACCGCPAAGCGA TGACCCGTCAG GCGA GAAGGAGAGCGAGCCAGCTCGA RATAGEV CAACAG GAT CGCG ATCA AGG CAGCTGATGCACACAG ACVEICGCCCCACCACGT TCG GACAG CAACGT C CGATAAAGTCCCCGTGAA CAGGCA GAAAG AAGA AAGA CCKV GAGGGC C CAGACGT TAC GTCGTAC GG C ATCG AG AAGAGGCA A TGCGCTATCTGGGCGGAT C CA GA TC C TA TE RG GGCCAA GAAA CACAAG GACGATACTCAACG T GCTGCAT CNLG AGG CACCCTGACAAGGG AACGGGGACACG AAGCCCCTG GC CAT TAGGGC GCT TAACAAGTD GACGA GN AC C C TACGCAAAAAGGC GCT CKKCAGGCGG AA GTCAGGAACA CCGG AGGAAC C CGTTGAC CGC CKSVK6  G GCAGCA G AGACGAA AGAATGAGACCA TCGCACGG AGGEAG KVL 9CGGAG G AGGAGAGGTA GGAG GAG GAGACA CCCCCG AGCCAA GSYIH TTGAGAAAAA AGGATCA AA G GAACAGAGAACGCGCAATGA GGCGE YPM H TA CA CGCA AGCCGTCA CGG AAGGAAG AGGGGTCGG TCG CGGCA A CAC CCGAGARGT CGTC CVVSNRGC TAAGAAA AAAACCC C CG C C KK AAA GCCGA AGGGC CAAACGGAGACAAACACCCTACA CGCAC EKLEQGTACATAAACAG G AGAGCG ACCG GGGGGCAAACACG AATGCALELCG GAGCACGT CC GAC ACGAGAGCAAGAGTCGAGCGCATGGSGCGTGG ALL KTC TGIGTAAGAG AAGCGGGTA GCGGCGTAAACCAAGG AAALP KC CTACACAG TCC CGACACA ACGATA GGAAG GAGACGCGA GTGTCGCEC CNL ETAC CAGA GAGAAT TA AGCGCGGT TGCGTTATCGG TCA HV GGAQALACACACGG CCACTAG AAACA GACA AGC C CCC TAAGGC MVSGA GAA A ACGAC C CGT CGG ATDIG GCG GAC CGCG GG G ACGAGCA EELTGTGGTA TAG GAGA C A G GAGTACCAGAAAG AG GCA GCGA AAT PPP ECACCCGCAGAACAAA GAGA GGV KG GACGAGTCCAACG G AGCA AEDRACCTTAAT CCT CTCAG GGAAAAC CT TGGGGAGTAA GGACGG TAGA CG FV RDLEGTAC CG GAGCC CGTGA AAGAT CA GAGAA GACTACAG G AGGAACACAGTA GGC C CATACVEGGCG GAGAG TGCG TGG G ATAG YAI ECAT CGCTG GCG G G G A G A G G G A GCCTGCACGTG AAC M YNIeA7L781

[0043] N LRTSKV TGACEANRAGGLA K RQ LK QSKRYVFNV CSYPQVV7  QN VL9LK DLDE RLL C EISKLLQ KPQ TLILHSHL QIAIIQ DELQ A LP KLP EAQY ADSGKA AEPK NMIVTV DIFVSA EETSCIAIMGRVP31unS881   Repressor Binding Element In some embodiments of the ON and / or OFF systems disclosed herein, the first polynucleotide of the ON and / or OFF dual polynucleotide system has a repressor binding element. A repressor binding element comprises a sequence, e.g., a DNA or RNA sequence, which is bound, e.g., recognized by a repressor described elsewhere in this disclosure. In some embodiments, the repressor binds to a sequence comprising the binding element, or a fragment thereof. In some embodiments, the repressor binds to a structure comprising the binding element, or a fragment thereof. In some embodiments, the composition or system comprises a repressor that binds to e.g., recognizes, the repressor binding element of the first polynucleotide in a dual polynucleotide system. In some embodiments, the repressor binding element of the first polynucleotide is situated upstream (5’) or downstream (3’), or in the open reading frame of the sequence encoding the polypeptide. In some embodiments, the repressor binding element of the first polynucleotide is situated upstream (5’) or downstream (3’) of a 5’ UTR of the first polynucleotide. In some embodiments, the binding element of the first polynucleotide is situated upstream (5’) or downstream (3’) of a 3’ UTR of the first polynucleotide. In some embodiments, the repressor binding element of the first polynucleotide is situated in the 5’ UTR of the first polynucleotide. In some embodiments, the repressor binding element of the first polynucleotide is situated downstream of a 3’ UTR of the first polynucleotide. In some embodiments, the repressor binding element of the first polynucleotide is situated adjacent, e.g., next to, a Poly A tail. In some embodiments, the repressor binding element is MS2. In some embodiments, the repressor binding element is PP7. In some embodiments, the repressor binding element is BoxB. In some embodiments, the repressor binding element is U1A hairpin. In some embodiments, the repressor binding element is PRE. In some embodiments, the repressor binding element is PRE2. In some embodiments, the repressor binding element is a kink-turn forming sequence. In some embodiments, the   repressor binding element is 7SK. In some embodiments, the repressor binding element is an RNA sequence / structure element that binds to a protein. In some embodiments, when the binding element is MS2 (e.g., wildtype MS2, or a variant or fragment thereof) the repressor is MBP (e.g., wildtype MBP, a variant or fragment thereof). In some embodiments, when the repressor binding element is PP7 (e.g., wildtype PP7, or a variant or fragment thereof) the repressor is PCP (e.g., wildtype PCP, or a variant or fragment thereof). PP7 can comprise the sequence of any one of the PP7 and variants thereof described in Lim F, and Peabody DS. Nucleic Acids Res. 2002;30(19):4138-4144, and US Patent No.9365831, incorporated by reference herein in its entirety. In some embodiments, when the repressor binding element is BoxB (e.g., wildtype BoxB, or a variant or fragment thereof) the repressor is Lambda N (e.g., wildtype Lambda N, or a variant or fragment thereof). In some embodiments, when the repressor binding element is U1A hairpin (e.g., wildtype U1A hairpin, or a variant or fragment thereof) the repressor is U1A (e.g., wildtype U1A, or a variant or fragment thereof). In some embodiments, when the repressor binding element is PRE (e.g., wildtype PRE, or a variant or fragment thereof) the repressor is PUF (e.g., wildtype PUF, or a variant or fragment thereof). In some embodiments, when the repressor binding element is a kink-turn forming sequence the repressor is 15.5kd (e.g., wildtype 15.5kd, or a variant or fragment thereof). In some embodiments, when the repressor binding element is a 7SK sequence repressor is LARP7 (e.g., wildtype LARP7, or a variant or fragment thereof). In some embodiments, the repressor binding element comprises a sequence comprising 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, 50, 60, 70, 80, 90 or 100 nucleotides. In some embodiments, the repressor binding element comprises a sequence comprising about 5-100, about 5-90, about 5-80, about 5- 70, about 5-60, about 5-50, about 5-40, about 5-30, about 5-25, about 5-20, about 5-19, about 5-18, about 5-17, about 5-16, about 5-15, about 5-14, about 5-13, about 5-12, about   5-11, about 5-10, about 5-9, about 5-8, about 5-7 or about 5-6 nucleotides. In some embodiments, the repressor binding element comprises a sequence comprising about 5- 100, about 6-100, about 7-100, about 8-100, about 9-100, about 10-100, about 11-100, about 12-100, about 13-100, about 14-100, about 15-100, about 16-100, about 17-100, about 18-100, about 19-100, about 20-100, about 21-100, about 22-100, about 23-100, about 24-100, about 25-100, about 30-100, about 40-100, about 50-100, about 60-100, about 70-100, about 80-100, or about 90-100 nucleotides. In some embodiments, the repressor binding element comprises a sequence comprising about 5-100, about 6-90, about 7-80, about 8-70, about 9-60, about 10-50, about 11-40, about 12-30, about 13-25, about 14-24, about 15-23, about 16-22, about 17-21, or about 18-20 nucleotides. In some embodiments, the repressor binding element comprises a sequence comprising 19 nucleotides. In some embodiments, the repressor binding element comprises a binding element nucleotide sequence provided in Table 4 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity thereof. In some embodiments, the  repressor binding element comprises a binding element sequence provided in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity thereof. In some embodiments of any of the compositions, systems, methods or uses disclosed herein, the repressor binding element comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20 or 30 repeats of the sequence bound by the second polypeptide. In some embodiments, the binding element comprises no more than 80, 70, 60, 50, 40 or 30 repeats of the sequence bound by the the second polypeptide. In some embodiments, the repressor binding element comprises about 1-30, about 1-20, about 1-10, about 1-9, about 1-8, about 1-7, about 1-6, about 1-5, about 1-4, about 1-3, or about 1-2 repeats of the sequence bound by the second polypeptide. In some embodiments, the repressor binding element comprises about 1-30, about 2-30, about 3-30, about 4-30 about, 5-30 about, 6-30, about 7-30, about 8-30, about 9-30, about 10-30, about 11-30, about 12-30, about 13-30, about 14-30, about 15-30, or about 20-30 repeats of the sequence bound by the second polypeptide. In some embodiments, the repressor binding element comprises   about 1-30, about 2-20, about 3-15, about 4-14, about 5-13, about 6-12, about 7-11, or about 8-10 repeats of the sequence bound by the second polypeptide. In some embodiments, the repressor binding element comprises 6 repeats of the sequence bound by the second polypeptide. In some embodiments of any of the compositions, systems, methods or uses disclosed herein, each repeat is separated by a spacer sequence comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, 50, 60, 70, 80, 90 or 100 nucleotides. In some embodiments, the spacer sequence comprises about 1- 100, about 1-90, about 1-80, about 1-70, about 1-60, about 1-50, about 1-40, about 1-30, about 1-25, about 1-20, about 1-19, about 1-18, about 1-17, about 1-16, about 1-15, about 1-14, about 1-13, about 1-12, about 1-11, about 1-10, about 1-9, about 1-8, about 1-7, about 1-6, about 1-5, about 1-4, about 1-3, or about 1-2 nucleotides. In some embodiments, the spacer sequence comprises about 1-100, about 2-100, about 3-100, about 4-100, about 5-100, about 6-100, about 7-100, about 8-100, about 9-100, about 10- 100, about 11-100, about 12-100, about 13-100, about 14-100, about 15-100, about 16- 100, about 17-100, about 18-100, about 19-100, about 20-100, about 21-100, about 22- 100, about 23-100, about 24-100, about 25-100, about 30-100, about 40-100, about 50- 100, about 60-100, about 70-100, about 80-100, or about 90-100 nucleotides. In some embodiments, the spacer sequence comprises about 1-100, about 2-90, about 3-80, about 4-70, about 5-60, about 6-50, about 7-40, about 8-40, about 9-30, about 10-25, about 11- 24, about 12-23, about 13-22, about 14-21, about 15-20, about 16-19, about 17-18 nucleotides. In some embodiment, the spacer sequence comprises 20 nucleotides. In some embodiments, the spacer sequence comprises a spacer sequence provided in Table 1 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity thereof. In some embodiments, the repressor binding element is an MS2 dimer which comprises monomers linked by a linker sequence. The linker sequence could be any peptide sequence known to link two protein sequences, including but not limited to those known in the art (See, e.g., Chen et al., Adv Drug Deliv Rev.( 2013) Oct 15; 65(10): 1357–1369).

[0044] UC C AU AUAAUCGGGAA U CCUG CAACGCGU G UG ACCGCAU CCU GG C AAU U CCGUGAGAGAUC CGUGC C UUGACGCGGCGCC U C CAAACAAAUGACA AAUU GU UGU GCACUC CUC CUCU UCUCU U CGGUCGU UGUC UCGAAC CUUGU AAUUCGUCU UCCUCCA ACACC CAGCAGCG U UCC CGA UA CACU G ACACA UCAGA U CC CA G GGAAGGAUCAA AAUCUACCUACUU GCGUUGGUGGCAGG G GUAG GGCG UACG G AGUG GUCUCACCUGG UCUUCCUCUAUCGCA GAUUA CG GAAGCCUGUGAUG AGGAA UACU AUGU CCUG UACCUGAA CUGUAGC C UGCUGGCA GCUC CAC C CAGCU CC AG G  CG GU A t UCA A GUACA AUGAGC CAGCG AUCAUAACG20GCG GCCCAACU UCAAUCCA G CUC G GU1neGUUUAG AGGAUC ACAACCGG GGUUACC CACU melCCCeUCUGCUGA UG U CU GCGGCCCCUGGU UGCGCGA UACUGUC AUU UCCAAC CUCUG AAGA GAAgCCA U iCGUGGCCA GUCnGCAUUG UGGCA UUGCC d ACCAUCCGGUUUGA AUCAAGACAACA AAACC niG U b GG ACACUUCA G ro UAAC C CGCGU UCUCU GCAAGG AUCA GAA GCUCA GAACCG CUAA A GAAAGA ssCCGCeGCGGUUAArGCUUCGAAUCCCG AGCU C GG G G UCAUUU A GACA CUGG U CA G GCGAAAAA p ACCUG UACUGAUCAAAGG GACU CUAACU G CG erU aeAC CG UC UCAC UG ACA G GUGC CUG GUA A GAAA fcU ACGCACG UAC U A AUGGAGUU U A G AUGGCC onesuUCG UGAA UAGACGCCG UAGGCA AACU UA eqGU ceGCUAAG AUGGAAGU A A A G A nSU GGC UCCCG GCAGC AGGGUCGUCU GCG G U A G UC CGCU A A C C C euqe1.ss21v ecyrn s S ’ao elcM 3 n_2eudpec it nx6 2S qmna eu_e n)e1See .MMs ad nil xu mqr qe 1 xx6 2Slo reof s v’6’_’ M b edEn R:S i 3 3 3 (ninu4 TeU l’3bQ a O1TESDIN2 3

[0045] UCC GG G GGAA A G A AA UA AA U CCA AA G AGC AU A A GA UA GA CCGUACCCACACGUC CG G U UG UG G AAUA CA A G A A UA A A CA A GA AGC CA G G U A U UA A U U G UCGUA A U G G ACGCUAGACA A UG AG AU UCUAUG G A A A U U AGCCGCUGA G A A UA AA UU CCC A GAAU U U A GCACUCU C A G A UU AU UA G A GCUG AA AG UACC CAACG GUCG G ACUA GU UU GG GCA UAGUUGU C UCUA A AAUG AU A AUCC CGCG A GU GUGACU UGCUGCACACA A U ACCACUUCAACA A AA UU UU UCG G GUAAGAGAAGGG UA UU CUG A A CA AGG CUGCGA UUA GCC ACC UCA GCAA A UG U UU CUG ACGC CGUU GGAGGU U U GCU U UC CUU ACU ACUU AU UU   GCG G AGAG UCA A GGCCACGGCAAU GCG ACGCGACG A GAG GUA G UCUU U UCUU3AC 01CG G A ACAG G A GUUA ACUACUUCUACGAGGUGACAUCGCACACGACGGCAGAUUAUGA CCCA UCG A ACUUCUUCAACUCU G UGAC CAAAAG GA ACUCACCUG AGCAUGUAAGCACG C ACA U C AGGUGUU UGAA UG CCA A AA GCGAA UCCGCUC C CGGGACACAGUUCC UGCC AACC ACA A A AAAGGC AUCACA AACGAUU UA GU AA UUGUGAGGCA A U GCGGAACG ACGCUCA G GGGGGAUUCGG ACGU ACGG UAA AC CA GG GAGU GUGAC CAAAAAGUUG GAAG GAUG G CCA G ACCAG AAUGA AGGAGAGGUU GG GA AUA A UCACACGCG GCUGAACA CACCCG U G A GAGAAAUACA C AUCAG UCGCU A ACU AG CCGACGGCU ACCCCC AUAUUGUACUUCC UUCCCUA CCUA GAAAUCAAAAAAAAAAAAAUA U U GGUUCACGCAGCUAUAAGAGGAUGAUG A AGUAA U G A AA AAAAAAAUA CG AC CCCG A A A AC CGAAAGGAAGAGGGGAAGGAGUA UCG G A U GU G AAAAACAGGAAAAGAGUUGUUGUU AGG G G A G A G A GCCGGGGUAGAGG GCU U U GG GCGAAGUGGCAGGG A AU UU UU U GCGCG G A G U G A U G G A G A G U A U A G A )tks’et5(aci Pn dd Bx x xn M3_3 3*eru 2etSniien )1_2_31c.n1e 1. knMlxre cnoig o2tp3_p4 p_p__p2_p2_2v’ u13 qv i 6 dees’k5’_5’n5u u e(q r seedE E E E E EnshtibRPRPRPRPRPRPR T4U’5 6 7 8 90111213141

[0046] A U CCG U U UUAA UU UUCAACA GU AA UU UG GUC CA UG UU UGUUUCUCAU UU A UCGU GCGU UU ACG G UUGU UU UUACUCGAAUUCA U U AUUUUCU UA GUCCGUUU UU AG AU UCU CAA UU AA AUAC CAU UU GA AUCGGGAU UU U GA UAGAAU UA AA AG GCAUAG UU AU AU GA UU UUUCCAGUUA UAUU AA GA GU U GA AU AU GA GUU ACGAA   AG G AACAA GCG AUC UU CGUGAG401GUCAUCAU UCG UAGUAGUA G UGCGA AGGA G ACACACUUCUAA AA U AUCAUCAUAAGAUGC CG G UGCUUUAA U CAACCC U AUAACG U AGU GGCAU AG UCGCGC CGU GCGGAU A U UGAUGAAG AA GGACAUAUUotG AUCGUCG GUG GGUU GC CGGGG AAsdGAAGAAU ACUCGU GA U CC niAUCG AUCG AUA ACG GUC CGUCbAU UUCAA ACUCC UCAUU AA GAUUUGAUPB AAUUG ACUUUG GGAUC RA AUAAGUAAU A GUUAUUAGCC C ehAAGA AAUA AGUUUG UUUCUUtGAA UA UUnGGAGUUGUUCAAGCAUAoiAUGAAGUUCCCGAGGA UCUgGAA GUG GUU GCU GGGA GAAAUer UU AU UU GA AC C CAeA U G U U UA CU G U G Ahtsesteax3x x ccind_3e ni4_3_uniep5_p6p qeB pr cn2_ _sE2E2E s xiaKeuo h S7uqRo BPR R e A1esP P nalUdelneic lsre5i 8 9 0 d16171M1 1 2 nu*   miRNA target site In some embodiments of the ON and / or OFF systems disclosed herein, the polynucleotide of the single polynucleotide system, the second polynucleotide of the ON and / or OFF dual polynucleotide system, and optionally the first polynucleotide of the ON and / or OFF dual polynucleotide system has one or more microRNA target sites (miRts). In some embodiments, the polynucleotide of the single polynucleotide system has one or more microRNA target sites (miRts). In some embodiments, the first polynucleotide of the dual polynucleotide system has one or more miRts. In some embodiments, the second polynucleotide of the dual polynucleotide system has one or more miRts. In some embodiments, the one or more miRts is on the second polynucleotide but not on the first polynucleotide of the dual polynucleotide system. In some embodiments, the one or more miRts is on the first polynucleotide and on the second polynucleotide of the dual polynucleotide system. In some embodiments, the one or more miRts are situated on the polynucleotide (e.g., any of the polynucleotides of the single or dual polynucleotide systems) upstream (5’) or downstream (3’) of the open reading frame encoding the polypeptide (i.e. the target protein) or the repressor. In some embodiments, the one or more miRts are situated on the polynucleotide downstream of the open reading frame encoding the polypeptide or the repressor (e.g., in the 3’ UTR). In some embodiments, the one or more miRts are situated on the polynucleotide upstream of the open reading frame encoding the polypeptide or the repressor (e.g., in the 5’ UTR). In some embodiments, the one or more miRts are situated on the polynucleotide between the repressor binding site and upstream of the open reading frame encoding the polypeptide. In some embodiments, the one or more miRts are situated on the polynucleotide downstream of the poly A tail. In some embodiments, the one or more miRts are situated on the second polynucleotide upstream (5’) of the open reading frame encoding the repressor. In some embodiments, the one or more miRts are situated on the second polynucleotide downstream (3’) of the open reading frame encoding the repressor. In some   embodiments, the one or more miRts are situated on the second polynucleotide between the open reading frame encoding the repressor and upstream of the poly A tail. In some embodiments, the one or more miRts are in a non-coding region of the polynucleotide. In some embodiments, the 3’ untranslated region (UTR) of the polynucleotide (e.g., an mRNA) comprises at least one miRts (e.g., an HSPC miRts). In some embodiments, the 3’ UTR of the mRNA comprises at least two repeats of one miRts (e.g., one HSPC miRts). In some embodiments, the 3’ UTR of the mRNA comprises six repeats of one miRts (e.g., one HSPC miRts). In some embodiments, the 5’ UTR of the polynucleotide (e.g., an mRNA) comprises at least one miRts. In some embodiments, the 5’ UTR of the polynucleotide (e.g., an mRNA) comprises at least two repeats of one miRts. In some embodiments, the 5’ UTR of the polynucleotide (e.g., an mRNA) comprises three repeats of one miRts. In some embodiments, the polynucleotide (e.g., an mRNA) has one or more miRts in the 3’ UTR and the 5’ UTR. In some embodiments, the miRNA target sequence is 100% complementary to the miRNA and selected from, but not limited to, the sequences in Table 5 below:

