Trem compositions and methods of use

Abstract

The invention relates generally to tRNA-based effector molecules having a non-naturally occurring modification and methods relating thereto.

Description

[0001]Attorney Docket No.: F2099-7038WO TREM COMPOSITIONS AND METHODS OF USE CLAIM OF PRIORITY This application claims priority to U.S. Provisional Application No.63 / 458,891, filed on April 12, 2023; U.S. Provisional Application No.63 / 458,894, filed on April 12, 2023; and U.S. Provisional Application No.63 / 458,911, filed on April 12, 2023. The entire contents of each of the foregoing applications are incorporated herein by reference in their entirety. BACKGROUND Transfer RNAs (tRNAs) are complex, naturally occurring RNA molecules that possess a number of functions including initiation and elongation of proteins. SUMMARY The present disclosure features modified tRNA-based effector molecules (TREMs, e.g., a TREM or TREM fragment), as well as related compositions and uses thereof. TREMs are complex molecules which can mediate a variety of cellular processes. For example, the TREMs described herein may have the ability to: (i) support protein synthesis, (ii) be charged by a tRNA synthetase, (iii) be bound by an elongation factor, (iv) introduce an amino acid into a peptide chain, (v) support protein elongation, or (vi) support initiation of protein synthesis, e.g., in a cell. Described herein are TREMs and related methods for optimizing the nucleotide sequence of a TREM, e.g., to improve a functional parameter of a TREM, e.g., to increase TREM stability. For example, the methods provided show that the nucleotide sequence of a TREM may be modified, e.g., by a substituting one nucleotide for another, to modulate a functional parameter of a TREM, for example to achieve an improvement in a functional parameter of a TREM. In an embodiment, the TREMs disclosed herein comprise at least one chemical modification (e.g., a non-naturally occurring modification), e.g., on a component nucleotide (e.g., a nucleobase or sugar) or within an internucleotide region, e.g., the TREM backbone. In another embodiment, the TREMs disclosed herein do not comprise a chemical modification (e.g., a non-naturally occurring modification), e.g., on a component nucleotide (e.g., a nucleobase or sugar) or within an internucleotide region, e.g., the TREM backbone). The present disclosure provides methods for tuning a functional parameter of a TREM by optimizing the nucleotide sequence, Attorney Docket No.: F2099-7038WO demonstrating a nucleotide sequence substitution (e.g., or further comprises a non-naturally occurring modification) may modulate a functional parameter of a TREM. In one aspect, provided herein is a TREM comprising a sequence of Formula (A): [L1]x- [ASt Domain1]-[L2]x-[DH Domain]-[L3]x-[ACH Domain]-[VL Domain]-[TH Domain]-[L4]x- [ASt Domain2]-[L5]x, wherein independently, [L1] and [VL Domain], are optional; x, independently for every occurrence, is 0 or 1; and one of [L1], [ASt Domain1], [L2]-[DH Domain], [L3], [ACH Domain], [VL Domain], [TH Domain], [L4], and [ASt Domain2] comprises a nucleotide substitution relative to a reference sequence (e.g., a second TREM), wherein the TREM comprises a nucleotide substitution (e.g., a nucleotide mutation) in the TREM capable of modulating a functional parameter of the TREM. In an embodiment, a TREM described herein comprises a plurality of nucleotide substitutions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, or 80, e.g., relative to a reference sequence). In another aspect, provided herein is a TREM comprising a sequence of Formula (A): [L1]x-[ASt Domain1]-[L2]x-[DH Domain]-[L3]x-[ACH Domain]-[VL Domain]-[TH Domain]- [L4]x-[ASt Domain2]-[L5]x, wherein independently, [L1] and [VL Domain], are optional; x, independently for every occurrence, is 0 or 1; and one of [L1], [ASt Domain1], [L2]-[DH Domain], [L3], [ACH Domain], [VL Domain], [TH Domain], [L4], and [ASt Domain2] comprises a nucleotide comprising a non-naturally occurring modification. In an embodiment, a TREM described herein comprises at least X contiguous nucleotides without a non-naturally occurring modification, wherein X is greater than 3, 4, 5, 6, 7, 8, 9, or 10; comprises at least 3, but less than all of the nucleotides of a type (e.g., A, T, C, G or U) comprise the same non- naturally occurring modification; comprises at least X nucleotides of a type (e.g., A, T, C, G or U) that do not comprise a non-naturally occurring modification, wherein X= than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, or 80; comprises no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, or 80 nucleotides of a type (e.g., A, T, C, G or U) that comprise a non-naturally occurring modification; and / or comprises no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, Attorney Docket No.: F2099-7038WO 64, 66, 68, 70, 72, 74, 76, 78, or 80 nucleotides of a type (e.g., A, T, C, G or U) that do not comprise a non-naturally occurring modification. In an embodiment, the TREM Domain comprising the non-naturally occurring modification has a function, e.g., a domain function described herein. In an aspect, provided herein is a TREM core fragment comprising a sequence of Formula B: [L1]y-[ASt Domain1]x-[L2]y-[DH Domain]y-[L3]y-[ACH Domain]x-[VL Domain]y-[TH Domain] y-[L4] y-[ASt Domain2] x, wherein x=1 and y=0 or 1; and one of [ASt Domain1], [ACH Domain], and [ASt Domain2] comprises a nucleotide having a non-naturally occurring modification. In an embodiment, the TREM has the ability to support protein synthesis. In an embodiment, the TREM has the ability to be able to be charged by a synthetase. In an embodiment, the TREM has the ability to be bound by an elongation factor. In an embodiment, the TREM has the ability to introduce an amino acid into a peptide chain. In an embodiment, the TREM has the ability to support elongation. In an embodiment, the TREM has the ability to support initiation. In an embodiment, the [ASt Domain 1] and / or [ASt Domain 2] comprising the non- naturally occurring modification has the ability to initiate or elongate a polypeptide chain. In an embodiment, the [ACH Domain] comprising the non-naturally occurring modification has the ability to mediate pairing with a codon. In an embodiment, y=1 for any one, two, three, four, five, six, all or a combination of [L1], [L2], [DH Domain], [L3], [VL Domain], [TH Domain], [L4]. In an embodiment, y=0 for any one, two, three, four, five, six, all or a combination of [L1], [L2], [DH Domain], [L3], [VL Domain], [TH Domain], [L4]. In an embodiment, y=1 for linker [L1], and L1 comprises a nucleotide having a non- naturally occurring modification. In an embodiment, y=1 for linker [L2], and L2 comprises a nucleotide having a non- naturally occurring modification. In an embodiment, y=1 for [DH Domain (DHD)], and DHD comprises a nucleotide having a non-naturally occurring modification. In an embodiment, the DHD comprising the non- Attorney Docket No.: F2099-7038WO naturally occurring modification has the ability to mediate recognition of aminoacyl-tRNA synthetase. In an embodiment, y=1 for linker [L3], and L3 comprises a nucleotide having a non- naturally occurring modification. In an embodiment, y=1 for [VL Domain (VLD)], and VLD comprises a nucleotide having a non-naturally occurring modification. In an embodiment, y=1 for [TH Domain (THD)], and THD comprises a nucleotide having a non-naturally occurring modification. In an embodiment, the THD comprising the non- naturally occurring modification has the ability to mediate recognition of the ribosome. In an embodiment, y=1 for linker [L4], and L4 comprises a nucleotide having a non- naturally occurring modification. In another aspect, the disclosure provides a TREM fragment comprising a portion of a TREM, wherein the TREM comprises a sequence of Formula A: [L1]-[ASt Domain1]-[L2]-[DH Domain]-[L3]-[ACH Domain] -[VL Domain]-[TH Domain]-[L4]-[ASt Domain2], and wherein the TREM fragment comprises a non-naturally occurring modification. In an embodiment, the TREM fragment comprises one, two, three or all or any combination of the following: (a) a TREM half (e.g., from a cleavage in the ACH Domain, e.g., in the anticodon sequence, e.g., a 5’half or a 3’ half); (b) a 5’ fragment (e.g., a fragment comprising the 5’ end, e.g., from a cleavage in a DH Domain or the ACH Domain); (c) a 3’ fragment (e.g., a fragment comprising the 3’ end, e.g., from a cleavage in the TH Domain); or (d) an internal fragment (e.g., from a cleavage in any one of the ACH Domain, DH Domain or TH Domain). In an embodiment, the TREM fragment comprise (a) a TREM half which comprises a nucleotide having a non-naturally occurring modification. In an embodiment, the TREM fragment comprise (b) a 5’ fragment which comprises a nucleotide having a non-naturally occurring modification. In an embodiment, the TREM fragment comprise (c) a 3’ fragment which comprises a nucleotide having a non-naturally occurring modification. In an embodiment, the TREM fragment comprise (d) an internal fragment which comprises a nucleotide having a non-naturally occurring modification. Attorney Docket No.: F2099-7038WO In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the TREM Domain comprises a plurality of nucleotides each having a non- naturally occurring modification. In an embodiment, the non-naturally occurring modification comprises a nucleobase modification, a sugar (e.g., ribose) modification, or a backbone modification. In an embodiment, tbe non-naturally occurring modification is a sugar (e.g., ribose) modification. In an embodiment, tbe non-naturally occurring modification is 2’-ribose modification, e.g., a 2’-OMe, 2’-halo (e.g., 2’-F), 2’-MOE, or 2’-deoxy modification. In an embodiment, tbe non-naturally occurring modification is a backbone modification, e.g., a phosphorothioate modification. In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the TREM sequence comprises a CCA sequence on a terminus, e.g., the 3’ terminus. In an embodiment, the TREM sequence does not comprise a CCA sequence on a terminus, e.g., the 3’ terminus. In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the non-naturally occurring modification is a modification in a base or a backbone of a nucleotide, e.g., a modification chosen from any one of Tables 5, 6, 7, 8 or or 9. In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the non-naturally occurring modification is a base modification chosen from a modification listed in Table 5. In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the TREM, TREM core fragment, or TREM fragment is encoded by a sequence provided in Table 1, e.g., any one of SEQ ID NOs 1-451. In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the TREM, TREM core fragment, or TREM fragment is encoded by a consensus sequence chosen from any one of SEQ ID NOs: 562-621. In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the TREM, TREM core fragment, or TREM fragment is encoded by a sequence provided in FIG.3, e.g., any one of SEQ ID NOs: 625-1151. In an embodiment, the TREM, TREM core fragment, or TREM fragment comprises a TREM having at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% sequence identity with a TREM provided in FIG.3, e.g., any one of SEQ ID NOs: 625-1151. In an embodiment, the TREM, TREM core fragment, or TREM Attorney Docket No.: F2099-7038WO fragment comprises a sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from a TREM provided in FIG.3, e.g., any one of SEQ ID NOs: 625-1151. In an embodiment, the TREM, TREM core fragment, or TREM fragment comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional non-naturally occurring modifications compared with a TREM, TREM core fragment, or TREM fragment provided in FIG.3, (e.g., 2’-ribose modifications or an internucleotide modification, e.g., 2’OMe, 2’-halo, 2’-MOE, 2’-deoxy, or phosphorothiorate modifications), e.g., any one of SEQ ID NOs: 625-1151. In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the TREM, TREM core fragment, or TREM fragment is a TREM provided in FIG.3, e.g., any one of SEQ ID NOs: 625-1151. In an embodiment, the TREM, TREM core fragment, or TREM fragment comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional non-naturally occurring modifications compared with a TREM provided in FIG.3 (e.g., 2’-ribose modifications or an internucleotide modification, e.g., 2’OMe, 2’-halo, 2’-MOE, 2’-deoxy, or phosphorothiorate modifications), e.g., any one of SEQ ID NOs.625-1151. In another aspect, the disclosure provides a pharmaceutical composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein. In another aspect, a TREM or a related composition thereof can be used, inter alia, to modulate a functional parameter (e.g., an expression parameter and / or a signaling parameter) of an RNA corresponding to, or a polypeptide encoded by, a nucleic acid sequence comprising an endogenous open reading frame (ORF) having a premature termination codon (PTC). In another aspect, provided herein is a method of modulating a functional parameter of an mRNA corresponding to, or polypeptide encoded by, an endogenous open reading frame (ORF) in a subject, which ORF comprises a premature termination codon (PTC), contacting the subject with a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein in an amount and / or for a time sufficient to modulate the functional parameter of the mRNA or polypeptide, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the codon having the first sequence, thereby modulating the functional parameter in the subject. In an embodiment, the functional parameter comprises a signaling parameter and / or an expression parameter, e.g., as described herein. In another aspect, disclosed herein is a method of modulating expression of a protein in a cell, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading Attorney Docket No.: F2099-7038WO frame (ORF), which ORF comprises a premature termination codon (PTC), comprising contacting the cell with a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein in an amount and / or for a time sufficient to modulate expression of the encoded protein, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the PTC, thereby modulating expression of the protein in the cell. In an embodiment, the PTC comprises UAA, UGA or UAG. In another aspect, provided herein is a method of increasing expression of a protein in a subject wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF), which ORF comprises a premature termination codon (PTC), comprising contacting the subject, in an amount and / or for a time sufficient to increase expression of the protein, with a TREM composition that (i) has an anticodon that pairs with the PTC, (ii) recognizes an aminoacyl-tRNA synthetase specific for Trp, Tyr, Cys, Glu, Lys, Gln, Ser, Leu, Arg, or Gly, (iii) comprises a sequence of Formula A, or (iv) comprises a non-naturally occurring modification. In an embodiment, the PTC comprises UAA, UGA or UAG. In an embodiment, the TREM composition comprises (i). In an embodiment, the TREM composition comprises (ii). In an embodiment, the TREM composition comprises (iii). In an embodiment, the TREM composition comprises (iv). In an embodiment, the TREM composition comprises two of (i)- (iv). In an embodiment, the TREM composition comprises three of (i)-(iv). In an embodiment, the TREM composition comprises each of (i)-(iv). In another aspect, the disclosure provides a method of treating a subject having an endogenous open reading frame (ORF) which comprises a premature termination codon (PTC), comprising providing a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein, wherein the TREM comprises an anticodon that pairs with the PTC in the ORF; contacting the subject with the composition comprising a TREM, TREM core fragment or TREM fragment in an amount and / or for a time sufficient to treat the subject, thereby treating the subject. In an embodiment, the PTC comprises UAA, UGA or UAG. In another aspect, the disclosure provides a method of treating a subject having an disease or disorder associated with a premature termination codon (PTC), comprising providing a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein; contacting the subject with the composition comprising a TREM, TREM core fragment or TREM fragment in an amount and / or for a time sufficient to treat the subject, thereby treating Attorney Docket No.: F2099-7038WO the subject. In an embodiment, the PTC comprises UAA, UGA or UAG. In an embodiment, the disease or disorder associated with a PTC is a disease or disorcer described herein, e.g., a cancer or a monogenic disease. In an embodiment of any of the methods disclosed herein, the codon having the first sequence comprises a mutation (e.g., a point mutation, e.g., a nonsense mutation), resulting in a premature termination codon (PTC) chosen from UAA, UGA or UAG. In an embodiment, the codon having the first sequence or the PTC comprises a UAA mutation. In an embodiment, the codon having the first sequence or the PTC comprises a UGA mutation. In an embodiment, the codon having the first sequence or the PTC comprises a UAG mutation In another aspect, the disclosure provides a method of making a TREM, a TREM core fragment, or a TREM fragment disclosed herein, comprising linking a first nucleotide to a second nucleotide to form the TREM. In an embodiment, the TREM, TREM core fragment or TREM fragment is non-naturally occurring (e.g., synthetic). In an embodiment, the TREM, TREM core fragment or TREM fragment is made by cell- free solid phase synthesis. In another aspect, the disclosure provides a method of modulating a tRNA pool in a cell comprising: providing a TREM, a TREM core fragment, or a TREM fragment disclosed herein, and contacting the cell with the TREM, TREM core fragment or TREM fragment, thereby modulating the tRNA pool in the cell. In an aspect, the disclosure provides a method of contacting a cell, tissue, or subject with a TREM, a TREM core fragment, or a TREM fragment disclosed herein, comprising: contacting the cell, tissue or subject with the TREM, TREM core fragment or TREM fragment, thereby contacting the cell, tissue, or subject with the TREM, TREM core fragment or TREM fragment. In another aspect, the disclosure provides a method of delivering a TREM, TREM core fragment or TREM fragment to a cell, tissue, or subject, comprising: providing a cell, tissue, or subject, and contacting the cell, tissue, or subject, a TREM, a TREM core fragment, or a TREM fragment disclosed herein. In an aspect, the disclosure provides a method of modulating a tRNA pool in a cell comprising an endogenous open reading frame (ORF), which ORF comprises a codon having a first sequence, comprising: Attorney Docket No.: F2099-7038WO optionally, acquiring knowledge of the abundance of one or both of (i) and (ii), e.g., acquiring knowledge of the relative amounts of: (i) and (ii) in the cell, wherein (i) is a tRNA moiety having an anticodon that pairs with the codon of the ORF having a first sequence (the first tRNA moiety) and (ii) is an isoacceptor tRNA moiety having an anticodon that pairs with a codon other than the codon having the first sequence (the second tRNA moiety) in the cell; contacting the cell with a TREM, a TREM core fragment, or a TREM fragment disclosed herein, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with: the codon having the first sequence; or the codon other than the codon having the first sequence, in an amount and / or for a time sufficient to modulate the relative amounts of the first tRNA moiety and the second tRNA moiety in the cell, thereby modulating the tRNA pool in the cell. In another aspect, the disclosure provides a method of modulating a tRNA pool in a subject having an ORF, which ORF comprises a codon having a first sequence, comprising: optionally, acquiring knowledge of the abundance of one or both of (i) and (ii), e.g., acquiring knowledge of the relative amounts of: (i) and (ii) in the subject, wherein (i) is a tRNA moiety having an anticodon that pairs with the codon of the ORF having a first sequence (the first tRNA moiety) and (ii) is an isoacceptor tRNA moiety having an anticodon that pairs with a codon other than the codon having the first sequence (the second tRNA moiety) in the subject; contacting the subject with a TREM, a TREM core fragment, or a TREM fragment disclosed herein, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with: the codon having the first sequence; or the codon other than the codon having the first sequence, in an amount and / or for a time sufficient to modulate the relative amounts of the first tRNA moiety and the second tRNA moiety in the subject, thereby modulating the tRNA pool in the subject. In an aspect, the disclosure provides a method of modulating a tRNA pool, e.g., a tRNA pool in a cell or subject having an endogenous ORF, comprising providing a composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein, wherein the TREM, TREM core fragment or TREM fragment comprises a nucleotide sequence modification and / or a non-naturally occurring modification; contacting the subject with the composition in an amount and / or for a time sufficient to modulate the tRNA pool in the subject,thereby modulating the tRNA pool in the subject. Attorney Docket No.: F2099-7038WO In an aspect, the disclosure provides a method of modulating expression of a protein in a cell, wherein the protein is encoded by a nucleic acid comprising an ORF, which ORF comprises a codon having a mutation, comprising: contacting the cell with a composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein in an amount and / or for a time sufficient to modulate expression of the encoded protein, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the codon having the mutation, thereby modulating expression of the protein in the cell. In another aspect, the disclosure provides a method of modulating expression of a protein in a subject, wherein the protein is encoded by a nucleic acid comprising an endogenous ORF, which ORF comprises a codon having a mutation, comprising: contacting the subject with a composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein, in an amount and / or for a time sufficient to modulate expression of the encoded protein, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the codon having the mutation, thereby modulating expression of the protein in the subject. In an embodiment of any of the methods disclosed herein, the mutation in the ORF is a nonsense mutation, e.g., resulting in a premature stop codon chosen from UAA, UGA or UAG. In an embodiment, the stop codon is UAA. In an embodiment, the stop codon is UGA. In an embodiment, the stop codon is UAG. In an embodiment of any of the methods disclosed herein, the TREM comprises an anticodon that pairs with a stop codon. TREMs of the disclosure include TREMs, TREM core fragments and TREM fragments. TREMs, TREM core fragments or TREM fragments can be modified with non-naturally occurring modifications to, e.g., increase the level and / or activity (e.g., stability) of the TREM. Pharmaceutical TREM compositions, e.g., comprising TREMs having a non-naturally occurring modification, can be administered to cells, tissues or subjects to modulate these functions, e.g., in vitro or in vivo. Disclosed herein are TREMs, TREM core fragments or TREM fragments Attorney Docket No.: F2099-7038WO comprising non-naturally occurring modifications, TREM compositions, preparations, methods of making TREM compositions and preparations, and methods of using the same. In an embodiment, the TREM, TREM core fragment, and TREM fragments comprise a non-naturally occurring modification that improves stability or enhances activity of the TREM, TREM core fragment, or TREM fragment. Additional features of any of the aforesaid TREMs, TREM core fragments, TREM fragments, TREM compositions, preparations, methods of making TREM compositions and preparations, and methods of using TREM compositions and preparations include one or more of the features in the Enumerated Embodiments, Figures, Description, Examples, or Claims. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following Enumerated Embodiments, Drawings, Description, Examples, or Claims. BRIEF DESCRIPTION OF DRAWINGS FIGs.1-2 are graphs showing activity of TREMs for read-though of a premature termination codon (PTC) engineered in a NanoLuc reporter protein to produce a functional NanoLuc protein in a cell line stably expressing the NanoLuc reporter protein upon transduction with TREM expression constructs. FIG.1 is a graph comparing the log2 PTC read-though activity of TREMs consisting of the nucleotide sequence scaffolds listed in Table 7 modified with each of the chemical modification patterns listed in Table 6. FIG.2 is a graph comparing the log2 PTC readthrough activity of TREMs consisting of the nucleotide sequence scaffolds listed in Table 7 comprising 0 to 41 chemically modified nucleotides. FIG.3 is a table listing exemplary TREMs described herein. FIG.4 shows the abundance of nucleotide substitutions at each position of various TREM scaffolds in a pool of hits resulting from a pooled screen for PTC read-through activity of TREMs comprising nucleotide substitutions. The SEQ ID NOs indicate reference TREMs from which the pool of TREMs having nucleotide substitutions is generated for screening. FIG.4A is a schematic representation of a TREM indicating regions where nucleotide substitutions typically result in increased PTC read-through activity, e.g., typically positive, typically result in decreased PTC read-through activity, e.g., typically negative, or result in increased PTC read- Attorney Docket No.: F2099-7038WO through activity for certain scaffolds, e.g., scaffold-specific positive. FIG.4B shows the normalized hit abundance for nucleotide substitutions at each position in various TREM scaffolds, e.g., the frequency at which each position within a TREM comprises a nucleotide substitution in the pool of hits from a screen for increased PTC read-through activity. FIG.5 is a heatmap showing the enrichment of nucleotide substitutions, e.g., mutated sites, at each position of various TREM scaffolds in a pool of hits resulting from a pooled screen for PTC read-through activity of TREMs comprising nucleotide substitutions, e.g., showing the frequency at which each position within a TREM comprises a nucleotide substitution in the pool of hits from a screen for increased PTC read-through activity. The SEQ ID NOs indicate reference TREMs from which the pool of TREMs comprising nucleotide substitutions is generated for screening. The boxed regions indicate positions where nucleotide substitutions result in increased activity of a TREM. FIGs.6-15 are graphs showing the abundance of nucleotide substitutions at each position of various TREM scaffolds in a pool of hits resulting from a pooled screen for PTC read-through activity of TREMs comprising nucleotide substitutions. The SEQ ID NOs indicate reference TREMs from which the pool of TREMs comprising nucleotide substitutions is generated for screening. FIG.6 shows the normalized hit abundance for nucleotide substitutions at each position in an Arg-TGA reference scaffold (SEQ ID NO: 1638). FIG.7 shows the normalized hit abundance for nucleotide substitutions at each position in a Gln-TAG reference scaffold (SEQ ID NO: 1835). FIG.8 shows the normalized hit abundance for nucleotide substitutions at each position in two Gln-TAG reference scaffolds (SEQ ID NOs: 1660 and 1654) resulting from the first round of pooled screening shown in FIG.7. FIG.9 shows the aggregate normalized hit abundance for nucleotide substitutions at each position in three Glu-TAG reference scaffolds (SEQ ID NOs: 1867, 2000, and 2001). FIG.10 shows the normalized hit abundance for nucleotide substitutions at each position in a Glu-TAG reference scaffold (SEQ ID NO: 1867). FIG.11 shows the normalized hit abundance for nucleotide substitutions at each position in a Glu-TAG reference scaffold (SEQ ID NO: 2000). FIG.12 shows the normalized hit abundance for nucleotide substitutions at each position in two Leu-TAG reference scaffolds (SEQ ID NOs: 2016 and 2017). FIG.13 shows the normalized hit abundance for nucleotide substitutions at each position in two Tyr-TAG reference scaffolds (SEQ ID NOs: 2022 and 2023). FIG.14 shows the normalized hit abundance for nucleotide substitutions at each position in two Ser-TAG Attorney Docket No.: F2099-7038WO reference scaffolds (SEQ ID NOs: 2020 and 2021). FIG.15 shows the normalized hit abundance for nucleotide substitutions at each position in two Lys-TAG reference scaffolds (SEQ ID NOs: 2018 and 2019). FIG.16 is a heatmap showing enrichment for disrupted base-pairing at each position of various TREM scaffolds resulting from a pooled screen for PTC read-through activity of TREMs having nucleotide substitutions. The SEQ ID NOs indicate reference TREMs from which the pool of TREMs comprising nucleotide substitutions is generated for screening. The boxed regions indicate positions where nucleotide substitutions that disrupt base pairing result in increased activity of a TREM. FIG.17 is a scatter plot showing the enrichment score for TREMs in a Gln-TAG pooled screen. Candidates are colored in gray, negative control TREMs in black, and human-based tRNAs with anticodons cognate to the TAG PTC in as positive controls magenta. The hit threshold is indicated as vertical and horizontal dashed lines, with candidates in the upper right quadrant designated as hits. FIG.18 is a graph showing a luciferase reporter assay performed on candidates shown in FIG.17 selected for hit validation. The starting sequence from which variants were then created is shown in magenta, and the activity of all tested sequences was evaluated at two concentrations. FIGs.19A-B show the enrichment score for TREMs in a Glu-TAG pooled screen. FIG. 19A shows candidate TREMs are colored in light gray, negative control TREMs in dark gray, and human-based tRNAs with anticodons cognate to the TAG PTC as positive controls in magenta. The hit threshold is indicated as vertical and horizontal dashed lines, with candidates in the upper right quadrant designated as hits. FIG.19B shows Glu-TAG TREM hits resulting from the screen. FIGs.20A-B show a luciferase reporter assay performed on candidates shown in FIG.19 selected for hit validation. FIGs.21A-C show schematics of TREMs from hits shown in FIG.20. FIG.21A shows the parent TREM. FIG.21B shows a Glu-TAG TREM hit. FIG.21C shows a Glu-TAG TREM hit. Attorney Docket No.: F2099-7038WO FIG.22 is a scatter plot showing the results of a luciferase reporter assay performed on candidate TREMs selected for hit validation as both synthesized oligonucleotides and as lentiviral particles. The parent sequence is shown in magenta, with hits shown in gray. FIG.23 is a table listing exemplary TREMs described herein. FIG.24 is a table listing the effect of nucleotide substitutions on the PTC read-through activity of TREMs listed in FIG.23. “Sub.” indicates substitution; “compens.” indicates compensatory; “rel.” indicates relative. FIG.25 is a table comparing the PTC read-through activity of hits from a pooled screen of TREMs comprising nucleotide substitutions measured by validation as synthesized oligonucleotides or by lentiviral delivery. