Affinity probes

Abstract

The disclosure relates to RNA-containing oligonucleotide affinity probes capable of wrapping around a targeted peptide thereby binding the targeted peptide with high affinity, and to oligoribonucleotide DNA aptamer-derived probes possessing enhanced affinity for target macromolecules for detection purposes, as well as to methods of use and kits including such oligoribonucleotides.

Description

[0001] Attorney Docket No.: BN00023.0071 AFFINITY PROBES CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to and benefits of GB Patent Application number 2218575.5 filed 9 December 2022, entitled ‘Affinity Probes’. The entire content of the aforementioned patent application is incorporated herein by this reference. FIELD OF THE INVENTION The instant disclosure relates generally to methods involving engineering of oligoribonucleotide probes having enhanced affinity for target macromolecules for detection purposes. BACKGROUND OF THE INVENTION Aptamers are DNA- or RNA-based oligonucleotides that bind their targets with high affinity and specificity. Aptamers specific for a particular peptide, polypeptide, or protein are commonly selected using the SELEX (systematic evolution of ligands by exponential enrichment) method (Ellington and Szostak. Nature. 346: 818–822). Targets for aptamers may vary from a single molecule to a complex target. The secondary and tertiary structures of an aptamer tend to drive the aptamer's recognition of a polypeptide target. Compared to other ligands, oligonucleotide aptamers have distinct advantages, such as cost-effective production, low immunogenicity, high affinity comparable to monoclonal antibodies, and an ability to penetrate solid tumors. Most importantly, they are produced synthetically with high reproducibility at the highest GMP standards. Aptamers are therefore attractive candidates for use as diagnostic probes, particularly in view of their specificity and affinity for target polypeptides, as well as the relative ease and cost- effectiveness with which nucleic acid synthesis and labelling can be performed. In spite of numerous efforts, however, aptamer specificity is limited and the aptamer production approach is by definition stochastic. There is a need for improved aptamers that possess enhanced target macromolecule binding properties based on a rational approach. BRIEF SUMMARY OF THE INVENTION The present disclosure, at least in part, provides for the rational engineering of oligonucleotides capable of binding to target macromolecules, where the engineered Attorney Docket No.: BN00023.0071 oligonucleotides possess improved properties (binding affinity, disassociation rate, etc.) that enable their use for enhanced detection of target macromolecules. Engineered forms of oligonucleotides are therefore provided, as are compositions and kits that include such engineered oligonucleotides. Certain aspects of the instant disclosure provide methods for producing oligonucleotide- based affinity probes that possess binding properties that are enhanced relative to art-recognized aptamer selection approaches. Such oligonucleotide-based affinity probes are therefore designed to specifically wrap around a target in a site-optimized manner for high affinity binding between the enwrapping oligonucleotide and the target. Targets are in principle any molecules or macromolecules with affinity to nucleic acids, mostly however to peptides and proteins. Advantages attributable to the "WRAP" approach of the instant disclosure derive from exploiting the combined information of charge, hydrophobicity / hydrophilicity, X-ray diffraction, and modeled “in-silico” representations of protein sequences and structures (e.g., three-dimensional protein structures) and optimization of Gibbs free energy values of individual nucleotide-amino acid binding interactions (or of optimizing numbers of interactions for individual amino acid- nucleotide pairings, or selecting based upon a combination of both Gibbs free energy values and numbers of interactions), summed across a given oligonucleotide-target peptide combination, which allows for design of a high affinity oligonucleotide probe in an informed and directed manner. The "WRAP" approach disclosed herein therefore specifically leverages proven affinities between biological components to monitor cellular component interactions in vivo or in vitro, and can be used to therapeutic benefit. The WRAPs as laid out in this