[0047] o5denlabaeTcnneiusqeecsnteeugqreasteAhtN,Riotmdeethit minlito.e6ti 1 ntsnutoei bt gi ,rs maot o2p rfd41mo etR rci feelmre esahArsow i yeA GA enacne 7  A GGUA CUCG GUG A CGUAGCAGAAAtCist seuq01CU CAU CCAeg hcetstA AAGGC CGCGr a eGUCAUU CGA U U atgCGG GCGC CA AUGC CAACA2m2si ratA U CUAGU UUUGACU AUACAA1RmsAsG A CACAGU GA GCA GCAi aUCUGCm hNeGR hc CCAA AGAACAG U G GGGAa ec imtaAC ACA G A U GAAUGsinUee eh msUiUC UGCUA UUG AACACU GU AUti uqt,A UUUUUAAAACUsAteestec mU nhtU e A UUCUAG AGGCAUA ACUgr eg at ieA scUCAC A CCCG GUACGatra snws cU ecnneACAC CUA AUAAG A tirecneA C euq CG UCAAC C CCAGNA NoFneuqA uqeeSGC AACA UCG U ACCACCUACG URorR.u e UsciAqeS Ctim e meghNsRterat npeAe o3 p p p p pht it,,stm gfranc it p3--aNna0 5-a 3-5a-5a-5b-p pb5-3p p-5-5-el neotoAec it p3Reiu m6r23 0 9 5 5 6 0 2 2 3 pm o11R-1R-2R-2R1219R15 4 2 2m R1 1R1 2a i dxd noeNna'e-m623Riuro1mqef i i i iRi i iRi iRiRiebmqefRi:aSnim m m m m m m m m m mr5oFme eh: Snim ee tsblbQ aE9 0 1 2 3modr: 5awelQ4T SDIO N5767778797088191919191 sn wol bIoteba ETSDIO N915