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS The present disclosure features tRNA-based effector molecules (TREMs), compositions, and related methods useful for optimizing a functional parameter of the TREM, for example, by introducing a nucleotide sequence modification, a non-naturally occurring chemical modification, or both into the TREM sequence. As disclosed herein, TREMs are complex molecules which can mediate a variety of cellular processes. The inventors have discovered that the nucleotide sequence of a TREM can be optimized to modulate a functional parameter of a TREM; the methods described herein describe how a plurality of sequences (e.g., tens, hundreds, or thousands) may be screened in order to select for a TREM sequence bearing a different functional readout. For example, out of a pooled screen of TREM sequences in which each nucleotide position of the TREM has been substituted with another nucleotide sequence, TREM sequences may be analyzed to select those TREMs that contain certain nucleotide substitutions that may, e.g., enhance the TREM for a certain function, such as improved readthrough of a premature termination codon (PTC), in a transcript. Pharmaceutical TREM compositions, e.g., the TREMs described herein, can be administered to a cell, a tissue, or to a subject to modulate certain cellular functions. Also disclosed herein are methods of modulating expression of a protein in a subject or cell, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF) having a first sequence, e.g., a mutation, e.g., a premature termination codon (PTC), and methods of treating a subject having an endogenous open reading frame (ORF) which comprises a Attorney Docket No.: F2099-7038WO premature termination codon (PTC). Further disclosed herein are TREMs comprising a non- naturally occurring modification, methods of making the same and compositions thereof. Definitions “Acquire” or “acquiring” as the terms are used herein, refer to obtaining possession of a value, e.g., a numerical value, by “directly acquiring” or “indirectly acquiring” the physical entity or value. “Directly acquiring” refers to performing a process (e.g., performing an analytical method) to obtain the value. “Indirectly acquiring” refers to receiving the value from another party or source (e.g., a third party laboratory that directly acquired the or value). A “disease or disorder associated with a PTC” as that term is used herein includes, but is not limited to, a disease or disorder in which cells express, or at one time expressed, a polypeptide encoded by an ORF comprising a PTC. In some embodiments, a disease associated with a PTC is chosen from: a proliferative disorder (e.g., a cancer), a genetic disorder, a metabolic disorder, an immune disorder, an inflammatory disorder or a neurological disorder. Exemplary diseases or disorders associated with a PTC are provided in any one of Tables 15, 16 and 17. In an embodiment, the disease associated with a PTC is a cancer. In an embodiment, the disease associated with a PTC is a monogenic disease. An “isoacceptor,” as that term is used herein, refers to a plurality of tRNA molecule or TREMs wherein each molecule of the plurality comprises a different naturally occurring anticodon sequence and each molecule of the plurality mediates the incorporation of the same amino acid and that amino acid is the amino acid that naturally corresponds to the anticodons of the plurality. A “modification,” as that term is used herein in regard to a TREM, may refer to a sequence modification or a chemical modification of the TREM. As this term is used to in reference to a sequence modification, the modification may include a nucleotide addition, nucleotide deletion or nucleotide substitution. As this term is used in reference to a chemical modification, the modification may include a modification of the chemical structure, e.g., a covalent modification, of the subject nucleotide. The chemical modification can be naturally occurring or non-naturally occurring. In an embodiment, the modification is non-naturally occurring. In an embodiment, the modification is naturally occurring. In an embodiment, the Attorney Docket No.: F2099-7038WO modification is a synthetic modification. In an embodiment, the modification is a modification provided in Table 5. A “naturally occurring nucleotide,” as that term is used herein, refers to a nucleotide that does not comprise a non-naturally occurring modification. In an embodiment, it includes a naturally occurring modification. A “non-naturally occurring modification,” as that term is used herein with reference to a nucleotide, refers to a chemical modification that: (a) a cell, e.g., a human cell, does not make on an endogenous tRNA; or (b) a cell, e.g., a human cell, can make on an endogenous tRNA but wherein such modification is in a location in which it does not occur on a native tRNA, e.g., the modification is in a domain, linker or arm, or on a nucleotide and / or at a position within a domain, linker or arm, which does not have such modification in nature. In either case, the modification is added synthetically, e.g., in a cell free reaction, e.g., in a solid state or liquid phase synthetic reaction. In an embodiment, the non-naturally occurring modification is a modification that is not present (in identity, location or position) if a sequence of the TREM is expressed in a mammalian cell, e.g., a HEK293 cell line. Exemplary non-naturally occurring modifications are found in Table 5. A “non-naturally modified nucleotide,” as that term is used herein, refers a nucleotide comprising a non-naturally occurring modification on or of a sugar, nucleobase, or phosphate moiety. A “nucleotide,” as that term is used herein, refers to an entity comprising a sugar, typically a pentameric sugar; a nucleobase; and a phosphate linking group. In an embodiment, a nucleotide comprises a naturally occurring, e.g., naturally occurring in a human cell, nucleotide, e.g., an adenine, thymine, guanine, cytosine, or uracil nucleotide. A “premature termination codon” or “PTC” as those terms are used herein, refer to a stop codon that occurs in an open reading frame (ORF) of a DNA or mRNA. In an embodiment, a PTC occurs at a position upstream of a naturally occurring stop codon in an ORF. In an embodiment, a PTC that occurs upstream of a naturally occurring stop codon, e.g., in an ORF, results in modulation of a production parameter of the corresponding mRNA or polypeptide encoded by the ORF. In an embodiment, a PTC can differ (or arise) from a pre-mutation sequence by a point mutation, e.g., a nonsense mutation. In an embodiment, a PTC can differ (or arise) from a pre-mutation sequence by a genetic change, e.g., abnormality, other than a point Attorney Docket No.: F2099-7038WO mutation, e.g., a frameshift, a deletion, an insertion, a rearrangement, an inversion, a translocation, a duplication, or a transversion. In an embodiment, a PTC results in the production of a truncated protein which lacks a native activity or which is associated with a mutant, disease, or other unwanted phenotype. In an embodiment, the ORF comprising the PTC is an ORF from a tumor suppressor gene. In an embodiment, the mutation giving rise to the PTC is a driver mutation, e.g., a mutation that provides a growth advantage to a tumor cell. A “functional parameter,” refers to an expression parameter and / or a signaling parameter. In an embodiment a functional parameter is an expression parameter. An expression parameter includes an expression parameter of a polypeptide or protein encoded by the endogenous ORF having a first sequence or PTC; or an expression parameter of an RNA, e.g., messenger RNA, encoded by the endogenous ORF having a first sequence or PTC. In an embodiment, an expression parameter can include: (a) protein translation; (b) expression level (e.g., of polypeptide or protein, or mRNA); (c) post-translational modification of polypeptide or protein; (d) folding (e.g., of polypeptide or protein, or mRNA), (e) structure (e.g., of polypeptide or protein, or mRNA), (f) transduction (e.g., of polypeptide or protein), (g) compartmentalization (e.g., of polypeptide or protein, or mRNA), (h) incorporation (e.g., of polypeptide or protein, or mRNA) into a supermolecular structure, e.g., incorporation into a membrane, proteasome, or ribosome, (i) incorporation into a multimeric polypeptide, e.g., a homo or heterodimer, and / or (j) stability. In an embodiment, a functional parameter is a signaling parameter. A signaling parameter can include: (1) modulation of a signaling pathway, e.g., a cellular signaling pathway which is downstream or upstream of the protein encoded by the endogenous ORF having a first sequence or PTC; (2) cell fate modulation; (3) ribosome occupancy modulation; (4) protein translation modulation; Attorney Docket No.: F2099-7038WO (5) mRNA stability modulation; (6) protein folding and structure modulation; (7) protein transduction or compartmentalization modulation; and / or (8) protein stability modulation. An “ORF having a PTC” as that phrase is used herein, refers to an open reading frame (ORF) which comprises a premature termination codon (PTC). In an embodiment, the ORF having the PTC is associated with a disease or disorder associated with a PTC, e.g., as described herein, e.g., a disease or disorder listed in any one of Tables 15, 16 and 17. In an embodiment, the ORF having the PTC is not associated with a disease or disorder associated with a PTC. A “stop codon” as that term is used herein, refers to a three nucleotide contiguous sequence within messenger RNA that specifies a termination of translation. For example, UAG, UAA, UGA (in RNA) and TAG, TAA or TGA (in DNA) are stop codons. The stop codons are also known as amber (UAG), ochre (UAA), and opal (UGA). A “tRNA-based effector molecule” or “TREM,” as that term is used herein, refers to an RNA molecule comprising a structure or property from (a)-(v) below, and which is a recombinant TREM, a synthetic TREM, or a TREM expressed from a heterologous cell. The TREMs described in the present invention are synthetic molecules and are made, e.g., in a cell free reaction, e.g., in a solid state or liquid phase synthetic reaction. TREMs are chemically distinct, e.g., in terms of primary sequence, type or location of modifications from the endogenous tRNA molecules made in cells, e.g., in mammalian cells, e.g., in human cells. A TREM can have a plurality (e.g., 2, 3, 4, 5, 6, 7, 8, 9) of the structures and functions of (a)-(v). In an embodiment, a TREM is non-native, as evaluated by structure or the way in which it was made. In an embodiment, a TREM comprises one or more of the following structures or properties: (a’) an optional linker region of a consensus sequence provided in the “Consensus Sequence” section, e.g., a Linker 1 region; (a) an amino acid attachment domain that binds an amino acid, e.g., an acceptor stem domain (AStD), wherein an AStD comprises sufficient RNA sequence to mediate, e.g., when present in an otherwise wildtype tRNA, acceptance of an amino acid, e.g., its cognate amino acid or a non-cognate amino acid, and transfer of the amino acid (AA) in the initiation or elongation Attorney Docket No.: F2099-7038WO of a polypeptide chain. Typically, the AStD comprises a 3’-end adenosine (CCA) for acceptor stem charging which is part of synthetase recognition. In an embodiment the AStD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring AStD, e.g., an AStD encoded by a nucleic acid in Table 1. In an embodiment, the TREM can comprise a fragment or analog of an AStD, e.g., an AStD encoded by a nucleic acid in Table 1, which fragment in embodiments has AStD activity and in other embodiments does not have AStD activity. (One of ordinary skill can determine the relevant corresponding sequence for any of the domains, stems, loops, or other sequence features mentioned herein from a sequence encoded by a nucleic acid in Table 1. E.g., one of ordinary skill can determine the sequence which corresponds to an AStD from a tRNA sequence encoded by a nucleic acid in Table 1.) In an embodiment the AStD falls under the corresponding sequence of a consensus sequence provided in the “Consensus Sequence” section, or differs from the consensus sequence by no more than 1, 2, 5, or 10 positions; In an embodiment, the AStD comprises residues R1-R2-R3-R4-R5-R6-R7and residues R65- R66-R67-R68-R69-R70-R71 of Formula I ZZZ, wherein ZZZ indicates any of the twenty amino acids; In an embodiment, the AStD comprises residues R1-R2-R3-R4 -R5-R6-R7 and residues R65- R66-R67-R68-R69-R70-R71of Formula IIZZZ, wherein ZZZ indicates any of the twenty amino acids; In an embodiment, the AStD comprises residues R1-R2-R3-R4-R5-R6-R7and residues R65- R66-R67-R68-R69-R70-R71 of Formula III ZZZ, wherein ZZZ indicates any of the twenty amino acids; (a’-1) a linker comprising residues R8-R9of a consensus sequence provided in the “Consensus Sequence” section, e.g., a Linker 2 region; (b) a dihydrouridine hairpin domain (DHD), wherein a DHD comprises sufficient RNA sequence to mediate, e.g., when present in an otherwise wildtype tRNA, recognition of aminoacyl-tRNA synthetase, e.g., acts as a recognition site for aminoacyl-tRNA synthetase for amino acid charging of the TREM. In embodiments, a DHD mediates the stabilization of the TREM’s tertiary structure. In an embodiment the DHD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring DHD, e.g., a DHD encoded by a nucleic acid in Table 1. In an embodiment, the TREM can comprise a fragment or analog of a DHD, e.g., a DHD encoded by a nucleic acid in Table 1, which fragment in embodiments has DHD activity and in other embodiments does not have DHD activity. Attorney Docket No.: F2099-7038WO In an embodiment the DHD falls under the corresponding sequence of a consensus sequence provided in the “Consensus Sequence” section, or differs from the consensus sequence by no more than 1, 2, 5, or 10 positions; In an embodiment, the DHD comprises residues R10-R11-R12-R13-R14R15-R16-R17-R18- R19-R20-R21-R22-R23-R24-R25-R26-R27-R28 of Formula I ZZZ, wherein ZZZ indicates any of the twenty amino acids; In an embodiment, the DHD comprises residues R10-R11-R12-R13-R14R15-R16-R17-R18- R19-R20-R21-R22-R23-R24-R25-R26-R27-R28 of Formula II ZZZ, wherein ZZZ indicates any of the twenty amino acids; In an embodiment, the DHD comprises residues R10-R11-R12-R13-R14R15-R16-R17-R18- R19-R20-R21-R22-R23-R24-R25-R26-R27-R28of Formula IIIZZZ, wherein ZZZ indicates any of the twenty amino acids; (b’-1) a linker comprising residue R29 of a consensus sequence provided in the “Consensus Sequence” section, e.g., a Linker 3 region; (c) an anticodon that binds a respective codon in an mRNA, e.g., an anticodon hairpin domain (ACHD), wherein an ACHD comprises sufficient sequence, e.g., an anticodon triplet, to mediate, e.g., when present in an otherwise wildtype tRNA, pairing (with or without wobble) with a codon; In an embodiment the ACHD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring ACHD, e.g., an ACHD encoded by a nucleic acid in Table 1. In an embodiment, the TREM can comprise a fragment or analog of an ACHD, e.g., an ACHD encoded by a nucleic acid in Table 1, which fragment in embodiments has ACHD activity and in other embodiments does not have ACHD activity. In an embodiment the ACHD falls under the corresponding sequence of a consensus sequence provided in the “Consensus Sequence” section, or differs from the consensus sequence by no more than 1, 2, 5, or 10 positions; In an embodiment, the ACHD comprises residues -R30-R31-R32-R33-R34-R35-R36-R37-R38- R39-R40-R41-R42-R43-R44-R45-R46of Formula IZZZ, wherein ZZZ indicates any of the twenty amino acids; In an embodiment, the ACHD comprises residues -R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42-R43-R44-R45-R46of Formula IIZZZ, wherein ZZZ indicates any of the twentyamino acids; Attorney Docket No.: F2099-7038WO In an embodiment, the ACHD comprises residues -R30-R31-R32-R33-R34-R35-R36-R37-R38- R39-R40-R41-R42-R43-R44-R45-R46 of Formula III ZZZ, wherein ZZZ indicates any of the twenty amino acids; (d) a variable loop domain (VLD), wherein a VLD comprises sufficient RNA sequence to mediate, e.g., when present in an otherwise wildtype tRNA, recognition of aminoacyl-tRNA synthetase, e.g., acts as a recognition site for aminoacyl-tRNA synthetase for amino acid charging of the TREM. In embodiments, a VLD mediates the stabilization of the TREM’s tertiary structure. In an embodiment, a VLD modulates, e.g., increases, the specificity of the TREM, e.g., for its cognate amino acid, e.g., the VLD modulates the TREM’s cognate adaptor function. In an embodiment the VLD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring VLD, e.g., a VLD encoded by a nucleic acid in Table 1. In an embodiment, the TREM can comprise a fragment or analog of a VLD, e.g., a VLD encoded by a nucleic acid in Table 1, which fragment in embodiments has VLD activity and in other embodiments does not have VLD activity. In an embodiment the VLD falls under the corresponding sequence of a consensus sequence provided in the “Consensus Sequence” section. In an embodiment, the VLD comprises residue -[R47]xof a consensus sequence provided in the “Consensus Sequence” section, wherein x=1-271 (e.g., x=1-250, x=1-225, x=1-200, x=1- 175, x=1-150, x=1-125, x=1-100, x=1-75, x=1-50, x=1-40, x=1-30, x=1-29, x=1-28, x=1-27, x=1-26, x=1-25, x=1-24, x=1-23, x=1-22, x=1-21, x=1-20, x=1-19, x=1-18, x=1-17, x=1-16, x=1-15, x=1-14, x=1-13, x=1-12, x=1-11, x=1-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70-271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271); (e) a thymine hairpin domain (THD), wherein a THD comprises sufficient RNA sequence, to mediate, e.g., when present in an otherwise wildtype tRNA, recognition of the ribosome, e.g., acts as a recognition site for the ribosome to form a TREM-ribosome complex during translation. In an embodiment the THD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring THD, e.g., a THD encoded by a nucleic acid in Table 1. In an Attorney Docket No.: F2099-7038WO embodiment, the TREM can comprise a fragment or analog of a THD, e.g., a THD encoded by a nucleic acid in Table 1, which fragment in embodiments has THD activity and in other embodiments does not have THD activity. In an embodiment the THD falls under the corresponding sequence of a consensus sequence provided in the “Consensus Sequence” section, or differs from the consensus sequence by no more than 1, 2, 5, or 10 positions; In an embodiment, the THD comprises residues -R48-R49-R50-R51-R52-R53-R54-R55-R56- R57-R58-R59-R60-R61-R62-R63-R64 of Formula I ZZZ, wherein ZZZ indicates any of the twenty amino acids; In an embodiment, the THD comprises residues -R48-R49-R50-R51-R52-R53-R54-R55-R56- R57-R58-R59-R60-R61-R62-R63-R64of Formula IIZZZ, wherein ZZZ indicates any of the twenty amino acids; In an embodiment, the THD comprises residues -R48-R49-R50-R51-R52-R53-R54-R55-R56- R57-R58-R59-R60-R61-R62-R63-R64of Formula IIIZZZ, wherein ZZZ indicates any of the twenty amino acids; (e’1) a linker comprising residue R72 of a consensus sequence provided in the “Consensus Sequence” section, e.g., a Linker 4 region; (f) under physiological conditions, it comprises a stem structure and one or a plurality of loop structures, e.g., 1, 2, or 3 loops. A loop can comprise a domain described herein, e.g., a domain selected from (a)-(e). A loop can comprise one or a plurality of domains. In an embodiment, a stem or loop structure has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring stem or loop structure, e.g., a stem or loop structure encoded by a nucleic acid in Table 1. In an embodiment, the TREM can comprise a fragment or analog of a stem or loop structure, e.g., a stem or loop structure encoded by a nucleic acid in Table 1, which fragment in embodiments has activity of a stem or loop structure, and in other embodiments does not have activity of a stem or loop structure; (g) a tertiary structure, e.g., an L-shaped tertiary structure; (h) adaptor function, i.e., the TREM mediates acceptance of an amino acid, e.g., its cognate amino acid and transfer of the AA in the initiation or elongation of a polypeptide chain; Attorney Docket No.: F2099-7038WO (i) cognate adaptor function wherein the TREM mediates acceptance and incorporation of an amino acid (e.g., cognate amino acid) associated in nature with the anti-codon of the TREM to initiate or elongate a polypeptide chain; (j) non-cognate adaptor function, wherein the TREM mediates acceptance and incorporation of an amino acid (e.g., non-cognate amino acid) other than the amino acid associated in nature with the anti-codon of the TREM in the initiation or elongation of a polypeptide chain; (k) a regulatory function, e.g., an epigenetic function (e.g., gene silencing function or signaling pathway modulation function), cell fate modulation function, mRNA stability modulation function, protein stability modulation function, protein transduction modulation function, or protein compartmentalization function; (l) a structure which allows for ribosome binding; (m) a post-transcriptional modification, e.g., a naturally occurring post-trasncriptional modification; (n) the ability to inhibit a functional property of a tRNA, e.g., any of properties (h)-(k) possessed by a tRNA; (o) the ability to modulate cell fate; (p) the ability to modulate ribosome occupancy; (q) the ability to modulate protein translation; (r) the ability to modulate mRNA stability; (s) the ability to modulate protein folding and structure; (t) the ability to modulate protein transduction or compartmentalization; (u) the ability to modulate protein stability; or (v) the ability to modulate a signaling pathway, e.g., a cellular signaling pathway. In an embodiment, a TREM comprises a full-length tRNA molecule or a fragment thereof. In an embodiment, a TREM comprises the following properties: (a)-(e). In an embodiment, a TREM comprises the following properties: (a) and (c). In an embodiment, a TREM comprises the following properties: (a), (c) and (h). In an embodiment, a TREM comprises the following properties: (a), (c), (h) and (b). In an embodiment, a TREM comprises the following properties: (a), (c), (h) and (e). Attorney Docket No.: F2099-7038WO In an embodiment, a TREM comprises the following properties: (a), (c), (h), (b) and (e). In an embodiment, a TREM comprises the following properties: (a), (c), (h), (b), (e) and (g). In an embodiment, a TREM comprises the following properties: (a), (c), (h) and (m). In an embodiment, a TREM comprises the following properties: (a), (c), (h), (m), and (g). In an embodiment, a TREM comprises the following properties: (a), (c), (h), (m) and (b). In an embodiment, a TREM comprises the following properties: (a), (c), (h), (m) and (e). In an embodiment, a TREM comprises the following properties: (a), (c), (h), (m), (g), (b) and (e). In an embodiment, a TREM comprises the following properties: (a), (c), (h), (m), (g), (b), (e) and (q). In an embodiment, a TREM comprises: (i) an amino acid attachment domain that binds an amino acid (e.g., an AStD, as described in (a) herein; and (ii) an anticodon that binds a respective codon in an mRNA (e.g., an ACHD, as described in (c) herein). In an embodiment the TREM comprises a flexible RNA linker which provides for covalent linkage of (i) to (ii). In an embodiment, the TREM mediates protein translation. In an embodiment a TREM comprises a linker, e.g., an RNA linker, e.g., a flexible RNA linker, which provides for covalent linkage between a first and a second structure or domain. In an embodiment, an RNA linker comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 ribonucleotides. A TREM can comprise one or a plurality of linkers, e.g., in embodiments a TREM comprising (a), (b), (c), (d) and (e) can have a first linker between a first and second domain, and a second linker between a third domain and another domain. In an embodiment, the TREM comprises a sequence of Formula A: [L1]-[ASt Domain1]- [L2]-[DH Domain]-[L3]-[ACH Domain] -[VL Domain]-[TH Domain]-[L4]-[ASt Domain2]. In an embodiment, a TREM comprises an RNA sequence at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical with, or which differs by no more than 1, 2, 3, 4, 5, 10, 15, 20, 25, or 30 ribonucleotides from, an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof. In an embodiment, a TREM comprises an Attorney Docket No.: F2099-7038WO RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof. In an embodiment, a TREM comprises an RNA sequence encoded by a DNA sequence at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical with a DNA sequence listed in Table 1, or a fragment or functional fragment thereof. In an embodiment, a TREM comprises a TREM domain, e.g., a domain described herein, comprising at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical with, or which differs by no more than 1, 2, 3, 4, 5, 10, or 15, ribonucleotides from, an RNA encoded by a DNA sequence listed in Table 1, or a fragment or a functional fragment thereof. In an embodiment, a TREM comprises a TREM domain, e.g., a domain described herein, comprising an RNA sequence encoded by DNA sequence listed in Table 1, or a fragment or functional fragment thereof. In an embodiment, a TREM comprises a TREM domain, e.g., a domain described herein, comprising an RNA sequence encoded by DNA sequence at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical with a DNA sequence listed in Table 1, or a fragment or functional fragment thereof. In an embodiment, a TREM is 76-90 nucleotides in length. In embodiments, a TREM or a fragment or functional fragment thereof is between 10-90 nucleotides, between 10-80 nucleotides, between 10-70 nucleotides, between 10-60 nucleotides, between 10-50 nucleotides, between 10-40 nucleotides, between 10-30 nucleotides, between 10-20 nucleotides, between 20- 90 nucleotides, between 20-80 nucleotides, 20-70 nucleotides, between 20-60 nucleotides, between 20-50 nucleotides, between 20-40 nucleotides, between 30-90 nucleotides, between 30- 80 nucleotides, between 30-70 nucleotides, between 30-60 nucleotides, or between 30-50 nucleotides. In an embodiment, a TREM is aminoacylated, e.g., charged, with an amino acid by an aminoacyl tRNA synthetase. In an embodiment, a TREM is not charged with an amino acid, e.g., an uncharged TREM (uTREM). In an embodiment, a TREM comprises less than a full length tRNA. In embodiments, a TREM can correspond to a naturally occurring fragment of a tRNA, or to a non-naturally occurring fragment. Exemplary fragments include: TREM halves (e.g., from a cleavage in the ACHD, e.g., in the anticodon sequence, e.g., 5’halves or 3’ halves); a 5’ fragment (e.g., a fragment comprising the 5’ end, e.g., from a cleavage in a DHD or the ACHD); a 3’ fragment Attorney Docket No.: F2099-7038WO (e.g., a fragment comprising the 3’ end, e.g., from a cleavage in the THD); or an internal fragment (e.g., from a cleavage in one or more of the ACHD, DHD or THD). A “TREM core fragment,” as that term is used herein, refers to a portion of the sequence of Formula B: [L1]y-[ASt Domain1]x-[L2]y-[DH Domain]y-[L3]y-[ACH Domain]x-[VL Domain] y-[TH Domain] y-[L4] y-[ASt Domain2] x, wherein: x=1 and y=0 or 1. A “TREM fragment,” as used herein, refers to a portion of a TREM, wherein the TREM comprises a sequence of Formula A: [L1]-[ASt Domain1]-[L2]-[DH Domain]-[L3]-[ACH Domain] -[VL Domain]-[TH Domain]-[L4]-[ASt Domain2]. A “cognate adaptor function TREM,” as that term is used herein, refers to a TREM which mediates initiation or elongation with the AA (the cognate AA) associated in nature with the anti-codon of the TREM. “Decreased expression,” as that term is used herein, refers to a decrease in comparison to a reference, e.g., in the case where altered control region, or addition of an agent, results in a decreased expression of the subject product, it is decreased relative to an otherwise similar cell without the alteration or addition. An “exogenous nucleic acid,” as that term is used herein, refers to a nucleic acid sequence that is not present in or differs by at least one nucleotide from the closest sequence in a reference cell, e.g., a cell into which the exogenous nucleic acid is introduced. In an embodiment, an exogenous nucleic acid comprises a nucleic acid that encodes a TREM. An “exogenous TREM,” as that term is used herein, refers to a TREM that: (a) differs by at least one nucleotide or one post transcriptional modification from the closest sequence tRNA in a reference cell, e.g., a cell into which the exogenous nucleic acid is introduced; (b) has been introduced into a cell other than the cell in which it was transcribed; (c) is present in a cell other than one in which it naturally occurs; or (d) has an expression profile, e.g., level or distribution, that is non-wildtype, e.g., it is expressed at a higher level than wildtype. In an embodiment, the expression profile can be mediated by a change introduced into a nucleic acid that modulates expression or by addition of an agent that modulates expression of the RNA molecule. In an embodiment an exogenous TREM comprises 1, 2, 3 or 4 of properties (a)-(d). Attorney Docket No.: F2099-7038WO A “GMP-grade composition,” as that term is used herein, refers to a composition in compliance with current good manufacturing practice (cGMP) guidelines, or other similar requirements. In an embodiment, a GMP-grade composition can be used as a pharmaceutical product. As used herein, the terms “increasing” and “decreasing” refer to modulating that results in, respectively, greater or lesser amounts of function, expression, or activity of a particular metric relative to a reference. For example, subsequent to administration to a cell, tissue or subject of a TREM described herein, the amount of a marker of a metric (e.g., protein translation, mRNA stability, protein folding) as described herein may be increased or decreased by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 98%, 2X, 3X, 5X, 10X or more relative to the amount of the marker prior to administration or relative to the effect of a negative control agent. The metric may be measured subsequent to administration at a time that the administration has had the recited effect, e.g., at least 12 hours, 24 hours, one week, one month, 3 months, or 6 months, after a treatment has begun. “Increased expression,” as that term is used herein, refers to an increase in comparison to a reference, e.g., in the case where altered control region, or addition of an agent, results in an increased expression of the subject product, it is increased relative to an otherwise similar cell without the alteration or addition. A “non-cognate adaptor function TREM,” as that term is used herein, refers to a TREM which mediates initiation or elongation with an AA (a non-cognate AA) other than the AA associated in nature with the anti-codon of the TREM. In an embodiment, a non-cognate adaptor function TREM is also referred to as a mischarged TREM (mTREM). A “non-naturally occurring sequence,” as that term is used herein, refers to a sequence wherein an Adenine is replaced by a residue other than an analog of Adenine, a Cytosine is replaced by a residue other than an analog of Cytosine, a Guanine is replaced by a residue other than an analog of Guanine, and a Uracil is replaced by a residue other than an analog of Uracil. An analog refers to any possible derivative of the ribonucleotides, A, G, C or U. In an embodiment, a sequence having a derivative of any one of ribonucleotides A, G, C or U is a non- naturally occurring sequence. Attorney Docket No.: F2099-7038WO A “pharmaceutical TREM composition,” as that term is used herein, refers to a TREM composition that is suitable for pharmaceutical use. Typically, a pharmaceutical TREM composition comprises a pharmaceutical excipient. In an embodiment the TREM will be the only active ingredient in the pharmaceutical TREM composition. In embodiments the pharmaceutical TREM composition is free, substantially free, or has less than a pharmaceutically acceptable amount, of host cell proteins, DNA, e.g., host cell DNA, endotoxins, and bacteria. A “post-transcriptional processing,” as that term is used herein, with respect to a subject molecule, e.g., a TREM, RNA or tRNAs, refers to a covalent modification of the subject molecule. In an embodiment, the covalent modification occurs post-transcriptionally. In an embodiment, the covalent modification occurs co-transcriptionally. In an embodiment the modification is made in vivo, e.g., in a cell used to produce a TREM. In an embodiment the modification is made ex vivo, e.g., it is made on a TREM isolated or obtained from the cell which produced the TREM. In an embodiment, the post-transcriptional modification is selected from a post-transcriptional modification listed in Table 2. A “tRNA”, as that term is used herein, refers to a naturally occurring transfer ribonucleic acid in its native state. A “TREM composition,” as that term is used herein, refers to a composition comprising a plurality of TREMs, a plurality of TREM core fragments and / or a plurality of TREM fragments. A TREM composition can comprise one or more species of TREMs, TREM core fragments or TREM fragments. In an embodiment, the composition comprises only a single species of TREM, TREM core fragment or TREM fragment. In an embodiment, the TREM composition comprises a first TREM, TREM core fragment or TREM fragment species; and a second TREM, TREM core fragment or TREM fragment species. In an embodiment, the TREM composition comprises X TREM, TREM core fragment or TREM fragment species, wherein X=2, 3, 4, 5, 6, 7, 8, 9, or 10. In an embodiment, the TREM, TREM core fragment or TREM fragment has at least 70, 75, 80, 85, 90, or 95, or has 100%, identity with a sequence encoded by a nucleic acid in Table 1. A TREM composition can comprise one or more species of TREMs, TREM core fragments or TREM fragments. In an embodiment, the TREM composition is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95 or 99% dry weight TREMs (for a liquid composition dry weight refers to the weight after removal of substantially all liquid, e.g., after lyophilization). In an embodiment, the composition is a liquid. In an embodiment, the composition is dry, e.g., a Attorney Docket No.: F2099-7038WO lyophilized material. In an embodiment, the composition is a frozen composition. In an embodiment, the composition is sterile. In an embodiment, the composition comprises at least 0.5 g, 1.0 g, 5.0 g, 10 g, 15 g, 25 g, 50 g, 100 g, 200 g, 400 g, or 500 g (e.g., as determined by dry weight) of TREM. In an embodiment, at least X% of the