disclosure are designed to enwrap a predefined amino acid sequence within a polypeptide or protein, or can be designed to enwrap specific characteristics of any charged or non-polar macro-molecular target. Other aspects of the instant disclosure provide a process for converting a DNA aptamer sequence into an RNA Affinity Probe (a "RAP), with the resulting RAP molecule possessing improved properties as compared to the DNA aptamer from which it derives, including, e.g., greater conformational stability, higher binding affinity, and / or immediate signal generation upon binding to target macromolecule. In some embodiments, aptamers (oligonucleotides) and / or RAPs that bind a human Tau polypeptide or other target polypeptide with an equilibrium binding constant (Kd) of less than 100 nM are provided. In another aspect, the Kdis from about 0.1 nM to Attorney Docket No.: BN00023.0071 about 100 nM (or from about 0.1 nM to about 50 nM, or from about 0.01 nM to about 10 nM, or from about 0.5 nM to about 10 nM, or from about 0.5 nM to about 5 nM). Accordingly, in one aspect, a method for making an oligonucleotide capable of binding a reference amino acid sequence with high affinity is provided, the method involving: (a) obtaining a structural representation of the reference amino acid sequence; (b) designing an oligonucleotide sequence complementing the reference amino acid sequence, where the designing involves selecting the nucleotide with the most negative Gibbs free energy (ΔG) values towards the target amino acid, selecting the nucleotide with the most predicted amino acid-nucleotide interactions towards the target amino acid, or a combination thereof, across a series of two or more individual amino acid-nucleotide interactions between two or more water-accessible amino acid residues of the reference amino acid sequence and a corresponding two or more nucleotides of the oligonucleotide, where the corresponding two or more nucleotides of the oligonucleotide are modeled to be the respective individual nucleotides in closest physical proximity to each of the respective two or more water-accessible amino acid residues of the reference amino acid sequence; and (c) synthesizing the oligonucleotide, thereby making an oligonucleotide capable of binding a reference amino acid sequence with high affinity. In certain embodiments, the structural representation of the reference amino acid sequence is an X-ray crystallography structure, a NMR structure, an in silico three-dimensional structural model of the reference amino acid sequence, a two-dimensional structural representation or a linear polypeptide sequence. Optionally, the structural representation of the reference amino acid sequence is obtained from a public database (e.g., NCBI, www.cgl.ucsf.edu / chimerax / , Uni-Fold or OpenFold). In one embodiment, the reference amino acid sequence is of 100 amino acids or less in length. Optionally, the reference amino acid sequence is of 50 amino acids or less in length. In some embodiments, the corresponding two or more nucleotides of the oligonucleotide are modeled for nucleotide residue spacing and / or structure. Optionally, such modeling is performed using UNAFold or other such oligonucleotide structure prediction software. In certain embodiments, the reference amino acid sequence includes at least five accessible amino acid residues in an aqueous solution. Optionally, the reference amino acid sequence includes at least ten accessible amino acid residues in an aqueous solution. Optionally, the reference amino acid sequence includes at least 15 accessible amino acid residues in an aqueous solution. Attorney Docket No.: BN00023.0071 Optionally, the reference amino acid sequence includes at least 20 accessible amino acid residues in an aqueous solution. In one embodiment, step (b) includes one or more of the following (i)-(iii): (i) Optimizing Gibbs free energy (ΔG) values across a series of three or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing Gibbs free energy (ΔG) values across four or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing Gibbs free energy (ΔG) values across five or more individual amino acid- nucleotide interactions. Optionally, step (b) includes optimizing Gibbs free energy (ΔG) values across six or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing Gibbs free energy (ΔG) values across seven or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing Gibbs free energy (ΔG) values across eight or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing Gibbs free energy (ΔG) values across nine or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing Gibbs free energy (ΔG) values across ten or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing Gibbs free energy (ΔG) values across eleven or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing Gibbs free energy (ΔG) values across twelve or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing Gibbs free energy (ΔG) values across thirteen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing Gibbs free energy (ΔG) values across fourteen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing Gibbs free energy (ΔG) values across fifteen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing Gibbs free energy (ΔG) values across sixteen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing Gibbs free energy (ΔG) values across seventeen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing Gibbs free energy (ΔG) values across eighteen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing Gibbs free energy (ΔG) values across nineteen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing Gibbs free energy (ΔG) values across twenty or more individual amino acid-nucleotide interactions. Attorney Docket No.: BN00023.0071 (ii) Optimizing number of amino acid-nucleotide interactions for each nucleotide selection across a series of three or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing number of amino acid-nucleotide interactions for each nucleotide selection across four or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing number of amino acid-nucleotide interactions for each nucleotide selection across five or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing number of amino acid-nucleotide interactions for each nucleotide selection across six or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing number of amino acid-nucleotide interactions for each nucleotide selection across seven or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing number of amino acid- nucleotide interactions for each nucleotide selection across eight or more individual amino acid- nucleotide interactions. Optionally, step (b) includes optimizing number of amino acid-nucleotide interactions for each nucleotide selection across nine or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing number of amino acid-nucleotide interactions for each nucleotide selection across ten or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing number of amino acid-nucleotide interactions for each nucleotide selection across eleven or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing number of amino acid-nucleotide interactions for each nucleotide selection across twelve or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing number of amino acid-nucleotide interactions for each nucleotide selection across thirteen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing number of amino acid-nucleotide interactions for each nucleotide selection across fourteen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing number of amino acid-nucleotide interactions for each nucleotide selection across fifteen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing number of amino acid-nucleotide interactions for each nucleotide selection across sixteen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing number of amino acid-nucleotide interactions for each nucleotide selection across seventeen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing number of amino acid-nucleotide interactions for each nucleotide selection across eighteen or more individual amino acid-nucleotide interactions. Attorney Docket No.: BN00023.0071 Optionally, step (b) includes optimizing number of amino acid-nucleotide interactions for each nucleotide selection across nineteen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing number of amino acid-nucleotide interactions for each nucleotide selection across twenty or more individual amino acid-nucleotide interactions. (iii) Optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across a series of three or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across four or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across five or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across six or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across seven