[0048] A8 01AAG UGC CAAA C AU CACG U C GCGA UCGGC CA UUAAA UUACAAC GAACGGCA GU AG AGG AA U U U UAU UCGUU AAAU U C UACA ACU AG CACAA CA AC AAACAA UUUUU ACUCU p3-ap p p p053-3-5-5-10-5242233R1 1 1 2iRiRiRiRim m m m m 596 919719819191   microRNAs In some embodiments of the ON and / or OFF systems disclosed herein, the expression of the polypeptide or repressor from the polynucleotides of the single or dual polynucleotide systems is influenced by the levels of one or more miRNAs present in the cell-type that comes in contact with the polynucleotide that has one or more microRNA target sites that are complementary to the one or more miRNAs. In some embodiments, miRNAs of interest can be determined from miRNA databases as referenced in sources known in the art, e.g., Kozomara A, et al., Nucleic Acids Res 201947:D155-D162; Kozomara A, Griffiths-Jones S., Nucleic Acids Res 201442:D68-D73; Kozomara A, Griffiths-Jones S. Nucleic Acids Res 201139:D152- D157; Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ. Nucleic Acids Res 2008 36:D154-D158; Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ. Nucleic Acids Res 200634:D140-D144; Griffiths-Jones S. Nucleic Acids Res 2004 32:D109-D111; Ambros V, et al., RNA 20039(3):277-279; and Meyers BC, et al., Plant Cell.200820(12):3186-3190. A nucleotide sequence that is a reverse complement of a miRNA sequence selected from such a database would be the mi microRNA expression can vary across different hematopoietic cells and at different stages of development. For instance, miR142 is specific to cells of the hematopoietic lineage. miR-150 is abundantly expressed in mature immune cells. In some instances, miRNAs of interest such as miR126-3p, miR130a-3p, miR125b-5p, miR196b-5p, and miR10a-5p are abundant in CD34+ bone marrow cells but not present at high levels in more differentiated immune cells where expression of a target is desired. miR126-3p, miR130a-3p, miR196b-5p are have been described as expressed in hematopoietic stem cells (HSCs) and early progenitors in both mice and humans, but not in more differentiated progeny. These miRs were shown to effectively repress reporter lentiviral vectors containing their target sites in both mouse and human hematopoietic stem and progenitor cells (HSPCs) (Gentner B. et al., Sci Trans. Med. 2010; 2(58) p.58ra84).   In some instances, miR126-3p, miR130a-3p, and miR196b-5p, miR29a-3p, miR125b-5p, miR125a-5p, are known to be enriched in hematopoietic stem cells profiled in mouse and human stem cell and progenitor cell populations by RT-qPCR, bead-based miR detection, and miR arrays. See e.g., Petriv O.I. et al., Proc. Natl. Acad. Sci, 2010; 107 (35) 15443-15448; Chung SS, et al., Ther Adv Hematol.2011 Oct;2(5):317-34; Bissels U, et al., Haematologica.2012 Feb;97(2):160-7. Epub 2011 Nov 4.). Modifications of Polynucleotides   In some embodiments of the ON and / or OFF systems disclosed herein, the design of the polynucleotides can be modified in order to increase efficacy of the outcome of miR target sites-miRNA interaction in an ON / OFF systems. For instance, a polynucleotide design modification described herein can enhance expression of the target protein in a desired cell type. In another instance, a polynucleotide design modification described herein can suppress expression of the target protein in a particular cell type, while enhancing expression of the target protein in another cell type. In some embodiments, the polynucleotide of the system (e.g., an mRNA) has one or more of the following design modifications: (1) an AU-rich element; (2) the one or more miRts comprise at least one mismatch to the microRNA that binds the one or more miRts; (3) structurally accessible UTRs; (4) a short polyA tail; and (5) the ability to form microRNA bridges when a microRNA binds to the one or more miRts. The 3’ UTR comprises an AU-rich element, which can be 60%-90% AU-rich, for example, about 70% AU-rich. The one or more miRts comprise one to three mismatches to the microRNA that binds the one or more miRts. In some embodiments, the polyA tail of any of the polynucleotides described herein is 40-100 nucleotides in length. In some embodiments, when one or more miRts are included in both the 5’ and the 3’ UTRs of the polynucleotide, a microRNA bridge is formed by the one or more miRts in the 5’ UTR and the 3’ UTR.   Cell-Specific Expression In some embodiments of the ON and / or OFF systems disclosed herein, the polypeptide and / or repressor of the ON and / or OFF compositions and systems are expressed in cells of the hematopoietic cell lineage. Cells of the hematopoietic cell lineage include, but are not limited to, hematopoietic stem cells (HSCs), hematopoietic stem and progenitor cells (HSPCs), mature bone marrow cells, multipotent progenitors (MPP), common lymphoid progenitors (CLP), granulocyte monocyte progenitors (GMP), common myeloid progenitors (CMP), and megakaryocyte-erythrocyte progenitors (MEP). In some embodiments, the expression of the polypeptide of interest is selectively turned OFF in HSCs. In some embodiments, the expression of the polypeptide of interest is selectively turned OFF in HSPCs. In some embodiments, the expression of the polypeptide of interest is selectively turned ON in mature immune cells (such as T cells, B cells, neutrophils, and macrophages). The selectivity of expression is the cell-type of interest is determined by the presence of the microRNAs in the particular cell type. For instance, miR142 is present in all immune cells. In an OFF system, when hematopoietic cells that express miR142 are exposed to target mRNA constructs with miR142ts, the expression of the target will be turned off in all those cells. A “hematopoietic stem cell” or “HSC” is an immature cell that can develop into all types of blood cells, including white blood cells, red blood cells, and platelets. Hematopoietic stem cells are found in the peripheral blood and the bone marrow. The defining property of a HSC is its ability to reconstitute hematopoiesis following transplantation. “Hematopoietic stem and progenitor cells” “ or “HSPCs” are a rare population of precursor cells that possess the capacity for self-renewal and multilineage differentiation. In the bone marrow (BM), HSPCs warrant blood cell homeostasis. In addition, they may also replenish tissue-resident myeloid cells and directly participate in innate immune responses once they home to peripheral tissues. See e.g., Schulz C, et al. Immunol Res.2009;44(1-3):160-8. HSPCs isolated from bone marrow have been successfully used for hematological transplantations. The different types of blood cell and their lineage relationships are summarized in Fig.1.3 in Janeway CA Jr, et al., Immunobiology: The Immune System in Health and   Disease.5th edition. New York: Garland Science; (2001). The myeloid progenitor is the precursor of the granulocytes, macrophages, dendritic cells, and mast cells of the immune system. The common lymphoid progenitor gives rise to the lymphocytes (T cells, and B cells). A third lineage of lymphoid cells, called natural killer cells, lack antigen-specific receptors and are part of the innate immune system. In some embodiments, the CMP cells are determined to be CD45RA- CD123+ / lo); GMP cells are CD45RA+ CD123+); MEP cells are CD45RA- CD123-; MPP cells are CD45+ CD34+ CD90- CD133+ CD45RA-); CLP cells are CD45+ CD34+ CD90- CD10+ CD45RA_; and mature bone marrow cells are CD45+ Lin+. A “mature immune cell” includes mature cells of the adaptive and / or innate immune systems. These include lymphocytes that mature in the bone marrow or thymus. Mature granulocytes include neutrophils, eosinophils, basophils, and mast cells, which all develop from GMP. Fang, P., et al. J Hematol Oncol 11, 97 (2018) In some embodiments, expression of certain immune therapies in HSCs may not be desirable e.g. targets that may induce monocyte differentiation or macrophage polarization whose expression in HSCs may reprogram bone marrow development. For such immune therapies, an miR-OFF system disclosed herein is desirable to limit off- target effects in HSCs / HSPCs. In some embodiments, an miR-ON system disclosed herein is desirable for in vivo gene editing of HSPCs, thereby allowing editing only in cells of interest, (e.g., HSCs), while reducing expression of a gene editor in all other cells. In some embodiments, endogenous miRNA in specific cell types can be harnessed at multiple levels to allow cell-type-selective gene editing from systemic delivery of editing components. For instance, the disclosed systems can be used to control protein output, protein stability, or control guide RNA activation in specific cells. An HSC miR- ON system can be used to preferentially allow mRNA encoding an editor to express protein appreciably in HSC cells only. In another instance, using self-splicing inteins, an editor protein can be fused to a degron domain in most cells that leads to rapid protein degradation. The degron domain expression can be turned OFF in select cells only (eg. HSC cells here) to allow maintenance of the editor protein. In another instance, single   guide RNA can be embedded between miR-target-sites to allow miR-dependent cleavage and selective activation in miR-containing cells only. In one instance of the HSC miR-ON system, the system can be used to bias expression of target proteins in HSCs only. In one instance, the system can be used to selectively kill HSCs as a replacement of chemotherapy / radiation for bone marrow conditioning prior to stem cell transplant. Methods of using the systems or compositions   The present disclosure provides compositions, which can be delivered to cells, e.g., target cells, e.g., in vitro or in vivo. For in vitro protein expression, the cell is contacted with the composition by incubating the composition and the cell ex vivo. Such cells may subsequently be introduced in vivo. For in vivo protein expression, the cell is contacted with the composition by administering the composition to a subject to thereby induce protein expression in or on the desired cells within the subject. For example, in one embodiment, the composition is administered intravenously. In another embodiment, the composition is administered intramuscularly. In yet other embodiment, the composition is administered by a route selected from the group consisting of subcutaneously, intranodally and intratumorally. For in vitro delivery, in one embodiment the cell is contacted with the composition by incubating the composition and the target cell ex vivo. In one embodiment, the cell is a human cell. Various types of cells have been demonstrated to be transfectable by the composition (e.g., the LNP). In another embodiment, the cell is contacted with the composition for, e.g., at least 30 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 12 hours or at least 24 hours. In one embodiment, the cell is contacted with the composition for a single treatment / transfection. In another embodiment, the cell is contacted with the composition for multiple treatments / transfections (e.g., two, three, four or more treatments / transfections of the same cells).   In another embodiment, for in vivo delivery, the cell is contacted with the composition by administering the composition to a subject to thereby deliver the polynucleotide(s) to cells within the subject. For example, in one embodiment, the composition is administered intravenously. In another embodiment, the composition is administered intramuscularly. In yet other embodiment, the composition is administered by a route selected from the group consisting of subcutaneously, intranodally and intratumorally. In an aspect, provided herein is a method of expressing a polypeptide in a cell, comprising administering to the cell a composition disclosed herein. In a related aspect, provided herein is a composition or system for use in a method of expressing a polypeptide in a cell in a cell. In another aspect, the disclosure provides a method of expressing a polypeptide in a cell in a subject, comprising administering to the subject an effective amount of a composition disclosed herein. In a related aspect, provided herein is a composition or system for use in a method of expressing a polypeptide in a cell in a subject. In yet another aspect, provided herein is a method of delivering a composition disclosed herein. In a related aspect, provided herein is a composition or system for use in a method of delivering the composition to a cell. In an embodiment, the method or use, comprises contacting the cell in vitro, in vivo or ex vivo with the composition or system. In an embodiment, the composition or system formulated as an LNP, a liposome composition, a lipoplex composition, or a polyplex composition of the present disclosure is contacted with cells, e.g., ex vivo or in vivo and can be used to deliver a secreted polypeptide, an intracellular polypeptide, a transmembrane polypeptide, or peptides, polypeptides or biologically active fragments thereof to a subject. In an aspect, the disclosure provides a method of delivering a composition or system disclosed herein to a subject having a disease or disorder, e.g., as described herein.   In a related aspect, provided herein is a composition or system for use in a method of delivering the composition or system to a subject having a disease or disorder, e.g., as described herein. In another aspect, provided herein is a method of modulating an immune response in a subject, comprising administering to the subject in need thereof an effective amount of a composition or system disclosed herein. In a related aspect, provided herein is a composition or system for use in a method of modulating an immune response in a subject, comprising administering to the subject an effective amount of the composition or system. In another aspect, provided herein is a method of delivering a secreted polypeptide, an intracellular polypeptide, a transmembrane polypeptide, or peptides, polypeptides or biologically active fragments thereof to a subject. In an aspect, provided herein is a method of treating, preventing, or preventing a symptom of, a disease or disorder comprising administering to a subject in need thereof an effective amount of a composition or system disclosed herein. In a related aspect, provided herein is a composition or system for use in a method of treating, preventing, or preventing a symptom of, a disease or disorder in a subject, comprising administering to the subject in need thereof an effective amount of the composition or system. In an embodiment, the first polynucleotide and / or the second polynucleotide of the system is formulated as an LNP. In an embodiment, the first polynucleotide of the system is formulated as an LNP. In an embodiment, the second polynucleotide of the system is formulated as an LNP. In an embodiment, both the first and the second polynucleotides of the system are formulated as LNPs. In an embodiment, the LNP comprising the first polynucleotide is the same as the LNP comprising the second polynucleotide. In an embodiment, the LNP comprising the first polynucleotide is different from the LNP comprising the second polynucleotide. In an embodiment, the LNP comprising the first polynucleotide is in a composition. In an embodiment, the LNP comprising the second polynucleotide is in a separate composition. In an embodiment, the LNP comprising the first polynucleotide   and the LNP comprising the second polynucleotide are in the same composition. In some embodiments, the first and second polynucleotides are in separate dosage forms packaged together. In some embodiments, the first and second polynucleotides are in a unit dosage form. In an embodiment, the LNP comprising the first polynucleotide and the LNP comprising the second polynucleotide are administered simultaneously, e.g., substantially simultaneously. In some embodiments, the LNP comprising the first polynucleotide and the LNP comprising the second polynucleotide are co-delivered. In an embodiment, the LNP comprising the first polynucleotide and the LNP comprising the second polynucleotide are administered sequentially. In an embodiment, the LNP comprising the first polynucleotide is administered first. In an embodiment, the LNP comprising the first polynucleotide is administered first followed by administration of the LNP comprising the second polynucleotide. In an embodiment, the LNP comprising the second polynucleotide is administered first. In an embodiment, the LNP comprising the second polynucleotide is administered first followed by administration of the LNP comprising the first polynucleotide. In some embodiments of the disclosed methods, the method comprises contacting the cell with a composition of the disclosure (for example a composition according to FIGs.1A-1B), wherein the cell expresses a microRNA or endonuclease that binds to the recognition site or cleavage site and reduces translation of the repressor from the second polynucleotide. In some embodiments, the method comprising contacting the cell with a composition of the disclosure, wherein the cell expresses a microRNA or endonuclease that binds to the recognition site or cleavage site, cleaves the repressor binding element from the first polynucleotide, and enhances translation of the first polypeptide from the first polynucleotide. In some embodiments of the disclosed methods, the method comprises contacting the cell with (a) a first polynucleotide comprising (i) a repressor binding element and (ii) an open reading frame encoding a polypeptide; and (b) a second polynucleotide   comprising (i) a sequence encoding a repressor that binds to the repressor binding element and (ii) a recognition site or cleavage site, wherein the cell expresses a microRNA or an endonuclease that binds to the recognition site or cleavage site and reduces translation of the repressor from the second polynucleotide. In some embodiments of the disclosed methods, the method comprises expressing a polypeptide in a cell, the method comprising contacting the cell with (a) a first polynucleotide comprising (i) a repressor binding element, (ii) a recognition site or cleavage site, and (iii) an open reading frame encoding a polypeptide; and (b) a second polynucleotide comprising a sequence encoding a repressor that binds to the repressor binding element, wherein the cell expresses a microRNA or endonuclease that binds to the recognition site or cleavage site, cleaves the repressor binding element from the first polynucleotide, and enhances translation of the polypeptide from the first polynucleotide. In some embodiments of the disclosed methods, the method comprises expressing a polypeptide in a cell in a subject, the method comprising administering to the subject: (a) a first polynucleotide comprising (i) a repressor binding element and (ii) an open reading frame encoding a polypeptide; and (b) a second polynucleotide comprising (i) a sequence encoding a repressor that binds to the repressor binding element and (ii) a recognition site or cleavage site, wherein the cell expresses a microRNA or an endonuclease that binds to the recognition site or cleavage site and reduces translation of the repressor from the second polynucleotide. In some embodiments of the disclosed methods, the method comprises expressing a polypeptide in a cell in a subject, the method comprising administering to the subject: (a) a first polynucleotide comprising (i) a repressor binding element, (ii) a recognition site or cleavage site, and (iii) an open reading frame encoding a polypeptide; and (b) a second polynucleotide comprising a sequence encoding a repressor that binds to the repressor binding element, wherein the cell expresses a microRNA or endonuclease that binds to the recognition site or cleavage site, cleaves the repressor binding element from the first polynucleotide, and enhances translation of the polypeptide from the first polynucleotide.   Sequence optimization and methods thereof In some embodiments, a polynucleotide of the disclosure comprises a sequence- optimized nucleotide sequence encoding a polypeptide disclosed herein, e.g., a polynucleotide encoding a polypeptide (e.g., a therapeutic or prophylactic protein), or a repressore. In some embodiments, the polynucleotide of the disclosure comprises an open reading frame (ORF) encoding a polypeptide or a repressor, wherein the ORF has been sequence optimized. The sequence-optimized nucleotide sequences disclosed herein are distinct from the corresponding wild type nucleotide acid sequences and from other known sequence- optimized nucleotide sequences, e.g., these sequence-optimized nucleic acids have unique compositional characteristics. In some embodiments, the percentage of uracil or thymine nucleobases in a sequence-optimized nucleotide sequence (e.g., encoding a polypeptide or a repressor, a functional fragment, or a variant thereof) is modified (e.g., reduced) with respect to the percentage of uracil or thymine nucleobases in the reference wild-type nucleotide sequence. Such a sequence is referred to as a uracil-modified or thymine-modified sequence. The percentage of uracil or thymine content in a nucleotide sequence can be determined by dividing the number of uracils or thymines in a sequence by the total number of nucleotides and multiplying by 100. In some embodiments, the sequence-optimized nucleotide sequence has a lower uracil or thymine content than the uracil or thymine content in the reference wild-type sequence. In some embodiments, the uracil or thymine content in a sequence-optimized nucleotide sequence of the disclosure is greater than the uracil or thymine content in the reference wild-type sequence and still maintain beneficial effects, e.g., increased expression and / or signaling response in desired cells and / or microenvironments when compared to the reference wild-type sequence. In some embodiments, the optimized sequences of the present disclosure contain unique ranges of uracils or thymine (if DNA) in the sequence. The uracil or thymine content of the optimized sequences can be expressed in various ways, e.g., uracil or thymine content of optimized sequences relative to the theoretical minimum (%UTM or %TTM), relative to the wild-type (%UWT or %TWT), and relative to the total nucleotide content (%UTL or %TTL). For DNA it is recognized that thymine (T) is present instead   of uracil (U), and one would substitute T where U appears. For RNA it is recognized that uracil (U) is present instead of thymine (T). One of skill in the art could readily obtain an RNA sequence when the DNA sequence is provided by substituting thymine in the DNA sequence to uracil. Thus, all the disclosures related to, e.g., %UTM, %UWT, or %UTL, with respect to RNA are equally applicable to %TTM, %TWT, or %TTL with respect to DNA. Uracil- or thymine- content relative to the uracil or thymine theoretical minimum, refers to a parameter determined by dividing the number of uracils or thymines in a sequence-optimized nucleotide sequence by the total number of uracils or thymines in a hypothetical nucleotide sequence in which all the codons in the hypothetical sequence are replaced with synonymous codons having the lowest possible uracil or thymine content and multiplying by 100. This parameter is abbreviated herein as %UTM or %TTM. In some embodiments, a uracil-modified sequence encoding a polypeptide, or a repressor of the disclosure has a reduced number of consecutive uracils with respect to the corresponding wild-type nucleic acid sequence. For example, two consecutive leucines can be encoded by the sequence CUUUUG, which includes a four uracil cluster. Such a subsequence can be substituted, e.g., with CUGCUC, which removes the uracil cluster. Phenylalanine can be encoded by UUC or UUU. Thus, even if phenylalanines encoded by UUU are replaced by UUC, the synonymous codon still contains a uracil pair (UU). Accordingly, the number of phenylalanines in a sequence establishes a minimum number of uracil pairs (UU) that cannot be eliminated without altering the number of phenylalanines in the encoded polypeptide. In some embodiments, a uracil-modified sequence encoding a polypeptide, or a repressor of the disclosure has a reduced number of uracil triplets (UUU) with respect to the wild-type nucleic acid sequence. In some embodiments, a uracil-modified sequence encoding a polypeptide, or a repressor has a reduced number of uracil pairs (UU) with respect to the number of uracil pairs (UU) in the wild-type nucleic acid sequence. In some embodiments, a uracil-modified sequence encoding olypeptide, or a repressor of the disclosure has a number of uracil pairs (UU) corresponding to the minimum possible number of uracil pairs (UU) in the wild-type nucleic acid sequence.   The phrase “uracil pairs (UU) relative to the uracil pairs (UU) in the wild type nucleic acid sequence”, refers to a parameter determined by dividing the number of uracil pairs (UU) in a sequence-optimized nucleotide sequence by the total number of uracil pairs (UU) in the corresponding wild-type nucleotide sequence and multiplying by 100. This parameter is abbreviated herein as %UUwt. In some embodiments, a uracil-modified sequence encoding a polypeptide, or a repressor has a %UUwt between below 100%. In some embodiments, the polynucleotide of the disclosure comprises a uracil- modified sequence encoding an encoding a polypeptide, or a repressor disclosed herein. In some embodiments, the uracil-modified sequence encoding a polypeptide, or a repressor comprises at least one chemically modified nucleobase, e.g., 5-methoxyuracil. In some embodiments, at least 95% of a nucleobase (e.g., uracil) in a uracil-modified sequence encoding a polypeptide, or a repressor of the disclosure are modified nucleobases. In some embodiments, at least 95% of uracil in a uracil-modified sequence encoding a polypeptide, or a repressor is 5-methoxyuracil. In some embodiments, a polynucleotide of the disclosure (e.g., a polynucleotide comprising a nucleotide sequence encoding a polypeptide, or a repressor (e.g., the wild- type sequence, functional fragment, or variant thereof) is sequence optimized. A sequence optimized nucleotide sequence (nucleotide sequence is also referred to as "nucleic acid" herein) comprises at least one codon modification with respect to a reference sequence (e.g., a wild-type sequence encoding a polypeptide, or a repressor. Thus, in a sequence optimized nucleic acid, at least one codon is different from a corresponding codon in a reference sequence (e.g., a wild-type sequence). In general, sequence optimized nucleic acids are generated by at least a step comprising substituting codons in a reference sequence with synonymous codons (i.e., codons that encode the same amino acid). Such substitutions can be effected, for example, by applying a codon substitution map (i.e., a table providing the codons that will encode each amino acid in the codon optimized sequence), or by applying a set of rules (e.g., if glycine is next to neutral amino acid, glycine would be encoded by a certain codon, but if it is next to a polar amino acid, it would be encoded by another codon). In addition to codon substitutions (i.e., "codon optimization") the sequence optimization   methods disclosed herein comprise additional optimization steps which are not strictly directed to codon optimization such as the removal of deleterious motifs (destabilizing motif substitution). Compositions and formulations comprising these sequence optimized nucleic acids (e.g., a RNA, e.g., an mRNA) can be administered to a subject in need thereof to facilitate in vivo expression of functionally active encoding a polypeptide, or a repressor. Additional and exemplary methods of sequence optimization are disclosed in International PCT application WO 2017 / 201325, filed on 18 May 2017, the entire contents of which are hereby incorporated by reference. Micro RNA (miRNA) and Endonuclease recognition sites Nucleic acid molecules (e.g., RNA, e.g., mRNA) of the disclosure include regulatory elements, for example, microRNA (miRNA) binding sites, endonuclease cleavage sites, structured mRNA sequences and / or motifs, artificial binding sites engineered to act as pseudo-receptors for endogenous nucleic acid binding molecules, and combinations thereof. A regulatory element on an RNA molecule of the disclosure regulates translation of the RNA molecule. In some embodiments, binding of the miRNA or endonuclease to the recognition site within the regulatory element results in cleavage of the RNA molecule at the site of recognition, thereby enhancing or suppressing translation. In other embodiments, binding of the miRNA to the regulatory element on an RNA molecule suppressing translation of the RNA molecule without cleavage. The recognition site may be bound by an miRNA or an endonuclease in a cell- type-specific manner. In some embodiments, the term “modification of the recognition site” refers to the binding of miRNA or endonuclease to the recognition site within the regulatory element, which results in cleavage or non-cleavage based translation repression. In some embodiments, a nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure comprises an open reading frame (ORF) encoding a first polypeptide of interest and further comprises one or more miRNA binding site(s). Inclusion or incorporation of miRNA binding site(s) provides for regulation of nucleic acid molecules (e.g., RNA, e.g., mRNA) of the disclosure, and in turn, of the polypeptides encoded   therefrom, based on tissue-specific, cell-type specific, and / or microenvironment specific expression of naturally-occurring miRNAs. A miRNA, e.g., a natural-occurring miRNA, is a 19-25 nucleotide long noncoding RNA that binds to a nucleic acid molecule (e.g., RNA, e.g., mRNA) and down-regulates gene expression either by reducing stability or by inhibiting translation of the polynucleotide. A miRNA sequence comprises a “seed” region, i.e., a sequence in the region of positions 2-8 of the mature miRNA. A miRNA seed can comprise positions 2-8 or 2-7 of the mature miRNA. In some embodiments, a miRNA seed can comprise 7 nucleotides (e.g., nucleotides 2-8 of the mature miRNA), wherein the seed- complementary site in the corresponding miRNA binding site is flanked by an adenosine (A) opposed to miRNA position 1. In some embodiments, a miRNA seed can comprise 6 nucleotides (e.g., nucleotides 2-7 of the mature miRNA), wherein the seed- complementary site in the corresponding miRNA binding site is flanked by an adenosine (A) opposed to miRNA position 1. See, for example, Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP; Mol Cell.2007 Jul 6;27(1):91-105. miRNA profiling of the target cells or tissues can be conducted to determine the presence or absence of miRNA in the cells or tissues. In some embodiments, a nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure comprises one or more microRNA binding sites, microRNA target sequences, microRNA complementary sequences, or microRNA seed complementary sequences. Such sequences can correspond to, e.g., have complementarity to, any known microRNA such as those taught in US Publication US2005 / 0261218 and US Publication US2005 / 0059005, the contents of each of which are incorporated herein by reference in their entirety. As used herein, the term “microRNA (miRNA or miR) binding site”, “miR target site” (miRts) or “miR recognition site” refers to a sequence within a nucleic acid molecule, e.g., within a DNA or within an RNA transcript, including in the 5′UTR and / or 3′UTR, that has sufficient complementarity to all or a region of a miRNA to interact with, associate with or bind to the miRNA. In some embodiments, a nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure comprises an ORF encoding a polypeptide of interest and further comprises one or more miRNA binding site(s). In exemplary   embodiments, a 5’UTR and / or 3’UTR of the nucleic acid molecule (e.g., RNA, e.g., mRNA) comprises the one or more miRNA binding site(s). A miRNA binding site having sufficient complementarity to a miRNA refers to a degree of complementarity sufficient to facilitate miRNA-mediated regulation of a nucleic acid molecule (e.g., RNA, e.g., mRNA), e.g., miRNA-mediated translational repression or degradation of the nucleic acid molecule (e.g., RNA, e.g., mRNA). In exemplary aspects of the disclosure, a miRNA binding site having sufficient complementarity to the miRNA refers to a degree of complementarity sufficient to facilitate miRNA-mediated degradation of the nucleic acid molecule (e.g., RNA, e.g., mRNA), e.g., miRNA-guided RNA-induced silencing complex (RISC)-mediated cleavage of mRNA. The miRNA binding site can have complementarity to, for example, a 19-25 nucleotide miRNA sequence, to a 19-23 nucleotide miRNA sequence, or to a 22 nucleotide miRNA sequence. A miRNA binding site can be complementary to only a portion of a miRNA, e.g., to a portion of the full length of a naturally-occurring miRNA sequence that is at least 15 nucleotides in length. Full or complete complementarity (e.g., full complementarity or complete complementarity over all or a significant portion of the length of a naturally-occurring miRNA) is preferred when the desired regulation is mRNA degradation. In some embodiments, a miRNA binding site includes a sequence that has complementarity (e.g., partial or complete complementarity) with a miRNA seed sequence. In some embodiments, the miRNA binding site includes a sequence that has complete complementarity with a miRNA seed sequence. In some embodiments, a miRNA binding site includes a sequence that has complementarity (e.g., partial or complete complementarity) with an miRNA sequence. In some embodiments, the miRNA binding site includes a sequence that has complete complementarity with a miRNA sequence. In some embodiments, a miRNA binding site has complete complementarity with a miRNA sequence but for 1, 2, or 3 nucleotide substitutions, terminal additions, and / or truncations. In some embodiments, the miRNA binding site is the same length as the corresponding miRNA. In other embodiments, the miRNA binding site is one, two, three,   four, five, six, seven, eight, nine, ten, eleven or twelve nucleotide(s) shorter than the corresponding miRNA at the 5’ terminus, the 3’ terminus, or both. In still other embodiments, the microRNA binding site is two nucleotides shorter than the corresponding microRNA at the 5’ terminus, the 3’ terminus, or both. The miRNA binding sites that are shorter than the corresponding miRNAs may still be capable of degrading the mRNA incorporating one or more of the miRNA binding sites or preventing the mRNA from translation. In some embodiments, the miRNA binding site binds the corresponding mature miRNA that is part of an active RISC containing Dicer. In another embodiment, binding of the miRNA binding site to the corresponding miRNA in RISC degrades the mRNA containing the miRNA binding site or prevents the mRNA from being translated. In some embodiments, the miRNA binding site has sufficient complementarity to miRNA so that a RISC complex comprising the miRNA cleaves the nucleic acid molecule (e.g., RNA, e.g., mRNA) comprising the miRNA binding site. In other embodiments, the miRNA binding site has imperfect complementarity so that a RISC complex comprising the miRNA induces instability in the nucleic acid molecule (e.g., RNA, e.g., mRNA) comprising the miRNA binding site. In another embodiment, the miRNA binding site has imperfect complementarity so that a RISC complex comprising the miRNA represses transcription of the nucleic acid molecule (e.g., RNA, e.g., mRNA) comprising the miRNA binding site. In some embodiments, the miRNA binding site has one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve mismatch(es) from the corresponding miRNA. In some embodiments, the miRNA binding site has at least about ten, at least about eleven, at least about twelve, at least about thirteen, at least about fourteen, at least about fifteen, at least about sixteen, at least about seventeen, at least about eighteen, at least about nineteen, at least about twenty, or at least about twenty-one contiguous nucleotides complementary to at least about ten, at least about eleven, at least about twelve, at least about thirteen, at least about fourteen, at least about fifteen, at least about sixteen, at least about seventeen, at least about eighteen, at least about nineteen, at least   about twenty, or at least about twenty-one, respectively, contiguous nucleotides of the corresponding miRNA. By engineering one or more miRNA binding sites into a nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure, the nucleic acid molecule (e.g., RNA, e.g., mRNA) can be targeted for degradation or reduced translation, provided the miRNA in question is available. This can reduce off-target effects upon delivery of the nucleic acid molecule (e.g., RNA, e.g., mRNA). For example, if a nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure is only intended to be delivered to a specific tissue or cell, then a miRNA abundant in that tissue or cell can inhibit the repression of the expression of the gene of interest on a first polynucleotide if one or multiple binding sites of the miRNA are engineered into the 5′UTR and / or 3′UTR of a second polynucleotide (e.g., an mRNA encoding a repressor). The expression of the gene of interest (e.g., a gene encoding a first polypeptide) would be suppressed in tissues / cells that do not express the miRNA. For example, one of skill in the art would understand that one or more miR binding sites can be included in a nucleic acid molecule (e.g., an RNA, e.g., mRNA) to minimize expression of the gene of interest in cell types other than liver cells (e.g., cells in the lymphoid, myeloid, endothelial, epithelial, or hematopoietic lineages). In one embodiment, a miR122 binding site can be used. In another embodiment, a miR126 binding site can be used. In another embodiment, a miR142 binding site can be used. In still another embodiment, multiple copies of these miR binding sites or combinations may be used. Regulation of expression of the gene of interest in specific tissues can be accomplished through introduction one or more miRNA binding sites, e.g., one or more distinct miRNA binding sites. The decision on which miRNA binding site to insert can be made based on miRNA expression patterns and / or their profiling in tissues and / or cells in development and / or disease. Identification of miRNAs, miRNA binding sites, and their expression patterns and role in biology have been reported (e.g., Bonauer et al., Curr Drug Targets 201011:943-949; Anand and Cheresh Curr Opin Hematol 201118:171- 176; Contreras and Rao Leukemia 201226:404-413 (2011 Dec 20. doi:   10.1038 / leu.2011.356); Bartel Cell 2009136:215-233; Landgraf et al, Cell, 2007 129:1401-1414; Gentner and Naldini, Tissue Antigens.201280:393-403 and all references therein; each of which is incorporated herein by reference in its entirety). miRNAs and miRNA binding sites can correspond to any known sequence, including non-limiting examples described in U.S. Publication Nos.2014 / 0200261, 2005 / 0261218, and 2005 / 0059005, each of which are incorporated herein by reference in their entirety. Examples of tissues where miRNA are known to regulate mRNA, and thereby protein expression, include, but are not limited to, liver (miR-122), muscle (miR-133, miR-206, miR-208), endothelial cells (miR-17-92, miR-126), myeloid cells (miR-142-3p, miR-142-5p, miR-16, miR-21, miR-223, miR-24, miR-27), adipose tissue (let-7, miR- 30c), heart (miR-1d, miR-149), kidney (miR-192, miR-194, miR-204), spleen (miR142), lymphoid cells (miR150) and lung epithelial cells (let-7, miR-133, miR-126). Specifically, miRNAs are known to be differentially expressed in immune cells (also called hematopoietic cells), such as antigen presenting cells (APCs) (e.g., dendritic cells and monocytes), monocytes, monocytes, B lymphocytes, T lymphocytes, granulocytes, natural killer cells, etc. Immune cell specific miRNAs are involved in immunogenicity, autoimmunity, the immune response to infection, inflammation, as well as unwanted immune response after gene therapy and tissue / organ transplantation. Immune cell specific miRNAs also regulate many aspects of development, proliferation, differentiation and apoptosis of hematopoietic cells (immune cells). For example, miR- 142 and miR-146 are exclusively expressed in immune cells, particularly abundant in myeloid dendritic cells. It has been demonstrated that the immune response to a nucleic acid molecule (e.g., RNA, e.g., mRNA) can be shut-off by adding miR-142 binding sites to the 3′-UTR of the polynucleotide, enabling more stable gene transfer in tissues and cells. miR-142 efficiently degrades exogenous nucleic acid molecules (e.g., RNA, e.g., mRNA) in antigen presenting cells and suppresses cytotoxic elimination of transduced cells (e.g., Annoni A et al., blood, 2009, 114, 5152-5161; Brown BD, et al., Nat med. 2006, 12(5), 585-591; Brown BD, et al., blood, 2007, 110(13): 4144-4152, each of which is incorporated herein by reference in its entirety).   In one example, a nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure can comprise a repressor, such as L7Ae under the control of miR142 or miR223 which are selectively abundant in immune cells such as APCs. This would lead to target RNA expression being selectively turned on in APCs (possibly other immune cells such as T cells as well), while target expression would be suppressed in cells (e.g., hepatocytes) that do not express these miRNAs or express them at a negligible level. In another example, the methods of this disclosure can be used to turn ON expression of a target gene only in APCs. For example, the expression of a target gene may be desired specifically in APCs post vaccination. This could help minimize any unintended events in bystander cells after e.g., intramuscular dosing. In some embodiments, the methods of this disclosure can be used in other immune applications where ON switches could be enabling / increase safety. For example, for Chimeric antigen receptor (CAR) T-cell therapy, it is detrimental to have the CAR expressed in tumor samples since it can mask the target epitope. It can also be detrimental to express the CAR in regulatory T cells (Treg cells). The methods of this disclosure can be used to turn ON expression only in specific T cells. In some embodiments, the methods of this disclosure can be used to turn ON expression in certain differentiated immune cells for use in immune-oncology applications. In some embodiments, the methods of this disclosure can be used to turn ON expression in particular cell lineages, e.g., hematopoietic progenitor cells in which gene editing is desired, thereby increasing safety of gene-editing technologies. Immune cell specific miRNAs include, but are not limited to, hsa-let-7a-2-3p, hsa-let-7a-3p, hsa-7a-5p, hsa-let-7c, hsa-let-7e-3p, hsa-let-7e-5p, hsa-let-7g-3p, hsa-let- 7g-5p, hsa-let-7i-3p, hsa-let-7i-5p, miR-10a-3p, miR-10a-5p, miR-1184, hsa-let-7f-1--3p, hsa-let-7f-2--5p, hsa-let-7f-5p, miR-125b-1-3p, miR-125b-2-3p, miR-125b-5p, miR- 1279, miR-130a-3p, miR-130a-5p, miR-132-3p, miR-132-5p, miR-142-3p, miR-142-5p, miR-143-3p, miR-143-5p, miR-146a-3p, miR-146a-5p, miR-146b-3p, miR-146b-5p, miR-147a, miR-147b, miR-148a-5p, miR-148a-3p, miR-150-3p, miR-150-5p, miR-151b, miR-155-3p, miR-155-5p, miR-15a-3p, miR-15a-5p, miR-15b-5p, miR-15b-3p, miR-16- 1-3p, miR-16-2-3p, miR-16-5p, miR-17-5p, miR-181a-3p, miR-181a-5p, miR-181a-2-3p,   miR-182-3p, miR-182-5p, miR-197-3p, miR-197-5p, miR-21-5p, miR-21-3p, miR-214- 3p, miR-214-5p, miR-223-3p, miR-223-5p, miR-221-3p, miR-221-5p, miR-23b-3p, miR- 23b-5p, miR-24-1-5p,miR-24-2-5p, miR-24-3p, miR-26a-1-3p, miR-26a-2-3p, miR-26a- 5p, miR-26b-3p, miR-26b-5p, miR-27a-3p, miR-27a-5p, miR-27b-3p,miR-27b-5p, miR- 28-3p, miR-28-5p, miR-2909, miR-29a-3p, miR-29a-5p, miR-29b-1-5p, miR-29b-2-5p, miR-29c-3p, miR-29c-5p,, miR-30e-3p, miR-30e-5p, miR-331-5p, miR-339-3p, miR- 339-5p, miR-345-3p, miR-345-5p, miR-346, miR-34a-3p, miR-34a-5p, , miR-363-3p, miR-363-5p, miR-372, miR-377-3p, miR-377-5p, miR-493-3p, miR-493-5p, miR-542, miR-548b-5p, miR548c-5p, miR-548i, miR-548j, miR-548n, miR-574-3p, miR-598, miR-718, miR-935, miR-99a-3p, miR-99a-5p, miR-99b-3p, and miR-99b-5p. Furthermore, novel miRNAs can be identified in immune cell through micro-array hybridization and microtome analysis (e.g., Jima DD et al, Blood, 2010, 116:e118-e127; Vaz C et al., BMC Genomics, 2010, 11,288, the content of each of which is incorporated herein by reference in its entirety.) In some embodiments, a miRNA binding site is inserted in the nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure in any position of the nucleic acid molecule (e.g., RNA, e.g., mRNA) (e.g., the 5’UTR and / or 3’UTR). In some embodiments, the 5’UTR comprises a miRNA binding site. In some embodiments, the 3’UTR comprises a miRNA binding site. In some embodiments, the 5’UTR and the 3’UTR comprise a miRNA binding site. The insertion site in the nucleic acid molecule (e.g., RNA, e.g., mRNA) can be anywhere in the nucleic acid molecule (e.g., RNA, e.g., mRNA) as long as the insertion of the miRNA binding site in the nucleic acid molecule (e.g., RNA, e.g., mRNA) does not interfere with the translation of a functional polypeptide in the absence of the corresponding miRNA; and in the presence of the miRNA, the insertion of the miRNA binding site in the nucleic acid molecule (e.g., RNA, e.g., mRNA) and the binding of the miRNA binding site to the corresponding miRNA are capable of degrading the polynucleotide or preventing the translation of the nucleic acid molecule (e.g., RNA, e.g., mRNA). In some embodiments, a miRNA binding site is inserted in at least about 30 nucleotides downstream from the stop codon of an ORF in a nucleic acid molecule (e.g.,   RNA, e.g., mRNA) of the disclosure comprising the ORF. In some embodiments, a miRNA binding site is inserted in at least about 10 nucleotides, at least about 15 nucleotides, at least about 20 nucleotides, at least about 25 nucleotides, at least about 30 nucleotides, at least about 35 nucleotides, at least about 40 nucleotides, at least about 45 nucleotides, at least about 50 nucleotides, at least about 55 nucleotides, at least about 60 nucleotides, at least about 65 nucleotides, at least about 70 nucleotides, at least about 75 nucleotides, at least about 80 nucleotides, at least about 85 nucleotides, at least about 90 nucleotides, at least about 95 nucleotides, or at least about 100 nucleotides downstream from the stop codon of an ORF in a polynucleotide of the disclosure. In some embodiments, a miRNA binding site is inserted in about 10 nucleotides to about 100 nucleotides, about 20 nucleotides to about 90 nucleotides, about 30 nucleotides to about 80 nucleotides, about 40 nucleotides to about 70 nucleotides, about 50 nucleotides to about 60 nucleotides, about 45 nucleotides to about 65 nucleotides downstream from the stop codon of an ORF in a nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure. miRNA gene regulation can be influenced by the sequence surrounding the miRNA such as, but not limited to, the species of the surrounding sequence, the type of sequence (e.g., heterologous, homologous, exogenous, endogenous, or artificial), regulatory elements in the surrounding sequence and / or structural elements in the surrounding sequence. The miRNA can be influenced by the 5′UTR and / or 3′UTR. As a non-limiting example, a non-human 3′UTR can increase the regulatory effect of the miRNA sequence on the expression of a polypeptide of interest compared to a human 3′UTR of the same sequence type. In one embodiment, other regulatory elements and / or structural elements of the 5′UTR can influence miRNA mediated gene regulation. One example of a regulatory element and / or structural element is a structured IRES (Internal Ribosome Entry Site) in the 5′UTR, which is necessary for the binding of translational elongation factors to initiate protein translation. EIF4A2 binding to this secondarily structured element in the 5′-UTR is necessary for miRNA mediated gene expression (Meijer HA et al., Science, 2013, 340, 82-85, herein incorporated by reference in its entirety). The nucleic acid   molecules (e.g., RNA, e.g., mRNA) of the disclosure can further include this structured 5′UTR in order to enhance microRNA mediated gene regulation. At least one miRNA binding site can be engineered into the 3′UTR of a polynucleotide of the disclosure. In this context, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or more miRNA binding sites can be engineered into a 3′UTR of a nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure. For example, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 2, or 1 miRNA binding sites can be engineered into the 3′UTR of a nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure. In one embodiment, miRNA binding sites incorporated into a nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure can be the same or can be different miRNA sites. A combination of different miRNA binding sites incorporated into a nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure can include combinations in which more than one copy of any of the different miRNA sites are incorporated. In another embodiment, miRNA binding sites incorporated into a nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure can target the same or different tissues in the body. As a non-limiting example, through the introduction of tissue-, cell-type-, or disease-specific miRNA binding sites in the 3′- UTR of a nucleic acid molecule (e.g., RNA, e.g., mRNA encoding a repressor) of the disclosure, the degree of expression of the gene of interest in specific cell types (e.g., hepatocytes, myeloid cells, endothelial cells, cancer cells, etc.) can be enhanced. In one embodiment, a miRNA binding site can be engineered near the 5′ terminus of the 3′UTR, about halfway between the 5′ terminus and 3′ terminus of the 3′UTR and / or near the 3′ terminus of the 3′UTR in a nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure. As a non-limiting example, a miRNA binding site can be engineered near the 5′ terminus of the 3′UTR and about halfway between the 5′ terminus and 3′ terminus of the 3′UTR. As another non-limiting example, a miRNA binding site can be engineered near the 3′ terminus of the 3′UTR and about halfway between the 5′ terminus and 3′ terminus of the 3′UTR. As yet another non-limiting example, a miRNA binding site can be engineered near the 5′ terminus of the 3′UTR and near the 3′ terminus of the 3′UTR.   In another embodiment, a 3′UTR can comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 miRNA binding sites. The miRNA binding sites can be complementary to a miRNA, miRNA seed sequence, and / or miRNA sequences flanking the seed sequence. A nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure can be engineered for more targeted expression in specific tissues, cell types, or biological conditions based on the expression patterns of miRNAs in the different tissues, cell types, or biological conditions. Through introduction of tissue-specific miRNA binding sites, a nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure can be designed for optimal protein expression in a tissue or cell, or in the context of a biological condition. In some embodiments, a nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure can comprise at least one miRNA binding site in the 3′UTR in order to selectively inhibit repression of mRNA therapeutics in the immune cells to subdue unwanted immunogenic reactions caused by therapeutic delivery. As a non-limiting example, the miRNA binding site can make a nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure that is encoding the repressor to target RNA, more unstable in antigen presenting cells. Non-limiting examples of these miRNAs include mir-142-5p, mir-142-3p, mir-146a-5p, and mir-146-3p. An endonuclease for use in the present disclosure could be effectively any known RNA endonuclease that is sequence or structure specific. See e.g., Tomecki R and Dziembowski A., RNA 2010.16: 1692-1724; and Schoenberg DR., Wiley Interdiscip Rev RNA.2011; 2(4): 582–600. In some embodiments, an endonuclease could be an engineered nuclease where a non-specific endonuclease is fused to a specific RNA recognition element (See eg. Choudhary et al. Nature Comm, 2012;3:1147.) An endonuclease cleavage site can be any site known in the art. See e.g., Mendez AS et al, Nucleic Acids Research,(2018), 46(22): 11968–11979; Zhou W et al Proceedings of the National Academy of Sciences Feb 2017, 114 (8) E1554-E1563; Floyd-Smith G et al., Science (1981) 212: 4498: 1030-1032.   IVT polynucleotide architecture In some embodiments, the polynucleotide of the present disclosure comprising an mRNA encoding a polypeptide, or a repressor is an IVT polynucleotide. Traditionally, the basic components of an mRNA molecule include at least a coding region, a 5′UTR, a 3′UTR, a 5′ cap and a poly-A tail. The IVT polynucleotides of the present disclosure can function as mRNA but are distinguished from wild-type mRNA in their functional and / or structural design features which serve, e.g., to overcome existing problems of effective polypeptide production using nucleic-acid based therapeutics. The primary construct of an IVT polynucleotide comprises a first region of linked nucleotides that is flanked by a first flanking region and a second flaking region. This first region can include, but is not limited to, the encoded polypeptide, or repressor. The first flanking region can include a sequence of linked nucleosides which function as a 5’ untranslated region (UTR) such as the 5’ UTR of any of the nucleic acids encoding the native 5’ UTR of the polypeptide or a non-native 5’UTR such as, but not limited to, a heterologous 5’ UTR or a synthetic 5’ UTR. The IVT encoding the polypeptide, or the repressor can comprise at its 5 terminus a signal sequence region encoding one or more signal sequences. The flanking region can comprise a region of linked nucleotides comprising one or more complete or incomplete 5′ UTRs sequences. The flanking region can also comprise a 5′ terminal cap. The second flanking region can comprise a region of linked nucleotides comprising one or more complete or incomplete 3′ UTRs which can encode the native 3’ UTR of the polypeptide, or the repressor or a non-native 3’ UTR such as, but not limited to, a heterologous 3’ UTR or a synthetic 3’ UTR. The flanking region can also comprise a 3′ tailing sequence. The 3’ tailing sequence can be, but is not limited to, a polyA tail, a polyA-G quartet and / or a stem loop sequence. Additional and exemplary features of IVT polynucleotide architecture are disclosed in International PCT application WO 2017 / 201325, filed on 18 May 2017, the entire contents of which are hereby incorporated by reference.   5’UTR and 3’ UTR A UTR can be homologous or heterologous to the coding region in a polynucleotide. In some embodiments, the UTR is homologous to the ORF encoding the polypeptide, or the repressor. In some embodiments, the UTR is heterologous to the ORF encoding the polypeptide, or the repressor. In some embodiments, the polynucleotide comprises two or more 5′ UTRs or functional fragments thereof, each of which has the same or different nucleotide sequences. In some embodiments, the polynucleotide comprises two or more 3′ UTRs or functional fragments thereof, each of which has the same or different nucleotide sequences. In some embodiments, the 5′ UTR or functional fragment thereof, 3′ UTR or functional fragment thereof, or any combination thereof is sequence optimized. In some embodiments, the 5′UTR or functional fragment thereof, 3′ UTR or functional fragment thereof, or any combination thereof comprises at least one chemically modified nucleobase, e.g., N1-methylpseudouracil or 5-methoxyuracil. UTRs can have features that provide a regulatory role, e.g., increased or decreased stability, localization and / or translation efficiency. A polynucleotide comprising a UTR can be administered to a cell, tissue, or organism, and one or more regulatory features can be measured using routine methods. In some embodiments, a functional fragment of a 5′ UTR or 3′ UTR comprises one or more regulatory features of a full length 5′ or 3′ UTR, respectively. Natural 5′UTRs bear features that play roles in translation initiation. They harbor signatures like Kozak sequences that are commonly known to be involved in the process by which the ribosome initiates translation of many genes. Kozak sequences have the consensus CCR(A / G)CCAUGG (SEQ ID NO: 205), where R is a purine (adenine or guanine) three bases upstream of the start codon (AUG), which is followed by another ‘G’.5′ UTRs also have been known to form secondary structures that are involved in elongation factor binding. By engineering the features typically found in abundantly expressed genes of specific target organs, one can enhance the stability and protein production of a   polynucleotide. For example, introduction of 5′ UTR of liver-expressed mRNA, such as albumin, serum amyloid A, Apolipoprotein A / B / E, transferrin, alpha fetoprotein, erythropoietin, or Factor VIII, can enhance expression of polynucleotides in hepatic cell lines or liver. Likewise, use of 5′UTR from other tissue-specific mRNA to improve expression in that tissue is possible for muscle (e.g., MyoD, Myosin, Myoglobin, Myogenin, Herculin), for endothelial cells (e.g., Tie-1, CD36), for myeloid cells (e.g., C / EBP, AML1, G-CSF, GM-CSF, CD11b, MSR, Fr-1, i-NOS), for leukocytes (e.g., CD45, CD18), for adipose tissue (e.g., CD36, GLUT4, ACRP30, adiponectin) and for lung epithelial cells (e.g., SP-A / B / C / D). In some embodiments, UTRs are selected from a family of transcripts whose proteins share a common function, structure, feature or property. For example, an encoded polypeptide can belong to a family of proteins (i.e., that share at least one function, structure, feature, localization, origin, or expression pattern), which are expressed in a particular cell, tissue or at some time during development. The UTRs from any of the genes or mRNA can be swapped for any other UTR of the same or different family of proteins to create a new polynucleotide. In some embodiments, the 5′ UTR and the 3′ UTR can be heterologous. In some embodiments, the 5′ UTR can be derived from a different species than the 3′ UTR. In some embodiments, the 3′ UTR can be derived from a different species than the 5′ UTR. Co-owned International Patent Application No. PCT / US2014 / 021522 (Publ. No. WO / 2014 / 164253, incorporated herein by reference in its entirety) provides a listing of exemplary UTRs that can be utilized in the polynucleotide of the present invention as flanking regions to an ORF. Exemplary UTRs of the application include, but are not limited to, one or more 5′UTR and / or 3′UTR derived from the nucleic acid sequence of: a globin, such as an α- or β-globin (e.g., a Xenopus, mouse, rabbit, or human globin); a strong Kozak translational initiation signal; a CYBA (e.g., human cytochrome b-245 α polypeptide); an albumin (e.g., human albumin7); a HSD17B4 (hydroxysteroid (17-β) dehydrogenase); a virus (e.g., a tobacco etch virus (TEV), a Venezuelan equine encephalitis virus (VEEV), a Dengue virus, a cytomegalovirus (CMV) (e.g., CMV immediate early 1 (IE1)), a hepatitis   virus (e.g., hepatitis B virus), a sindbis virus, or a PAV barley yellow dwarf virus); a heat shock protein (e.g., hsp70); a translation initiation factor (e.g., elF4G); a glucose transporter (e.g., hGLUT1 (human glucose transporter 1)); an actin (e.g., human α or β actin); a GAPDH; a tubulin; a histone; a citric acid cycle enzyme; a topoisomerase (e.g., a 5′UTR of a TOP gene lacking the 5′ TOP motif (the oligopyrimidine tract)); a ribosomal protein Large 32 (L32); a ribosomal protein (e.g., human or mouse ribosomal protein, such as, for example, rps9); an ATP synthase (e.g., ATP5A1 or the β subunit of mitochondrial H+-ATP synthase); a growth hormone e (e.g., bovine (bGH) or human (hGH)); an elongation factor (e.g., elongation factor 1 α1 (EEF1A1)); a manganese superoxide dismutase (MnSOD); a myocyte enhancer factor 2A (MEF2A); a β-F1- ATPase, a creatine kinase, a myoglobin, a granulocyte-colony stimulating factor (G- CSF); a collagen (e.g., collagen type I, alpha 2 (Col1A2), collagen type I, alpha 1 (Col1A1), collagen type VI, alpha 2 (Col6A2), collagen type VI, alpha 1 (Col6A1)); a ribophorin (e.g., ribophorin I (RPNI)); a low density lipoprotein receptor-related protein (e.g., LRP1); a cardiotrophin-like cytokine factor (e.g., Nnt1); calreticulin (Calr); a procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (Plod1); and a nucleobindin (e.g., Nucb1). In some embodiments, the 5′ UTR is selected from the group consisting of a β-globin 5′ UTR; a 5′UTR containing a strong Kozak translational initiation signal; a cytochrome b- 245 α polypeptide (CYBA) 5′ UTR; a hydroxysteroid (17-β) dehydrogenase (HSD17B4) 5′ UTR; a Tobacco etch virus (TEV) 5′ UTR; a Venezuelen equine encephalitis virus (TEEV) 5′ UTR; a 5′ proximal open reading frame of rubella virus (RV) RNA encoding nonstructural proteins; a Dengue virus (DEN) 5′ UTR; a heat shock protein 70 (Hsp70) 5′ UTR; a eIF4G 5′ UTR; a GLUT15′ UTR; functional fragments thereof and any combination thereof. In some embodiments, the 3′ UTR is selected from the group consisting of a β-globin 3′ UTR; a CYBA 3′ UTR; an albumin 3′ UTR; a growth hormone (GH) 3′ UTR; a VEEV 3′ UTR; a hepatitis B virus (HBV) 3′ UTR; α-globin 3′UTR; a DEN 3′ UTR; a PAV barley yellow dwarf virus (BYDV-PAV) 3′ UTR; an elongation factor 1 α1 (EEF1A1) 3′ UTR; a manganese superoxide dismutase (MnSOD) 3′ UTR; a β subunit of mitochondrial H(+)-   ATP synthase (β-mRNA) 3′ UTR; a GLUT13′ UTR; a MEF2A 3′ UTR; a β-F1-ATPase 3′ UTR; functional fragments thereof and combinations thereof. Wild-type UTRs derived from any gene or mRNA can be incorporated into the polynucleotides of the disclosure. In some embodiments, a UTR can be altered relative to a wild type or native UTR to produce a variant UTR, e.g., by changing the orientation or location of the UTR relative to the ORF; or by inclusion of additional nucleotides, deletion of nucleotides, swapping or transposition of nucleotides. In some embodiments, variants of 5′ or 3′ UTRs can be utilized, for example, mutants of wild type UTRs, or variants wherein one or more nucleotides are added to or removed from a terminus of the UTR. Additionally, one or more synthetic UTRs can be used in combination with one or more non-synthetic UTRs. See, e.g., Mandal and Rossi, Nat. Protoc.20138(3):568-82, the contents of which are incorporated herein by reference in their entirety. UTRs or portions thereof can be placed in the same orientation as in the transcript from which they were selected or can be altered in orientation or location. Hence, a 5′ and / or 3′ UTR can be inverted, shortened, lengthened, or combined with one or more other 5′ UTRs or 3′ UTRs. In some embodiments, the polynucleotide comprises multiple UTRs, e.g., a double, a triple or a quadruple 5′ UTR or 3′ UTR. For example, a double UTR comprises two copies of the same UTR either in series or substantially in series. For example, a double beta-globin 3′UTR can be used (see US2010 / 0129877, the contents of which are incorporated herein by reference in its entirety). In certain embodiments, the polynucleotides of the disclosure comprise a 5′ UTR and / or a 3′ UTR selected from any of the UTRs disclosed herein, e.g., in Table 6.