TREMs in a TREM composition has a non-naturally occurring modification at a selected position, and X is 80, 90, 95, 96, 97, 98, 99, or 99.5. In an embodiment, at least X% of the TREMs in a TREM composition has a non- naturally occurring modification at a first position and a non-naturally occurring modification at a second position, and X, independently, is 80, 90, 95, 96, 97, 98, 99, or 99.5. In embodiments, the modification at the first and second position is the same. In embodiments, the modification at the first and second position are different. In embodiments, the nucleiotide at the first and second position is the same, e.g., both are adenine. In embodiments, the nucleiotide at the first and second position are different, e.g., one is adenine and one is thymine. In an embodiment, at least X% of the TREMs in a TREM composition has a non- naturally occurring modification at a first position and less than Y% have a non-naturally occurring modification at a second position, wherein X is 80, 90, 95, 96, 97, 98, 99, or 99.5 and Y is 20, 20, 5, 2, 1, .1, or .01. In embodiments, the nucleotide at the first and second position is the same, e.g., both are adenine. In embodiments the nucleotide at the first and second position are different, e.g., one is adenine and one is thymine. TREM, TREM core fragment and TREM fragment A “tRNA-based effector molecule” or “TREM” refers to an RNA molecule comprising one or more of the properties described herein. A TREM can comprise a non-naturally occurring modification, e.g., as provided in Table 5. A TREM may further comprise a nucleotide modification, for example, a nucleotide substitution, nucleotide deletion, or nucleotide addition, relative to a second TREM. In an embodiment, a TREM includes a TREM comprising a sequence of Formula A; a TREM core fragment comprising a sequence of Formula B; or a TREM fragment comprising a portion of a TREM which TREM comprises a sequence of Formula A. Attorney Docket No.: F2099-7038WO In an embodiment, a TREM comprises a sequence of Formula A: [L1]-[ASt Domain1]- [L2]-[DH Domain]-[L3]-[ACH Domain] -[VL Domain]-[TH Domain]-[L4]-[ASt Domain2]. In an embodiment, [VL Domain] is optional. In an embodiment, [L1] is optional. In an embodiment, a TREM core fragment comprises a sequence of Formula B: [L1]y- [ASt Domain1] x-[L2] y-[DH Domain]y-[L3] y-[ACH Domain]x-[VL Domain] y-[TH Domain] y- [L4] y-[ASt Domain2] x, wherein: x=1 and y=0 or 1. In an embodiment, y=0. In an embodiment, y=1.. In an embodiment, a TREM fragment comprises a portion of a TREM, wherein the TREM comprises a sequence of Formula A: [L1]-[ASt Domain1]-[L2]-[DH Domain]-[L3]- [ACH Domain] -[VL Domain]-[TH Domain]-[L4]-[ASt Domain2], and wherein the TREM fragment comprises: one, two, three or all or any combination of the following: a TREM half (e.g., from a cleavage in the ACH Domain, e.g., in the anticodon sequence, e.g., a 5’half or a 3’ half); a 5’ fragment (e.g., a fragment comprising the 5’ end, e.g., from a cleavage in a DH Domain or the ACH Domain); a 3’ fragment (e.g., a fragment comprising the 3’ end, e.g., from a cleavage in the TH Domain); or an internal fragment (e.g., from a cleavage in any one of the ACH Domain, DH Domain or TH Domain). Exemplary TREM fragments include TREM halves (e.g., from a cleavage in the ACHD, e.g., 5’TREM halves or 3’ TREM halves), a 5’ fragment (e.g., a fragment comprising the 5’ end, e.g., from a cleavage in a DHD or the ACHD), a 3’ fragment (e.g., a fragment comprising the 3’ end of a TREM, e.g., from a cleavage in the THD), or an internal fragment (e.g., from a cleavage in one or more of the ACHD, DHD or THD). In an embodiment, a TREM, a TREM core fragment or a TREM fragment can be charged with an amino acid (e.g., a cognate amino acid); charged with a non-cognate amino acid (e.g., a mischarged TREM (mTREM)); or not charged with an amino acid (e.g., an uncharged TREM (uTREM)). In an embodiment, a TREM, a TREM core fragment or a TREM fragment can be charged with an amino acid selected from alanine, arginine, asparagine, aspartate, cysteine, glutamine, glutamate, glycine, histidine, isoleucine, methionine, leucine, lysine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine. In some embodiments, a non-extended anticodon is an anticodon of no more than three nucleotides. In an embodiment, a non-extended codon pairs with no more than three codon nucleotides on a nucleic acid being translated. Attorney Docket No.: F2099-7038WO In an embodiment, the TREM, TREM core fragment or TREM fragment is a cognate TREM. In an embodiment, the TREM, TREM core fragment or TREM fragment is a non- cognate TREM. In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes a codon provided in Table 2 or Table 3. Table 2: List of codons AAA GAG AAC GAU Attorney Docket No.: F2099-7038WO Table 3: Amino acids and corresponding codons Amino Acid mRNA codons Alanine GCU, GCC, GCA, GCG In an embodiment, a TREM comprises a ribonucleic acid (RNA) sequence encoded by a deoxyribonucleic acid (DNA) sequence disclosed in Table 1, e.g., any one of SEQ ID NOs: 1- 451 disclosed in Table 1. In an embodiment, a TREM comprises an RNA sequence at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to an RNA sequence encoded by a DNA sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 1. In an embodiment, a TREM comprises an RNA sequence encoded by a DNA sequence at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to a DNA sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 1. In an embodiment, a TREM, a TREM core fragment, or TREM fragment comprises at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence encoded by a DNA Attorney Docket No.: F2099-7038WO sequence disclosed in Table 1, e.g., at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence encoded by any one of SEQ ID NOs: 1-451 disclosed in Table 1. In an embodiment, a TREM, a TREM core fragment, or TREM fragment comprises at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to an RNA sequence encoded by a DNA sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 1. In an embodiment, a TREM, a TREM core fragment, or TREM fragment comprises at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence encoded by a DNA sequence at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to a DNA sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 1. In an embodiment, a TREM core fragment or a TREM fragment comprises at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of an RNA sequence encoded by a DNA sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 1. In an embodiment, a TREM core fragment or a TREM fragment comprises at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of an RNA sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to an RNA sequence encoded by a DNA sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 1. In an embodiment, a TREM core fragment or a TREM fragment comprises at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of an RNA sequence encoded by a DNA sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to a DNA sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 1. In an embodiment, a TREM core fragment or a TREM fragment comprises at least 5 ribonucleotides (nt), 10 nt, 15 nt, 20 nt, 25 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, 55 nt or 60 nt (but less than the full length) of an RNA sequence encoded by a DNA sequence disclosed in Table 1, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 1. In an embodiment, a TREM core fragment or a TREM fragment comprises at least 5 ribonucleotides (nt), 10 nt, 15 nt, 20 nt, 25 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, 55 nt or 60 nt (but less than the full length) of an RNA sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to an RNA Attorney Docket No.: F2099-7038WO sequence encoded by a DNA sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 1. In an embodiment, a TREM core fragment or a TREM fragment comprises at least 5 ribonucleotides (nt), 10 nt, 15 nt, 20 nt, 25 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, 55 nt or 60 nt (but less than the full length) of an RNA sequence encoded by a DNA sequence with at least 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, 99% or 100% identity to a DNA sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 1. In an embodiment, a TREM core fragment or a TREM fragment comprises a sequence of a length of between 10-90 ribonucleotides (rnt), between 10-80 rnt, between 10-70 rnt, between 10-60 rnt, between 10-50 rnt, between 10-40 rnt, between 10-30 rnt, between 10-20 rnt, between 20-90 rnt, between 20-80 rnt, 20-70 rnt, between 20-60 rnt, between 20-50 rnt, between 20-40 rnt, between 30-90 rnt, between 30-80 rnt, between 30-70 rnt, between 30-60 rnt, or between 30- 50 rnt Table 1: List of tRNA Sequences SEQ ID tRNA name tRNA sequence NO T C C C C C C C C C C Attorney Docket No.: F2099-7038WO Ala_AGC_chr14:8944 GGGGAATTAGCTCAAGTGGTAGAGCGCTCGC 5442-89445514 (+) TTAGCATGCGAGAGGTAGTGGGATCGATGCC C C T T T T T T C C C C T T Attorney Docket No.: F2099-7038WO Ala_CGC_chr2:15725 GGGGATGTAGCTCAGTGGTAGAGCGCGCGCT 7281-157257352 (+) TCGCATGTGTGAGGTCCCGGGTTCAATCCCC T T T T T T T T A A A C Attorney Docket No.: F2099-7038WO Arg_CCT_chr17:7303 GCCCCAGTGGCCTAATGGATAAGGCACTGGC 0001-73030073 (+) CTCCTAAGCCAGGGATTGTGGGTTCGAGTCC C C C C A A A A A A A Attorney Docket No.: F2099-7038WO Arg_TCT_chr17:8024 GGCTCTGTGGCGCAATGGATAGCGCATTGGA 243-8024330 (+) CTTCTAGTGACGAATAGAGCAATTCAAAGGT A A G A G Attorney Docket No.: F2099-7038WO Asn_GTT_chr1:16847 GTCTCTGTGGCGCAATCGGTTAGCGCGTTCG 080-16847153 (-) GCTGTTAACTGAAAGGTTGGTGGTTCGAGCC C C C C C C C Attorney Docket No.: F2099-7038WO Cys_GCA_chr7:14905 GGGGGTATAGCTCAGGGGTAGAGCATTTGAC 2766-149052837 (-) TGCAGATCAAGAGGTCCCCAGTTCAAATCTG C C C C C C C C C C C C Attorney Docket No.: F2099-7038WO Cys_GCA_chr17:3702 GGGGGTATAGCTCAGTGGTAGAGCATTTGAC 5545-37025616 (-) TGCAGATCAAGAGGTCCCTGGTTCAAATCCG A C A C C T Attorney Docket No.: F2099-7038WO Gln_TTG_chr17:4726 GGTCCCATGGTGTAATGGTTAGCACTCTGGA 9890-47269961 (+) CTTTGAATCCAGCGATCCGAGTTCAAATCTC G T T G G T G G T Attorney Docket No.: F2099-7038WO Gly_GCC_chr1:16141 GCATGGGTGGTTCAGTGGTAGAATTCTCGCC 3094-161413164 (+) TGCCACGCGGGAGGCCCGGGTTCGATTCCCG T G T G T T Attorney Docket No.: F2099-7038WO Ile_AAT_chr6:272429 GGCTGGTTAGCTCAGTTGGTTAGAGCGTGGT 90-27243063 (-) GCTAATAACGCCAAGGTCGCGGGTTCGATCC C T T C T C T C T T Attorney Docket No.: F2099-7038WO Ile_TAT_chr6:285053 GCTCCAGTGGCGCAATCGGTTAGCGCGCGGT 67-28505460 (+) ACTTATAAGACAGTGCACCTGTGAGCAATGC G G G G G G C G T G T G Attorney Docket No.: F2099-7038WO Leu_CAA_chr1:16158 GTCAGGATGGCCGAGCAGTCTTAAGGCGCTG 1736-161581819 (-) CGTTCAAATCGCACCCTCCGCTGGAGGCGTG C C A A A A G G G T A A C Attorney Docket No.: F2099-7038WO Lys_CTT_chr19:5242 GCAGCTAGCTCAGTCGGTAGAGCATGAGACT 5393-52425466 (-) CTTAATCTCAGGGTCATGGGTTCGTGCCCCAT A C A A C A A C A C A C A C A C A C A C A C Attorney Docket No.: F2099-7038WO Lys_TTT_chr11:5932 GCCCGGATAGCTCAGTCGGTAGAGCATCAGA 3902-59323974 (+) CTTTTAATCTGAGGGTCCGGGGTTCAAGTCCC A C A C C T T C A A Attorney Docket No.: F2099-7038WO Phe_GAA_chr6:28775 GCCGAGATAGCTCAGTTGGGAGAGCGTTAGA 610-28775682 (-) CTGAAGATCTAAAGGTCCCTGGTTCAATCCC A A T T G T G T G T G T G T T G Attorney Docket No.: F2099-7038WO Ser_AGA_chr6:27509 GTAGTCGTGGCCGAGTGGTTAAGGCGATGGA 554-27509635 (-) CTAGAAATCCATTGGGGTTTCCCCGCGCAGG A A A A A G A G Attorney Docket No.: F2099-7038WO Ser_GCT_chr6:26305 GGAGAGGCCTGGCCGAGTGGTTAAGGCGATG 718-26305801 (-) GACTGCTAATCCATTGTGCTCTGCACGCGTG A A A A T C C Attorney Docket No.: F2099-7038WO Thr_CGT_chr6:28615 GGCTCTGTGGCTTAGTTGGCTAAAGCGCCTG 984-28616057 (-) TCTCGTAAACAGGAGATCCTGGGTTCGAATC C C T T T T T C C C Attorney Docket No.: F2099-7038WO Trp_CCA_chr7:99067 GACCTCGTGGCGCAACGGCAGCGCGTCTGAC 307-99067378 (+) TCCAGATCAGAAGGTTGCGTGTTCAAATCAC A T A G A A A T A T A A A A T A T Attorney Docket No.: F2099-7038WO Tyr_GTA_chr14:2112 CCTTCGATAGCTCAGCTGGTAGAGCGGAGGA 8117-21128210 (-) CTGTAGACTGCGGAAACGTTTGTGGACATCC A C G C G C A C G C G T C G C G C Attorney Docket No.: F2099-7038WO Val_CAC_chr1:14929 GTTTCCGTAGTGTAGTGGTTATCACGTTCGCC 8555-149298627 (-) TCACACGCGAAAGGTCCCCGGTTCGAAACTG C C A T T T C G C C G T C Attorney Docket No.: F2099-7038WO Asn_GTT_chr1:17216 TGTCTCTGTGGCGCAATCGGTTAGCGCGTTCG 171-17216245 (+) GCTGTTAACCGAAAGATTGGTGGTTCGAGCC A C T G G Attorney Docket No.: F2099-7038WO Val_CAC_chr1:14929 GTTTCCGTAGTGTAGTGGTTATCACGTTCGCC 8554-149298627 (-) TCACACGCGAAAGGTCCCCGGTTCGAAACTG C C C G C C T G C C Attorney Docket No.: F2099-7038WO Glu_TTC_chr1:16158 CGCGTTGGTGGTGTAGTGGTGAGCACAGCTG 2507-161582579 (+) CCTTTCAAGCAGTTAACGCGGGTTCGATTCCC T T G G A C A G G G C G G T Attorney Docket No.: F2099-7038WO Ala_CGC_chr2:15725 GGGGGATGTAGCTCAGTGGTAGAGCGCGCGC 7280-157257352 (+) TTCGCATGTGTGAGGTCCCGGGTTCAATCCCC T G A C C C C G C G T G T C C G C G A C Attorney Docket No.: F2099-7038WO Val_CAC_chr5:18064 GTTTCCGTAGTGTAGTGGTTATCACGTTCGCC 9394-180649467 (-) TCACACGCGAAAGGTCCCCGGTTCGAAACCG C G A C G G C G G Attorney Docket No.: F2099-7038WO Val_CAC_chr6:26538 GGTTTCCGTAGTGTAGTGGTTATCACGTTCGC 281-26538354 (+) CTCACACGCGAAAGGTCCCCGGTTCGAAACC C C T C G A C C G T G C C Attorney Docket No.: F2099-7038WO Val_CAC_chr6:27248 GCTTCTGTAGTGTAGTGGTTATCACGTTCGCC 048-27248121 (-) TCACACGCGAAAGGTCCCCGGTTCGAAACCG C A C C A C T C T Attorney Docket No.: F2099-7038WO Ala_AGC_chr6:28831 GGGGGTGTAGCTCAGTGGTAGAGCGCGTGCT 461-28831533 (-) TAGCATGCACGAGGCCCCGGGTTCAATCCCC G A T G T G G G T C G Attorney Docket No.: F2099-7038WO Cys_GCA_chr7:14938 GGGGATATAGCTCAGGGGTAGAGCATTTGAC 8271-149388343 (-) TGCAGATCAAGAGGTCCCCGGTTCAAATCCG G G G C A C A G T T Attorney Docket No.: F2099-7038WO Leu_TAA_chr11:5931 TACCAGAATGGCCGAGTGGTTAAGGCGTTGG 9227-59319310 (+) ACTTAAGATCCAATGGATTCATATCCGCGTG G A A C A G T G C A T A C Attorney Docket No.: F2099-7038WO Asn_GTT_chr13:3124 GTCTCTGTGGCGCAATCGGTTAGCGCGTTCG 8100-31248174 (-) GCTGTTAACCGAAAGGTTGGTGGTTCGAGCC T T G T T A G G T A Attorney Docket No.: F2099-7038WO Glu_TTC_chr15:2632 TCCCACATGGTCTAGCGGTTAGGATTCCTGGT 7380-26327452 (-) TTTCACCCAGGCGGCCCGGGTTCGACTCCCG T G G G G G A T C Attorney Docket No.: F2099-7038WO Leu_TAG_chr16:2220 GGTAGCGTGGCCGAGTGGTCTAAGGCGCTGG 7031-22207113 (-) ATTTAGGCTCCAGTCATTTCGATGGCGTGGGT G G C T G G A A Attorney Docket No.: F2099-7038WO Thr_AGT_chr17:8090 CGGCGCCGTGGCTTAGTTGGTTAAAGCGCCT 477-8090551 (+) GTCTAGTAAACAGGAGATCCTGGGTTCGAAT C C C T G A T C A C C Attorney Docket No.: F2099-7038WO 442 Arg_CCG_chr17:6601 GACCCAGTGGCCTAATGGATAAGGCATCAGC 6012-66016085 (-) CTCCGGAGCTGGGGATTGTGGGTTCGAGTCC G C G C C T T C Nucleotide Sequence Modifications The present disclosure describes TREMs comprising a nucleotide sequence modification, e.g., relative to a first TREM nucleotide sequence, that may modulate a functional parameter of the TREM. These TREMs may further comprise a non-naturally occurring chemical modification, or may not. For example, a TREM comprising a nucleotide sequence modification may exhibit improved activity or stability, e.g., in vitro or in a cell. The nucleotide sequence Attorney Docket No.: F2099-7038WO modification may be a nucleotide substitution, e.g., a change of a nucleotide at a given position in the TREM sequence to a different nucleotide. In an embodiment, the nucleotide substitution is an A to U substitution. In an embodiment, the nucleotide substitution is an A to G substitution. In an embodiment, the nucleotide substitution is an A to C substitution. In an embodiment, the nucleotide substitution is a U to A substitution. In an embodiment, the nucleotide substitution is a U to G substitution. In an embodiment, the nucleotide substitution is a U to C substitution. In an embodiment, the nucleotide substitution is a G to A substitution. In an embodiment, the nucleotide substitution is a G to U substitution. In an embodiment, the nucleotide substitution is a G to C substitution. In an embodiment, the nucleotide substitution is a C to A substitution. In an embodiment, the nucleotide substitution is a C to U substitution. In an embodiment, the nucleotide substitution is a C to G substitution. In one aspect, the present disclosure features a TREM comprising a nucleotide substitution at a nucleotide within the TREM sequence. In an embodiment, the nucleotide substitution is within a domain of the TREM, e.g., the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], or the [ASt Domain2]. In an embodiment, the nucleotide substitution is within the [ASt Domain1]. In an embodiment, the nucleotide substitution is within the [DH Domain]. In an embodiment, the nucleotide substitution is within the [ACH Domain]. In an embodiment, the nucleotide substitution is within the [VL Domain]. In an embodiment, the nucleotide substitution is within the [TH Domain]. In an embodiment, the nucleotide substitution is within the [ASt Domain2]. In an embodiment, the nucleotide substitution is at any of positions 1, 2, 3, 4, 5, 6, 7, 8, or 9 within the [ASt Domain1]. In an embodiment, the nucleotide substitution is at any of positions 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 within the [DH Domain]. In an embodiment, the nucleotide substitution is at any of positions 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 within the [ACH Domain]. In an embodiment, the nucleotide substitution is at any of positions 44, 45, 46, 47, 48, or 49 within the [VL Domain]. In an embodiment, the nucleotide substitution is at any of positions 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, or 64 within the [TH Domain]. In an embodiment, the nucleotide substitution is at any of positions 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, or 76 within the [ASt Domain2]. In an embodiment, a nucleotide substitution is at a position within the TREM sequence, e.g., nucleotide position 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, 26, 27, 28, 29, 30, Attorney Docket No.: F2099-7038WO 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 1 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 2 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 3 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 4 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 5 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 6 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 7 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 8 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 9 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 10 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 11 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 12 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 13 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 14 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 15 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 16 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 17 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 18 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 19 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 20 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 21 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 22 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 23 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 24 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 25 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 26 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 27 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 28 within the TREM Attorney Docket No.: F2099-7038WO sequence. In an embodiment, the nucleotide substitution is at position 29 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 30 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 31 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 32 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 33 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 34 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 35 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 36 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 37 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 38 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 39 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 40 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 41 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 42 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 43 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 44 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 45 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 46 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 47 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 48 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 49 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 50 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 51 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 52 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 53 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 54 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 55 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 56 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 57 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 58 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 59 within the TREM Attorney Docket No.: F2099-7038WO sequence. In an embodiment, the nucleotide substitution is at position 60 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 61 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 62 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 63 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 64 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 65 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 66 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 67 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 68 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 69 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 70 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 71 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 72 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 73 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 74 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 75 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 76 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 77 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 78 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 79 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 80 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 81 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 82 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 83 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 84 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 85 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 86 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 87 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 88 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 89 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 90 within the TREM Attorney Docket No.: F2099-7038WO sequence. In an embodiment, the nucleotide substitution is at position 91 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 92 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 93 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 94 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 95 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 96 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 97 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 98 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 99 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 100 within the TREM sequence. In an embodiment, a TREM comprises multiple nucleotide substitutions, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more nucleotide substitutions. In an embodiment, a TREM comprises 1 nucleotide substitution. In an embodiment, a TREM comprises 2 nucleotide substitutions. In an embodiment, a TREM comprises 3 nucleotide substitutions. In an embodiment, a TREM comprises 4 nucleotide substitutions. In an embodiment, a TREM comprises 5 nucleotide substitutions. In an embodiment, a TREM comprises 6 nucleotide substitutions. In an embodiment, a TREM comprises 7 nucleotide substitutions. In an embodiment, a TREM comprises 8 nucleotide substitutions. In an embodiment, a TREM comprises 9 nucleotide substitutions. In an embodiment, a TREM comprises 10 nucleotide substitutions. In an embodiment, a TREM comprises 11 nucleotide substitutions. In an embodiment, a TREM comprises 12 nucleotide substitutions. In an embodiment, a TREM comprises 13 nucleotide substitutions. In an embodiment, a TREM comprises 14 nucleotide substitutions. In an embodiment, a TREM comprises 15 nucleotide substitutions. In an embodiment, a TREM comprises 16 nucleotide substitutions. In an embodiment, a TREM comprises 17 nucleotide substitutions. In an embodiment, a TREM comprises 18 nucleotide substitutions. In an embodiment, a TREM comprises 19 nucleotide substitutions. In an embodiment, a TREM comprises 20 nucleotide substitutions. In an embodiment, a TREM comprises more than 20 nucleotide substitutions. In an embodiment, a TREM comprises nucleotide substitutions in more than one TREM domain, e.g., more than one of [ASt Domain1], [DH Domain], [ACH Domain], [VL Domain], [TH Domain], or [ASt Domain2]. In an embodiment, a TREM comprises nucleotide substitutions in one TREM Attorney Docket No.: F2099-7038WO domain. In an embodiment, a TREM comprises nucleotide substitutions in two TREM domains. In an embodiment, a TREM comprises nucleotide substitutions in three TREM domains. In an embodiment, a TREM comprises nucleotide substitutions in four TREM domains. In an embodiment, a TREM comprises nucleotide substitutions in five TREM domains. In an embodiment, a TREM comprises nucleotide substitutions in six TREM domains. In an embodiment, a TREM comprises nucleotide substitutions in the [ASt Domain1] and the [DH Domain]. In an embodiment, a TREM comprises nucleotide substitutions in the [ASt Domain1] and the [ACH Domain]. In an embodiment, a TREM comprises nucleotide substitutions in the [ASt Domain1] and the [VL Domain]. In an embodiment, a TREM comprises nucleotide substitutions in the [ASt Domain1] and the [TH Domain]. In an embodiment, a TREM comprises nucleotide substitutions in the [ASt Domain1] and the [ASt Domain2]. In an embodiment, a TREM comprises nucleotide substitutions in the [DH Domain] and the [ACH Domain]. In an embodiment, a TREM comprises nucleotide substitutions in the [DH Domain] and the [ACH Domain]. In an embodiment, a TREM comprises nucleotide substitutions in the [DH Domain] and the [VL Domain]. In an embodiment, a TREM comprises nucleotide substitutions in the [DH Domain] and the [TH Domain]. In an embodiment, a TREM comprises nucleotide substitutions in the [DH Domain] and the [ASt Domain2]. In an embodiment, a TREM comprises nucleotide substitutions in the [ACH Domain] and the [VL Domain]. In an embodiment, a TREM comprises nucleotide substitutions in the [ACH Domain] and the [TH Domain]. In an embodiment, a TREM comprises nucleotide substitutions in the [ACH Domain] and the [ASt Domain2]. In an embodiment, a TREM comprises nucleotide substitutions in the [VL Domain] and the [TH Domain]. In an embodiment, a TREM comprises nucleotide substitutions in the [VL Domain] and the [ASt Domain2]. In an embodiment, a TREM comprises nucleotide substitutions in the [TH Domain] and the [ASt Domain2]. In an embodiment, a TREM comprises nucleotide substitutions in the [ASt Domain1] and the [ASt Domain1]. In an embodiment, a TREM comprises nucleotide substitutions in the [DH Domain] and the [DH Domain]. In an embodiment, a TREM comprises nucleotide substitutions in the [ACH Domain] and the [ACH Domain]. In an embodiment, a TREM comprises nucleotide substitutions in the [VL Domain] and the [VL Domain]. In an embodiment, a TREM comprises nucleotide substitutions in the [TH Domain] and the [TH Domain]. In an embodiment, a TREM comprises nucleotide substitutions in the [ASt Domain2] and the [ASt Domain2]. In an embodiment, the nucleotide substitution is Attorney Docket No.: F2099-7038WO within a loop of the TREM secondary structure, e.g., an unpaired region of the TREM. In an embodiment, the nucleotide substitution is at any of unpaired positions 8, 9, 14, 15, 16, 17, 17A, 18, 19, 20, 20A, 20B, 21, 32, 33, 34, 35, 36, 37, 38, 45, e11, e12, e13, e14, e15, e16, e17, e1, e2, e3, e4, e5, e27, e26, e25, e24, e23, e22, e21, 46, 47, 48, 54, 55, 56, 57, 58, 59, 60, 73, 74, 75, or 76 according to the universal tRNA numbering scheme, e.g., the nucleotide position numbering as provided in FIG.4. In an embodiment, the nucleotide substitution is within a stem of the TREM secondary structure, e.g., within a base-paired region of the TREM. In an embodiment, the nucleotide substitution is at any of base-paired positions 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13, 22, 23, 24, 25, 27, 28, 29, 30, 31, 39, 40, 41, 42, 43, 49, 50, 51, 52, 53, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, or 72 according to the universal tRNA numbering scheme, e.g., the nucleotide position numbering as provided in FIG.4. In an embodiment, a nucleotide substitution maintains the secondary structure, e.g., base-pairing, of the TREM. In an embodiment, a nucleotide substitution does not maintain the secondary structure, e.g., base-pairing, of the TREM. In an embodiment, a TREM comprising a first nucleotide substitution at a base-paired position further comprises a second compensatory nucleotide substitution, e.g., a nucleotide substitution at the second position that maintains base-pairing with the first nucleotide substitution. In an embodiment, the compensatory nucleotide substitution for a first A nucleotide substitution is a U. In an embodiment, the compensatory nucleotide substitution for a first U nucleotide substitution is an A. In an embodiment, the compensatory nucleotide substitution for a first G nucleotide substitution is a C. In an embodiment, the compensatory nucleotide substitution for a first C nucleotide substitution is a G. In an embodiment, both nucleotide positions of a base-pair comprise nucleotide substitutions, e.g., both nucleotide positions of any of base-pairs 1:72, 2:71, 3:70, 4:69, 5:68, 6:67, 7:66, 10:25, 11:24, 12:23, 13:22, 27:43, 28:42, 29:41, 30:40, 31:39, 49:65, 50:64, 51:63, 52:62, or 53:61, wherein the number preceding the colon represents the first nucleotide position of the base-pair and the number following the colon represents the second nucleotide position of the base-pair. In an embodiment, both nucleotides of the base-pair at positions 1 and 72 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 2 and 71 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 3 and 70 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 4 and 69 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 5 and Attorney Docket No.: F2099-7038WO 68 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 6 and 67 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 7 and 68 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 10 and 25 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 11 and 24 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 12 and 23 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 13 and 22 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 27 and 43 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 28 and 42 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 29 and 41 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 30 and 40 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 31 and 39 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 49 and 65 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 50 and 64 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 51 and 63 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 52 and 63 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 53 and 61 comprise nucleotide substitutions. In an embodiment, a TREM comprises multiple pairs of nucleotide substitutions and compensatory nucleotide substitutions, e.g., multiple pairs of nucleotide substitutions that maintain base pairing, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more pairs of nucleotide substitutions and compensatory nucleotide substitutions. In an embodiment, a TREM comprises 1 pair of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises 2 pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises 3 pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises 4 pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises 5 pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises 6 pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an Attorney Docket No.: F2099-7038WO embodiment, a TREM comprises 7 pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises 8 pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises 9 pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises 10 pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises more than 10 pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, the nucleotide substitutions at a first position and a second compensatory position result in a lower energy base pair, e.g., a change from a G:C or C:G base pair to an A:U or U:A base pair. In an embodiment, the nucleotide substitutions at a first position and a second compensatory position result in a higher energy base pair, e.g., a change from an A:U or U:A base pair to a G:C or C:G base pair. In an embodiment, the nucleotide substitutions at a first position and a second compensatory position result in a neutral energy base pair, e.g., a change from an A:U base pair to a U:A base pair or a C:G base pair to a G:C base pair. In an embodiment, a nucleotide substitution results in a wobble base pair, e.g., a G:U base pair. In an embodiment, the nucleotide substitutions at a first position and a second compensatory position result in a wobble base pair, e.g., a G:U base pair. In an embodiment, a nucleotide substitution disrupts base-pairing. In an embodiment, a nucleotide substitution results in modulation of the activity of the TREM, e.g., results in an increase or a decrease in activity of the TREM. For example, a nucleotide substitution may modulate the ability of the TREM to (i) support protein synthesis, (ii) be charged by a tRNA synthetase, (iii) be bound by an elongation factor, (iv) introduce an amino acid into a peptide chain, (v) support protein elongation, (vi) support initiation of protein synthesis, or (vii) read-through a premature termination codon (PTC), e.g., in a cell. In an embodiment, a nucleotide substitution modulates the ability of a TREM to support protein synthesis. In an embodiment, a nucleotide substitution modulates the ability of a TREM to be charged by a tRNA synthetase. In an embodiment, a nucleotide substitution modulates the ability of a TREM to be bound by an elongation factor. In an embodiment, a nucleotide substitution modulates the ability of a TREM to introduce an amino acid into a peptide chain. In an embodiment, a nucleotide substitution modulates the ability of a TREM to support protein elongation. In an embodiment, a nucleotide substitution modulates the ability of a TREM to support initiation of protein synthesis. In an embodiment, a nucleotide substitution modulates the Attorney Docket No.: F2099-7038WO ability of a TREM to read-through a PTC. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the capability of the TREM to support protein synthesis, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the capability of the TREM to be charged by a tRNA synthetase, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the capability of the TREM to be bound by an elongation factor, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the capability of the TREM to introduce an amino acid into a peptide chain, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the capability of the TREM to support protein elongation, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the capability of the TREM to support initiation of protein synthesis, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the capability of the TREM to read-through a premature termination codon, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the capability of the TREM to support protein synthesis, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, Attorney Docket No.: F2099-7038WO 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the capability of the TREM to be charged by a tRNA synthetase, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the capability of the TREM to be bound by an elongation factor, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the capability of the TREM to introduce an amino acid into a peptide chain, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the capability of the TREM to support protein elongation, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the capability of the TREM to support initiation of protein synthesis, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the capability of the TREM to read-through a premature termination codon, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution results in modulation of the stability of the TREM, e.g., results in an increase or a decrease in stability of the TREM. For example, a nucleotide substitution may modulate the (i) localization of the TREM, (ii) the amount of time before the TREM is degraded, (iii) the amount of time the TREM is charged with an amino acid, (iv) the amount of time the TREM interacts with a ribosome, (v) the amount of time the TREM Attorney Docket No.: F2099-7038WO interacts with an elongation factor, (vi) modification of the TREM, or (vii) interaction of the TREM with tRNA degradation proteins, e.g., within a cell. In an embodiment, a nucleotide substitution modulates the localization of a TREM. In an embodiment, a nucleotide substitution modulates the amount of time before the TREM is degraded. In an embodiment, a nucleotide substitution modulates the amount of time the TREM is charged with an amino acid. In an embodiment, a nucleotide substitution modulates the amount of time the TREM interacts with a ribosome. In an embodiment, a nucleotide substitution modulates the amount of time the TREM interacts with an elongation factor. In an embodiment, a nucleotide substitution modulates modification of a TREM. In an embodiment, a nucleotide substitution modulates interaction of the TREM with tRNA degradation proteins. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in proper localization of a TREM, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the amount of time before a TREM is degraded, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the amount of time a TREM is charged with an amino acid, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the amount of time a TREM interacts with a ribosome, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the amount of time a TREM interacts with an elongation factor, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in modification of a TREM, e.g., within a cell, e.g., by about 1%, Attorney Docket No.: F2099-7038WO 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in interaction of the TREM with tRNA degradation proteins, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in proper localization of a TREM, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the amount of time before a TREM is degraded, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the amount of time a TREM is charged with an amino acid, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the amount of time a TREM interacts with a ribosome, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the amount of time a TREM interacts with an elongation factor, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in modification of a TREM, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in interaction of the TREM with tRNA degradation Attorney Docket No.: F2099-7038WO proteins, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. Exemplary nucleotide sequence modifications are outlined below. A TREM may comprise a nucleotide mutation relative to the nucleotide sequence of SEQ ID NO: 734. In an embodiment, the nucleotide mutation relative to the nucleotide sequence of SEQ ID NO: 734 is a nucleotide substitution. In an embodiment, the TREM comprises a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734 in the [VL Domain]. In an embodiment, the TREM comprises one nucleotide substitution. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 40 and 50. In an embodiment, the nucleotide substitution is at nucleotide position 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In an embodiment, the nucleotide substitution is at position 44. In an embodiment, the nucleotide substitution is an A to G substitution. In an embodiment, the nucleotide substitution is A44G. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 743. In an embodiment, the TREM having SEQ ID NO: 743 comprises a non- naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 743 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 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, 26, 27, 28, 29, 30, 31, and 32. A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734 is present in each of [ASt Domain1] and the [ASt Domain2]. In an embodiment, the TREM comprises eight nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 1 and 10. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 60 and 70. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 70 and 80. In an embodiment, the nucleotide substitution is at nucleotide position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In an embodiment, the nucleotide substitution is at nucleotide position 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70. In an embodiment, the nucleotide substitution is at nucleotide position 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80. In an embodiment, the nucleotide substitution is at position 2. In an embodiment, the nucleotide substitution is at position 4. In an embodiment, the nucleotide substitution is at position 5. In an embodiment, the nucleotide substitution is at Attorney Docket No.: F2099-7038WO position 6. In an embodiment, the nucleotide substitution is at position 67. In an embodiment, the nucleotide substitution is at position 68. In an embodiment, the nucleotide substitution is at position 69. In an embodiment, the nucleotide substitution is at position 71. In an embodiment, the nucleotide substitution is a G to C substitution. In an embodiment, the nucleotide substitution is a U to C substitution. In an embodiment, the nucleotide substitution is a C to G substitution. In an embodiment, the nucleotide substitution is a C to A substitution. In an embodiment, the nucleotide substitution is a G to U substitution. In an embodiment, the nucleotide substitution is an A to G substitution. In an embodiment, the nucleotide substitution is a U to G substitution. In an embodiment, the nucleotide substitution is G2C. In an embodiment, the nucleotide substitution is U4C. In an embodiment, the nucleotide substitution is C5G. In an embodiment, the nucleotide substitution is C6A. In an embodiment, the nucleotide substitution is G67U. In an embodiment, the nucleotide substitution is G68C. In an embodiment, the nucleotide substitution is A69G. In an embodiment, the nucleotide substitution is U71G. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 639. In an embodiment, the TREM having SEQ ID NO: 639 comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 639 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 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, 26, 27, 28, 29, 30, 31, and 32. A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], and the [ASt Domain2]. In an embodiment, the TREM comprises seventeen nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 1 and 10. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 10 and 20. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 20 and 30. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 30 and 40. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 40 and 50. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 60 and 70. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 70 and 80. In an embodiment, the nucleotide substitution is at nucleotide position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In an embodiment, the nucleotide substitution is Attorney Docket No.: F2099-7038WO at nucleotide position 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In an embodiment, the nucleotide substitution is at nucleotide position 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In an embodiment, the nucleotide substitution is at nucleotide position 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40. In an embodiment, the nucleotide substitution is at nucleotide position 40, 41, 41, 43, 44, 45, 46, 47, 48, 49, or 50. In an embodiment, the nucleotide substitution is at nucleotide position 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, and 70. In an embodiment, the nucleotide substitution is at nucleotide position 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80. In an embodiment, the nucleotide substitution is at position 2. In an embodiment, the nucleotide substitution is at position 12. In an embodiment, the nucleotide substitution is at position 13. In an embodiment, the nucleotide substitution is at position 22. In an embodiment, the nucleotide substitution is at position 23. In an embodiment, the nucleotide substitution is at position 28. In an embodiment, the nucleotide substitution is at position 31. In an embodiment, the nucleotide substitution is at position 39. In an embodiment, the nucleotide substitution is at position 40. In an embodiment, the nucleotide substitution is at position 42. In an embodiment, the nucleotide substitution is at position 43. In an embodiment, the nucleotide substitution is at position 44. In an embodiment, the nucleotide substitution is at position 46. In an embodiment, the nucleotide substitution is at position 49. In an embodiment, the nucleotide substitution is at position 65. In an embodiment, the nucleotide substitution is at position 71. In an embodiment, the nucleotide substitution is at position 72. In an embodiment, the nucleotide substitution is a G to C substitution. In an embodiment, the nucleotide substitution is a C to U substitution. In an embodiment, the nucleotide substitution is a G to A substitution. In an embodiment, the nucleotide substitution is a C to G substitution. In an embodiment, the nucleotide substitution is a U to C substitution. In an embodiment, the nucleotide substitution is an A to C substitution. In an embodiment, the nucleotide substitution is a U to G substitution. In an embodiment, the nucleotide substitution is an A to G substitution. In an embodiment, the nucleotide substitution is a C to G substitution. In an embodiment, the nucleotide substitution is a G to U substitution. In an embodiment, the nucleotide substitution is G2C. In an embodiment, the nucleotide substitution is G12C. In an embodiment, the nucleotide substitution is C13U. In an embodiment, the nucleotide substitution is G22A. In an embodiment, the nucleotide substitution is C23G. In an embodiment, the nucleotide substitution is U28C. In an embodiment, the nucleotide substitution is A31C. In an embodiment, the nucleotide substitution is U39G. In an embodiment, Attorney Docket No.: F2099-7038WO the nucleotide substitution is U40C. In an embodiment, the nucleotide substitution is A42G. In an embodiment, the nucleotide substitution is A43G. In an embodiment, the nucleotide substitution is A44G. In an embodiment, the nucleotide substitution is G46A. In an embodiment, the nucleotide substitution is C49G. In an embodiment, the nucleotide substitution is G65U. In an embodiment, the nucleotide substitution is U71G. In an embodiment, the nucleotide substitution is C72U. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 1149. In an embodiment, the TREM having SEQ ID NO: 1149 comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 1149 has a non- naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 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, 26, 27, 28, 29, 30, 31, and 32. A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in each of the [ASt Domain1] and the [ASt Domain2]. In an embodiment, the TREM comprises four nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 1 and 10. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 60 and 70. In an embodiment, the nucleotide substitution is at nucleotide position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In an embodiment, the nucleotide substitution is at nucleotide position 60, 61, 62, 63, 64, 64, 65, 66, 67, 68, 69, or 70. In an embodiment, the nucleotide substitution is at position 4. In an embodiment, the nucleotide substitution is at position 7. In an embodiment, the nucleotide substitution is at position 66. In an embodiment, the nucleotide substitution is at position 69. In an embodiment, the nucleotide substitution is a U to C substitution. In an embodiment, the nucleotide substitution is a G to A substitution. In an embodiment, the nucleotide substitution is a C to U substitution. In an embodiment, the nucleotide substitution is an A to G substitution. In an embodiment, the nucleotide substitution is U4C. In an embodiment, the nucleotide substitution is G7A. In an embodiment, the nucleotide substitution is C66U. In an embodiment, the nucleotide substitution is A69G. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 652. In an embodiment, the TREM having SEQ ID NO: 652 comprises a non- naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 652 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 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, 26, 27, 28, 29, 30, 31, and 32. Attorney Docket No.: F2099-7038WO A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in the [ACH Domain]. In an embodiment, the TREM comprises nine nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 20 and 30. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 30 and 40. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 40 and 50. In an embodiment, the nucleotide substitution is at nucleotide position 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In an embodiment, the nucleotide substitution is at nucleotide position 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40. In an embodiment, the nucleotide substitution is at nucleotide position 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In an embodiment, the nucleotide substitution is at position 27. In an embodiment, the nucleotide substitution is at position 28. In an embodiment, the nucleotide substitution is at position 29. In an embodiment, the nucleotide substitution is at position 31. In an embodiment, the nucleotide substitution is at position 39. In an embodiment, the nucleotide substitution is at position 40. In an embodiment, the nucleotide substitution is at position 41. In an embodiment, the nucleotide substitution is at position 42. In an embodiment, the nucleotide substitution is at position 43. In an embodiment, the nucleotide substitution is a U to A substitution. In an embodiment, the nucleotide substitution is a U to C substitution. In an embodiment, the nucleotide substitution is a G to C substitution. In an embodiment, the nucleotide substitution is an A to U substitution. In an embodiment, the nucleotide substitution is a C to G substitution. In an embodiment, the nucleotide substitution is an A to G substitution. In an embodiment, the nucleotide substitution is U27A. In an embodiment, the nucleotide substitution is U28C. In an embodiment, the nucleotide substitution is G29C. In an embodiment, the nucleotide substitution is A31U. In an embodiment, the nucleotide substitution is U39A. In an embodiment, the nucleotide substitution is U40C. In an embodiment, the nucleotide substitution is C41G. In an embodiment, the nucleotide substitution is A42G. In an embodiment, the nucleotide substitution is A43U. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 702. In an embodiment, the TREM having SEQ ID NO: 702 comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 702 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 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, 26, 27, 28, 29, 30, 31, and 32. Attorney Docket No.: F2099-7038WO A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in each of the [ASt Domain1] and the [ASt Domain2]. In an embodiment, the TREM comprises eight nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 1 and 10. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 60 and 70. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 70 and 80. In an embodiment, the nucleotide substitution is at nucleotide position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In an embodiment, the nucleotide substitution is at nucleotide position 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70. In an embodiment, the nucleotide substitution is at nucleotide position 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80. In an embodiment, the nucleotide substitution is at position 1. In an embodiment, the nucleotide substitution is at position 2. In an embodiment, the nucleotide substitution is at position 4. In an embodiment, the nucleotide substitution is at position 5. In an embodiment, the nucleotide substitution is at position 68. In an embodiment, the nucleotide substitution is at position 69. In an embodiment, the nucleotide substitution is at position 71. In an embodiment, the nucleotide substitution is at position 72. In an embodiment, the nucleotide substitution is a G to A substitution. In an embodiment, the nucleotide substitution is a G to C substitution. In an embodiment, the nucleotide substitution is a U to A substitution. In an embodiment, the nucleotide substitution is a C to A substitution. In an embodiment, the nucleotide substitution is a G to U substitution. In an embodiment, the nucleotide substitution is an A to U substitution. In an embodiment, the nucleotide substitution is a U to G substitution. In an embodiment, the nucleotide substitution is a C to U substitution. In an embodiment, the nucleotide substitution is G1A. In an embodiment, the nucleotide substitution is G2C. In an embodiment, the nucleotide substitution is U4A. In an embodiment, the nucleotide substitution is C5A. In an embodiment, the nucleotide substitution is G68U. In an embodiment, the nucleotide substitution is A69U. In an embodiment, the nucleotide substitution is U71G. In an embodiment, the nucleotide substitution is C72U. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 627. In an embodiment, the TREM having SEQ ID NO: 627 comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 627 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 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, 26, 27, 28, 29, 30, 31, and 32. Attorney Docket No.: F2099-7038WO A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in each of the [ASt Domain1], the [DH Domain], the [VL Domain], and the [ASt Domain2]. In an embodiment, the TREM comprises five nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 1 and 10. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 20 and 30. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 40 and 50. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 60 and 70. In an embodiment, the nucleotide substitution is at nucleotide position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In an embodiment, the nucleotide substitution is at nucleotide position 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In an embodiment, the nucleotide substitution is at nucleotide position 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In an embodiment, the nucleotide substitution is at nucleotide position 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70. In an embodiment, the nucleotide substitution is at position 4. In an embodiment, the nucleotide substitution is at position 26. In an embodiment, the nucleotide substitution is at position 49. In an embodiment, the nucleotide substitution is at position 65. In an embodiment, the nucleotide substitution is at position 69. In an embodiment, the nucleotide substitution is a U to C substitution. In an embodiment, the nucleotide substitution is an A to G substitution. In an embodiment, the nucleotide substitution is a C to G substitution. In an embodiment, the nucleotide substitution is a G to C substitution. In an embodiment, the nucleotide substitution is U4C. In an embodiment, the nucleotide substitution is A26G. In an embodiment, the nucleotide substitution is C49G. In an embodiment, the nucleotide substitution is G65C. In an embodiment, the nucleotide substitution is A69G. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 1150. In an embodiment, the TREM having SEQ ID NO: 1150 comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 1150 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 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, 26, 27, 28, 29, 30, 31, and 32. A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in each of the [VL Domain] and the [ASt Domain2]. In an embodiment, the TREM comprises two nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 40 and 50. Attorney Docket No.: F2099-7038WO In an embodiment, the nucleotide substitution is at a nucleotide position between positions 60 and 70. In an embodiment, the nucleotide substitution is at nucleotide position 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In an embodiment, the nucleotide substitution is at nucleotide position 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70. In an embodiment, the nucleotide substitution is at position 49. In an embodiment, the nucleotide substitution is at position 65. In an embodiment, the nucleotide substitution is a C to G substitution. In an embodiment, the nucleotide substitution is a G to C substitution. In an embodiment, the nucleotide substitution is C49G. In an embodiment, the nucleotide substitution is G65C. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 1151. In an embodiment, the TREM having SEQ ID NO: 1151 comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 1151 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 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, 26, 27, 28, 29, 30, 31, and 32. A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in each of the [ASt Domain1] and the [ASt Domain2]. In an embodiment, the TREM comprises five nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 1 and 10. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 60 and 70. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 70 and 80. In an embodiment, the nucleotide substitution is at nucleotide position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In an embodiment, the nucleotide substitution is at nucleotide position 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70. In an embodiment, the nucleotide substitution is at nucleotide position 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80. In an embodiment, the nucleotide substitution is at position 1. In an embodiment, the nucleotide substitution is at position 2. In an embodiment, the nucleotide substitution is at position 4. In an embodiment, the nucleotide substitution is at position 69. In an embodiment, the nucleotide substitution is at position 72. In an embodiment, the nucleotide substitution is a G to U substitution. In an embodiment, the nucleotide substitution is a G to A substitution. In an embodiment, the nucleotide substitution is a U to A substitution. In an embodiment, the nucleotide substitution is an A to U substitution. In an embodiment, the nucleotide substitution is a C to A substitution. In an embodiment, the nucleotide substitution is G1U. In an embodiment, the nucleotide substitution is G2A. In an Attorney Docket No.: F2099-7038WO embodiment, the nucleotide substitution is U4A. In an embodiment, the nucleotide substitution is A69U. In an embodiment, the nucleotide substitution is C72A. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 794. In an embodiment, the TREM having SEQ ID NO: 794 comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 794 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 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, 26, 27, 28, 29, 30, 31, and 32. A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in each of the [ASt Domain1], the [ACH Domain], and the [ASt Domain2]. In an embodiment, the TREM comprises four nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 1 and 10. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 20 and 30. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 40 and 50. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 70 and 80. In an embodiment, the nucleotide substitution is at nucleotide position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In an embodiment, the nucleotide substitution is at nucleotide position 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In an embodiment, the nucleotide substitution is at nucleotide position 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In an embodiment, the nucleotide substitution is at nucleotide position 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80. In an embodiment, the nucleotide substitution is at position 2. In an embodiment, the nucleotide substitution is at position 27. In an embodiment, the nucleotide substitution is at position 43. In an embodiment, the nucleotide substitution is at position 71. In an embodiment, the nucleotide substitution is a G to C substitution. In an embodiment, the nucleotide substitution is a U to G substitution. In an embodiment, the nucleotide substitution is an A to C substitution. In an embodiment, the nucleotide substitution is G2C. In an embodiment, the nucleotide substitution is U27G. In an embodiment, the nucleotide substitution is A43C. In an embodiment, the nucleotide substitution is U71G. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 641. In an embodiment, the TREM having SEQ ID NO: 641 comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 641 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 1, Attorney Docket No.: F2099-7038WO 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, and 32. A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in the [ACH Domain]. In an embodiment, the TREM comprises four nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 20 and 30. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 30 and 40. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 40 and 50. In an embodiment, the nucleotide substitution is at nucleotide position 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In an embodiment, the nucleotide substitution is at nucleotide position 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40. In an embodiment, the nucleotide substitution is at nucleotide position 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In an embodiment, the nucleotide substitution is at position 28. In an embodiment, the nucleotide substitution is at position 31. In an embodiment, the nucleotide substitution is at position 39. In an embodiment, the nucleotide substitution is at position 42. In an embodiment, the nucleotide substitution is a U to C substitution. In an embodiment, the nucleotide substitution is an A to U substitution. In an embodiment, the nucleotide substitution is a U to A substitution. In an embodiment, the nucleotide substitution is an A to G substitution. In an embodiment, the nucleotide substitution is U28C. In an embodiment, the nucleotide substitution is A31U. In an embodiment, the nucleotide substitution is U39A. In an embodiment, the nucleotide substitution is A42G. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 710. In an embodiment, the TREM having SEQ ID NO: 710 comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 710 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 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, 26, 27, 28, 29, 30, 31, and 32. Table 7: Exemplary TREM sequences Substitutions Attorney Docket No.: F2099-7038WO G2C, G12C, C13U, G22A, C23G, U28C, A31C, 3 1149 17 U39G, U40C, A42G, A43G, A44G, G46A, C49G, a e o e , a ay co p se a uc eo e seque ce sca o , e.g., a y o e of Scaffold Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. In an embodiment, a TREM may comprise a chemical modification pattern, e.g., any one of Pattern Nos: 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, 26, 27, 28, 29, 30, 31, and 32. In an embodiment, a TREM may comprise a nucleotide sequence scaffold, e.g., any one of Scaffold Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12, and a chemical modification pattern, e.g., any one of Pattern Nos: 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, 26, 27, 28, 29, 30, 31, and 32. In an embodiment, a functional parameter of a TREM may be modulated by the sequence scaffold. In an embodiment, a functional parameter of a TREM may be modulated by the chemical modification pattern. In an embodiment, a functional parameter of a TREM may be modulated by both the sequence scaffold and the modification pattern. In an embodiment, the functional parameter of the TREM that is modulated by the nucleotide sequence scaffold, the chemical modification pattern, or both the nucleotide sequence scaffold and the chemical modification pattern is the log2 activity of the TREM relative to mock, e.g., log2 activity of the TREM as provided in FIG.1. In an embodiment, the log2 activity of a TREM can be modulated to be between 1 and 1024. In an embodiment, the log2 activity of a TREM can be modulated to be between 1-4, 4-16, 16-64, 64-256, or 256-1024. In an embodiment, the log2 activity of a TREM can be modulated to be between about 1 to about 40. In an embodiment, the log2 activity of a TREM can be modulated to be between about 2 to about 60. In an embodiment, the log2 activity of a TREM can be modulated to be between about 3 to about 60. In an embodiment, the log2 activity of a TREM can be modulated to be between about 3 to about 50. Attorney Docket No.: F2099-7038WO In an embodiment, the log2 activity of a TREM can be modulated to be between about 2 to about 128. In an embodiment, the log2 activity of a TREM can be modulated to be between about 3 to about 30. In an embodiment, the log2 activity of a TREM can be modulated to be between about 3 to about 512. In an embodiment, the log2 activity of a TREM can be modulated to be between about 4 to about 15. In an embodiment, the log2 activity of a TREM can be modulated to be between about 8 to about 100. In an embodiment, the log2 activity of a TREM can be modulated to be between about 3 to about 70. In an embodiment, the log2 activity of a TREM can be modulated to be between about 3 to about 512. In an embodiment, the log2 activity of a TREM can be modulated to be between about 3 to about 128. In an embodiment, the log2 activity of a TREM can be modulated to be between about 3 to about 70. In an embodiment, the log2 activity of a TREM can be modulated to be between about 4 to about 128. In an embodiment, the log2 activity of a TREM can be modulated to be between about 32 to about 256. In an embodiment, the log2 activity of a TREM can be modulated to be between about 30 to about 512. In an embodiment, the log2 activity of a TREM can be modulated to be between about 60 to about 512. In an embodiment, the log2 activity of a TREM can be modulated to be between about 32 to about 512. In an embodiment, the log2 activity of a TREM can be modulated to be between about 64 to about 512. In an embodiment, the log2 activity of a TREM can be modulated to be between about 8 to about 256. In an embodiment, the log2 activity of a TREM can be modulated to be between about 10 to about 256. In an embodiment, the log2 activity of a TREM can be modulated to be between about 10 to about 400. In an embodiment, the log2 activity of a TREM can be modulated to be between about 64 to about 500. In an embodiment, the log2 activity of a TREM can be modulated to be between about 128 to about 800. In an embodiment, the log2 activity of a TREM can be modulated to be between about 14 to about 400. In an embodiment, the log2 activity of a TREM can be modulated to be between about 128 to about 700. In an embodiment, the log2 activity of a TREM can be modulated to be between about 8 to about 300. In an embodiment, the log2 activity of a TREM can be modulated to be between about 40 to about 512. In an embodiment, the log2 activity of a TREM can be modulated to be between about 100 to about 512. In an embodiment, the log2 activity of a TREM can be modulated to be between about 128 to about 400. In an embodiment, the log2 activity of a TREM can be modulated to be between about 64 to about 512. In an embodiment, the log2 activity of a TREM can be modulated to be between about 200 to about 512. In an embodiment, the log2 activity of a Attorney Docket No.: F2099-7038WO TREM can be modulated by Pattern No: 1 to be between about 1 to about 40. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 2 to be between about 2 to about 60. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 3 to be between about 3 to about 60. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 4 to be between about 3 to about 50. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 5 to be between about 2 to about 128. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 6 to be between about 3 to about 30. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 7 to be between about 3 to about 512. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 8 to be between about 4 to about 15. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 9 to be between about 8 to about 100. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 10 to be between about 3 to about 70. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 11 to be between about 3 to about 512. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 12 to be between about 3 to about 128. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 13 to be between about 3 to about 70. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 14 to be between about 4 to about 128. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 15 to be between about 32 to about 256. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 16 to be between about 30 to about 512. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 17 to be between about 60 to about 512. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 18 to be between about 32 to about 512. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 19 to be between about 64 to about 512. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 20 to be between about 8 to about 256. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 21 to be between about 10 to about 256. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 22 to be between about 10 to about 400. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 23 to be between about 64 to about 500. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 24 to be between about 128 to about 800. In an embodiment, the log2 activity of a Attorney Docket No.: F2099-7038WO TREM can be modulated by Pattern No: 25 to be between about 14 to about 400. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 26 to be between about 128 to about 700. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 27 to be between about 8 to about 300. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 28 to be between about 40 to about 512. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 29 to be between about 100 to about 512. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 30 to be between about 128 to about 400. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 31 to be between about 64 to about 512. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 32 to be between about 200 to about 512. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 1 to be between about 1 to about 800. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 2 to be between about 4 to about 400. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 3 to be between about 3 to about 512. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 4 to be between about 3 to about 400. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 5 to be between about 3 to about 512. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 6 to be between about 2 to about 256. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 7 to be between about 3 to about 700. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 8 to be between about 2 to about 600. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 9 to be between about 3 to about 200. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 10 to be between about 3 to about 800. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 11 to be between about 3 to about 300. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 12 to be between about 1 to about 400. In an embodiment, a TREM may comprise a nucleotide sequence scaffold, e.g., any one of Scaffold Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. In an embodiment, a TREM may comprise non-naturally occurring modifications, e.g., 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, Attorney Docket No.: F2099-7038WO 41, or more non-naturally occurring modifications. In an embodiment, a TREM may comprise a nucleotide sequence scaffold, e.g., any one of Scaffold Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12, and non-naturally occurring modifications, e.g., 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or more non-naturally occurring modifications. In an embodiment, a functional parameter of a TREM may be modulated by the sequence scaffold. In an embodiment, a functional parameter of a TREM may be modulated by the number of non-naturally occurring modifications. In an embodiment, a functional parameter of a TREM may be modulated by both the sequence scaffold and the number of non-naturally occurring modifications. In an embodiment, the functional parameter of the TREM that is modulated by the nucleotide sequence scaffold, the number of non-naturally occurring modifications, or both the nucleotide sequence scaffold and the number of non-naturally occurring modifications is the log2 activity of the TREM relative to mock, e.g., log2 activity of the TREM as provided in FIG.2. In an embodiment, the log2 activity of a TREM can be modulated by zero non-naturally occurring modifications to be between about 60 and about 256. In an embodiment, the log2 activity of a TREM can be modulated by four non-naturally occurring modifications to be between about 128 and about 800. In an embodiment, the log2 activity of a TREM can be modulated by five non-naturally occurring modifications to be between about 256 and about 600. In an embodiment, the log2 activity of a TREM can be modulated by six non-naturally occurring modifications to be between about 200 and about 512. In an embodiment, the log2 activity of a TREM can be modulated by eight non- naturally occurring modifications to be between about 150 and about 700. In an embodiment, the log2 activity of a TREM can be modulated by ten non-naturally occurring modifications to be between about 3 and about 100. In an embodiment, the log2 activity of a TREM can be modulated by thirteen non-naturally occurring modifications to be between about 3 and about 100. In an embodiment, the log2 activity of a TREM can be modulated by fourteen non-naturally occurring modifications to be between about 8 and about 400. In an embodiment, the log2 activity of a TREM can be modulated by fifteen non-naturally occurring modifications to be between about 32 and about 250. In an embodiment, the log2 activity of a TREM can be modulated by sixteen non-naturally occurring modifications to be between about 8 and about 400. In an embodiment, the log2 activity of a TREM can be modulated by nineteen non-naturally occurring modifications to be between about 60 and about 400. In an embodiment, the log2 Attorney Docket No.: F2099-7038WO activity of a TREM can be modulated by twenty-one non-naturally occurring modifications to be between about 3 and about 128. In an embodiment, the log2 activity of a TREM can be modulated by twenty-two non-naturally occurring modifications to be between about 8 and about 256. In an embodiment, the log2 activity of a TREM can be modulated by twenty-four non- naturally occurring modifications to be between about 12 and about 500. In an embodiment, the log2 activity of a TREM can be modulated by twenty-five non-naturally occurring modifications to be between about 2 and about 60. In an embodiment, the log2 activity of a TREM can be modulated by twenty-six non-naturally occurring modifications to be between about 3 and about 55. In an embodiment, the log2 activity of a TREM can be modulated by twenty-seven non- naturally occurring modifications to be between about 60 and about 500. In an embodiment, the log2 activity of a TREM can be modulated by twenty-eight non-naturally occurring modifications to be between about 2 and about 100. In an embodiment, the log2 activity of a TREM can be modulated by twenty-nine non-naturally occurring modifications to be between about 55 and about 600. In an embodiment, the log2 activity of a TREM can be modulated by thirty non-naturally occurring modifications to be between about 4 and about 128. In an embodiment, the log2 activity of a TREM can be modulated by thirty-one non-naturally occurring modifications to be between about 1 and about 32. In an embodiment, the log2 activity of a TREM can be modulated by thirty-two non-naturally occurring modifications to be between about 3 and about 128. In an embodiment, the log2 activity of a TREM can be modulated by thirty-three non-naturally occurring modifications to be between about 64 and about 512. In an embodiment, the log2 activity of a TREM can be modulated by thirty-four non-naturally occurring modifications to be between about 32 and about 512. In an embodiment, the log2 activity of a TREM can be modulated by thirty-five non-naturally occurring modifications to be between about 20 and about 512. In an embodiment, the log2 activity of a TREM can be modulated by thirty-six non-naturally occurring modifications to be between about 2 and about 512. In an embodiment, the log2 activity of a TREM can be modulated by thirty-seven non- naturally occurring modifications to be between about 3 and about 512. In an embodiment, the log2 activity of a TREM can be modulated by forty non-naturally occurring modifications to be between about 100 and about 512. In an embodiment, the log2 activity of a TREM can be modulated by forty-one non-naturally occurring modifications to be between about 6 and about 256. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 1 to be Attorney Docket No.: F2099-7038WO between about 1 to about 400. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 2 to be between about 4 to about 512. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 3 to be between about 4 to about 512. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 4 to be between about 3 to about 400. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 5 to be between about 3 to about 700. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 6 to be between about 3 to about 256. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 7 to be between about 3 to about 800. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 8 to be between about 2 to about 600. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 9 to be between about 3 to about 256. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 10 to be between about 3 to about 800. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 11 to be between about 3 to about 500. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 12 to be between about 1 to about 256. In an embodiment, the TREM is not a TREM provided in FIG.3. In an embodiment, the TREM does not have the nucleotide sequence of a TREM provided in FIG.3. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 743. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 652. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 702. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 627. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 1150. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 1151. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 794. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 641. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 710. In an embodiment, the TREM does not comprise a pattern of non-naturally occurring modifications according to a pattern in Table 6 (e.g., a pattern selected from Pattern Nos.1-32). In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.1 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.2 in Attorney Docket No.: F2099-7038WO Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.3 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.4 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.5 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.6 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.7 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.8 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.9 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.10 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.11 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.12 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.13 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.14 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.15 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.16 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.17 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.18 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.19 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.20 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.21 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.22 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring Attorney Docket No.: F2099-7038WO modifications according to Pattern No.23 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.24 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.25 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.26 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.27 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.28 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.29 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.30 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.31 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No.32 in Table 6. In an embodiment, a TREM comprises a nucleotide sequence, e.g., any one of the sequences provided in FIGs.3 or 23. In an embodiment, a functional parameter of a TREM is modulated by a nucleotide substitution, e.g., a nucleotide substitution relative to a reference TREM sequence. In an embodiment, the functional parameter of the TREM that is modulated by a nucleotide substitution is the premature termination codon (PTC) read-through activity of the TREM, e.g., the ability of a TREM to decode a premature termination codon and continue translation within the coding sequence of a protein. For example, a nucleotide substitution may modulate the relative abundance of a TREM in a pool of hits resulting from a screen of a library of TREMs comprising nucleotide substitutions for PTC readthrough activity. In an embodiment, a nucleotide substitution at a given position in a TREM sequence increases the hit abundance of TREMs comprising said nucleotide substitution relative to a TREM library composition. In an embodiment, a TREM comprises a nucleotide substitution in a particular region of the TREM. In an embodiment, the nucleotide substitution in a particular region of a TREM modulates a functional parameter of the TREM, e.g., the activity or stability of the TREM. In an embodiment, a nucleotide substitution in a particular region of a TREM modulates activity, e.g., PTC read-through activity, of a TREM. For example, a nucleotide substitution in a particular Attorney Docket No.: F2099-7038WO region of a TREM may increase activity of the TREM and a nucleotide substitution in a second region of a TREM may decrease activity of the TREM. In an embodiment, the activity that is modulated by the nucleotide substitution is the PTC read-through activity of the TREM, e.g., the ability of the TREM to support translation of a premature termination codon (PTC) in a protein coding sequence. In an embodiment, the PTC read-through activity of a TREM modulates the abundance of the TREM in a pool of hits resulting from a pooled screen of a plurality of TREMs comprising nucleotide substitutions. In an embodiment, a TREM having increased PTC read- through activity has greater abundance, e.g., relative to a reference standard, in a pool of hits resulting from a pooled screen of TREMs comprising nucleotide substitutions. In an embodiment, a TREM having decreased PTC read-through activity has lesser abundance, e.g., relative to a reference standard, in a pool of hits resulting from a pooled screen of TREMs comprising nucleotide substitutions. In an embodiment, a nucleotide substitution in a particular region of a TREM modulates the abundance of the TREM in a pool of hits resulting from a pooled screen for PTC read-through activity. In an embodiment, a nucleotide substitution in a particular region of a TREM increases the abundance of the TREM in a pool of hits resulting from a pooled screen. In an embodiment, a nucleotide substitution in the stem, e.g., base-paired region, formed between the [ASt Domain1] and the [ASt Domain2], e.g., the stem formed between positions 1-7 and 66-72, increases the abundance of a TREM in a pool of hits resulting from a pooled screen. In an embodiment, a nucleotide substitution in the stem formed between base pairs at positions 1 and 72, 2 and 71, 3 and 70, 4 and 69, 5 and 68, 6 and 67, and 7 and 66 increases the abundance of a TREM in a pool of hits resulting from a pooled screen, e.g., as shown in FIG.4A. In an embodiment, a nucleotide substitution in the stem of the [ACH Domain], e.g., the stem formed between positions 27-31 and 39-43, increases the abundance of a TREM in a pool of hits resulting from a pooled screen. In an embodiment, a nucleotide substitution in the stem formed between base pairs at positions 27 and 43, 28 and 42, 29 and 41, 30 and 40, and 31 and 39 increases the abundance of a TREM in a pool of hits resulting from a pooled screen, e.g., as shown in FIG.4A. In an embodiment, a nucleotide substitution in a particular region of a TREM decreases the abundance of a TREM in a pool of hits resulting from a pooled screen. In an embodiment, a nucleotide substitution in the loop region of the [ACH Domain], e.g., positions 32-38 decreases the abundance of a TREM in a pool of hits resulting from a pooled screen. In an embodiment, a nucleotide substitution in the loop formed at positions Attorney Docket No.: F2099-7038WO 32, 33, 34, 35, 36, 37, and 38 decreases the abundance of a TREM in a pool of hits resulting from a pooled screen, e.g., as shown in FIG.4A. In an embodiment, a nucleotide substitution in a particular region of a TREM modulates the abundance of various TREM scaffolds, e.g., TREMs specific to various amino acids, e.g., TREMs having the ability to be charged with various amino acids, in a pool of hits resulting from a pooled screen. In an embodiment, a nucleotide substitution in a particular position of a TREM increases the abundance of certain TREM scaffolds in a pool of hits resulting from a pooled screen, e.g., nucleotide substitutions in the base-pair formed between positions 51 and 63. In an embodiment, a nucleotide substitution in the base pair formed between positions 51 and 63 increases the abundance of certain TREM scaffolds in a pool of hits resulting from a pooled screen, e.g., as shown in FIG.4A. In an embodiment, the abundance of a nucleotide substitution at a particular position in a TREM in a pool of hits resulting from a pooled screen is modulated by the activity of the TREM, e.g., the PTC read-through activity of the TREM. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 4.5, e.g., as provided in FIG. 4B. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 3.5. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 2.5. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 2. In an embodiment, the enrichment, e.g., abundance, of a nucleotide substitution at a particular position in a TREM in a pool of hits resulting from a pooled screen is modulated by the activity of the TREM, e.g., the PTC read-through activity of the TREM. In an embodiment, a nucleotide substitution at a particular position in a TREM is enriched in a pool of hits resulting from a pooled screen, e.g., is more abundant in the pool of hits than the starting pool composition. In an embodiment, a nucleotide substitution at a particular position in a TREM is depleted in a pool of hits resulting from a pooled screen, e.g., is more abundant in the pool of hits than the starting pool composition. In an embodiment, a nucleotide substitution at a particular position in a TREM is enriched to be between about 0 and about 4, e.g., as provided in FIG.5. In an embodiment, a nucleotide substitution at any of positions 1, 2, 3, 4, 5, 6, 7, 16, 17, 20a, 27, 28, 29, 30, 31, 39, 40, 41, 42, 43, 51, 59, 60, 63, 66, 67, 68, 69, 70, 71, 72, or 73 increases the abundance of a TREM in a pool of hits resulting from a pooled screen, e.g., as provided in FIG. 5. In an embodiment, a nucleotide substitution at any of positions 1, 2, 3, 4, 5, 6, 7, 16, 17, 20a, Attorney Docket No.: F2099-7038WO 27, 28, 29, 30, 31, 39, 40, 41, 42, 43, 51, 59, 60, 63, 66, 67, 68, 69, 70, 71, 72, or 73 increases premature termination codon (PTC) read-through activity of a TREM, e.g., as provided in FIG. 5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at any of positions 1, 2, 3, 4, 5, 6, or 7, e.g., within the [ASt Domain1], e.g., as shown in FIG.5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at any of positions 16 or 17, e.g., within the [DH Domain], e.g., as shown in FIG.5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at position 20a, e.g., within the [DH Domain], e.g., as shown in FIG.5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at any of positions 27, 28, 29, 30, or 31, e.g., within the [ACH Domain], e.g., as shown in FIG.5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at any of positions 39, 40, 41, 42, or 43, e.g., within the [ACH Domain], e.g., as shown in FIG.5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at position 51, e.g., within the [TH Domain], e.g., as shown in FIG.5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at any of positions 59 or 60, e.g., within the Attorney Docket No.: F2099-7038WO [TH Domain], e.g., as shown in FIG.5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at position 63, e.g., within the [TH Domain], e.g., as shown in FIG.5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at any of positions 66, 67, 68, 69, 70, 71, 72, or 73, e.g., within the [ASt Domain2], e.g., as shown in FIG.5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is decreased by a nucleotide substitution at any of positions 32, 33, 34, 35, 36, 37, or 38, e.g., within the [ACH Domain], e.g., as shown in FIG.5. In an embodiment, the abundance of a nucleotide substitution at a particular position in a TREM in a pool of hits resulting from a pooled screen is modulated by the activity of the TREM, e.g., the PTC read-through activity of the TREM. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 3.6, e.g., as provided in FIG.6. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 8, e.g., as provided in FIG.7. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 3.5, e.g., as provided in FIG.8. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 5, e.g., as provided in FIG.9. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 5, e.g., as provided in FIG.10. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 12, e.g., as provided in FIG.11. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 2.1, e.g., as provided in FIG.12. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 2.4, e.g., as provided in FIG.13. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 4, e.g., as provided in FIG.14. In an Attorney Docket No.: F2099-7038WO embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 4.5, e.g., as provided in FIG.15. In an embodiment, the enrichment, e.g., abundance, of a nucleotide substitution at a particular position in a TREM in a pool of hits resulting from a pooled screen is modulated by the activity of the TREM, e.g., the PTC read-through activity of the TREM. In an embodiment, the nucleotide substitution disrupts base-pairing at a particular position in a TREM. In an embodiment, a nucleotide substitution that disrupts base-pairing is enriched in a pool of hits resulting from a pooled screen. In an embodiment, a nucleotide substitution that disrupts base- pairing is depleted in a pool of hits resulting from a pooled screen. In an embodiment, a nucleotide substitution that disrupts base-pairing is enriched to be about 0 toa bout 4, e.g., as provided in FIG.16. In an embodiment, the enrichment of a TREM comprising a nucleotide substitution in a pool of hits, e.g., a pool of TREMs having increased activity, e.g., increased PTC read-through activity, is reproducible between replicate screens, e.g., as shown in FIGs.17 and 19A-B. In an embodiment, the log2 PTC read-through activity of a TREM comprising a nucleotide substitution, e.g., relative to a parent TREM sequence, e.g., starting TREM sequence, is modulated by the nucleotide substitution. In an embodiment, the log2 PTC read-through activity of a TREM is modulated by a nucleotide substitution to be between about -0.5 to about 6.8, e.g., as provided in FIG.18. In an embodiment, the log2 PTC read-through activity of a TREM is modulated by a nucleotide substitution to be between about -0.5 to about 4 at a low TREM dose. In an embodiment, the log2 PTC read-through activity of a TREM is modulated by a nucleotide substitution to be between about 0.5 to about 6.8 at a high TREM dose. In an embodiment, delivery of a TREM comprising a nucleotide substitution does not affect the activity of the TREM, e.g., the PTC read-through activity of the TREM. In an embodiment, the PTC read-through activity of a TREM delivered as a synthesized oligonucleotide or by lentivirus is about equivalent, e.g., as provided in FIG.22 and FIG.25. In an embodiment, the normalized log2 activity of a TREM comprising nucleotide substitutions delivered by lentivirus is between about -2 and about 4. In an embodiment, the normalized log2 activity of a TREM comprising nucleotide substitutions delivered as a synthesized oligonucleotide, e.g., oligo, is between about -2.1 and about 4. Attorney Docket No.: F2099-7038WO In an embodiment, a TREM comprises a nucleotide substitution at a nucleotide position relative to a nucleotide position within reference sequence, e.g., a reference TREM. In an embodiment, the TREM comprising the nucleotide substitution modulates, e.g., increases or decreases, a functional parameter of a TREM, e.g., the activity or stability of the TREM, relative to a reference TREM. In an embodiment, the functional parameter of a TREM that is modulated by nucleotide substitution relative to a reference TREM is the premature termination codon (PTC) read-through activity of the TREM. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 1638. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 1654. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 1660. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 1835. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 1867. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2000. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2001. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2016. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2017. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2018. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2019. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2020. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2021. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2022. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2023. In an embodiment, the PTC read-through activity of a TREM is Attorney Docket No.: F2099-7038WO increased by a nucleotide substitution relative to a parent TREM, e.g., a parent TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 1638. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 1654. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 1660. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 1835. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 1867. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2000. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2001. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2016. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2017. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2018. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2019. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2020. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2021. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2022. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2023. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 1% to about 500% or more, e.g., about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, or more than 500%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, Attorney Docket No.: F2099-7038WO 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 1%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 5%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a parent TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 10%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 20%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 30%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 40%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 50%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 60%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 70%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 80%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 90%. In an Attorney Docket No.: F2099-7038WO embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 100%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 150%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 200%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 250%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 300%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 350%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 400%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 450%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 500%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by more than about 500%. Attorney Docket No.: F2099-7038WO In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 2- fold to about 500-fold or more, e.g., about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50- fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350- fold, 400-fold, 450-fold, 500-fold, or more than 500-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 2-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 5-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 10-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 20-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 30-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 40-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 50-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 60-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, Attorney Docket No.: F2099-7038WO 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 70-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 80-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 90-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 100-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 150-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 200-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 250-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 300-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 350-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 400-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, Attorney Docket No.: F2099-7038WO increases the PTC read-through of a TREM by about 450-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 500-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by more than about 500-fold. In an embodiment, a nucleotide substitution, e.g., a nucleotide substitution listed in FIG.24, modulates activity of a TREM relative to a reference TREM. In an embodiment, a nucleotide substitution listed in FIG. 24 increases the activity of a TREM relative to a reference TREM. In an embodiment, a nucleotide substitution listed in FIG.24 decreases the activity of a TREM relative to a reference TREM. In an embodiment, a TREM having a nucleotide substitution is a TREM listed in FIG.24, e.g., any of SEQ ID NOs: 1457-2001. In an embodiment, the nucleotide substitution is a nucleotide substitution listed in FIG.24. In an embodiment, the nucleotide substitution increases premature termination codon (PTC) read-through activity of the TREM, e.g., as provided in FIG. 24. In an embodiment, the nucleotide substitution that increases PTC read-through activity of a TREM is a nucleotide substitution comprised by any of SEQ ID NOs: 1469, 1473, 1480, 1639, 1640, 1641, 1642, 1645, 1646, 1649, 1651, 1652, 1654, 1655, 1658, 1659, 1660, 1661, 1662, 1665, 1666, 1668, 1669, 1671, 1672, 1673, 1677, 1679, 1680, 1682, 1685, 1686, 1687, 1688, 1689, 1694, 1695, 1696, 1697, 1699, 1704, 1705, 1707, 1709, 1711, 1725, 1726, 1727, 1729, 1730, 1731, 1732, 1736, 1738, 1739, 1740, 1746, 1750, 1751, 1752, 1758, 1764, 1767, 1768, 1769, 1770, 1775, 1777, 1780, 1783, 1792, 1793, 1795, 1797, 1799, 1803, 1808, 1814, 1818, 1820, 1823, 1824, 1830, 1832, 1833. In an embodiment, a TREM comprising an Arg-TGA scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1638, comprises a nucleotide substitution at any one of the positions shown in FIG.6. In an embodiment, a TREM comprising an Arg-TGA scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1638, comprises a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, or 7, e.g., in the [ASt Domain1], e.g., as shown in FIG.6. In an embodiment, a TREM comprising an Arg- TGA scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1638, Attorney Docket No.: F2099-7038WO comprises a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG.6. In an embodiment, a TREM comprising an Arg-TGA scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1638, comprises a nucleotide substitution at any of nucleotide positions 65, 66, 67, 68, 69, 70, 71, 72, or 73, e.g., in the [ASt Domain2], e.g., as shown in FIG.6. In an embodiment, the activity of a TREM comprising an Arg-TGA scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1638, comprising a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, or 7 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, about 3-fold, or about 3.6-fold, e.g., as shown in FIG.6. In an embodiment, the activity of a TREM comprising an Arg-TGA scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1638, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG.6. In an embodiment, the activity of a TREM comprising an Arg-TGA scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1638, comprising a nucleotide substitution at any of nucleotide positions 65, 66, 67, 68, 69, 70, 71, 72, or 73 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 3.6-fold, e.g., as shown in FIG.6. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1835, comprises a nucleotide substitution at any one of the positions shown in FIG.7. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1835, comprises a nucleotide substitution at any of nucleotide positions 26, 27, 28, 29, 30, or 31, e.g., in the [ACH Domain], e.g., as shown in FIG.7. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1835, comprises a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG.7. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1835, comprises a nucleotide substitution at any of nucleotide positions 39, 40, 41, 42, 43, or 44, e.g., in the [ACH Domain], e.g., as shown in FIG.7. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ Attorney Docket No.: F2099-7038WO ID NO: 1835, comprising a nucleotide substitution at any of nucleotide positions 26, 27, 28, 29, 30, or 31 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 5-fold, about 6-fold, about 7-fold, or about 8-fold, e.g., as shown in FIG.7. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1835, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG.7. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1835, comprising a nucleotide substitution at any of nucleotide positions 39, 40, 41, 42, 43, or 44 is increased, e.g., relative to a reference sequence, e.g., increased by about 2-fold, about 5-fold, about 6-fold, about 7-fold, or about 8-fold, e.g., as shown in FIG.7. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprises a nucleotide substitution at any one of the positions shown in FIG.8. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprises a nucleotide substitution at any of nucleotide positions 3, 4, 5, 6, or 7, e.g., in the [ASt Domain1], e.g., as shown in FIG.8. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprises a nucleotide substitution at nucleotide position 20a, e.g., in the [DH Domain], e.g., as shown in FIG.8. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprises a nucleotide substitution at any of nucleotide positions 26, 27, 28, 29, or 30, e.g., in the [ACH Domain], e.g., as shown in FIG.8. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprises a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG.8. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprises a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, 44, or 45, e.g., in the [ACH Domain], e.g., as shown in FIG.8. In an embodiment, a TREM comprising a Gln- TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or Attorney Docket No.: F2099-7038WO 1654, comprises a nucleotide substitution at nucleotide position 49, e.g., in the [TH Domain], e.g., as shown in FIG.8. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprises a nucleotide substitution at any of nucleotide positions 65, 66, 67, 68, 69, 70, 71, 72, or 73, e.g., in the [ASt Domain2], e.g., as shown in FIG.8. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprising a nucleotide substitution at any of nucleotide positions 3, 4, 5, 6, or 7 is increased, e.g., relative to a reference sequence, e.g., increased by about 2.5-fold, about 3-fold, or about 3.5-fold, e.g., as shown in FIG.8. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprising a nucleotide substitution at nucleotide position 20a is increased, e.g., relative to a reference sequence, e.g., increased by about 2.5-fold or about 3-fold, e.g., as shown in FIG.8. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprises a nucleotide substitution at any of nucleotide positions 26, 27, 28, 29, or 30 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as shown in FIG.8. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG.8. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprising a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, 44, or 45 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as shown in FIG.8. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprising a nucleotide substitution at nucleotide position 49 is increased, e.g., relative to a reference sequence, e.g., increased by about 2-fold, e.g., as shown in FIG.8. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprising a nucleotide substitution at any of nucleotide positions 65, 66, 67, 68, 69, 70, 71, 72, or 73 is increased, e.g., Attorney Docket No.: F2099-7038WO relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, or about 3.5-fold, e.g., as shown in FIG.8. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprises a nucleotide substitution at any one of the positions shown in FIG.9. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprises a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, e.g., in the [ASt Domain1] or the [DH Domain], e.g., as shown in FIG.9. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprises a nucleotide substitution at any of nucleotide positions 20a, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31, e.g., in the [DH Domain] or the [ACH Domain], e.g., as shown in FIG.9. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprises a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG.9. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprises a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, 44, or 45, e.g., in the [ACH Domain], e.g., as shown in FIG.9. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprises a nucleotide substitution at any of nucleotide positions 46 or 48, e.g., in the [VL Domain], e.g., as shown in FIG.9. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprises a nucleotide substitution at any of nucleotide positions 59 or 60, e.g., in the [TH Domain], e.g., as shown in FIG.9. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprises a nucleotide substitution at any of nucleotide positions 66, 67, 68, 69, 70, 71, 72, or 73, e.g., in the [ASt Domain2], e.g., as shown in FIG.9. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprising a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 increases activity, e.g., relative to a Attorney Docket No.: F2099-7038WO reference sequence, e.g., increases by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as shown in FIG.9. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprising a nucleotide substitution at any of nucleotide positions 20a, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5- fold, about 2-fold, about 2.5-fold, or about 3-fold, e.g., as shown in FIG.9. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG.9. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprising a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, 44, or 45 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG.9. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprising a nucleotide substitution at any of nucleotide positions 46 or 48 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG.9. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprising a nucleotide substitution at any of nucleotide positions 59 or 60 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, e.g., as shown in FIG.9. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprising a nucleotide substitution at any of nucleotide positions 66, 67, 68, 69, 70, 71, 72, or 73 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as shown in FIG.9. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprises a nucleotide substitution at any one of the positions shown in FIG.10. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ Attorney Docket No.: F2099-7038WO ID NO: 1867, comprises a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, e.g., in the [ASt Domain1] or the [DH Domain], e.g., as shown in FIG.10. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprises a nucleotide substitution at any of nucleotide positions 20a, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31, e.g., in the [DH Domain] or the [ACH Domain], e.g., as shown in FIG.10. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprises a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG.10. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprises a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, 44, or 45, e.g., in the [ACH Domain], e.g., as shown in FIG.10. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprises a nucleotide substitution at any of nucleotide positions 46, 48, or 49, e.g., in the [VL Domain], e.g., as shown in FIG.10. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprises a nucleotide substitution at any of nucleotide positions 59 or 60, e.g., in the [TH Domain], e.g., as shown in FIG.10. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprises a nucleotide substitution at any of nucleotide positions 66, 67, 68, 69, 70, 71, 72, or 73, e.g., in the [ASt Domain2], e.g., as shown in FIG.10. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprising a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 increases activity, e.g., relative to a reference sequence, e.g., increases by about 1.5-fold, about 2-fold, about 2.5-fold, or about 3-fold, e.g., as shown in FIG.10. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprising a nucleotide substitution at any of nucleotide positions 20a, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, about 2.5-fold, or about 3-fold, e.g., as shown in FIG.10. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference Attorney Docket No.: F2099-7038WO sequence, e.g., SEQ ID NO: 1867, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG.10. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprising a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, 44, or 45 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG.10. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprising a nucleotide substitution at any of nucleotide positions 46 or 48 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG.10. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprising a nucleotide substitution at any of nucleotide positions 59 or 60 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, e.g., as shown in FIG.10. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprising a nucleotide substitution at any of nucleotide positions 66, 67, 68, 69, 70, 71, 72, or 73 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, or about 2-fold, e.g., as shown in FIG.10. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2000, comprises a nucleotide substitution at any one of the positions shown in FIG.11. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2000, comprises a nucleotide substitution at any of nucleotide positions 31 or 32, e.g., in the [ACH Domain], e.g., as shown in FIG.11. In an embodiment, a TREM comprising a Glu- TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2000, comprises a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG.11. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2000, comprising a nucleotide substitution at any of nucleotide positions 31 or 32 is increased, e.g., relative to a reference sequence, e.g., increased by about 5-fold or about 11-fold, e.g., as shown in FIG.11. In an embodiment, the activity of a TREM comprising a Glu-TAG Attorney Docket No.: F2099-7038WO scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2000, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG.11. In an embodiment, a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprises a nucleotide substitution at any one of the positions shown in FIG.12. In an embodiment, a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprises a nucleotide substitution at any of nucleotide positions 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, 26, 27, 28, 29, or 30, e.g., in the [ASt Domain1], the [DH Domain], or the [ACH Domain], e.g., as shown in FIG.12. In an embodiment, a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprises a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG.12. In an embodiment, a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprises a nucleotide substitution at any of nucleotide positions 39, 40, 41, 42, 43, 44, 45, V11, V12, V13, V14, V15, V16, V17, V1, V2, V3, V4, V5, V27, V26, V25, V24, V23, V22, V21, 46, 47, 48, 49, or 50, e.g., in the [ACH Domain], the [VL Domain], or the [TH Domain], e.g., as shown in FIG.12. In an embodiment, a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprises a nucleotide substitution at nucleotide positions 59, e.g., in the [TH Domain], e.g., as shown in FIG.12. In an embodiment, a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprises a nucleotide substitution at any of nucleotide positions 64, 65, 66, 67, 68, 69, 70, 71, 72, or 73, e.g., in the [TH Domain] or the [ASt Domain2], e.g., as shown in FIG.12. In an embodiment, the activity of a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprising a nucleotide substitution at any of nucleotide positions 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, 26, 27, 28, 29, or 30 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG.12. In an embodiment, the activity of a TREM comprising a Leu-TAG scaffold, Attorney Docket No.: F2099-7038WO e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG.12. In an embodiment, the activity of a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprising a nucleotide substitution at any of nucleotide positions 39, 40, 41, 42, 43, 44, 45, V11, V12, V13, V14, V15, V16, V17, V1, V2, V3, V4, V5, V27, V26, V25, V24, V23, V22, V21, 46, 47, 48, 49, or 50 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG.12. In an embodiment, the activity of a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprising a nucleotide substitution at nucleotide position 59 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG. 12. In an embodiment, the activity of a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprising a nucleotide substitution at any of nucleotide positions 64, 65, 66, 67, 68, 69, 70, 71, 72, or 73 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG.12. In an embodiment, a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprises a nucleotide substitution at any one of the positions shown in FIG.13. In an embodiment, a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprises a nucleotide substitution at any of nucleotide positions 4, 5, 6, or 7, e.g., in the [ASt Domain1], e.g., as shown in FIG.13. In an embodiment, a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprises a nucleotide substitution at any of nucleotide positions 16, 17, or 20, e.g., in the [DH Domain], e.g., as shown in FIG.13. In an embodiment, a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprises a nucleotide substitution at any of nucleotide positions 28, 29, or 30, e.g., in the [ACH Domain], e.g., as shown in FIG.13. In an embodiment, a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprises a nucleotide substitution at any of nucleotide positions 32, 33, Attorney Docket No.: F2099-7038WO 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG.13. In an embodiment, a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprises a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, or 44, e.g., in the [ACH Domain], e.g., as shown in FIG.13. In an embodiment, a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprises a nucleotide substitution at any of nucleotide positions 47, 48, 49, 50, or 51, e.g., in the [VL Domain] or the [TH Domain], e.g., as shown in FIG.13. In an embodiment, a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprises a nucleotide substitution at any of nucleotide positions 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70, e.g., in the [TH Domain] or the [ASt Domain2], e.g., as shown in FIG.13. In an embodiment, the activity of a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprising a nucleotide substitution at any of nucleotide positions 4, 5, 6, or 7 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as shown in FIG.13. In an embodiment, the activity of a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprising a nucleotide substitution at any of nucleotide positions 16, 17, or 20 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG.13. In an embodiment, the activity of a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprising a nucleotide substitution at any of nucleotide positions 28, 29, or 30 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as shown in FIG. 13. In an embodiment, the activity of a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG.13. In an embodiment, the activity of a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprising a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, or 44 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as Attorney Docket No.: F2099-7038WO shown in FIG.13. In an embodiment, the activity of a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprising a nucleotide substitution at any of nucleotide positions 47, 48, 49, 50, or 51 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as shown in FIG.13. In an embodiment, the activity of a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprising a nucleotide substitution at any of nucleotide positions 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as shown in FIG.13. In an embodiment, a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprises a nucleotide substitution at any one of the positions shown in FIG.14. In an embodiment, a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprises a nucleotide substitution at any of nucleotide positions 3, 4, 5, or 6, e.g., in the [ASt Domain1], e.g., as shown in FIG.14. In an embodiment, a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprises a nucleotide substitution at any of nucleotide positions 29, 30 31, 32, or 33, e.g., in the [ACH Domain], e.g., as shown in FIG.14. In an embodiment, a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprises a nucleotide substitution at any of nucleotide positions 34, 35, or 36, e.g., in the [ACH Domain], e.g., as shown in FIG.14. In an embodiment, a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprises a nucleotide substitution at any of nucleotide positions 37, 38, 39, 40, or 41, e.g., in the [ACH Domain], e.g., as shown in FIG.14. In an embodiment, a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprises a nucleotide substitution at nucleotide position 51, e.g., in the [TH Domain], e.g., as shown in FIG.14. In an embodiment, a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprises a nucleotide substitution at nucleotide position 63, e.g., in the [TH Domain], e.g., as shown in FIG.14. In an embodiment, a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprises a nucleotide Attorney Docket No.: F2099-7038WO substitution at nucleotide position 67, e.g., in the [ASt Domain2], e.g., as shown in FIG.14. In an embodiment, the activity of a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprising a nucleotide substitution at any of nucleotide positions 3, 4, 5, or 6 is increased, e.g., relative to a reference sequence, e.g., increased by about 2-fold or about 3-fold, e.g., as shown in FIG.14. In an embodiment, the activity of a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprising a nucleotide substitution at any of nucleotide positions 29, 3031, 32, or 33 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG.14. In an embodiment, the activity of a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprising a nucleotide substitution at any of nucleotide positions 34, 35, or 36 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG.14. In an embodiment, the activity of a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprising a nucleotide substitution at any of nucleotide positions 37, 38, 39, 40, or 41 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, about 2.5-fold, or about 3-fold, e.g., as shown in FIG. 14. In an embodiment, the activity of a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprising a nucleotide substitution at nucleotide position 51 is increased, e.g., relative to a reference sequence, e.g., increased by about 4-fold, e.g., as shown in FIG.14. In an embodiment, the activity of a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprising a nucleotide substitution at nucleotide position 63 is increased, e.g., relative to a reference sequence, e.g., increased by about 4-fold, e.g., as shown in FIG.14. In an embodiment, the activity of a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprising a nucleotide substitution at nucleotide position 67 is increased, e.g., relative to a reference sequence, e.g., increased by about 3-fold, e.g., as shown in FIG.14. In an embodiment, a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprises a nucleotide substitution at any one of the positions shown in FIG.15. In an embodiment, a TREM Attorney Docket No.: F2099-7038WO comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprises a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, or 7, e.g., in the [ASt Domain1], e.g., as shown in FIG.15. In an embodiment, a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprises a nucleotide substitution at any of nucleotide positions 17 or 18, e.g., in the [DH Domain], e.g., as shown in FIG.15. In an embodiment, a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprises a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG.15. In an embodiment, a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprises a nucleotide substitution at nucleotide position 37, e.g., in the [ACH Domain], e.g., as shown in FIG.15. In an embodiment, a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprises a nucleotide substitution at nucleotide position 50, e.g., in the [TH Domain], e.g., as shown in FIG.15. In an embodiment, a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprises a nucleotide substitution at any of nucleotide positions 64, 65, 66, 67, 68, 69, 70, 71, 72, or 73, e.g., in the [DH Domain] or the [ASt Domain2], e.g., as shown in FIG.15. In an embodiment, the activity of a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprising a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, or 7 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 4-fold, e.g., as shown in FIG.15. In an embodiment, the activity of a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprising a nucleotide substitution at any of nucleotide positions 17 or 18 is increased, e.g., relative to a reference sequence, e.g., increased by about 2-fold or about 3-fold, e.g., as shown in FIG.15. In an embodiment, the activity of a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG.15. In an embodiment, the activity of a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ Attorney Docket No.: F2099-7038WO ID NO: 2018 or 2019, comprising a nucleotide substitution at nucleotide position 37 is increased, e.g., relative to a reference sequence, e.g., increased by about 3-fold, e.g., as shown in FIG.15. In an embodiment, the activity of a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprising a nucleotide substitution at nucleotide position 50 is increased, e.g., relative to a reference sequence, e.g., increased by about 3-fold, e.g., as shown in FIG.15. In an embodiment, the activity of a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprising a nucleotide substitution at any of nucleotide positions 64, 65, 66, 67, 68, 69, 70, 71, 72, or 73 is increased, e.g., relative to a reference sequence, e.g. increased by about 1.5-fold, about 2-fold, about 2.5-fold, about 3.5-fold, or about 4-fold, e.g., as shown in FIG.15. Non-naturally occurring modification A TREM, a TREM core fragment or a TREM fragment described herein may comprise a non-naturally occurring modification, e.g., a modification described in Table 5. A non-naturally occurring modification can be made according to methods known in the art. In an embodiment, a non-naturally occurring modification is a modification that a cell, e.g., a human cell, does not make on an endogenous tRNA. In an embodiment, a non-naturally occurring modification is a modification that a cell, e.g., a human cell, can make on an endogenous tRNA, but wherein such modification is in a location in which it does not occur on a native tRNA. In an embodiment, the non-naturally occurring modification is in a domain, linker or arm which does not have such modification in nature. In an embodiment, the non-naturally occurring modification is at a position within a domain, linker or arm, which does not have such modification in nature. In an embodiment, the non-naturally occurring modification is on a nucleotide which does not have such modification in nature. In an embodiment, the non-naturally occurring modification is on a nucleotide at a position within a domain, linker or arm, which does not have such modification in nature. Attorney Docket No.: F2099-7038WO In an embodiment, a TREM, a TREM core fragment or a TREM fragment described herein comprises a modification provided in Table 5, or a combination thereof. The modifications provided in Table 5 are non-naturally occurring or occur naturally in RNAs, and are used herein on a synthetic TREM, a TREM core fragment or a TREM fragment at a position that does not occur in nature. Table 5: Exemplary modifications Chemical Modification (S)-constrained ethyl (cEt) 5-(methoxycarbonyl-methyl)uracil Attorney Docket No.: F2099-7038WO 1-(3,4-Dimethoxybenzyl)pseudouridine 5-bromo-uridine 1-(3-Amino-3-carboxypropyl)pseudo-uridine 5-carbamoylmethyl-2’-O-methyluridine r Attorney Docket No.: F2099-7038WO 1,3-(diaza)-2-(oxo)-phenoxazin-1-yl 5-methylaminomethyluridine 1,3,5-(triaza)-2,6-(dioxa)-naphthalene 5-methylcytidine Attorney Docket No.: F2099-7038WO -Methyl-6-amino-pseudo-uridine 6-Butyl-pseudo-uridine -Methyl-6-bromo-pseudo-uridine 6-Chloro-pseudo-uridine Attorney Docket No.: F2099-7038WO ’-alpha-Ethynyluridine 7-(deaza)guanine ’-alpha-Trifluoromethyladenosine7-(guanidiniumalkylhydroxy)-1-(aza)-2--- Attorney Docket No.: F2099-7038WO ’-Deoxy-2’-beta-aminoguanosine 8-(alkynyl)guanine ’-Deoxy-2’-beta-aminouridine 8-(amino)adenine Attorney Docket No.: F2099-7038WO ’-OH-ara-cytidine azaguanine ’-OH-ara-guanosinebis-ortho-(aminoalkylhydroxy)-6-phenyl- Attorney Docket No.: F2099-7038WO -aminoadenine l -Methyl-6-(4-thiomorpholino)-pseudo- uridine Attorney Docket No.: F2099-7038WO ’-methyl, 2’-amino, 2’-azido, 2’fluro-uridine Locked nucleic acid (LNA) -methyladenosine l-taurinomethyl-1-methyl-uridine Attorney Docket No.: F2099-7038WO -thio-pseudouridine N6-(19-Amino-pentaoxanonadecyl)adenosine -thiouridine N6-(cis-hydroxyisopentenyl)adenosine -n-- - Attorney Docket No.: F2099-7038WO -(thio)uracil peroxywybutosine ,2’-O-dimethylcytidine phenanthracenyl - Attorney Docket No.: F2099-7038WO 5 substituted pyrimidines Pseudo-uridine-N1-p-benzoic acid 5-(1,3-diazole-l-alkyl)uracil Pseudo-uridine-N1-7-heptanoic acid A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the Attorney Docket No.: F2099-7038WO [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [DH Domain] and the [ACH Domain]. In some embodiments, the TREM comprises twenty-one non-naturally occurring modifications. In some embodiments, the TREM comprises fifteen 2’-O-methyl modifications. In some embodiments, the TREM comprises one 2’-fluoro modification. In some embodiments, the TREM comprises five phosphorothioate modifications. In some embodiments, the TREM comprises fifteen 2’-O- methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], one 2’-fluoro modification in the [ACH Domain], and five phosphorothioate modifications in the [DH Domain] and the [ACH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 1 in Table 6: 1-m, 14-m, 15-m, 16-m, 17-m, 18-m, 19-*, 20-m, 21-*, 33-f, 34-m, 35- *, 37-*, 38-*, 41-m, 42-m, 43-m, 44-m, 50-m, 52-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1] and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification and an internucleotide modification in each of the [ASt Domain1] and the [ASt Domain2]. In some embodiments, the TREM comprises six non-naturally occurring modifications. In some embodiments, the TREM comprises three 2’-O-methyl modifications. In some embodiments, the TREM comprises three phosphorothioate