or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across eight or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across nine or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across ten or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across eleven or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across twelve or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across thirteen or more individual amino acid-nucleotide interactions. Attorney Docket No.: BN00023.0071 Optionally, step (b) includes optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across fourteen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across fifteen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across sixteen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across seventeen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across eighteen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across nineteen or more individual amino acid-nucleotide interactions. Optionally, step (b) includes optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions for each nucleotide selection across twenty or more individual amino acid-nucleotide interactions. In certain embodiments, step (b) further includes adding a 5'-terminal sequence, a 3'- terminal sequence, or a 5'-terminal sequence and a 3'-terminal sequence to the oligonucleotide, where the 5'-terminal sequence, the 3'-terminal sequence, or the 5'-terminal sequence and the 3'- terminal sequence are capable of forming a double-stranded stem region (optionally when annealing with an end region of the oligonucleotide sequence corresponding to the reference amino acid sequence – e.g., when only a 5'-terminal region is added to the oligonucleotide sequence corresponding to the reference amino acid sequence, the added 5'-terminal region will anneal with the extant 3'-terminal region of the oligonucleotide sequence corresponding to the reference amino acid sequence, or when only a 3'-terminal region is added to the oligonucleotide sequence corresponding to the reference amino acid sequence, the added 3'-terminal region will anneal with the extant 5'-terminal region of the oligonucleotide sequence corresponding to the reference amino acid sequence, and / or it is also contemplated that added 3'-terminal and / or 5'-terminal sequences can interact with extant sequences of the oligonucleotide sequence corresponding to the reference Attorney Docket No.: BN00023.0071 amino acid sequence in forming the terminal stem structure), under conditions sufficient for hybridization to occur, thereby forming an oligonucleotide having a double-stranded stem region, a 5'-terminus and a 3'-terminus. In another embodiment, step (b) further includes identifying a consensus nucleic acid sequence from a series of initial selected sequences of step (b) that have been optimized for Gibbs free energy (ΔG) values, number of amino acid-nucleotide interactions, and / or a combination thereof. Optionally, the consensus sequence is identified by optimizing for summed Gibbs free energy values across the consensus sequence derived from such initially designed sequences. In some embodiments, the double-stranded stem region has a negative free energy value of -15 kcal / mol or less. Optionally, of -20 kcal / mol or less. Optionally, the double-stranded stem region has a negative free energy value that is substantially less negative than the free energy generated when the oligonucleotide having the double-stranded stem region binds to the reference amino acid sequence. Optionally, the double-stranded stem region has a Tmof 37 ℃ or more. In one embodiment, the 5'-terminus or the 3'-terminus includes a fluorescent moiety, a lanthanide or a quenching moiety. Optionally, the fluorescent moiety, lanthanide or quenching moiety is attached to a terminal nucleotide of the oligonucleotide. Optionally, the fluorescent moiety, lanthanide or quenching moiety is covalently attached. In some embodiments, the oligonucleotide having a double-stranded stem region, a 5'- terminus and a 3'-terminus includes both a fluorescent moiety or a lanthanide and a quenching moiety. In certain embodiments, the fluorescent moiety or lanthanide is attached to a 5'-terminal nucleotide residue of the oligonucleotide having a double-stranded stem region, a 5'-terminus and a 3'-terminus. In another embodiment, the fluorescent moiety or lanthanide is attached to a 3'-terminal nucleotide residue of the oligonucleotide