[0049] U CC UU GCCG CCUCC CCCC CU U GAUG GA ACU AACCC CUC CGC CUG G A)1ACGCA GAUGAGGAC CUU G U GCA U GCAUC CU UC CU GUCU GCUCUGtAnaGU UAU C UCUCGU G GG UGCUGCUGCC AirGC CGa CCGC CUAA UCG UCG UCU GU v CCUAUCUCUUCAU CCCs AUCGGCC GUU GCGUGCGCCUetCCU GUAAC CisACCCCU U CU UCA UA U G UCG UCCAUGCG GCAgUG GCGCUACACUAC CCAni CU UACC CCC C C C U AGCAd AGCUCUCCGG GCA UUC C CUC C CACUnAUAUib CUCAUCUUG GCG GU GCG GU A GCCA ACUA CGAp3ACCeCU UCGUCUCAC -ACG cUne C CG)etuGUiGUC)C AetiGUA A)GCG6GCA CA GU CAC etiGCCCU21GCCUACsGCC C CGsGCCUGCCGG GsAGAU AGCqeU S ACAgnUC U GgnUCA UCGC gnUUCUCC CRiUUCCCC UiCdnCC C C id CCA iCGA G) CCAGidGUCGU mGUCCUGniCGUset CGU GGniAUUGdnAUCGCUAbGA G ACUbGA CUisGA CAGbAUCCGaAUU GCC p3G GCAp3A GCU gA U GCAp3A UCUUp3A UCAUCA A -2GCUU G-6GCC niGCAG-2AGUG -2AGCGC 4 CU2 CUd CUA4U A UA GUAGUAU n UGC C G4C U7 CCGG 1CCUCGCRiGCAG1CCUCURiGCG GibCCUCAU 1CAC C1CAC31U GUCCRiUCCCARiUCCAC CCAGmGCG CCmGC G RiGCU GCG mC U mGUUmGCCGUGhtiAC CUhtiAC C oAC CGhtiAGCGht AGA GAGG wU AGCG wU AGC nU AGCA wUiU AUCG wAUA A AU GCA GC ,GCA GUCGA GCAG AGCA ACACA ACA G s GCAARecUCTUCARTUG CRTUG CURTUGC ACGRTUGG CUGUAU U U UAUUAUAUAUAAUAC CCU G UACA nCC AU’eGC C C3(G UCCUA’G G A3(UCCU’G G3(UCCUA’U G G G3(UCCCGCAC ’U G G3(UCU C G uqesR T U:’O 3NsedcnDIne1a82838485868QuREqesT SUR’T5Uy’r3alpmexE:6elbaT