modifications. In some embodiments, the TREM comprises three 2’-O-methyl modifications in the [ASt Domain1] and the [ASt Domain2] and three phosphorothioate modifications in the [ASt Domain1] and the [ASt Domain2]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 2 in Table 6: 1-m*, 2-m*, 74-*, 75-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1] and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ASt Domain1], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises seven non-naturally occurring modifications. In some embodiments, the TREM comprises three 2’-O-methyl modifications. In some embodiments, the TREM comprises four Attorney Docket No.: F2099-7038WO phosphorothioate modifications. In some embodiments, the TREM comprises three 2’-O-methyl modifications in the [ASt Domain1] and the [ASt Domain2] and four phosphorothioate modifications in the [ASt Domain1], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 3 in Table 6: 1-m*, 2-m*, 52-*, 74-*, 75-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [DH Domain], the [ACH Domain], and the [TH Domain]. In some embodiments, the TREM comprises thirty-one non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-three 2’-O-methyl modifications. In some embodiments, the TREM comprises eight phosphorothioate modifications. In some embodiments, the TREM comprises twenty-three 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2] and eight phosphorothioate modifications in the [DH Domain], the [ACH Domain], and the [TH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 4 in Table 6: 1-m, 2- m, 3-m, 4-m, 5-m, 6-m, 13-m, 14-m, 15-m, 16-m, 17-m, 18-m, 19-*, 20-m, 21-*, 25-m, 33-*, 34- m, 35-*, 37-*, 38-*, 49-m, 50-m, 51-m, 52-m, 53-m, 54-*, 55-*, 61-m, 65-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ASt Domain1] and the [ASt Domain2]. In some embodiments, the TREM comprises ten non-naturally occurring modifications. In some embodiments, the TREM comprises four 2’-O-methyl modifications. In some embodiments, the TREM comprises three 2’-fluoro modifications. In some embodiments, the TREM comprises three phosphorothioate modifications. In some embodiments, the TREM comprises four 2’-O- methyl modifications in the [ASt Domain1], the [TH Domain], and the [ASt Domain2], three 2’- Attorney Docket No.: F2099-7038WO fluoro modifications in the [DH Domain] and the [TH Domain], and three phosphorothioate modifications in the [ASt Domain1] and the [ASt Domain2]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 5 in Table 6: 1-m*, 2- m*, 13-f, 14-f, 54-f, 59-m, 75-*, 76-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain] and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ACH Domain] and the [TH Domain]. In some embodiments, the TREM comprises twenty-six non-naturally occurring modifications. In some embodiments, the TREM comprises sixteen 2’-O-methyl modifications. In some embodiments, the TREM comprises two 2’-fluoro modifications. In some embodiments, the TREM comprises eight phosphorothioate modifications. In some embodiments, the TREM comprises sixteen 2’-O- methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], two 2’-fluoro modifications in the [ACH Domain] and the [VL Domain], and eight phosphorothioate modifications in the [ACH Domain] and the [TH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 6 in Table 6: 1-m, 13-m, 17-m, 18-m, 25-m, 33-*, 34-m, 35- *, 37-*, 38-*, 41-f, 42-m, 43-m, 44-f, 49-m, 50-m, 52-m, 54-*, 55-*, 56-m, 57-*, 58-*, 59-m, 61- m, 65-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [DH Domain] and the [TH Domain]. In some embodiments, the TREM comprises twenty-five non-naturally occurring modifications. In some embodiments, the TREM comprises nineteen 2’-O-methyl modifications. In some embodiments, the TREM comprises two 2’-fluoro modifications. In some embodiments, the TREM comprises four phosphorothioate modifications. In some embodiments, the TREM comprises nineteen 2’- Attorney Docket No.: F2099-7038WO O-methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], two 2’-fluoro modifications in the [ACH Domain] and the [VL Domain], and four phosphorothioate modifications in the [DH Domain] and the [TH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 7 in Table 6: 1-m, 13-m, 14-m, 15-m, 16-m, 17-m, 18-m, 19- *, 20-m, 21-*, 25-m, 41-f, 42-m, 43-m, 44-f, 49-m, 50-m, 51-m, 52-m, 53-m, 54-*, 55-*, 61-m, 65-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises ten non-naturally occurring modifications. In some embodiments, the TREM comprises eight 2’-O-methyl modifications. In some embodiments, the TREM comprises two 2’-fluoro modifications. In some embodiments, the TREM comprises eight 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], and the [ASt Domain2] and two 2’-fluoro modifications in the [DH Domain] and the [ACH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 8 in Table 6: 1-m, 19-m, 20-m, 21-f, 22-m, 40-f, 41-m, 42-m, 43-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [ACH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [ACH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in the [ASt Domain1]. In some embodiments, the TREM comprises sixteen non- naturally occurring modifications. In some embodiments, the TREM comprises thirteen 2’-O- methyl modifications. In some embodiments, the TREM comprises two 2’-fluoro modifications. In some embodiments, the TREM comprises one phosphorothioate modification. In some embodiments, the TREM comprises thirteen 2’-O-methyl modifications in the [ASt Domain1], the [ACH Domain], and the [ASt Domain2], two 2’-fluoro modifications in the [ACH Domain], and one phosphorothioate modification in the [ASt Domain1]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 9 in Table 6: 1-m*, 2- m, 3-m, 4-m, 5-m, 6-m, 27-m, 28-m, 29-f, 30-m, 40-f, 41-m, 42-m, 43-m, 73-m. Attorney Docket No.: F2099-7038WO A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in the [ASt Domain1]. In some embodiments, the TREM comprises twenty-three non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-one 2’-O-methyl modifications. In some embodiments, the TREM comprises one 2’-fluoro modification. In some embodiments, the TREM comprises one phosphorothioate modification. In some embodiments, the TREM comprises twenty-one 2’-O- methyl modifications in the [ASt Domain1], the [VL Domain], the [TH Domain], and the [ASt Domain2], one 2’-fluoro modification in the [TH Domain], and one phosphorothioate modification in the [ASt Domain1]. In some embodiments, the TREM comprises the non- naturally occurring modification pattern of Pattern No: 10 in Table 6: 1-m*, 2-m, 3-m, 4-m, 5-m, 6-m, 49-m, 50-m, 51-m, 52-m, 53-m, 61-m, 62-m, 63-f, 64-m, 65-m, 66-m, 67-m, 68-m, 69-m, 71-m, 72-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in the [ASt Domain1]. In some embodiments, the TREM comprises thirty-one non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-eight 2’-O-methyl modifications. In some embodiments, the TREM comprises one 2’-fluoro modification. In some embodiments, the TREM comprises two phosphorothioate modifications. In some embodiments, the TREM comprises twenty-eight 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], one 2’-fluoro modification in the [TH Domain], and two phosphorothioate modifications in the [ASt Domain1]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 11 in Table 6: 1-m*, 2-m*, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 12-m, 13-m, 22-m, 23-m, 24-m, 25-m, 49-m, 50-m, 51-m, 52-m, 53-m, 54-m, 61-m, 62-m, 63-f, 64-m, 65-m, 66-m, 67-m, 68-m, 73-m. Attorney Docket No.: F2099-7038WO A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ASt Domain1] and the [ACH Domain]. In some embodiments, the TREM comprises thirty-two non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-three 2’-O-methyl modifications. In some embodiments, the TREM comprises four 2’-fluoro modifications. In some embodiments, the TREM comprises five phosphorothioate modifications. In some embodiments, the TREM comprises twenty-three 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], four 2’-fluoro modifications in the [ACH Domain] and the [VL Domain], and five phosphorothioate modifications in the [ASt Domain1] and the [ACH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 12 in Table 6: 1-m*, 2-m*, 3-m, 4-m, 5-m, 6-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-m, 44-m, 45-m, 46-f, 47-f, 48-f, 49-m, 50-m, 51-m, 52-m, 53-m, 54-m, 56-m, 59-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in the [ACH Domain]. In some embodiments, the TREM comprises twenty-nine non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-one 2’-O-methyl modifications. In some embodiments, the TREM comprises five 2’- fluoro modifications. In some embodiments, the TREM comprises three phosphorothioate modifications. In some embodiments, the TREM comprises twenty-one 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], five 2’-fluoro modifications in the [ACH Domain], the [VL Domain], and the [TH Domain], and three phosphorothioate modifications in the [ACH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern Attorney Docket No.: F2099-7038WO No: 13 in Table 6: 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 16-m, 17-m, 18-m, 33-f, 35-*, 37-*, 38-*, 44- m, 45-m, 46-f, 47-f, 48-f, 56-m, 59-m, 61-m, 62-m, 63-f, 64-m, 65-m, 66-m, 67-m, 68-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ASt Domain1] and the [ACH Domain]. In some embodiments, the TREM comprises forty-three non-naturally occurring modifications. In some embodiments, the TREM comprises thirty-one 2’-O-methyl modifications. In some embodiments, the TREM comprises seven 2’-fluoro modifications. In some embodiments, the TREM comprises five phosphorothioate modifications. In some embodiments, the TREM comprises forty-three 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], seven 2’-fluoro modifications in the [DH Domain], the [ACH Domain], the [VL Domain], and the [TH Domain], and five phosphorothioate modifications in the [ASt Domain1] and the [ACH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 14 in Table 6: 1-m*, 2-m*, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 12-m, 13-m, 14-m, 15-f, 16-m, 17-m, 18-m, 19-f, 20-m, 22-m, 23-m, 24-m, 25-m, 33-f, 35-*, 37-*, 38-*, 44-m, 45-m, 46-f, 47-f, 48-f, 56-m, 59-m, 61-m, 62-m, 63-f, 64-m, 65-m, 66-m, 67-m, 68-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ASt Domain1] and the [ACH Domain]. In some embodiments, the TREM comprises twenty-six non-naturally occurring modifications. In some embodiments, the TREM comprises seventeen 2’-O-methyl modifications. In some embodiments, the TREM comprises four 2’-fluoro modifications. In some embodiments, the TREM comprises five phosphorothioate modifications. In some embodiments, the TREM comprises seventeen 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the Attorney Docket No.: F2099-7038WO [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], four 2’-fluoro modifications in the [ACH Domain] and the [VL Domain], and five phosphorothioate modifications in the [ASt Domain1] and the [ACH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 15 in Table 6: 1-m*, 2-m*, 3-m, 4-m, 5-m, 6-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-m, 44-m, 45-m, 46-f, 47-f, 48-f, 56-m, 59-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises six non-naturally occurring modifications. In some embodiments, the TREM comprises six 2’-O-methyl modifications. In some embodiments, the TREM comprises six 2’-O- methyl modifications in the [ASt Domain1], the [DH Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 16 in Table 6: 1-m, 17-m, 18-m, 50-m, 52-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in the [TH Domain]. In some embodiments, the TREM comprises fifteen non-naturally occurring modifications. In some embodiments, the TREM comprises eleven 2’-O-methyl modifications. In some embodiments, the TREM comprises two 2’-fluoro modifications. In some embodiments, the TREM comprises two phosphorothioate modifications. In some embodiments, the TREM comprises eleven 2’-O- methyl modifications in the [ASt Domain1], the [DH Domain], the [TH Domain], and the [ASt Domain2], two 2’-fluoro modifications in the [DH Domain], and two phosphorothioate modifications in the [TH Domain]. In some embodiments, the TREM comprises the non- naturally occurring modification pattern of Pattern No: 17 in Table 6: 1-m, 14-m, 15-f, 16-m, 17- m, 18-m, 19-f, 20-m, 54-m*, 55-*, 56-m, 57-m, 59-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the Attorney Docket No.: F2099-7038WO [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [DH Domain], the [ACH Domain], the [VL Domain], and the [TH Domain]. In some embodiments, the TREM comprises twenty-nine non-naturally occurring modifications. In some embodiments, the TREM comprises fifteen 2’-O-methyl modifications. In some embodiments, the TREM comprises four 2’-fluoro modifications. In some embodiments, the TREM comprises ten phosphorothioate modifications. In some embodiments, the TREM comprises fifteen 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], the [TH Domain], and the [ASt Domain2], four 2’-fluoro modifications in the [ACH Domain], the [VL Domain], and the [TH Domain], and ten phosphorothioate modifications in the [DH Domain], the [ACH Domain], the [VL Domain], and the [TH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 18 in Table 6: 1-m, 10-m, 13-m, 17-*, 18-m, 19-*, 20-m, 25- m, 29-m, 33-f, 35-*, 37-*, 38-*, 41-f*, 43-m, 44-f, 46-*, 50-m, 52-m, 54-*, 55-*, 56-m, 57-*, 62- m, 63-f, 65-m, 71-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises thirteen non-naturally occurring modifications. In some embodiments, the TREM comprises twelve 2’-O-methyl modifications. In some embodiments, the TREM comprises one 2’-fluoro modification. In some embodiments, the TREM comprises twelve 2’-O-methyl modifications in the [ASt Domain1], the [TH Domain], and the [ASt Domain2] and one 2’-fluoro modification in the [ASt Domain2]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 19 in Table 6: 1-m, 61-m, 62-m, 64-m, 65-m, 66-m, 67-m, 68-m, 69-m, 70-f, 71-m, 72-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Attorney Docket No.: F2099-7038WO Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in the [ACH Domain]. In some embodiments, the TREM comprises nineteen non-naturally occurring modifications. In some embodiments, the TREM comprises thirteen 2’-O-methyl modifications. In some embodiments, the TREM comprises three 2’-fluoro modifications. In some embodiments, the TREM comprises three phosphorothioate modifications. In some embodiments, the TREM comprises thirteen 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], three 2’-fluoro modifications in the [ACH Domain], and three phosphorothioate modifications in the [ACH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 20 in Table 6: 1-m, 14-m, 15-f, 16-m, 17-m, 18-m, 19-f, 20-m, 33-f, 35-*, 37-*, 38-*, 41-m, 42-m, 43-m, 44-m, 50- m, 52-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in the [TH Domain]. In some embodiments, the TREM comprises twenty-eight non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-six 2’-O-methyl modifications. In some embodiments, the TREM comprises one 2’- fluoro modification. In some embodiments, the TREM comprises one phosphorothioate modification. In some embodiments, the TREM comprises twenty-six 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], one 2’-fluoro modification in the [TH Domain], and one phosphorothioate modification in the [TH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 21 in Table 6: 1-m, 2-m, 3-m, 4- m, 5-m, 6-m, 14-m, 15-m, 16-m, 17-m, 18-m, 20-m, 25-m, 41-m, 42-m, 43-m, 44-m, 49-m, 50- m, 52-m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 65-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in Attorney Docket No.: F2099-7038WO each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ACH Domain] and the [TH Domain]. In some embodiments, the TREM comprises thirty-two non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-five 2’-O-methyl modifications. In some embodiments, the TREM comprises three 2’-fluoro modifications. In some embodiments, the TREM comprises four phosphorothioate modifications. In some embodiments, the TREM comprises twenty-five 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], three 2’-fluoro modifications in the [ACH Domain], the [VL Domain], and the [TH Domain], and four phosphorothioate modifications in the [ACH Domain] and the [TH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 22 in Table 6: 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 14-m, 15-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-m, 42-m, 43-m, 44-f, 49-m, 50-m, 52-m, 54-m, 55-*, 56-m, 57-f, 59- m, 61-m, 65-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ACH Domain] and the [TH Domain]. In some embodiments, the TREM comprises twenty-seven non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-one 2’-O-methyl modifications. In some embodiments, the TREM comprises one 2’-fluoro modification. In some embodiments, the TREM comprises five phosphorothioate modifications. In some embodiments, the TREM comprises twenty-one 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], one 2’-fluoro modification in the [ACH Domain], and five phosphorothioate modifications in the [ACH Domain] and the [TH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 23 in Table 6: 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 16- Attorney Docket No.: F2099-7038WO m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-m, 42-m, 43-m, 44-m, 49-m, 50-m, 52-m, 54-*, 55-*, 61-m, 65-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ACH Domain] and the [TH Domain]. In some embodiments, the TREM comprises thirty-four non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-six 2’-O-methyl modifications. In some embodiments, the TREM comprises four 2’-fluoro modifications. In some embodiments, the TREM comprises four phosphorothioate modifications. In some embodiments, the TREM comprises twenty-six 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], four 2’-fluoro modifications in the [ACH Domain], the [VL Domain], and the [TH Domain], and four phosphorothioate modifications in the [ACH Domain] and the [TH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 24 in Table 6: 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 12-m, 13-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-f, 42-m, 43-m, 44-f, 49-m, 50-m, 52-m, 54-m, 55-*, 56- m, 57-f, 59-m, 61-m, 65-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ACH Domain] and the [TH Domain]. In some embodiments, the TREM comprises thirty-seven non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-nine 2’-O-methyl modifications. In some embodiments, the TREM comprises four 2’-fluoro modifications. In some embodiments, the TREM comprises four phosphorothioate modifications. In some embodiments, the TREM comprises twenty-nine 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the Attorney Docket No.: F2099-7038WO [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], four 2’-fluoro modifications in the [DH Domain], the [ACH Domain], and the [TH Domain], and four phosphorothioate modifications in the [ACH Domain] and the [TH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 25 in Table 6: 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 12-m, 13-m, 14-m, 15-f, 16-m, 17-m, 18-m, 19-f, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-m, 42-m, 43-m, 44-m, 49-m, 50-m, 52- m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 65-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ACH Domain] and the [TH Domain]. In some embodiments, the TREM comprises thirty-six non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-eight 2’-O-methyl modifications. In some embodiments, the TREM comprises four 2’-fluoro modifications. In some embodiments, the TREM comprises four phosphorothioate modifications. In some embodiments, the TREM comprises twenty-eight 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], four 2’-fluoro modifications in the [ACH Domain], the [VL Domain], and the [TH Domain], and four phosphorothioate modifications in the [ACH Domain] and the [TH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 26 in Table 6: 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 16-m, 17-m, 18-m, 20-m, 22-m, 23-m, 24-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-m, 42-m, 43-m, 44-m, 45-m, 46-f, 48-f, 49-m, 50-m, 52-m, 54- m, 55-*, 56-m, 57-f, 59-m, 61-m, 65-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in the [TH Domain]. In some embodiments, the TREM comprises Attorney Docket No.: F2099-7038WO thirty-one non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-eight 2’-O-methyl modifications. In some embodiments, the TREM comprises two 2’- fluoro modifications. In some embodiments, the TREM comprises one phosphorothioate modification. In some embodiments, the TREM comprises twenty-eight 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], two 2’-fluoro modifications in the [TH Domain], and one phosphorothioate modification in the [TH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 27 in Table 6: 1-m, 2- m, 3-m, 4-m, 5-m, 6-m, 14-m, 15-m, 16-m, 17-m, 18-m, 20-m, 25-m, 41-m, 42-m, 43-m, 44-m, 49-m, 50-m, 52-m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 62-m, 63-f, 64-m, 65-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ACH Domain] and the [TH Domain]. In some embodiments, the TREM comprises thirty-three non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-four 2’-O-methyl modifications. In some embodiments, the TREM comprises five 2’-fluoro modifications. In some embodiments, the TREM comprises four phosphorothioate modifications. In some embodiments, the TREM comprises twenty-four 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], five 2’-fluoro modifications in the [ACH Domain], the [VL Domain], and the [TH Domain], and four phosphorothioate modifications in the [ACH Domain] and the [TH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 28 in Table 6: 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-f, 42-m, 43-m, 44-f, 49-m, 50-m, 52-m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 62- m, 63-f, 64-m, 65-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in Attorney Docket No.: F2099-7038WO each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ACH Domain] and the [TH Domain]. In some embodiments, the TREM comprises thirty-five non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-six 2’-O-methyl modifications. In some embodiments, the TREM comprises five 2’-fluoro modifications. In some embodiments, the TREM comprises four phosphorothioate modifications. In some embodiments, the TREM comprises twenty-six 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], five 2’-fluoro modifications in the [ACH Domain], the [VL Domain], and the [TH Domain], and four phosphorothioate modifications in the [ACH Domain] and the [TH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 29 in Table 6: 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 14-m, 15-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-f, 42-m, 43-m, 44-f, 49-m, 50-m, 52-m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 62-m, 63-f, 64-m, 65-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises sixteen non-naturally occurring modifications. In some embodiments, the TREM comprises fifteen 2’-O-methyl modifications. In some embodiments, the TREM comprises one 2’-fluoro modification. In some embodiments, the TREM comprises fifteen 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], and the [ASt Domain2] and one 2’-fluoro modification in the [ACH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 30 in Table 6: 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 14-m, 17-m, 18-m, 20-m, 22-m, 25-m, 27-m, 33-f, 71-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [VL Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [VL Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification Attorney Docket No.: F2099-7038WO in the [ASt Domain1]. In some embodiments, the TREM comprises fourteen non-naturally occurring modifications. In some embodiments, the TREM comprises eleven 2’-O-methyl modifications. In some embodiments, the TREM comprises two 2’-fluoro modifications. In some embodiments, the TREM comprises one phosphorothioate modification. In some embodiments, the TREM comprises eleven 2’-O-methyl modifications in the [ASt Domain1], the [VL Domain], and the [ASt Domain2], two 2’-fluoro modifications in the [VL Domain], and one phosphorothioate modification in the [ASt Domain1]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 31 in Table 6: 1-m*, 2-m, 3-m, 4-m, 5-m, 6-m, 44-m, 45-m, 46-f, 47-f, 48-m, 49-m, 73-m. A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ASt Domain1], the [ACH Domain], and the [TH Domain]. In some embodiments, the TREM comprises forty-two non-naturally occurring modifications. In some embodiments, the TREM comprises thirty-one 2’-O-methyl modifications. In some embodiments, the TREM comprises four 2’-fluoro modifications. In some embodiments, the TREM comprises seven phosphorothioate modifications. In some embodiments, the TREM comprises thirty-one 2’-O-methyl modifications in the [ASt Domain1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], four 2’-fluoro modifications in the [ACH Domain], the [VL Domain], and the [TH Domain], and seven phosphorothioate modifications in the [ASt Domain1], the [ACH Domain], and the [TH Domain]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 32 in Table 6: 1-m*, 2-m*, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 12-m, 13-m, 17-m, 18-m, 22-m, 23-m, 24-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-f, 42-m, 43-m, 44- f, 49-m, 50-m, 51-m, 52-m, 53-m, 54-*, 55-*, 61-m, 62-m, 63-f, 64-m, 65-m, 66-m, 67-m, 68-m, 73-m. Table 6: Exemplary non-naturally occurring modification patterns of TREMs Attorney Docket No.: F2099-7038WO Pattern No. Modification Pattern *, - - m, , f, - , m Attorney Docket No.: F2099-7038WO 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 14-m, 15-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 22 35-*, 37-*, 38-*, 41-m, 42-m, 43-m, 44-f, 49-m, 50-m, 52-m, 54-m, 55-*, 56-m, 57-f, - , , - , m, , TREM, TREM core fragment and TREM fragment fusions In an embodiment, a TREM, a TREM core fragment or a TREM fragment disclosed herein comprises an additional moiety, e.g., a fusion moiety. In an embodiment, the fusion moiety can be used for purification, to alter folding of the TREM, TREM core fragment or TREM fragment, or as a targeting moiety. In an embodiment, the fusion moiety can comprise a tag, a linker, can be cleavable or can include a binding site for an enzyme. In an embodiment, the fusion moiety can be disposed at the N terminal of the TREM or at the C terminal of the TREM, TREM core fragment or TREM fragment. In an embodiment, the fusion moiety can be encoded by the same or different nucleic acid molecule that encodes the TREM, TREM core fragment or TREM fragment. Attorney Docket No.: F2099-7038WO TREM Consensus sequence In an embodiment, a TREM disclosed herein comprises a consensus sequence provided herein. In an embodiment, a TREM disclosed herein comprises a consensus sequence of Formula IZZZ, whereinZZZindicates any of the twenty amino acids and Formula I corresponds to all species. In an embodiment, a TREM disclosed herein comprises a consensus sequence of Formula IIZZZ, whereinZZZindicates any of the twenty amino acids and Formula II corresponds to mammals. In an embodiment, a TREM disclosed herein comprises a consensus sequence of Formula IIIZZZ, whereinZZZindicates any of the twenty amino acids and Formula III corresponds to humans. In an embodiment, ZZZ indicates any of the twenty amino acids: alanine, arginine, asparagine, aspartate, cysteine, glutamine, glutamate, glycine, histidine, isoleucine, methionine, leucine, lysine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine. In an embodiment, a TREM disclosed herein comprises a property selected from the following: a) under physiological conditions residue R0forms a linker region, e.g., a Linker 1 region; b) under physiological conditions residues R1-R2-R3-R4 -R5-R6-R7 and residues R65-R66- R67-R68-R69-R70-R71 form a stem region, e.g., an AStD stem region; c) under physiological conditions residues R8-R9forms a linker region, e.g., a Linker 2 region; d) under physiological conditions residues -R10-R11-R12-R13-R14 R15-R16-R17-R18-R19-R20- R21-R22-R23-R24-R25-R26-R27-R28 form a stem-loop region, e.g., a D arm Region; e) under physiological conditions residue -R29forms a linker region, e.g., a Linker 3 Region; f) under physiological conditions residues -R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40- R41-R42-R43-R44-R45-R46form a stem-loop region, e.g., an AC arm region; g) under physiological conditions residue -[R47]x comprises a variable region, e.g., as described herein; Attorney Docket No.: F2099-7038WO h) under physiological conditions residues -R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58- R59-R60-R61-R62-R63-R64 form a stem-loop region, e.g., a T arm Region; or i) under physiological conditions residue R72 forms a linker region, e.g., a Linker 4 region. Alanine TREM Consensus sequence In an embodiment, a TREM disclosed herein comprises the sequence of Formula IALA (SEQ ID NO: 562), R0- R1-R2- R3-R4-R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66-R67- R68-R69-R70-R71-R72, wherein R is a ribonucleotide residue and the consensus for Ala is: R^= absent; R^^, R^^=are independently A or absent; R^^= A, C, G or absent; R^, R^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^= are independently N or absent; R^^, R^^, R^^= are independently A, C, U or absent; R^, R^, R^^, R^^, R^^, R^^, R^^, R^^= are independently A, G or absent; R^, R^^, R^^, R^^, R^^, R^^, R^^, R^^= are independently A, G, U or absent; R^^, R^^= are independently A, U or absent; R^^, R^^=are independently C or absent; R^, R^= are independently C, G or absent; R^^, R^^, R^^, R^^, R^^= are independently C, G, U or absent; R^^, R^^, R^^, R^^, R^^, R^^, R^^= are independently C, U or absent; R^^, R^^, R^^= are independently G or absent; R^= G, U or absent; R^, R^^, R^^= are independently U or absent; [R47] x = N or absent; wherein, e.g., x=1-271 (e.g., x=1-250, x=1-225, x=1-200, x=1-175, x=1-150, x=1-125, x=1-100, x=1-75, x=1-50, x=1-40, x=1-30, x=1-29, x=1- 28, x=1-27, x=1-26, x=1-25, x=1-24, x=1-23, x=1-22, x=1-21, x=1-20, x=1-19, x=1-18, x=1-17, x=1-16, x=1-15, x=1-14, x=1-13, x=1-12, x=1-11, x=1-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70-271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent. Attorney Docket No.: F2099-7038WO In an embodiment, a TREM disclosed herein comprises the sequence of Formula IIALA(SEQ ID NO: 563), R0- R1-R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66-R67- R68-R69-R70-R71-R72 wherein R is a ribonucleotide residue and the consensus for Ala is: R^, R18= are absent; R^^, R^^, R^^=are independently A or absent; R^^, R^^, R^^= are independently A, C, G or absent; R^^, R^^, R^^, R^^= are independently N or absent; R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^= are independently A, C, U or absent; R^, R^, R^, R^^, R^^, R^^, R^^, R^^, R^^, R^^= are independently A, G or absent; R^, R^^, R^^, R^^, R^^, R^^, R^^, R^^= are independently A, G, U or absent; R^, R^^, R^^= are independently A, U or absent; R^^, R^^, R^^, R^^= are independently C or absent; R^= C, G or absent; R^^, R^^, R^^= are independently C, G, U or absent; R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^= are independently C, U or absent; R^, R^^, R^^, R^^, R^^, R^^= are independently G or absent; R^, R^, R^^= are independently G, U or absent; R^^, R^^= are independently U or absent; [R47] x = N or absent; wherein, e.g., x=1-271 (e.g., x=1-250, x=1-225, x=1-200, x=1-175, x=1-150, x=1-125, x=1-100, x=1-75, x=1-50, x=1-40, x=1-30, x=1-29, x=1-28, x=1-27, x=1-26, x=1-25, x=1-24, x=1-23, x=1-22, x=1-21, x=1-20, x=1-19, x=1-18, x=1-17, x=1-16, x=1-15, x=1-14, x=1-13, x=1-12, x=1-11, x=1-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, Attorney Docket No.: F2099-7038WO x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent. In an embodiment, a TREM disclosed herein comprises the sequence of Formula IIIALA (SEQ ID NO: 564), R0- R1-R2- R3-R4-R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66-R67- R68-R69-R70-R71-R72wherein R is a ribonucleotide residue and the consensus for Ala is: R^, R18= are absent; R^^, R^^, R^^, R^^=are independently A or absent; R^^, R^^, R^^= are independently A, C, G or absent; R^^, R^^, R^^= are independently N or absent; R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^, R^^= are independently A, C, U or absent; R^, R^, R^^, R^^, R^^, R^^, R^^, R^^, R^^= are independently A, G or absent; R^, R^^, R^^, R^^, R^^, R^^, R^^= are independently A, G, U or absent; R^, R^^= are independently A, U or absent; R^^, R^^...