having a double-stranded stem region, a 5'-terminus and a 3'-terminus. In some embodiments, the quenching moiety is attached to a 5'-terminal nucleotide residue of the oligonucleotide having a double-stranded stem region, a 5'-terminus and a 3'-terminus. In one embodiment, the quenching moiety is attached to a 3'-terminal nucleotide residue of the oligonucleotide having a double-stranded stem region, a 5'-terminus and a 3'-terminus. Attorney Docket No.: BN00023.0071 In certain embodiments, a fluorescent moiety or lanthanide is attached to a 5'-terminal nucleotide residue of the oligonucleotide having a double-stranded stem region, a 5'-terminus and a 3'-terminus, and a quenching moiety is attached to a 3'-terminal nucleotide residue of the oligonucleotide having a double-stranded stem region, a 5'-terminus and a 3'-terminus. In another embodiment, a fluorescent moiety or lanthanide is attached to a 3'-terminal nucleotide residue of the oligonucleotide having a double-stranded stem region, a 5'-terminus and a 3'-terminus, and a quenching moiety is attached to a 5'-terminal nucleotide residue of the oligonucleotide having a double-stranded stem region, a 5'-terminus and a 3'-terminus. In some embodiments, the fluorescent moiety is Atto 495, Atto 390, Atto 425, Atto 465, Atto 488, Atto 520, Atto 532, Atto 550, Atto 565, Atto 590, Atto 594, Atto 620, Atto 633, Atto 647N, Atto 655, Atto Rho6G, Atto Rho11, Atto Rho12, Atto Rho101, 5- or 6-carboxyfluorescein (FAM™), VIC™, NED™, fluorescein, fluorescein isothiocyanate (FITC), IRDYE-700 / 800, cyanine dyes, such as CY3™, CY5™, CY3.5™, CY5.5™, Cy7™, xanthen, 6-carboxy-2',4',7',4,7- hexachlorofluorescein (HEX), 6-carboxy-l,4-dichloro-2',7'-dichloro-fluorescein (TET®), 6- carboxy-4',5'-dichloro-2',7'-dimethodyfluorescein (JOE™), N,N,N',N'-tetramethyl-6- carboxyrhodamine (TAMRA™), 6-carboxy-X-rhodamine (ROX), 5-carboxyrhodamine-6G (R6G5), 6-carboxyrhodamine-6G (RG6), rhodamine, rhodamine green, rhodamine red, rhodamine 110, Rhodamin 6G®, BODIPY dyes, such as BODIPY TMR, Oregon green, coumarines, such as umbelliferone, benzimides, such as Hoechst 33258; phenanthridines, such as Texas Red®, California Red®, Yakima Yellow, Alexa Fluor® 350, Alexa Fluor® 405, Alexa Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 500, Alexa Fluor® 514, Alexa Fluor®532, Alexa Fluor® 546, Alexa Fluor® 555, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 610, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Fluor® 680, Alexa Fluor® 700, Alexa Fluor® 750, PET®, ethidium bromide, acridinium dyes, carbazol dyes, phenoxazine dyes, porphyrine dyes, polymethin dyes, BMN™-5, BMN™-6, CEQ8000 D2, CEQ8000 D3, CEQ8000 D4, DY-480XL, DY-485XL, DY-495, DY-505, DY-510XL, DY-521XL, DY-521XL, DY-530, DY-547, DY-550, DY- 555, DY-610, DY-615, DY-630, DY-631, DY-633, DY-635, DY-647, DY-651, DY-675, DY-676, DY-680, DY-681, DY-700, DY-701, DY-730, DY-731, DY-732, DY-750, DY-751, DY- 776, DY-780, DY-781, DY-782, 6-carboxy-4',5'-dichloro-2',7'-dimethoxyfluorescein (JOE), TET™, CAL Fluor® Gold 540, CAL Fluor RED 590, CAL Fluor Red 610, CAL Fluor Red 635, IRDye® 700Dx, IRDye® 800CW, Marina Blue®, Pacific Blue®, Yakima Yellow®, 6-(4,7- Attorney Docket No.: BN00023.0071 Dichloro-2',7'-diphenyl-3',6'-dipivaloylfluorescein-6-carboxamido)-hexyl-l-0-(2-cyanoethyl)- (N,N-diisopropyl)-phosphoramidite (SIMA), CAL Fluor® Gold 540, CAL Fluor® Orange 560, CAL Fluor Red 635, Quasar 570, Quasar 670, LIZ, Sunnyvale Red, LC Red® 610, LC Red® 640, LC Red® 670, LC Red® 705, a squaraine dye, or a combination thereof. In certain embodiments, the quenching moiety is TAMRA or a dark quencher. Optionally, the dark quencher is Black Hole Quencher 1, 3' (BHQ1), DQ, dimethylaminoazobenzenesulfonic acid (DABCYL) or Iowa Black® (IWB). In one embodiment, the oligonucleotide having a double-stranded stem region, a 5'- terminus and a 3'-terminus is capable of binding the reference amino acid sequence with high affinity. Optionally, the oligonucleotide having the double-stranded stem region, the 5'-terminus and the 3'-terminus is capable of binding the reference amino acid sequence with an equilibrium binding constant (Kd) of less than 100 nM. Optionally, the oligonucleotide having the double- stranded stem region, the 5'-terminus and the 3'-terminus is capable of binding the reference amino acid sequence with an equilibrium binding constant (Kd) from about 0.01 nM to about 50 nM. In some embodiments, the oligonucleotide