[0050] U GCCA UUCG UA CCGCUCUCUCUgCC CGC CUC AACUACUCUAUCGGCni C CGCCCGAGCCGAUUdGAU AUGU A U UUCU A GUACGniU GUCUAUG GGCACGbUGCGUCG CCA UUCUUU GA CU GG CUU G GUp CU GCCU GUA CUG3UUGUCU GUA -2 CGCCUG CUCGCUUCC CG4UCGC C AACU GGUU GC CU 1CUUAA AA GUU GACG GCAGUGACCU ACU GG G ACG CCGUCCG U UA CC U U CCUURiU AA CCUmAC AAUCCCUCCUUGUAC G ACCAUGCUGCU1 C UAGC GUGCGCUU UGUU UGC dC CUGCU UGUA nGUAC GG UC AGG)sGCUCUCU)s CUCCU CCasGCC GAUU UCUC )sAGetiUCU)AUUCAetiAUCG UetUC A)UCCAGetAUsGU CCAetiUC CUsUCCUGisGUUetU ACCAGisAGgGCCUsCC CCCC gCCGUCGgGCCUCis ACCCC gUAniUCCC gUCCUGniUCACGni CUC AGgCCGAGniAGdC UnibCCUGniUCGUGdCGUG dnUCCGdn C AGni AGACGdnnUGAUCibUGCG Ui CCGCCdnCUC UGiCCU GAUCGiCUCCG C G UC GUb AG G GACi UUC AU UbU CGp3ACCGbGUCGGp5GUC AAp5G AC UGb A CCG Cp5CA-2GCCCGGp5U -GCUCCUU-2U GCUCCUG-24GCCAUp5- UUCA CU CCG-5A4G UU2AGG4 AG G U5CC5 CA1 UCGG4UU CAA1UUUA UC1 UCCG C A5 CUCUC18CURi CCAA1 GC CUGRiGCACURi CCC1C CGA AURi3AmGCUGRi AGUGU mAGCCGmGCCG URi AUA CG1A UA3GUGU mGU AGAC3GUA AUCA2GUCCmGA CUCAm3GG CUhtiACUCAGC CUhtiA UC UCU CACGhtiA UCCCCACA AhtiACUCAU GCGhtiA UCUCA GACAhtiC CUwA AUGCRAGCGwAGUCCACAwA A G RACUUwAGCGUCARAGA A AGCAwAGCCUwCA AUGAA U U UG R RAURCCUTGUAUCATU AATUUA A UAA ACA AC TU AUCATUG A A UGTG’GUCUU’G GAUUU’G G GCCU’)eUAUU’GUCGU’A(UGCU CGCA G U G UA G A(UCG A U( sUCG A(UCU U G3(UCG3 3 G 3 ti C 3UAACC U3(7888980919

[0051] CCU GGUgGAU GAUCA U GA GiCUCUC CACA CU UnA GCCUGCACUCU G GCUCUCUC CUAACGdnGCCCCCCGCAGCCGACUiCU UCU UCU ACU UCU GUUGbUG G GU CG GGGU UCG U CAU CC AA p3CCCU -2GCG ACGCAUU ACG AUU UCG GUUC CUUUUGACU UCG CGUUU GCC U4 CCUC GCAGCU GCC GAAU UCC A1RAC CGC)AC CGC)GC CG AC)GGUC CAUU GGCUCUC AGCCGiUAmCGCnoi CCG1 AGCC tr CGCnoiU AUCnoi UC CG U G AGCeUGCC tre CCCC treAUC CCU CGCUCGUU CUCdCU n AUAsnCU UAsnCACAsG n UGC A CAA GAUCAG U UUCAG aACiCs1G UiG e ACGCCPGC2GAUi3UGUU G UCGCCPUAGCCP CUCU)GCU)eUUseUAGCC tiUCCCAGtiGC CG,eGC CG,eGACG,e AUUC C tiGU CGsACG ACCGsGC CCCAGti GCAUGgnAGAC s CGCG ti GGCG tiCCC A sGCACG gnUAC s CG AAC sUCGCAUidUUCGgnUC CUC gnC CACidCUCUGniGUCGGid C UCGgCGGniU dCUCGgGGniU d UC CCGidUACGniGGUGni CAGGbUAU CCCCAbA CCGpAUUGniCUUGniCG AUGniCUAUC b CAUGpUCCUbGU CCUbGACCUbGU CCU CGpGGCU3- UU C CUCC UCU 5- ACAC55UGUGpUA3A - GCUGpAAUGpUCCGG5- AGCUG24GGUA3- G A3GUU -GUCUG24GAUA1CCGACCU1A  C CGRAUACAiCU CACG2CU4UC CC1 UU CA CG2CU41 UA CC CG2CU4 AU1UCCCGU AG1GU RCGRi 9iUCGCUm3URiGCCCURGCCCUR GAGUUA GACCUg 1GAUCCA Am2GC CGmGACGimGUCGiGUGGG UmGACGniACCACUhAGUAhACAUAhACCUAmhAA CUAC3AAUAdUGCAAtiUGCAtiUCAtiUGCAtiUC A CUhtiUUCAulAGAUA AwAU GCAwAUUAGC CAwAGCAwAGUCCGwAA UGACGRAGU CURAAU CURA U GCURAGUCCAcni UCARACU CURAGGCCUTU A UUAC CATU UACACA ATU A U ATU U U AUCAGCCATU AUGAU AAUACA ATGCG’)eUC’C’UC’ ’UC U’UC CG GA G U(U ACG G G U(UC CG G UUU G G U(UCC G A(UC CG U U AC C3(tisC 3 3 C 3 G 3 CG U3(293949596979

[0052] CCCAUCC GAUGCCU CG GA CAUCAUCCG ACUCUC CU AA GU UA CCGUUCG C GAA GCAG)UU2Ct GCAUCCGCAU U GA U U UA UCU GCUGnUCU UCGU UAGUUUGGUCAaiUGUCUA CCGCCGC CC AGrCGCGUCCUA UCG UUA GC C aUUG UG GCUAUUUCA CAGCUCCUUGC CAAUGU vUUCC CCCs CU UCG Uet UiC CUGUCACUUAU CCGGCGCGU ACCGsGU GUG ACUGCUUCU AUGCAgACA AUG AA ACCAC CCGniUCAC GCG CUCCCCCCC CCC CUAGCCA AdCnC C U)C3U CCCC )3 AG CGAC C C CUiC CtC CAtCU GAU GCA G U AUAUbGAnUnAU GA)eU GCU)eU GCG)eACUApU GCCairGU G GairACUAGCC tiUCGtiUCA CtiACGCA3- UCAavUCCG avACGUCGsg GUCCC sg GUAsAGgGC CG U62GUAC eGUC eGCGACGnGCCGnG CUGnGCGCU1 GCA GGtisGC ACtisGCCCUCACid C CA Gid C CACidAUA U Ri C CGGg C C CUGgAG U CUCG GniUCC CniUCCG GCAGniUUC CUCACniUCCGniUUUb CCGGGb CGGGbGCG m UUdCCGUGd CCGACdGCGACG Up3 CG- GAUG CGp3 C- GAUGpU3A - AUCGnCaGAGGnGiCbGAUGnGiA b AU ACC 2AC2ACU2UCGCACUUGCUA4GCAU4GCUG4A UCUUp3A GCAUp3A GCAGp3ACGCUG1GCCG A1GCCA1AGUG -2GCAG-2GCUU- U 6 AG UCC URiUCA GRiUCUGRiCACA4UCUA G4UCUG A2CA0 CCGC C CmCC UCUmCCGUCmCUCGC1CCAU 1CC AG1CU41GUCUgGCAC gGCG ACCGniGU CCUniGU CUAgUCCniGCCARiGCCCRiGC CURiUCGCUCUmGCCUmGUGCmGG UCUAdAGCAulACAGdc UGAAulACGc UGCAdC UulA c UGUGhACUUCGtiUGCGhACCAtiUCCU GCGhtiA UG U AGCUAni AGAAni AG G U AGGA ACCCnAi A AGCUCCwA AGCAwA C GCA ACAwA CA AG UUCARUUGURUG UC CRUG C ACGRTUG CURTUG CARTUGAUCCATU’AUAATU’AUAATU’ACUCCUG U’AU UAAU’AU UAUUACU GCG G UA G UA’UCC A U3(UCC G G3(UCC(G G A3UCCCGCACG3(G UCCUA G G3(G UCCUA G A3(G UCC 8900103 4 59 9 1 1010101

[0053] CU G CG A ACU GA GCUCA CCUCCGC CCCUC ACACU CU CCGG U UAGCUACUGCUGCU GUGU GA UCGCCUCCUCCUA UAAU AACCA CU UCU CG)2GCU CG) CU 2UCG) C2UGCG GUCG G GACGUU CC CCAGCG UtA n ACG UtCnUCG UtCnUUU GUC CCUU GUAU C UCAU CG airAU CG air UU AG air UCCGCGC CUACGCCCCACCA AC CCavU AC CCavCGC CCavCGUU GA CAA A CUAAUCC AC )2 UG GCnG oCGCnoAA UCnU o AC AUCCCCU)2UCCU U C CGGtn CAGC itr CGC itrUCC itUC AU)UGUACtnUGCC CGGCACai CUCAe UUGraAUCUCAe CCAC rAe CCCCU 2tAGC G ai AGU UsniGUUsniGC sAUniGUA nC aGGC AraC GGCGGGvsACACG1GCCG2GAG3GCC Gir AUUU UCCvsAU UCCCAGetA i GCC CP,UCC CPUAC CPUC AavUCCU AGetUCCCAUs CCGeCAGgGtGCCG,etGGCG,etGUUetU ACCAGisU ACG AGCAGisGGCG isGGCG isGCCUCis ACCCC g ACA CUAniUU CAGdC CnGg CUUACCGg CAACCg CC AGgCCGAGniCCCGUGGniCC UCibACUC UU GGniCU G U GniCC AG ni AGACGdn AGCGdC CUGdCG G UGdCGCACGdCUC UAGibCUCUCUpAUCUniGUCUniGACUniGACGni U UCU CUGpUUCAUG3CCA-2AUCGbAUUC C CGbAACGbAC UGb AUCUCCA5- AUCCC GUAp3GGUAp3GA UUAp3GC AUp5CUCCG5U CUU ACUCA41AAUG-2GAUG-2G  CCA AUG-2GCUG-5CC CCU51CCAR CUCCU4U U CCU4UC CCU4UCCCA5CGUC ACRCGC 14ACUi CCAAmUC CC1CGCCC1CGCCC1C CC CG1 CAAA CUiCAA1GC CURiU GACRiU GUCRiG GUCU Ri AGUUCGmAGUUAUA G3AGUG AmACUG AmACUG AmAC ACUmAC UCA A3ACCAG htiUGCAht UACAht UCCAht UC CGht UC ACAhtiUCAACU UwAUCAiAUCCAiAG GCAiAG GCAiG AGCCG UwACGA GCCU RAG GU CUwAAU CUwA U GCUwAGCCAwAUGA UARAUA G AACCUTU GUCUCARUC CARU ARUUCARUGAATUGA ATATUC T TUGUG’GCAU’ACAU’AUCAU’AUAUU’AGUCGU’AGG G G U G3(UCCCG GA G U3(U ACG G U3(G UCCCG G U3(G UCCUA G A3(G UCUAACCU U3(G UCU A 607 8 9 0 110101011111

[0054] C U GgC GnC CA C CGCGC CA C CGCGC CA UCC UCCCCG C U UGU CUGUCUAU G U GA GiGCU GCU GCACG AACGCUdnGiUAU UCU U UA UUA U UU Ab CUCG GU UU UCG ACU GAApU3C CGCUUC CGCUCCGCUU UUU UUU AAUCUG G U CAUACCUG G CAUCA U -2 CGCG G UGCGGGCGCA UA 4U1C CGUGUCGCUC CUC CU AC CC CA AC CCGAA ACCRGU GU GU i UUG AUG AUG U UC CGUUGCC CUUCCCGACA UCA UCACG AGCGCAmCCCCCG ACGCGGCG UG U1 CCCCCCGUCUGUC CG UCdCC UCC UCCAGU GUAG AG AGnaGCGUCGCUCGCUUCU CCACCGGUCCACCGCU CCsAGetCGiUC AG UC AG UCG G UCCC U GCACCC UG ACU s GC CCUAGC CUAGCGC GC CGCAC CCCGCACUCUAGgGUni CCC CGUCUGCCC CGU UCUGCC ACGCAUG GUCCAUG G GCUC CGCG U UGdUCCUG AG UCUG U UCG CAni C CCCG UGCC CCCG UGCC C UCC CGCCCU CA UU U G UUCCA UU)GsAU CbGU GU GAC CUC CUeh C UCGpG G G G G G) G AAAG AAAG AU)UC AA AUC AActC CCUC5- A GC CG GC CG GCUG GpA GUC CG UUC CGaACU AU55GC CU GC CU)GGCAU3- GCUGUC UCUGUCmAUCG1 UC AGU C AGAUCUG62 UGA ACUACGACUsiAC 2 CCARCi C CCCAA))C CCCAAT- C CCU AA1RCUGCCCGGA UGCCCGmh AG A4A G1CG2G G CmG A2CA22GC CGiGCACACCACAti CU A U AU2)AUG CAC 1AUUG CAC1r AUU mG CGC (ACA G GUCCA G CA)A U GCAwACC UAht Gi2tUCCCURimUCCCUimUCCCU1.1U G AGAUst6U G GGCAUst6UG AnAG G AG G(AG G A A A A AG CGwC R airAGCCA ( RAGCCARAGCCAvRAGCCAU GA21U RAGCAU GA21RAU CUaUG A UG ATUG A UA G U G U UTAUv’ eAUCCUC3(tisGCATAUCAUU’GCA ACCATAUC CUiAGC CUiG A AUU’U G AUU’GGUUUC U A3(UUC U A3(UUC U A3(U GCCCUmx CU CCmxGA A U3(G UUCCU A A U3(G UCU 2131413 4 51 1 1414141

[0055] ACUC CCGU U U U GA G UUGGUUCU G GCA AUU GAA UUU G UUGAUGCACA G AGG AGUU A CG GGCCUCUCUAU GC CGC CCG GG UUG ACCCU A UU AAU UA ACUGAG GCCG UACGAUUCAAU AUACUUCUUUCG UGUU G ACGCGCCCUGCCCA GACA UUCCC CCCUCCCAAACAAGCUAAA UAAA C ACCCCG UA GU C CCAC UCCU CCA GUA AU GUAU C G CUACUGCCCUG A AGCUCGU G UUUCAUAG CUUUCUCGG GCCU G UCGCCU GUCUAGCUGUCUAAG AUAAG C CAC G G GGUG GUACUCAGUACAAA CAAGCUAA CAA GC CCUUCGCU G AUCC CGACUCGGC CACAAGC CACAAG CUCUU CCCGGGU CCCAGGCCCGGCCG AAAGG AAAGG CGG GC CA ACUC CA UCUCAUG UCU U AGCUAG A UU UGGUCG GCCG ACG G G G AGG CCG AUGGCGCCUU U GU U AGU AGAUAGGAUAGG A G A GCUGCACAUGACAUGA CAGAGCUCUU UG UCCUU U UU CCAG UAAUA UAAUA CCCG UCUCG GGC UCCCGCCC ACU CAG A UU CAG A UUC AA GC CUACA GC C C CGUCACUCAG GUGCUCAG GUCCCCUUCG UCGGUU ACG GGU A GC CGUUAUC A GUCUUACACG AGG G AGG G A G A G C GC CUCGGU A G GAA G GAA UA AU UGACCU GGGACU GAGCCA GAUAA)stGAUAA A  C CCCUCAG G AC UGACU A GC CAU CGUUGCAUAUCA05 UAUCA34GUC CACU GCGC CUGAU GA1 CUGAU1CUCCCA GCA CGCCA GCCACCA CA)GCGACAA GUA GAGUA UA GUGGARiGUGGA A)A G U)A G UsACsG AsG AtAAA G)AAAGAmAAAAA AtU U CCG AtU UaUGstUGxUG U2A UU G A0A UA0U AUCUaAAACUU3_AAACU AA21U C A GG 51AUUGA31G ACCU01AGACUhAGCAU AU G ARU GCGRUCACCGRGU UCU RUGUAUciA UGU UUGGiU AGGCiAAC U AUCU ACiGA AAAC CUiAGGC C rUC CCmC CUmCUAG UU AGGUU G UxG AxGGAmxCUC(GCGGmxU U AGC GUGUG GU U G(U U U A G(U UACUG UCU3(UCAC C3(U U U3 3 AA G 647 8 1 2141415151

[0056] UA GUU A GA AACA A AA U AA AU AA UCCU UAGGCACCA G A G GCUCU GCAACGAUCA GGAG A GACA GAAA UGG GG AACUCUACA UA A AG AGAACUCAGCGAACACAGGAU A AUG UG UGACU AACGAACUA GA A G UGAAA GAGACUACUU GCU A A A GGAG A GCUAU AACACGGAUC CAUGA A AGGUGG AGA A G AG AAAA A GACAACGCU UAGGGG AAUG A UU ACAUAGA UU GACAU G U CACUAAU UAG CAU AA A AAGU AACUA GCUA G UGACA AAA G GAACAAAG AUCGAAGACAGAA UUG CUAGCAA G UCA AAUG U GUAUUGCCA GGCUG U ACCUAU UA AG AGG AUAAAAC CAACAACU AAA UCAUGA AAAAUA CAAA U AUCAAAU A U G AU AUUG G UACAC CUU UA UUCA UCA UCAAG UUAAA ACUCU ACACCUA CUUA U U AUUAA A ACUCU AAU U AUCAGAUA UUUAC UAGUCGCAUCAG UAACAUUAA GUA GCAAACC CACACUUCAU CA AUGCCUGC U CA AUAUCUA GCA A A AC) CACUCGU GC CAA AGCA AGCU UA ACACU G)G A U AGCU G G AAGU A G)G UUCAU)mU Um GUCGUAAU m UACU m mAG AA _ GACACGmAAUAAUG AAUUUUU mAGAGA A ACm s U UA t GA AGCGA UU U G A AG_UU )AUACG_GAUAUUG_0 AUUstGAUAACGstGAUACUAstGAUACAGst4 5 UU UUG01 CUUAAUG5 UUAACUA21 CACAUGA4 UUAAUGA21 CACAUGU 4 UAU GC C 61 CUUUAAG2141RiGAAAAUURiGUCAUGU RiGUCAAUCRGAAAUUGRmGU A AACACUCG mGA AAAUCGAAUAGUiGUCAACGix3UACUA A UA U Ax C CG mxAC CAUCGmxAACACUUmx_hAGAC AGA UA AU G UA A A U AU UGG6 ACA6 AACA6 G ACG6ciAAUAAUU_hAUCAAC_hAUCUUC _hAC CAUUA_hr UGUAGCUciA UCAUU ACA AciA UCAAACAciAAAUAGAciAGAGrA UA CrAUCUCUrUUGAAGUrU UGCGUAC C CUCU AC CAAAA AGCAUU GGAAGA U UCU A(A GA U U G U U G AA(U AACA UACAA U AA(GA U AACUCCUA A A AA(G UGCAUA U A UGCU GA(35455561 1 151

[0057] CU AUU CCAAUAG UUU AGUACA C AG CA C UC CU U CA CUCCACG CGUCA UAGCUCAUAU GCCA U A GUCU U AGC CACUU U CUCGACUUCAAUCCACG A CACA UCGUAU UAUCGA UUCUCUA UUACU UCUCACAAUCG UAU A UAAGA ACACA UCCA GCU UU A ACCAGC CU UG ACCU A AUCACU AUA UACAGCCUAUA ACC CA UUAUUU CUCG UCAUCAA A ACUC CCUCUC C CA UAUAGAAUA AUCU UA G UU U AAUAACGACGCUAGUA CGCUA CGACUUAACUUAG U AUAUU AC CUUUUUC C CUACCG GGUAAAU)UAU UAUCU AUUAA A GUA AUUACCUUCCCUCCA U ACACG m U mACA AUUAC CA CA AACGC CA CGAGUC CAAAU _sA AUCUCG A A ACAACG AACU UCCC AUCUC ta AUAACAUA U UCU UAAUACUAU UCG UCAG GCGC C CGGU G)sUUA tAU AC 0A G31UU AUAUCU UAC UUUCAUAUG UUAUAUCCCU CCAUaCA GRAUAU ACG AAU GCG UUUi CA ACAUACAUA UCCU CUC CU0UAA CCUG31CAUCU UACUA U A UAUGRCAUACA mCx2 CCAA AUA UCA AUCAACA U) CAC AA CU CCACACCC A AA GC i +UAC )U AUCCUmGU A AGA mGU A AGCAU mG U AUUCG UmAUUUCAGUCGCx2G G AUA G A mGAAAUUCm G G_GCG G mGGAGCA GCUUUGACAC+sG AUU A_sGAUAACGstGAAU A_sGAAAUAAGt6UAGCACUt UAUAGACCa UACU At UAUAC 5 CGGU CC CU2CU U AC 62CUUUAAG03CAACA CA22CAUAG41AGU1G A AUUACG1GAUAUUG1GU UCU1GUUUA GCUUACRiGUGUA GRiGUAAAAGRiGA GAARiGAUAU AG U GUCGmAA AG AAGxGUC CmAGC2UGCUAGx2UUCACUUmAU AAUCGxAUUAmAUA A AA6UCUUAxUC CCACAGC CAC _hACA UUG_hAC CAUUA_hACAUU3_ACAAU ACAAUGciAAC CAGciAAGUAGAciAU C UUhcAUCAU UACAUG GrUU AUCACUU ACGrU ACGUAAG AUUU UA GU UACAC CACUU iU U GCACAUA AU Ur rAA GGUC U U UU G G A UCU UAUA CG A(U UCG UCG(UCUUU G A U A G(UCACAU U G A UUC GA(UGC U UA A G A AU U A 758 9 0 1151516161