Claims

Attorney Docket No.: F2099-7038WO What is claimed is:

1. A tRNA effector molecule (TREM) comprising a sequence of Formula (I): [L1]x-[ASt Domain1]-[L2]x-[DH Domain]-[L3]x-[ACH Domain] -[VL Domain]-[TH Domain]-[L4]x-[ASt Domain2]-[L5]x (I), wherein: independently, [L1] and [VL Domain], are optional; x is 0 or 1; and the TREM comprises a nucleotide substitution (e.g., a nucleotide mutation) in the TREM capable of modulating a functional parameter of the TREM.

2. The TREM of claim 1, wherein the functional parameter comprises activity of the TREM or stability of the TREM.

3. The TREM of any one of the preceding claims, wherein the functional parameter comprises premature termination codon (PTC) readthrough activity of the TREM (e.g., an increased level of PTC readthrough activity or decreased PTC readthrough activity), e.g., in a sample (e.g., a cell) or in a subject.

4. The TREM of any one of the preceding claims, wherein the functional parameter comprises stability of the TREM (e.g., increased stability of the TREM or decreased stability of the TREM), e.g., in a sample (e.g., a cell) or in a subject.

5. The TREM of any one of the preceding claims, wherein the functional parameter is selected from: (a) protein translation; (b) expression level (e.g., of polypeptide or protein, or mRNA); (c) post-translational modification of polypeptide or protein; (d) folding (e.g., of polypeptide or protein, or mRNA), (e) structure (e.g., of polypeptide or protein, or mRNA), (f) transduction (e.g., of polypeptide or protein),Attorney Docket No.: F2099-7038WO (g) compartmentalization (e.g., of polypeptide or protein, or mRNA), (h) incorporation (e.g., of polypeptide or protein, or mRNA) into a supermolecular structure, e.g., incorporation into a membrane, proteasome, or ribosome, (i) incorporation into a multimeric polypeptide, e.g., a homo or heterodimer, and / or (j) stability.

6. The TREM of claim 5, wherein the functional parameter further comprises: (1) modulation of a signaling pathway, e.g., a cellular signaling pathway which is downstream or upstream of the protein encoded by the endogenous ORF having a first sequence or PTC; (2) cell fate modulation; (3) ribosome occupancy modulation; (4) protein translation modulation; (5) mRNA stability modulation; (6) protein folding and structure modulation; (7) protein transduction or compartmentalization modulation; and / or (8) protein stability modulation.

7. The TREM of any one of the preceding claims, wherein the TREM comprises a TREM having at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% sequence identity with a TREM provided in FIGs.3 or 23.

8. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide sequence that differs by 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides from the nucleotide sequence of a TREM provided in FIGs.3 or 23.

9. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide sequence that differs by 10, 15, 20, 25, 30, 35 or 40 nucleotides from the nucleotide sequence of a TREM provided in FIGs.3 or 23.Attorney Docket No.: F2099-7038WO 10. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide sequence that differs by more than 5 nucleotides from the nucleotide sequence of a TREM provided in FIGs.3 or 23.

11. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide sequence that differs by more than 10 nucleotides from the nucleotide sequence of a TREM provided in FIGs.3 or 23.

12. The TREM of any one of the preceding claims, wherein the TREM comprises a sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the nucleotide sequence of a TREM provided in FIGs.3 or 23.

13. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide sequence that differs by no more than 10, 15, 20, 25, 30, 35 or 40 nucleotides from the nucleotide sequence of a TREM provided in FIGs.3 or 23.

14. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide sequence that differs by no more than 1 nucleotide from the nucleotide sequence of a TREM provided in FIGs.3 or 23.

15. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide sequence that differs by no more than 5 nucleotides from the nucleotide sequence of a TREM provided in FIGs.3 or 23.

16. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide sequence that differs by no more than 10 nucleotides from the nucleotide sequence of a TREM provided in FIGs.3 or 23.

17. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution within the [ASt Domain1], e.g., the nucleotide substitution is at any of positions 1, 2, 3, 4, 5, 6, 7, 8, or 9 within the [ASt Domain1].Attorney Docket No.: F2099-7038WO 18. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution within the [DH Domain], e.g., the nucleotide substitution is at any of positions 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 within the [DH Domain].

19. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution within the [ACH Domain], e.g., the nucleotide substitution is at any of positions 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 within the [ACH Domain].

20. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution within the [VL Domain], e.g., the nucleotide substitution is at any of positions 44, 45, 46, 47, 48, or 49 within the [VL Domain].

21. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution within the [TH Domain], e.g., the nucleotide substitution is at any of positions 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, or 64 within the [TH Domain].

22. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution within the [ASt Domain2], e.g., the nucleotide substitution is at any of positions 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, or 76 within the [ASt Domain2].

23. The TREM of any one of the preceding claims, wherein the TREM has a sequence selected from a sequence provided in FIGs.3 or 23.

24. The TREM of any one of the preceding claims, wherein the TREM comprises a plurality of nucleotide substitutions.Attorney Docket No.: F2099-7038WO 25. The TREM of any one of any one of the preceding claims, wherein the nucleotide substitution comprises substituting a first naturally occurring nucleotide with an adenosine, guanosine, cytosine, or uracil nucleotide.

26. The TREM of any one of the preceding claims, wherein the TREM is selected from SEQ ID NOs.625-700, 701-800, 801-900, 901-1000, 1001-1100, 1101-1151, 1290-1300, 1301-1400, or 1401-1456 in FIG.

3.

27. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution does not exhibit a difference in a functional parameter from a TREM in FIGs.3 or 23.

28. The TREM of any one of claims 1-26, wherein the TREM comprising a nucleotide substitution exhibits a difference in a functional parameter from a TREM in FIGs.3 or 23.

29. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution exhibits an improvement in a functional parameter from a TREM in FIGs. 3 or 23.

30. The TREM of any one of the preceding claims, wherein the improvement comprises an improvement of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%.45%, 50%.55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or greater, e.g., compared with the functional parameter of a TREM provided in FIGs.3 or 23.

31. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution exhibits a reduction in a functional parameter from a TREM in FIGs.3 or 23.

32. The TREM of any one of the preceding claims, wherein the reduction comprises a reduction of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%.45%, 50%.55%, 60%, 65%,Attorney Docket No.: F2099-7038WO 70%, 75%, 80%, 85%, 90%, 95%, or greater, e.g., compared with the functional parameter of a TREM provided in FIGs.3 or 23.

33. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution at any of positions 1, 2, 3, 4, 5, 6, or 7, e.g., within the [ASt Domain1].

34. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution at any of positions 16, 17, or 20a, e.g., within the [DH Domain].

35. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution at any of positions 27, 28, 29, 30, 31, 39, 40, 41, 42, or 43, e.g., within the [ACH Domain].

36. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution at any of positions 51, 59, 60, or 63, e.g., within the [TH Domain].

37. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution at any of positions 66, 67, 68, 69, 70, 71, 72, or 73, e.g., within the [ASt Domain2].

38. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution at any of positions 32, 33, 34, 35, 36, 37, or 38, e.g., within the [ACH Domain].

39. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution at any of positions 1, 2, 3, 4, 5, 6, or 7, e.g., within the [ASt Domain1], exhibits an improvement in a functional parameter of the TREM.

40. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution at any of positions 16, 17, or 20a, e.g., within the [DH Domain], exhibits an improvement in a functional parameter of the TREM.Attorney Docket No.: F2099-7038WO 41. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution at any of positions 27, 28, 29, 30, 31, 39, 40, 41, 42, or 43, e.g., within the [ACH Domain], exhibits an improvement in a functional parameter of the TREM.

42. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution at any of positions 51, 59, 60, or 63, e.g., within the [TH Domain], exhibits an improvement in a functional parameter of the TREM.

43. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution at any of positions 66, 67, 68, 69, 70, 71, 72, or 73, e.g., within the [ASt Domain2], exhibits an improvement in a functional parameter of the TREM.

44. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution at any of positions 32, 33, 34, 35, 36, 37, or 38, e.g., within the [ACH Domain], exhibits a reduction in a functional parameter of the TREM.

45. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution comprises a scaffold, e.g., an Arg-TGA, Gln-TAG, Glu-TAG, Leu-TAG, Tyr-TAG, Ser-TAG, or Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence of SEQ ID NO: 1638, 1835, 1660, 1654, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, or 2019.

46. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution corresponds to a reference sequence of SEQ ID NO: 1638, 1835, 1660, 1654, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, or 2019.

47. The TREM of any one of the preceding claims, wherein the TREM comprises a non- naturally occurring modification.Attorney Docket No.: F2099-7038WO 48. The TREM of claim 47, wherein the non-naturally occurring modification is present on the 2’-position of a nucleotide sugar or within the internucleotide region (e.g., a backbone modification).

49. The TREM of any one of claims 47-48, wherein the non-naturally occurring modification is selected from a 2’-O-methyl (2-OMe), 2’-halo (e.g., 2’F or 2’Cl), 2’-O-methoxyethyl (2’MOE), or 2’deoxy modification.

50. The TREM of any one of claims 47-49, wherein the non-naturally occurring modification is a phosphorothioate modification.

51. The TREM of any one of claims 47-50, wherein the TREM comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional non-naturally occurring modifications compared with a TREM provided in FIG.3 (e.g., 2’-ribose modifications or an internucleotide modification, e.g., 2’OMe, 2’-halo, 2’- MOE, 2’-deoxy, or phosphorothiorate modifications).

52. The TREM of any one of claims 47-51, wherein the TREM comprises a pattern of non- naturally occurring modifications selected from the patterns listed in Table 6.

53. The TREM of any one of the preceding claims, wherein: (i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 1-9 of SEQ ID NO: 734; and / or (ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.

54. The TREM of any one of the preceding claims, wherein: (i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 10-19 of SEQ ID NO: 734; and / or (ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.Attorney Docket No.: F2099-7038WO 55. The TREM of any one of the preceding claims, wherein: (i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 20-29 of SEQ ID NO: 734; and / or (ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.

56. The TREM of any one of the preceding claims, wherein: (i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 30-39 of SEQ ID NO: 734; and / or (ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.

57. The TREM of any one of the preceding claims, wherein: (i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 40-49 of SEQ ID NO: 734; and / or (ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.

58. The TREM of any one of the preceding claims, wherein: (i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 50-59 of SEQ ID NO: 734; and / or (ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.

59. The TREM of any one of the preceding claims, wherein: (i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 60-69 of SEQ ID NO: 734; and / or (ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.

60. The TREM of any one of the preceding claims, wherein:Attorney Docket No.: F2099-7038WO (i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 70-76 of SEQ ID NO: 734; and / or (ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.

61. The TREM of any one of the preceding claims, wherein the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 1-76, according to the CtNS.

62. A pharmaceutical composition comprising a TREM of any one of the preceding claims.

63. The pharmaceutical composition of claim 90, further comprising a pharmaceutically acceptable component, e.g., an excipient.

64. A lipid nanoparticle formulation comprising a TREM of any one of claims 1-91.

65. A lipid nanoparticle formulation comprising a pharmaceutical composition of claim 92.

66. A composition for use in treating a subject having a disease or disorder associated with a PTC comprising administering to the subject a TREM described herein (e.g., a TREM of any one of the preceding claims).

67. The composition for use of claim 66, wherein the disease or disorder associated with a PTC comprises Hemophilia B, Fabry disease, Usher syndrome, or CLN2 disease.

68. A method of treating a subject having a disease or disorder associated with a PTC comprising administering to the subject a TREM described herein (e.g., a TREM of any one of the preceding claims), thereby treating the subject having the disease or disorder.

69. The method of claim 68, wherein the disease or disorder associated with a PTC comprises Hemophilia B, Fabry disease, Usher syndrome, or CLN2 disease.Attorney Docket No.: F2099-7038WO 70. A method of modulating a functional parameter of a tRNA effector molecule (TREM), wherein the TREM comprises a sequence of Formula (A): [L1]x-[ASt Domain1]-[L2]x-[DH Domain]-[L3]x-[ACH Domain] -[VL Domain]-[TH Domain]-[L4]x-[ASt Domain2]-[L5]x (A), wherein: independently, [L1] and [VL Domain], are optional; x is 0 or 1; and the TREM comprises a nucleotide substitution (e.g., a nucleotide mutation) in the TREM capable of modulating a functional parameter of the TREM ; thereby modulating the functional parameter of the TREM.

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