[0058] U G CGG A GCAAGUG AC+CUCUCCCUACU CCACCC UCCU UC A GACGAUA RG G AGCG GG G G A A UCUUC TUUU GCU AAU)UU A GACCUG AACA A UGA G A UC ) CCU CG)GU GCG UstG UUCCU GAUAUCCCCUC'3 CUCG Ust6 CACCGst2AGCUG05CCCAUACUCGCGCAAUCCC A0.AAU UC 2UCUG2A1UCAUU G AUG21GUCUA1CGRiACCU GU A GGCGCAvGC R A CARG A GUCU AUCG AC(GAGCAGC CGiCAmC C CCiCmUACCm CGxUACU G A ACU CGCU AGUAGCC CCAx3ACGACC CCU x3U GCCG3_UC CCC CU GGCGG ACCGUU_C2UGUC_GCGUG2v'ACCGU C GGUGC ))GU UCCGCUGCGv'GGC A2v'GGCCU U3(AGCUG C UUCGG2XACCA UG GCGCGUC3(UGC CUA 3(AGUG AGCU A UUCCGGAC 3U P GCGGG AU UU UC ACCC CACUCGCGUUCC GCCCAGCACCA CAU U UCC CGA CU CCUG U ACCCGGUU UCA G C GCG ACG / nAGCA AG ACCCUCGC CCCG UGUCCA ACUCCCC U ACGGAG UUoitA UUCUA G UCGACGA CGUCGGCGCG GCCG GAUCGciAUCCAUUCGAUGC CGAAGGCA GCAGCCCGA UCUUAG GAde CCUCCCACUCCUGA AUCCCGUCUCUUGUCC A)ACA GrUU pCUUUCUU GGU CA UUA UCCAUAU CG GGUU CCmU GUACUClaCm_GUCUAUrCAu GCGtGGC CAC C CUG AC C C CG AC C CA CUGAC CcGAACCA GU A GU CCACGGU GUCCA AGGU GUC CUAUGUCC G AC sUGCUCGUUGCUUGCUUC CU AGt2 CAUAAur C tGCCCCU GGAGCGGAACG GGACUG GGG64AGUC21AUUAAsR(CCAAACAG CCUCAC CCUCAGCCGCAU1i CA A GCAUpCGCA AUCUCCG ACUCCG ACUA A GCACUCCG GmACU U GGAAs_ CCG G AG p3C CACAC C UCAC CGCAC C ACGx6UGAAAst UUACU U-C CU GCACUCGCCACUCGGCUC CGCUGU0GC24 UGCACAUG U U_hA G GG 51 CG GGGCUC1 CG U GGAACGCAUCGUUACGU G AGCUCAUCGUAAGUU AGUU GAciGArUGGCURiAUACURiA U GA GAA U GCAAGGGCGAGAUACUCUmxA U G ACG G GmAGC CGA UGGA G UA UAGCG C GCUUG UC CA ACU3UCUC CU UCG UA U UCU UCGCUA U A A U UCA GCA(UUC GAC U3(U GU X U C CU A 26364 5 6 71 161616161

[0059] C CC G)U GUUUsCtCU C G UCU AAGACUC AAA UCU G U)AAAU G)GsA t UCaCG0GUGG AU GGAA GAAGA AC CAA UAmAAAG UAA UaUAUA1ARCAU CG)AAA UGACG A A AGAC C CAmAUUUCG G0G 3 GAUUiU U G AGCG3A2CAGAGA UGAAAU24 ACUAAGG1GACCm CGxGGUA2AA AAUG A G A GUGA ACAC 1RAUA AC CURiA A CG3_ UCGU CCRiUCA AG A G AAU GAGAAiUAACACG C AmC C CA2G AmUA G A GACmU G Cx3AvACAAAGA AAU AXACAAG UCCU CC 'U A3(AC CGxU3AUCAAUAAGAGA6cAAUUU G_2 CGCUCAC C_U UC 2UUAACAGCAAUG GAAc_UCACUAG Uv'3UGUCGCAGCAv'3UUU A UAAACAACAAUGaU A UUCA U A(AGCU GCA(AA U A Gpp AAA GGGGCAAUCG UAAAGACAA UCCGU UCCA GCUUUACC CUAUUAA AGAUCAAUak'UACACAG GCCCGG GUUCAG GCA AUGUCU ACG A AACAG3(CAAA GU ACUCGCGU AC CGC CA UA UUU AA GUAAG G UUAAC CA UUCGG U UGUCAUUC CUG UG U U AGG AA ACCUCU AGUAAU AACA AGAA UG UG GAGCAAGCG AUG GGAUUUUUACAUUAAGC GACU AGA UUAUCCAGGGCAUGA AUA AACCG A UA AUGU AUCGGA AAAU CGCUCC AUGU GUCUGUCUU U AAU ACCUA A AAGUGUCUAAA CAAC C CCGA A AUGUAA G GAA CCU AUUC CG GCG GGU UUGA A GG UGUU ACGGUCGG UGUCAAUCU)GAUUU UGAAUGG ACU)UCGCUCAGUCCG UGCACACUA mGA AGG UAAC CAGACUAUm AUGG GAGCAG GA UUG U AAAACA m_GA UUAUUAGAGUUm_7 CCG CACCACUGCAG CGCCUCCAC CGG UACCACCUCCUUCAAACA2G CA41CCAAAUGUG UCCAAGC UAUC 241UC C CAUU41CACCAAAC CGCA AC AAUCGCAC C CUCUCURiC AAUAGU GC AAUG GRiAUG GUC CC CA AA U AAmC C CAUCAC CAACA AUm UAUCG UGUUGAGUCC CA GA AUCAACUCCUA A AX UCAAAACAUCAAUG XUG U UA AGAA C G GAA AGUCCUAGA GCU6CGAGACUC_GUAUc C CUU ACAA AACUCAGAUAC 3CUAGUUCC_cC CUA UACA GACCA UAGCCUAGAAA U Ac2v'ACUCAAAAAGAAC c2v'UCACUAAGA U G A U U U G ACACACAA A U UUC AA G G G A3(U AACUCCU AUU A A A U U U GCA3(8696071721 1 1 171

[0060] UUA UCA UAUU A CUAUC C A C G AG G AG GG GAA G CGAUGUCG GCGAUU GA CAGGUUU G C GA GU G AGGGAGGA AG A) CUGCA CAUCA G ACACUGCA CAUCA CA AAUCAAUCA G mCUCACUACA AUACCUAUACU C GAUG UAUAAA m_AACGGCAU AACGGCAU C AUUCACUUCACGGCU GGstUU GUA CAAA UU GUA)CAAAm UAG AC_A 2 UAG AC_A 2 UGGAGG05U ACAUGA U ACAUGA m GA A A A G GUAUv'G Av'GAGU GGG1UA UCGCU)sUA UCGCU_sUUAG3(AU U UAG3(AAUAAURiUUUGCAUt6AUUGAUt6CUUU UAC CUUU G AUAC C CU G AAGCAU ACGmxA6CACUA UAAGG21 CAAC CUA AAGG 21A AUAUG AGGUCGCRUUCGCRCAA ACCAAGAC C CAA AA GG ACCAC C CU GGUCUG_hCUUUCAiUmCAUUCAim G AAAUGAcirAACACAAUxACAACAAUxA UAA AGG AAA AGG ACACAA ACUAGUUCUG6_AUUUCUG6_UCUAG U UCUAG UAAACU AA ACUGAUC ChcUCACUCGChcAUA U UA U U U GAU GAUCUUUU_U 2AUCAAAirU AUAAAA irCA A GG AGG U ACAU ACAGA UCGv' CU AGUU UCUCU UU AUCU U CA G AUA UA G AUA UAAACCA3(UACCAGAU AUA_UACACUUA_UU CCAGUU CACAUCCACCAACUCUA2CAA ACUAUA2GAAGCGAAGC CGUUGCUGCGAUGUUv'GUG3C(GAUU AUv'3(GG GU GUGGU GGCAACGGUACAU GUAC CU G G GG G A AU G G GA G G A GA G G A)GAU A AGCAGGG AAACGA A UGACGA AACGGA A G AA GA A UAAmGAU UUUUGGAU UACU G UUU UGA ACA G8 CAUCA G CUGAU)sCAU UGCA mG AU_sCU AUAAUGG C AAA UUCA UUAG UAACG U CGCA UUAG UAC C4AG1At0 CtC CUCU C GUA AG A UG U GA5 CC U U0GGA5 CU A ACACUCGCAAAU G A AU G AG CAUCAC CUACU A A1A A1A AACAAAG GC CGCUCA AACCG U CURiUC A GA RiUCGAC GA UGUCACAUUCUUCACAUUC UACCU G A GAUAAUC GGC G AUU GGC G GACUmGA mA AAUU AU xU UUxU GUAACA AUAGAAACA AGA AGA AGUAG AUAGA AGU AGGC C 3_AGU UcAGGC C 3_AGAUG UCGAU AAG AU AA UhUhAG U GGUA U Gcr AGAAGA AG U U G U U G A U GCAUUCAG A U A G U U GCAUUCU U G U GirU UiA U A G U 374 5 6 7171717171

[0061] CUCA CUUG UC ACAAGAUUGC AUUCAGAA UC CCAGC CAACU C UACG UCG CUUCUA CUAUUUUAGC CG UCUCA U AUAG UCA UAA A GUUU UAU G GCCG CACCA CUAC CAC CU)UCACUA UUCA AAG U UCG)AAU CACG CA UACG UA AU UAGAmUUACUC CACA UCCAstU U UACmACAUACAU UA aUACA U UUA_UU U GC CUA AGCC CCA03AUCGCAUAAG UCUstCCAGCC AC_CUAUAA)UC CCCA AAU U1UUAUACU UCAUaAA U AUC 0A A2AC CACAm U ACUAARiAUAGAAG CUAAG CGU31AUA UAUv'3 AA CUC CU m_GCUAmCAUUAA AUUCUCRCiG AUUU( CGUU ACUAC stGCGCGUUCGx2UUAUUCUAU A UAAAmUUAACGUAUCA2UAC 2A AU C CU U+stCCA AACU ACUUACCGx6CAAA GCACAGC C 1R CC CAU6ACG AUU)AAUCUAU_ACCA AC CAACCUACUCiUC CC C21A UAAUCmA UUAUAUhciA A UAACG AUAUUA mxU AC CCGGURiUCUUAAm_s UACUCUArUCUCG U G UCAAGC6_CGAUG AA UUCCCCGmAUACGta AUA U UUAUCUAUAUU UACCCUA hcUx2C_UA G AUUU03CA 1 UA A ACA AUCA_CU 2 UAACUAGCUA U A A A UUACUirCUUGCACUCA UCACACA CGU CCCCUGhciCAUA A Ri CAUUAUv'3A (CAC AACCAAC CU A GU GU CCUrGA UUC CUmxGAUACU A U GACGC CUC GAUA GC CGUAU_2UUCUGGAGA A G A UA_ 2G AUUCGGUUUU GUUCACAv'GGAAG A AC C_AAUU2 +G A A GG UAAAGCGG)GGAGACC3(GAG AG2GAG AUv'mGAUAGC CGA AACU UAmGAA A AUAC 9 CUC CUv'G CCAGU3(CAC CU3(mG CUAAUC_st CA C UUAAGG UUAUUGCCAAAA mG U A ACAG41UCCA_st CC U U AGCGCCCGUUACCAUACG6U GUCGCUGU2 CAAA AACAGCAUCU2U 2CAUUAA ACG CAG ACA AAAGCUCGUCGC1 CAGRiUUCCGCAUUUCUGAA A1 CUA U AUG AUCG UUCAUA RiUCACAACCG GGCCAUGGGCCU UGmGUCAC A UAGAGCUCA A mGCCAUUCU AAACAUGAAACUCAGx2AAGAAGUACA U CUUx3ACAAUUG AU AUCUUGAU UUAGU A UU_hACUAUUCAUCC CU_ UChACAUAGA G U GCACACG U AcA r G U UCUA A G UGU C A G UACAUCA A U UrUACCCAAGA U G A UCG Ui ciA U U U 8797081821 1 1 181

[0062] UUCAC UUUCAUA GA AU A G AU GCCG U GACC CA A GCAGCACA GCGACG AACAAACAAUCA GACU AU GGACACAACUGU CAAUU GCA ACAAG UUAU AACA AA AAG UCAGGCUCUUAGUA A)AUUCAGGACGGCUAG UUACUACCUA AGAmCA AGG UACCA UCGCAUA AUAGA))A U UUAUG UAAUCA U m_A A AUUAAUAA UC CUUUUCA UUG2CU XUAAA GAGACAsA Ut3UCAUGAAAACGACUU GU GUAAC 3UCUCUPACCCA ACACUU UCG AAU A2AA UAAU UUCUUU GA GCGGCG / A n UAG ACGAUGAC C 2ARAUCAU AAU AACU AC CAC CUCUAGCAAUCAGiU AAUAAo mUU G UCAU_A 2 AUUCAUC UAAit AUAGU UUAA U AU U U GUx6 AU Uv'U AUUUCA CUAUAciCA AUCG UACUUACC _ CA AAU UACU3( C CACAUU ACCAAUdeU U A AAAA AAA A UUAAhcUAU A AA UGACAUUUUG A GAArp CA AU UGirCUGAGG UGCACUUA ACAAAUAUC CU U UGAUAlAUGGAA GarGACCUU AU UCUCUGUAAUCGC)UUAAUCUGCUutAUG U A UA GUAAUAU A_AG AUAG UAAGmAUUUGCCG GGCUcuG G ACGA) CU G AUCAU2GAUAUUG mCA UAC ACCU U CCUCUrtGAAUAmUAAAUUv'3GAU U UAAG_CsCAAAAG CUUACs(UCAAUA mCCAUUAU(UCUAACUCUt3 CGUUCCG U GCGCGCGGU GpsGUAUU_sAtGAUU GCACGACAUUG22GUAC A GGGGUG_sGCA AUA32GUA A AUUGGUCAUGA A ARCACUC CGA GU A GGA ACUtGGACG05GAG CUA2CARiGAUAUAGC GAA AGCGCAUA AGUiGA G UAUCAG ACA AAUUCmx UAA A AAC 0 CGCUA1G CUAUGRiCAUAU C UmG U AUUA G UG GUUUUx3 CCCUAGU3 CUUUUAUUGCCCAAUCCG_sGC CUCCC51AAUCA CCCUCAm U G3CCUCAU UUC _CA AAUC A UCACAt3GU A U GCGxUhc CA UUCAC CGC C CAUCA22AACCUACA CAGCG_UiAU A A U GCG2UCAACAGrUCACUA AUUCAACU ACURiAGAAU GGAUCUUv'A G AAGUGCAAC GA UA GAAC CA AUAmACACA UC CAC 3 AC U G GAAAUC AGAAC A GAA UUGAACA AG U(A UU AAxU AGC CUGCAAUAGC_2U v'AUCAUGUAGAAUCA3_hAGCAUG AGGCGGAGAU U U ACA C(UCAUA A G A UCGA C AGA A U U G ACAU G A G UrUGCAUA U U UCG G U3 ciU A UGC3848586861 1 1 102

[0063] G AUUUUGA A A A G A A A A G UCAUGG A)A A A A A A A U UUCAUU Um U G U U U U U GAUAUCUUmA A G A A A A ACAUAGC 62UAA U U U U A UACC CUA1ACA A A A A UCCAAGCRiA A A A A A A CCAA G UCGAm AUU A A A A U G U G AUACCGCACAU CGCGX G CG6ACACC)A G G G G 1C CC)ACC)3A A A A U_ACApCA2pApA A A A GAU U UAAAA CCA GU G A A AC nUC nGA CnoG G G A UCA GU UA CUCCC_A ACGoiA t AC oiA t ACitiA A A A A ACAUCA3AiGiGsA A A V U GAsUAsUAoU U U ACAU AUCAAUGccG GGopGGopGGptG G G A)UA Um UGCU AACA UGG aC2A AAtA v G UAaeGAtAaA e GACaA A A e G G G mU A'A GUtAUtAtiA A A A6ACAC C CC21 CAUAAAC3(A AAisAAisAA UsA A A A UUGACUUCG AUgGgGgG G G A AnUn C niCRiCGCAUGCG A GmCGAUAGAGA AidA AAidA AAdA A A A AC CC U A AAniAAniACnA AibA ACACGX6GCUAU AG ACU UG ACGbAA GbAApA AA AA A_GG AGCGCUCAG GCAp3GAp3GA3- G GCC GCGU C AGUCAAUUG A UA-2AA-2AG2  A_3G CCAACU GGCCAAU G GG C4G A AA1GG4GG4A)A 1 G)tG ACG RAA1RAARArG atACG C AC )tCr 1at51UV GcCUUGAUAA G GAiGC iGUiG G G Am s-G Gs- GcCU CaC CUUUA AU ’CAAAGACUACAGmAA htiAmAG A A A UhtiAAhtiACAC1AG)1 CA . AG1.A3(UCUU C UCGUUCUCUA wUCwUAwUCv(UG1UG1GA UUC CAC CACGU A C A AG A G AC)A AAAA AA AvA ACARAC RACAC vA AAA ARAR RUT T CRCRCG AU A UCAUCAC TATAATAA A GGUCUACTACTAGC AUCAACUUA ACUACAA GAU’GGUU U U G G5(GA’GA GAU’G GCG A(G G(GC ’GG U5GA-’G GCAU’G GCAU’U G U5 5( A G5(G G5(A G5(S E C 7N0E 52U1617181910212Q1 1 1 1 1 1 1ESRT U’5

[0064] A ACA A A A A A A A A UCA A A A A A A A A U U A G U U U U U A U A A A A A A A U U A A A U U U U U U U U A A A A A A A A A A A A U A A A U A A A U A A A A A A A A A A G G A A G G G G G G G G G A G U A A A A A A A A A A G U A A A A A A U A A G A G G G G G G G G G U A A A A A A A A A A A A A A A A A A A UCA U U UUU U U U U G GCG G G A U G G G G A A A A A A G G G GAC A G GAC G G A G G A A A A A A A A A ACC A A A A AAA A A G U G G G G G G G G A U A A)A) )A A A ACA A A A RARA)RA A)A)A A AR)A)U)A)A ARC TATATARA UT TRTARTARTARTGTGUAUAUA A G GUGU AU A A CU U U UAUG G UmAmG G G G AmA AmAmAmA A A Gma  Ae UaearGert C aerGmaeGaerGaerGaerGmaerGmaerGmae2r5GrtsCGts AAtArtAtAtAtAtAtAt 1p CspGsGsGsGsGsGsGsGsApCuAUAUApUApApApApApApApC (( A(U ( AUAU( AU( AU( UU( AU(UAC2 A C C C C C C C CA ( U A0 C4GC 0A0UC800UC9UC ,0AC1UC2UC3UC4UC5UCC6RG - UA AC 0- AA00RAC- AA1AC 0- AA1AC 0- AA1AC 0- AA1AC 0- AA1AC 0- AA1AC 0- AA1AC 0- ACARACACRACRACRARARARARARGGTGAUG GCTCUGGT′GAU′GGTGAUGGTGAUGGT CGAUGGT CGAUGGT CGAUGGT CGAUGGT CGAUGGTGAUG G’5G A5G G5G G′ 5G G′ 5G G′ 5G G′ 5G G′ 5G G′ 5G G′ 5G G′ 52232425262728292031 21 1 1 1 1 1 1 1 13131

[0065] AAA CAU A U C AAGAAG ACA AGUUA GAAAGCACUUUCA ACGCUAU UCACGAG UCCAG AAG A G AACG U AG AUCAGCCUC CUCUC CUCA AGCAG CGACAGACUAAAGAGCUACG ACG UCAUCCUCGCCAG A AA GGCCU U UACAUCAUUC C CAG UUAAA UACG UA U AU AG GCUCUG GCA AU UUGGCU UA U ACG CA AG UG GUA UGCACGCAU UGCCAA GGG AAC C CACA ACG GCACAG UGC UU ACA ))A GCA AU ACUG A G U AAUA ACAGAGCUGGCUCGU UCGU AGACUG GA G G AG GUCGGCG CGU UAU N RAA UGACCAC CA GACCCUAACAC CUUA C A GUCCteGGA UACA GAA A UCCCGC gAAA UUU ACGCGCCUG AAUG raG A AAUUCCCACGCA GAUCtrAUA A AGG UCAGG UGCAGA GGGAGCUAUGCGGCAGCU GGU CAAUCoUfUAG UUCAAAAUAA) CG)ACGG GGGgn CCA AR UTCARCAG UA A G AGA UCAUinCAUCA UGGUUCGTUA ACUUAGG UUC AUUG A UiaUAACUA GUCAUCAAUACAsAetA AU A GGGUtnGCA GAU A GmaAAC mGCAGU   AeCisAA)GACUocACA ACU3rGUC aerACCAAA2ACRC CGUnrGUU GGA5GtsGAA UACts ACA GCU AGCUA GA ACASAGUMC C TU AGCCUUCuAA t A A GACGCU AU1ApAU(C p CUAU UGGU( G ACX6 GUCAGCA G GCACUC’5GC UGknC)AAA )sUC CAikAGUCstAUC stAC7A1UG8AC 0- CGG1A GCUht GAA0- AGGUA AUGUGCiUUsGAU A(UAAC 2UGG6CwAU AUelCC C CRCAGG2AGA v AAUA4AAC2C1AGAC1A GCRAUARAUA GTACAUTGGGGGCUCRTAUiUGUA_AAARGGmAGUUTGGUC iAAARiG GAUCGAUCUAUG AGU UGA2GAUCK'GAAmxA GGAmxG G′ 5UCU′ 5GGC G U UUC’5G Uv(G U A A5(G A ACC3(G A UCC3(33435373839301 1 1 1 1 141

[0066] AAG AACAACAGGCACCG UA GG CACACCCCCAUCCA UCAG GCA UCUACCAUUCCCG UAAUCCAAA CCACU A G CACU GAU AAA GC4  AAC5GCAA1AACA AUA)UGstAAA2AGCA21AAAC RGAUC iA GGAC mxG A UC3(141

[0067] Stop codon = bold miR 142-3p binding site = underline miR 126-3p binding site = bold underline miR 155-5p binding site = italicized miR 142-5p binding site = italicized and bold underline In certain embodiments, the 5′ UTR and / or 3′ UTR sequence of the disclosure comprises a nucleotide sequence at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to a sequence provided in Table 6. In some embodiments, the 5’ UTR comprises a nucleotide sequence at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to a sequence provided in Table 6. In some embodiments, the 3’ UTR comprises a nucleotide sequence at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to a sequence provided in Table 6. In some embodiments, the polynucleotide disclosed herein, e.g., the polynucleotide encoding a polypeptide, or a repressor, comprises a 5’ UTR having the sequence of a 5’ UTR provided in Table 6, or a sequence with at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identity thereto. In some embodiments, the polynucleotide comprises a 5’ UTR comprising the sequence of any one of SEQ ID NOs: 115-135, or a sequence with at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identity thereto. In some embodiments, the polynucleotide disclosed herein, e.g., the polynucleotide encoding a polypeptide, or a repressor comprises a 3’ UTR having the   sequence of a 3’ UTR provided in Table 6, or a sequence with at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identity thereto. In some embodiments, the polynucleotide comprises a 3’ UTR comprising the sequence of any one of SEQ ID NOs: 81-114, or a sequence with at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identity thereto. The polynucleotides of the disclosure can comprise combinations of features. For example, the ORF can be flanked by a 5′UTR that comprises a strong Kozak translational initiation signal and / or a 3′UTR comprising an oligo(dT) sequence for templated addition of a poly-A tail. A 5′UTR can comprise a first polynucleotide fragment and a second polynucleotide fragment from the same and / or different UTRs (see, e.g., US2010 / 0293625, herein incorporated by reference in its entirety). Other non-UTR sequences can be used as regions or subregions within the polynucleotides of the disclosure. For example, introns or portions of intron sequences can be incorporated into the polynucleotides of the disclosure. Incorporation of intronic sequences can increase protein production as well as polynucleotide expression levels. In some embodiments, the polynucleotide of the disclosure comprises an internal ribosome entry site (IRES) instead of or in addition to a UTR (see, e.g., Yakubov et al., Biochem. Biophys. Res. Commun.2010394(1):189-193, the contents of which are incorporated herein by reference in their entirety). In some embodiments, the polynucleotide comprises an IRES instead of a 5′ UTR sequence. In some embodiments, the polynucleotide comprises an ORF and a viral capsid sequence. In some embodiments, the polynucleotide comprises a synthetic 5′ UTR in combination with a non-synthetic 3′ UTR. In some embodiments, the UTR can also include at least one translation enhancer polynucleotide, translation enhancer element, or translational enhancer elements (collectively, "TEE," which refers to nucleic acid sequences that increase the amount of polypeptide or protein produced from a polynucleotide. As a non-limiting example, the   TEE can be located between the transcription promoter and the start codon. In some embodiments, the 5′ UTR comprises a TEE. In one aspect, a TEE is a conserved element in a UTR that can promote translational activity of a nucleic acid such as, but not limited to, cap-dependent or cap-independent translation. Regions having a 5’ cap The disclosure also includes a polynucleotide that comprises both a 5′ Cap and a polynucleotide of the present disclosure (e.g., a polynucleotide comprising a nucleotide sequence encoding a polypeptide, or a repressor).  The 5′ cap structure of a natural mRNA is involved in nuclear export, increasing mRNA stability and binds the mRNA Cap Binding Protein (CBP), which is responsible for mRNA stability in the cell and translation competency through the association of CBP with poly(A) binding protein to form the mature cyclic mRNA species. The cap further assists the removal of 5′ proximal introns during mRNA splicing. Endogenous mRNA molecules can be 5′-end capped generating a 5′-ppp-5′- triphosphate linkage between a terminal guanosine cap residue and the 5′-terminal transcribed sense nucleotide of the mRNA molecule. This 5′-guanylate cap can then be methylated to generate an N7-methyl-guanylate residue. The ribose sugars of the terminal and / or ante-terminal transcribed nucleotides of the 5′ end of the mRNA can optionally also be 2′-O-methylated.5′-decapping through hydrolysis and cleavage of the guanylate cap structure can target a nucleic acid molecule, such as an mRNA molecule, for degradation. In some embodiments, the polynucleotides of the present disclosure (e.g., a polynucleotide comprising a nucleotide sequence encoding a first polypeptide, a polypeptide, or a repressor) incorporate a cap moiety. In some embodiments, polynucleotides of the present disclosure (e.g., a polynucleotide comprising a nucleotide sequence encoding a polypeptide, or a repressor) comprise a non-hydrolyzable cap structure preventing decapping and thus increasing   mRNA half-life. Because cap structure hydrolysis requires cleavage of 5′-ppp-5′ phosphorodiester linkages, modified nucleotides can be used during the capping reaction. For example, a Vaccinia Capping Enzyme from New England Biolabs (Ipswich, MA) can be used with α-thio-guanosine nucleotides according to the manufacturer’s instructions to create a phosphorothioate linkage in the 5′-ppp-5′ cap. Additional modified guanosine nucleotides can be used such as α-methyl-phosphonate and seleno-phosphate nucleotides. Additional modifications include, but are not limited to, 2′-O-methylation of the ribose sugars of 5′-terminal and / or 5′-anteterminal nucleotides of the polynucleotide (as mentioned above) on the 2′-hydroxyl group of the sugar ring. Multiple distinct 5′-cap structures can be used to generate the 5′-cap of a nucleic acid molecule, such as a polynucleotide that functions as an mRNA molecule. Cap analogs, which herein are also referred to as synthetic cap analogs, chemical caps, chemical cap analogs, or structural or functional cap analogs, differ from natural (i.e., endogenous, wild-type or physiological) 5′-caps in their chemical structure, while retaining cap function. Cap analogs can be chemically (i.e., non-enzymatically) or enzymatically synthesized and / or linked to the polynucleotides of the invention. For example, the Anti-Reverse Cap Analog (ARCA) cap contains two guanines linked by a 5′-5′-triphosphate group, wherein one guanine contains an N7 methyl group as well as a 3′-O-methyl group (i.e., N7,3′-O-dimethyl-guanosine-5′-triphosphate-5′- guanosine (m7G-3′mppp-G; which can equivalently be designated 3′ O-Me- m7G(5’)ppp(5’)G). The 3′-O atom of the other, unmodified, guanine becomes linked to the 5′-terminal nucleotide of the capped polynucleotide. The N7- and 3′-O-methlyated guanine provides the terminal moiety of the capped polynucleotide. Another exemplary cap is mCAP, which is similar to ARCA but has a 2′-O- methyl group on guanosine (i.e., N7,2′-O-dimethyl-guanosine-5′-triphosphate-5′- guanosine, m7Gm-ppp-G). In some embodiments, the cap is a dinucleotide cap analog. As a non-limiting example, the dinucleotide cap analog can be modified at different phosphate positions with a boranophosphate group or a phosphoroselenoate group such as the dinucleotide   cap analogs described in U.S. Patent No. US 8,519,110, the contents of which are herein incorporated by reference in its entirety. In another embodiment, the cap is a cap analog is a N7-(4-chlorophenoxyethyl) substituted dinucleotide form of a cap analog known in the art and / or described herein. Non-limiting examples of a N7-(4-chlorophenoxyethyl) substituted dinucleotide form of a cap analog include a N7-(4-chlorophenoxyethyl)-G(5’)ppp(5’)G and a N7-(4- chlorophenoxyethyl)-m3’-OG(5’)ppp(5’)G cap analog (See, e.g., the various cap analogs and the methods of synthesizing cap analogs described in Kore et al. Bioorganic & Medicinal Chemistry 201321:4570-4574; the contents of which are herein incorporated by reference in its entirety). In another embodiment, a cap analog of the present invention is a 4-chloro / bromophenoxyethyl analog. While cap analogs allow for the concomitant capping of a polynucleotide or a region thereof, in an in vitro transcription reaction, up to 20% of transcripts can remain uncapped. This, as well as the structural differences of a cap analog from an endogenous 5′-cap structures of nucleic acids produced by the endogenous, cellular transcription machinery, can lead to reduced translational competency and reduced cellular stability. Polynucleotides of the disclosure (e.g., a polynucleotide comprising a nucleotide sequence encoding a polypeptide, or a repressor), can also be capped post-manufacture (whether IVT or chemical synthesis), using enzymes, to generate more authentic 5′-cap structures. As used herein, the phrase "more authentic" refers to a feature that closely mirrors or mimics, either structurally or functionally, an endogenous or wild type feature. That is, a "more authentic" feature is better representative of an endogenous, wild-type, natural or physiological cellular function and / or structure as compared to synthetic features or analogs, etc., of the prior art, or which outperforms the corresponding endogenous, wild-type, natural or physiological feature in one or more respects. Non- limiting examples of more authentic 5′cap structures of the present invention are those that, among other things, have enhanced binding of cap binding proteins, increased half- life, reduced susceptibility to 5′ endonucleases and / or reduced 5′decapping, as compared to synthetic 5′cap structures known in the art (or to a wild-type, natural or physiological 5′cap structure). For example, recombinant Vaccinia Virus Capping Enzyme and   recombinant 2′-O-methyltransferase enzyme can create a canonical 5′-5′-triphosphate linkage between the 5′-terminal nucleotide of a polynucleotide and a guanine cap nucleotide wherein the cap guanine contains an N7 methylation and the 5′-terminal nucleotide of the mRNA contains a 2′-O-methyl. Such a structure is termed the Cap1 structure. This cap results in a higher translational-competency and cellular stability and a reduced activation of cellular pro-inflammatory cytokines, as compared, e.g., to other 5′cap analog structures known in the art. Cap structures include, but are not limited to, 7mG(5’)ppp(5’)N,pN2p (cap 0), 7mG(5’)ppp(5’)NlmpNp (cap 1), and 7mG(5’)- ppp(5’)NlmpN2mp (cap 2). As a non-limiting example, capping chimeric polynucleotides post-manufacture can be more efficient as nearly 100% of the chimeric polynucleotides can be capped. This is in contrast to ~80% efficiency when a cap analog is linked to a chimeric polynucleotide during an in vitro transcription reaction. According to the present invention, 5′ terminal caps can include endogenous caps or cap analogs. According to the present invention, a 5′ terminal cap can comprise a guanine analog. Useful guanine analogs include, but are not limited to, inosine, N1- methyl-guanosine, 2′fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino- guanosine, LNA-guanosine, and 2-azido-guanosine. Poly A Tails In some embodiments, the polynucleotides of the present disclosure (e.g., a polynucleotide comprising a nucleotide sequence encoding a polypeptide, or a repressor) further comprise a poly-A tail. In further embodiments, terminal groups on the poly-A tail can be incorporated for stabilization. In other embodiments, a poly-A tail comprises des-3’ hydroxyl tails. During RNA processing, a long chain of adenine nucleotides (poly-A tail) can be added to a polynucleotide such as an mRNA molecule to increase stability. Immediately after transcription, the 3’ end of the transcript can be cleaved to free a 3’ hydroxyl. Then poly-A polymerase adds a chain of adenine nucleotides to the RNA. The process, called polyadenylation, adds a poly-A tail that can be between, for example, approximately 80   to approximately 250 residues long, including approximately 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 residues long. In one embodiment, the poly-A tail is 100 nucleotides in length (SEQ ID NO: 149). aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa (SEQ ID NO: 149) PolyA tails can also be added after the construct is exported from the nucleus. According to the present disclosure, terminal groups on the poly A tail can be incorporated for stabilization. Polynucleotides of the present disclosure can include des- 3’ hydroxyl tails. They can also include structural moieties or 2’-Omethyl modifications as taught by Junjie Li, et al. (Current Biology, Vol.15, 1501–1507, August 23, 2005, the contents of which are incorporated herein by reference in its entirety). The polynucleotides of the present disclosure can be designed to encode transcripts with alternative polyA tail structures including histone mRNA. According to Norbury, "Terminal uridylation has also been detected on human replication-dependent histone mRNAs. The turnover of these mRNAs is thought to be important for the prevention of potentially toxic histone accumulation following the completion or inhibition of chromosomal DNA replication. These mRNAs are distinguished by their lack of a 3ʹ poly(A) tail, the function of which is in...

Claims

What is claimed is:

1. A composition comprising a messenger RNA (mRNA) comprising (i) an open reading frame encoding a polypeptide, and (ii) one or more microRNA target sites present in hematopoietic stem and progenitor cells (HSPC miRts).

2. The composition of claim 1, wherein the one or more HSPC miRts comprise miR- 126-3p, miR-130a-3p, miR-10a-5p, miR-29a-3p, miR125a-5p, miR125b-5p, or miR196b-5p.

3. The composition of claim 1, wherein the polypeptide is a gene editor, a cytokine, an apoptotic protein, a transcription factor, a DNA-binding protein, a receptor, an enzyme, or a chimeric antigen receptor.

4. The composition of any one of claims 1 to 3, wherein the composition comprises one or more delivery agents selected from a group consisting of a lipid nanoparticle, a liposome, a lipoplex, a polyplex, a lipidoid, a polymer, a microvesicle, an exosome, a peptide, a protein, cells transfected with polynucleotides, hyaluronidase, nanoparticle mimics, nanotubes, and conjugates.

5. The composition of any one of claims 1 to 3, wherein the composition comprises a lipid nanoparticle.

6. The composition of claim 5, wherein the lipid nanoparticle comprises an ionizable amino lipid of Formula (I): (I) or a salt thereof, wherein R’ais R’branched; wherein  R’branchedis: ; wherein denotes a point of attachment; wherein Raα, Raβ, Raγ, and Raδare each independently selected from the group consisting of H, C2-12 alkyl, and C2-12 alkenyl; R2and R3are each independently selected from the group consisting of C1-14alkyl and C2-14alkenyl; R4is selected from the group consisting of -(CH2)nOH, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, and , wherein denotes a point of attachment; wherein R10is N(R)2; each R is independently selected from the group consisting of C1-6 alkyl, C2-3alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R5is independently selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H; each R6is independently selected from the group consisting of C1-3alkyl, C2-3 alkenyl, and H; M and M’ are each independently selected from the group consisting of -C(O)O- and -OC(O)-; R’ is a C1-12alkyl or C2-12alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13.

7. The composition of claim 6, wherein the ionizable amino lipid has the formula:  (Compound II) or a salt thereof.

8. The composition of any one of claims 5 to 7, wherein the lipid nanoparticle further comprises a PEG-lipid.

9. The composition of claim 8, wherein the PEG-lipid has the formula: (Compound I).

10. The composition of any one of claims 1 to 9, wherein the one or more HSPC miRts comprise at least one microRNA target site specific for miR126.

11. The composition of any one of claims 1 to 10, wherein the one or more HSPC miRts comprise at least two microRNA target sites specific for miR126.

12. The composition of any one of claims 1 to 9, wherein the one or more HSPC miRts comprise at least one microRNA target site specific for miR130a.

13. The composition of any one of claims 1 to 12, wherein the one or more HSPC miRts comprise at least two microRNA target sites specific for miR130a.

14. The composition of any one of claims 1 to 9, wherein the one or more HSPC miRts comprise at least two microRNA target sites specific for miR126 and at least two microRNA target sites specific for miR130a.

15. The composition of any one of claims 1 to 14, wherein the one or more HSPC miRts are in a non-coding region of the mRNA.

16. The composition of claim 15, wherein the 3’ untranslated region (UTR) of the mRNA comprises at least one HSPC miRts.

17. The composition of claim 15, wherein the 3’ UTR of the mRNA comprises at least two repeats of one HSPC miRts.

18. The composition of claim 15, wherein the 3’ UTR of the mRNA comprises six repeats of one HSPC miRts.

19. The composition of claim 15, wherein the 5’ UTR of the mRNA comprises at least one HSPC miRts.

20. The composition of claim 15, wherein the 5’ UTR of the mRNA comprises at least two repeats of one HSPC miRts.

21. The composition of claim 15, wherein the 5’ UTR of the mRNA comprises three repeats of one HSPC miRts.

22. The composition of claim 1, wherein the mRNA has one or more HSPC miRts in the 3’ UTR and the 5’ UTR.

23. The composition of claim 1, wherein the mRNA has one or more of the following features: (1) an AU-rich element; (2) the one or more HSPC miRts comprise at least one mismatch to the microRNA that binds the one or more HSPC miRts; (3) structurally accessible UTRs; (4) a short polyA tail; and (5) the ability to form microRNA bridges when a microRNA binds to the one or more HSPC miRts.

24. The composition of any one of claims 16-21, wherein the 5’ UTR and / or the 3’ UTR comprises an AU-rich element.

25. The composition of claim 24, wherein the 3’ UTR is 60%-90% AU-rich.

26. The composition of claim 24, wherein the 3’ UTR is about 70% AU-rich.

27. The composition of claim 23, wherein the one or more HSPC miRts comprise one to three mismatches to the microRNA that binds the one or more HSPC miRts.

28. The composition of claim 23, wherein the polyA tail is 20-100 nucleotides in length.

29. The composition of claim 23, wherein the microRNA bridge is formed by one or more miRts in the 5’ UTR and the 3’ UTR of the mRNA.

30. A method of preferentially expressing a polypeptide in hematopoietic cell types other than hematopoietic stem and progenitor cells (HSPCs), the method comprising contacting a population of hematopoietic cells with the composition of any one of claims 1 to 29, wherein the population of hematopoietic cells comprises HSPCs and hematopoietic cell types other than HSPCs.

31. The method of claim 30, wherein the contacting of the population of hematopoietic cells occurs ex vivo.

32. The method of claim 30, wherein the contacting of the population of hematopoietic cells occurs in vivo.

33. A composition comprising: (a) a first polynucleotide comprising (i) a repressor binding element, (ii) an open reading frame encoding a polypeptide, and (iii) optionally one or more microRNA target sites present in non-hematopoietic stem and progenitor cells (non-HSPC miRts); and (b) a second polynucleotide comprising (i) a sequence encoding a repressor that binds to the repressor binding element and (ii) one or more microRNA target sites present in hematopoietic stem and progenitor cells (HSPC miRts), wherein binding of the repressor to the repressor binding element reduces translation of the polypeptide from the first polynucleotide.

34. The composition of claim 33, wherein the one or more HSPC miRts comprise miR-126-3p, miR-130a-3p, miR-10a-5p, miR-29a-3p, miR125a-5p, miR125b-5p, or miR196b-5p.

35. The composition of claim 33 or 34, wherein the one or more non-HSPC miRts comprise miR142-3p, miR150-5p, miR223-3p, or miR122-5p.

36. The composition of any one of claims 33 to 35, wherein the polypeptide is toxic to HSPCs.

37. The composition of any one of claims 33 to 35, wherein the polypeptide is a gene editor, a cytokine, an apoptotic protein, a transcription factor, a DNA-binding protein, a receptor, an enzyme, or a chimeric antigen receptor.

38. The composition of any one of claims 33 to 37, wherein the one or more HSPC miRts comprise at least one microRNA target site specific for miR126.

39. The composition of any one of claims 33 to 37, wherein the one or more HSPC miRts comprise at least two microRNA target sites specific for miR126.

40. The composition of any one of claims 33 to 39, wherein the one or more HSPC miRts comprise at least one microRNA target site specific for miR130a.

41. The composition of any one of claims 33 to 39, wherein the one or more HSPC miRts comprise at least two microRNA target sites specific for miR130a.

42. The composition of any one of claims 33 to 37, wherein the one or more HSPC miRts comprise at least two microRNA target sites specific for miR126 and at least two microRNA target sites specific for miR130a.

43. The composition of any one of claims 33 to 42, wherein the one or more microRNA target sites are in the non-coding region of each of the first and second polynucleotides, wherein each of the first and second polynucleotides is an mRNA.

44. The composition of claim 43, wherein the 3’ UTR of the first and second polynucleotides each comprises one microRNA target site.

45. The composition of claim 43, wherein the 3’ UTR of the first and second polynucleotides each comprises at least two repeats of one microRNA target site.

46. The composition of claim 43, wherein the 3’ UTR of the first and second polynucleotides each comprises six repeats of one microRNA target site.

47. The composition of claim 43, wherein the 5’ UTR of the first and second polynucleotides each comprises one microRNA target site.

48. The composition of claim 43, wherein the 5’ UTR of the first and second polynucleotides each comprises at least two repeats of one microRNA target site.

49. The composition of claim 43, wherein the 5’ UTR of the first and second polynucleotides each comprises three repeats of one microRNA target site.

50. The composition of claim 43, wherein the mRNA has one or more HSPC miRts in the 3’ UTR and the 5’ UTR.

51. The composition of claim 43, wherein the mRNA has one or more of the following features: (1) an AU-rich element; (2) the one or more HSPC miRts comprise at least one mismatch to the microRNA that binds the one or more HSPC miRts; (3) structurally accessible UTRs; (4) a short polyA tail; and (5) the ability to form microRNA bridges when a microRNA binds to the one or more HSPC miRts.

52. The composition of any one of claims 44-49, wherein the 5’ UTR and / or the 3’ UTR comprises an AU-rich element.

53. The composition of claim 52, wherein the 3’ UTR is 60%-90% AU-rich.

54. The composition of claim 52, wherein the 3’ UTR is about 70% AU-rich.

55. The composition of claim 51, wherein the one or more HSPC miRts comprise one to eight mismatches to the microRNA that binds the one or more HSPC miRts.

56. The composition of claim 51, wherein the polyA tail is 40-100 nucleotides in length.

57. The composition of claim 51, wherein the microRNA bridge is formed by one or more miRts in the 5’ UTR and the 3’ UTR of the mRNA.

58. The composition of any one of claims 33 to 42, wherein the first and the second polynucleotide each is an mRNA and comprises a polyA tail or is a DNA.

59. The composition of any one of claims 33 to 42 and 58, wherein the one or more HSPC miRts in the second polynucleotide are in the non-coding portion of the second polynucleotide.

60. The composition of any one of claims 33 to 42 and 58, wherein the one or more HSPC miRts in the second polynucleotide are (a) positioned between the sequence encoding the repressor and a polyA tail; or (b) positioned between a 5’ cap and a start codon, wherein the second polynucleotide is an mRNA.

61. The composition of any one of claims 33 to 60, wherein the repressor binding element comprises a kink-turn forming sequence.

62. The composition of claim 61, wherein the repressor binding element is selected from the group consisting of PRE, PRE2, MS2, PP7, BoxB, U1A hairpin, and 7SK.

63. The composition of any one of claims 33 to 62, wherein the repressor is selected from the group consisting of Snu13, 50S ribosomal L7Ae protein, Pumilio and FBF (PUF) protein, PUF2 protein, MBP-LacZ, MBP, PCP, Lambda N, U1A, 15.5kd, LARP7, L30e, and other RNA-binding proteins.

64. The composition of any one of claims 33 to 63, wherein the composition comprises one or more delivery agents selected from a group consisting of a lipid nanoparticle, a liposome, a lipoplex, a polyplex, a lipidoid, a polymer, a microvesicle, an exosome, a peptide, a protein, cells transfected with polynucleotides, hyaluronidase, nanoparticle mimics, nanotubes, and conjugates.

65. The composition of any one of claims 33 to 63, wherein the composition comprises a lipid nanoparticle.

66. The composition of claim 65, wherein the lipid nanoparticle comprises an ionizable amino lipid of Formula (I):  (I) or a salt thereof, wherein R’ais R’branched; wherein R’branchedis: ; wherein denotes a point of attachment; wherein Raα, Raβ, Raγ, and Raδare each independently selected from the group consisting of H, C2-12alkyl, and C2-12alkenyl; R2and R3are each independently selected from the group consisting of C1-14alkyl and C2-14 alkenyl; R4is selected from the group consisting of -(CH2)nOH, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, and , wherein denotes a point of attachment; wherein R10is N(R)2; each R is independently selected from the group consisting of C1-6alkyl, C2-3alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R5is independently selected from the group consisting of C1-3 alkyl, C2-3alkenyl, and H; each R6is independently selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H;  M and M’ are each independently selected from the group consisting of -C(O)O- and -OC(O)-; R’ is a C1-12 alkyl or C2-12 alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13.

67. The composition of claim 66, wherein the ionizable amino lipid has the formula: (Compound II) or a salt thereof.

68. The composition of any one of claims 65 to 67, wherein the lipid nanoparticle further comprises a PEG-lipid.

69. The composition of claim 68, wherein the PEG-lipid has the formula: (Compound I).

70. A method of preferentially expressing a polypeptide in hematopoietic stem and progenitor cells (HSPCs), the method comprising contacting a population of hematopoietic cells with the composition of any one of claims 33 to 69, wherein the population of hematopoietic cells comprises HSPCs.

71. The method of claim 70, wherein the contacting of the population of hematopoietic cells occurs ex vivo.

72. The method of claim 70, wherein the contacting of the population of hematopoietic cells occurs in vivo.

73. A method of expressing a polypeptide in a hematopoietic stem and progenitor cell (HSPC), the method comprising contacting the cell with: (a) a first polynucleotide comprising (i) a repressor binding element, (ii) an open reading frame encoding a polypeptide, and (iii) optionally one or more non-hematopoietic stem cell- microRNA target sites present in non-hematopoietic stem and progenitor cells (non-HSPC miRts), wherein modification of the one or more non-HSPC miRts reduces translation of the polypeptide from the first polynucleotide; and (b) a second polynucleotide comprising (i) a sequence encoding a repressor that binds to the repressor binding element and (ii) one or more microRNA target sites present in hematopoietic stem and progenitors (HSPC miRts), wherein the HSPC expresses one or more microRNAs that bind to the one or more HSPC miRts and reduces translation of the repressor from the second polynucleotide.

74. A method of expressing a polypeptide in a hematopoietic stem and progenitor cell in a subject, the method comprising administering to the subject: (a) a first polynucleotide comprising (i) a repressor binding element, (ii) an open reading frame encoding a polypeptide, and (iii) optionally one or more microRNA target sites present in non-hematopoietic stem and progenitor cells (non-HSPC miRts), wherein modification of the one or more non-HSPC miRts reduces translation of the polypeptide from the first polynucleotide; and (b) a second polynucleotide comprising (i) a sequence encoding a repressor that binds to the repressor binding element and (ii) one or more microRNA target sites present in hematopoietic stem and progenitor cells (HSPC miRts), wherein the HSPC expresses one or more microRNAs that bind to the one or more HSPC miRts and reduces translation of the repressor from the second polynucleotide.

75. A composition comprising:  (a) a first polynucleotide comprising (i) a repressor binding element, (ii) an open reading frame encoding a polypeptide, and (iii) optionally one or more microRNA target sites present in hematopoietic stem and progenitor cells (HSPC miRts); and (b) a second polynucleotide comprising (i) a sequence encoding a repressor that binds to the repressor binding element and (ii) one or more microRNA target sites present in non-hematopoietic stem and progenitor cells (non-HSPC miRts), wherein binding of the repressor to the repressor binding element reduces translation of the polypeptide from the first polynucleotide.

76. The composition of claim 75, wherein the one or more HSPC miRts comprise miR-126-3p, miR-130a-3p, miR-10a-5p, miR-29a-3p, miR125a-5p, miR125b-5p, or miR196b-5p.

77. The composition of claim 75 or 76, wherein the one or more non-HSPC miRts comprise a microRNA target site present in an immune cell or in a hepatocyte.

78. The composition of claim 77, wherein the microRNA target site present in an immune cell is miR142-3p, miR150-5p, or miR223-3p.

79. The composition of claim 77, wherein the microRNA target site present in a hepatocyte is miR-122-5p.

80. The composition of any one of claims 75 to 79, wherein the polypeptide is a gene editor, a cytokine, an apoptotic protein, a transcription factor, a DNA-binding protein, a receptor, an enzyme, or a chimeric antigen receptor.

81. The composition of any one of claims 75 to 80, wherein the one or more microRNA target sites are in the non-coding region of each of the first and second polynucleotides, wherein each of the first and second polynucleotides is an mRNA.

82. The composition of claim 81, wherein the 3’ UTR of the first and second polynucleotides each comprises one microRNA target site.

83. The composition of claim 81, wherein the 3’ UTR of the first and second polynucleotides each comprises at least two repeats of one microRNA target site.

84. The composition of claim 81, wherein the 3’ UTR of the first and second polynucleotides each comprises six repeats of one microRNA target site.

85. The composition of claim 81, wherein the 5’ UTR of the first and second polynucleotides each comprises one microRNA target site.

86. The composition of claim 81, wherein the 5’ UTR of the first and second polynucleotides each comprises at least two repeats of one microRNA target site.

87. The composition of claim 81, wherein the 5’ UTR of the first and second polynucleotides each comprises three repeats of one microRNA target site.

88. The composition of claim 81, wherein the mRNA has one or more HSPC miRts in the 3’ UTR and the 5’ UTR.

89. The composition of claim 81, wherein the mRNA has one or more of the following features: (1) an AU-rich element; (2) the one or more HSPC miRts comprise at least one mismatch to the microRNA that binds the one or more HSPC miRts; (3) structurally accessible UTRs; (4) a short polyA tail; and (5) the ability to form microRNA bridges when a microRNA binds to the one or more HSPC miRts.

90. The composition of any one of claims 82-87, wherein the 3’ UTR comprises an AU-rich element.

91. The composition of claim 90, wherein the 3’ UTR is 60%-90% AU-rich.

92. The composition of claim 90, wherein the 3’ UTR is about 70% AU-rich.

93. The composition of claim 89, wherein the one or more HSPC miRts comprise one to three mismatches to the microRNA that binds the one or more HSPC miRts.

94. The composition of claim 89, wherein the microRNA bridge is formed by one or more miRts in the 5’ UTR and the 3’ UTR of the mRNA.

95. The composition of any one of claims 75 to 80, wherein the first and second polynucleotide each is an mRNA and comprises a polyA tail or is a DNA.

96. The composition of any one of claims 75 to 80 and 95, wherein the one or more microRNA target sites in the second polynucleotide are (a) positioned between the sequence encoding the repressor and a polyA tail; or (b) positioned between a 5’ cap and a start codon, wherein the second polynucleotide is an mRNA.

97. The composition of any one of claims 75 to 96, wherein the repressor binding element comprises a kink-turn forming sequence.

98. The composition of claim 97, wherein the repressor binding element is selected from the group consisting of PRE, PRE2, MS2, PP7, BoxB, U1A hairpin, and 7SK.

99. The composition of any one of claims 75 to 98, wherein the repressor is selected from the group consisting of Snu13, 50S ribosomal L7Ae protein, Pumilio and FBF (PUF) protein, PUF2 protein, MBP-LacZ, MBP, PCP, Lambda N, U1A, 15.5kd, LARP7, L30e, and other RNA-binding proteins.

100. The composition of any one of claims 75 to 99, wherein the composition comprises one or more delivery agents selected from a group consisting of a lipid nanoparticle, a liposome, a lipoplex, a polyplex, a lipidoid, a polymer, a microvesicle, an exosome, a peptide, a protein, cells transfected with polynucleotides, hyaluronidase, nanoparticle mimics, nanotubes, and conjugates.

101. The composition of any one of claims 75 to 99, wherein the composition comprises a lipid nanoparticle.

102. The composition of claim 101, wherein the lipid nanoparticle comprises an ionizable amino lipid of Formula (I): (I) or a salt thereof,  wherein R’ais R’branched; wherein R’branchedis: ; wherein denotes a point of attachment; wherein Raα, Raβ, Raγ, and Raδare each independently selected from the group consisting of H, C2-12alkyl, and C2-12alkenyl; R2and R3are each independently selected from the group consisting of C1-14alkyl and C2-14 alkenyl; R4is selected from the group consisting of -(CH2)nOH, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, and , wherein denotes a point of attachment; wherein R10is N(R)2; each R is independently selected from the group consisting of C1-6alkyl, C2-3alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R5is independently selected from the group consisting of C1-3 alkyl, C2-3alkenyl, and H; each R6is independently selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H; M and M’ are each independently selected from the group consisting of -C(O)O- and -OC(O)-; R’ is a C1-12alkyl or C2-12alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and  m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13.

103. The composition of claim 102, wherein the ionizable amino lipid has the formula: (Compound II) or a salt thereof.

104. The composition of any one of claims 101 to 103, wherein the lipid nanoparticle further comprises a PEG-lipid.

105. The composition of claim 104, wherein the PEG-lipid has the formula: (Compound I).

106. A method of preferentially expressing a polypeptide in hematopoietic cell types other than hematopoietic stem and progenitor cells (HSPCs), the method comprising contacting a population of hematopoietic cells with the composition of any one of claims 75 to 105, wherein the population of hematopoietic cells comprises HSPCs and hematopoietic cell types other than HSPCs.

107. The method of claim 106, wherein the contacting of the population of hematopoietic cells occurs ex vivo.

108. The method of claim 106, wherein the contacting of the population of hematopoietic cells occurs in vivo.

109. A method of expressing a polypeptide in a hematopoietic cell other than a hematopoietic stem and progenitor cell (HSPC), the method comprising contacting the cell with (a) a first polynucleotide comprising (i) a repressor binding element, (ii) an open reading frame encoding a polypeptide, and (iii) optionally one or more microRNA target  sites present in hematopoietic stem and progenitor cells (HSPC miRts), wherein modification of the one or more HSPC miRts reduces translation of the polypeptide from the polynucleotide; and (b) an second polynucleotide comprising (i) a sequence encoding a repressor that binds to the repressor binding element and (ii) one or more non-HSPC miRts, wherein the hematopoietic cell expresses one or more microRNAs that bind to the one or more non-HSPC miRts and reduces translation of the repressor from the second polynucleotide.

110. A method of expressing a polypeptide in a hematopoietic cell other than a hematopoietic stem and progenitor cell (HSPC) in a subject, the method comprising administering to the subject: (a) a first polynucleotide comprising (i) a repressor binding element, (ii) an open reading frame encoding a polypeptide, and (iii) optionally one or more microRNA target sites present in hematopoietic stem and progenitor cell (HSPC miRts), wherein modification of the one or more HSPC miRts reduces translation of the polypeptide from the first polynucleotide; and (b) a second polynucleotide comprising (i) a sequence encoding a repressor that binds to the repressor binding element and (ii) one or more non-HSPC miRts, wherein the hematopoietic cell expresses one or more microRNAs that bind to the one or more non- HSPC miRts and reduces translation of the repressor from the second polynucleotide.

111. A composition comprising a first messenger RNA (mRNA) comprising (i) a first open reading frame encoding a first polypeptide, and (ii) at least six miR142 target sites.

112. The composition of claim 111, wherein the first polypeptide is a secreted protein.

113. The composition of claim 111 or 112, wherein the at least six miR142 target sites are in the 3’ UTR of the first mRNA.

114. The composition of any one of claims 111 to 113, wherein the at least six miR142 target sites each comprise the sequence UCCAUAAAGUAGGAAACACUACA (SEQ ID NO:191).

115. The composition of any one of claims 111 to 113, wherein the at least six miR142 target sites each comprise the sequence UUACAAAAGUAGGAAACACUACA (SEQ ID NO:197).

116. The composition of any one of claims 111 to 115, further comprising a second mRNA comprising (i) a second open reading frame encoding a second polypeptide, and (ii) at least one miR target site.

117. The composition of claim 116, wherein the second mRNA comprises at least two miR target sites.

118. The composition of claim 116, wherein the second mRNA comprises at least three miR target sites.

119. The composition of claim 116, wherein the second mRNA comprises at least four miR target sites.

120. The composition of claim 116, wherein the second mRNA comprises at least five miR target sites.

121. The composition of claim 116, wherein the second mRNA comprises at least six miR target sites.

122. The composition of any one of claims 116-121, wherein the at least one, at least two, at least three, at least four, at least five, or at least six miR target sites of the second mRNA are miR142 target sites.

123. The composition of claim 122, wherein the at least one, at least two, at least three, at least four, at least five, or at least six miR target sites of the second mRNA each comprise the sequence UCCAUAAAGUAGGAAACACUACA (SEQ ID NO:191).

124. The composition of claim 122, wherein the at least one, at least two, at least three, at least four, at least five, or at least six miR target sites of the second mRNA each comprise the sequence UUACAAAAGUAGGAAACACUACA (SEQ ID NO:197).

125. The composition of any one of claims 116-121, wherein the at least one, at least two, at least three, at least four, at least five, or at least six miR target sites sites of the second mRNA are selected from the group consisting of miR-126-3p, miR-130a-3p, miR-10a-5p, miR-29a-3p, miR125a-5p, miR125b-5p, miR196b-5p, miR150-5p, miR223- 3p, and miR-122-5p target sites.

126. The composition of claim 125, wherein the second mRNA does not comprise a miR142 target site.

127. The composition of any one of claims 111-126, wherein the first and / or second mRNA comprise a 3’ UTR comprising the sequence UGAUAAUAGGCUGGAGCCUCAUUAAUCCAUAAAGUAGGAAACACUACAUA UAAAGUAAAAUUUCCAUAAAGUAGGAAACACUACACACCAUUUUAAUUAU CCAUAAAGUAGGAAACACUACAUAAUAAAAAUAAAGUCCAUAAAGUAGGA AACACUACAUAUAUAAUUCAUAGUCCAUAAAGUAGGAAACACUACAUACC CCCGUGGUCUUCCAUAAAGUAGGAAACACUACAUUAAAUAAAGUCUAAGU GGGCGGC (SEQ ID NO:154).

128. The composition of any one of claims 111-126, wherein the first and / or second mRNA comprise a 3’ UTR comprising the sequence UGAUAAUAGGCUGGAGCCUCAUUAAUUACAAAAGUAGGAAACACUACAUA UAAAGUAAAAUUUUACAAAAGUAGGAAACACUACACACCAUUUUAAUUAU UACAAAAGUAGGAAACACUACAUAAUAAAAAUAAAGUUACAAAAGUAGGA AACACUACAUAUAUAAUUCAUAGUUACAAAAGUAGGAAACACUACAUACC CCCGUGGUCUUUACAAAAGUAGGAAACACUACAUUAAAUAAAGUCUAAGU GGGCGGC (SEQ ID NO:155).

129. The composition of any one of claims 111-126, wherein the first and / or second mRNA comprise a 3’ UTR comprising the sequence  UAAAGCUCCCCGGGGGCUGGAGCCUCAUUAAUUACAAAAGUAGGAAACAC UACAUAUAAAGUAAAAUUUUACAAAAGUAGGAAACACUACACACCAUUUU AAUUAUUACAAAAGUAGGAAACACUACAUAAUAAAAAUAAAGUUACAAAA GUAGGAAACACUACAUAUAUAAUUCAUAGUUACAAAAGUAGGAAACACUA CAUACCCCCGUGGUCUUUACAAAAGUAGGAAACACUACAUUAAAUAAAGU CUAAGUGGGCGGC (SEQ ID NO:170).

130. The composition of any one of claims 111-126, wherein the first and / or second mRNA comprise a 3’ UTR comprising the sequence  UAAAGCUCCCCGGGGGCCUCAUUAAUUACAAAAGUAGGAAACACUACAUA UAAAGUAAAAUUUUACAAAAGUAGGAAACACUACACACCAUUUUAAUUAU UACAAAAGUAGGAAACACUACAUAAUAAAAAUAAAGUUACAAAAGUAGGA AACACUACAUAUAUAAUUCAUAGUUACAAAAGUAGGAAACACUACAUACC CCCGUGGUCUUUACAAAAGUAGGAAACACUACAUUAAAUAAAGUCUAAGU GGGCGGC (SEQ ID NO:171).

131. The composition of any one of claims 111 to 130, wherein the composition comprises one or more delivery agents selected from a group consisting of a lipid nanoparticle, a liposome, a lipoplex, a polyplex, a lipidoid, a polymer, a microvesicle, an exosome, a peptide, a protein, cells transfected with polynucleotides, hyaluronidase, nanoparticle mimics, nanotubes, and conjugates.

132. The composition of any one of claims 111 to 130, wherein the composition comprises a lipid nanoparticle.

133. A method of expressing a polypeptide in a subject, the method comprising administering to the subject the composition of any one of claims 111 to 132.

134. The method of claim 133, wherein the method comprises multiple administrations of the composition to the subject.

135. The method of claim 134, wherein the method comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten administrations of the composition to the subject.