sequence corresponding to the reference amino acid sequence is capable of binding the reference amino acid sequence with an equilibrium binding constant (Kd) of less than 100 nM. Optionally, the oligonucleotide sequence corresponding to the reference amino acid sequence is capable of binding the reference amino acid sequence with an equilibrium binding constant (Kd) from about 0.01 nM to about 50 nM. In another embodiment, the oligonucleotide sequence corresponding to the reference amino acid sequence is capable of binding the reference amino acid sequence in a sample without prior purification. Optionally, the oligonucleotide sequence corresponding to the reference amino acid sequence binding the reference amino acid sequence in a sample causes immediate signal generation upon binding to the reference amino acid sequence in the sample. In a related embodiment, the sample is a blood sample, a sputum sample, a cerebrospinal fluid (CSF) sample, an aspirate sample, section sample, a biopsy sample or a distinct body fluid sample. Optionally, the sample is a crude sample. In a further related embodiment, the sample is derived from fluids or liquified solids found in the food and beverage industry, from environmental samples and / or from industrial processing fluids. In one embodiment, at least one of the nucleotides of the oligonucleotide sequence corresponding to the reference amino acid sequence is a 2'-O-methyl-ribonucleotide. Optionally, Attorney Docket No.: BN00023.0071 multiple nucleotides of the oligonucleotide sequence corresponding to the reference amino acid sequence are 2'-O-methyl-ribonucleotide nucleotides. Optionally, all nucleotides of the oligonucleotide sequence corresponding to the reference amino acid sequence are 2'-O-methyl- ribonucleotides. In another embodiment, the structural representation of the reference amino acid sequence is a two-dimensional structural representation or is a linear polypeptide sequence. Optionally, designing includes evaluating hydrophilicity / hydrophobicity values at individual residues of the polypeptide. Optionally, designing includes employing a scanning window of hydrophilicity / hydrophobicity values and / or Gibbs free energy (ΔG) values across a range of amino acid residues for evaluation of individual amino acid residues and assignment of a corresponding nucleotide residue. Optionally, the scanning window range of amino acid residues is 10 or more amino acid residues. Optionally, the scanning window range of amino acid residues is 20 or more amino acid residues. Optionally, the scanning window range of amino acid residues is 25 or more amino acid residues. Optionally, the scanning window range of amino acid residues is 30 or more amino acid residues. Optionally, the scanning window range of amino acid residues is 35 or more amino acid residues. Optionally, the scanning window range of amino acid residues is 40 or more amino acid residues. Optionally, the scanning window range of amino acid residues is 45 or more amino acid residues. Optionally, the scanning window range of amino acid residues is 50 or more amino acid residues. Another aspect of the instant disclosure provides an oligonucleotide capable of binding TDP-43 and possessing an equilibrium binding constant (Kd) of less than 100 nM. In a related embodiment, the oligonucleotide capable of binding TDP-43 possesses an equilibrium binding constant (Kd) for TDP-43 from about 0.01 nM to about 50 nM. A further aspect of the disclosure provides a TDP-43-binding motif for DNA or RNA oligonucleotide sequences including 5'- GCATGCATGAAAAAGAGAAAGATGAAAAGCATGC-3' (SEQ ID NO: 26), 5'- GCATGCTCAACGTAAAACAACACCAAAAATGCATGC-3' (SEQ ID NO: 27), 5'- GCAUGCAUGAAAAAGUGAUAGAUGUUAAGCAUGC-3' (SEQ ID NO: 28), or 5'- GCAUGCAUAAAAUAAAAAAACACUAAAAUGCAUGC-3' (SEQ ID NO: 29). In some embodiments, a TDP-43-binding motif for RNA oligonucleotide sequences includes 5’-GCAUGCAUGAAAAAGUGAUAGAUGUUAAGCAUGC-3' (SEQ ID NO: 28) Attorney Docket No.: BN00023.0071 where each "U" residue is a 2'-O-methyluridine-3’-phosphate. In some embodiments a TDP-43- binding motif for RNA oligonucleotide sequences includes 5’-GCAUGCAUGAAAAAGUGAUAGAUGUUAAGCAUGC-3' (SEQ ID NO: 28) where each "U" residue is a 2'-O-methyluridine-3’-phosphate and all other residues are 2'-O- methyl-ribonucleotides. In some embodiments, a TDP-43-binding motif for RNA oligonucleotide sequences includes 5’-GCAUGCAUAAAAUAAAAAAACACUAAAAUGCAUGC-3' (SEQ ID NO: 29).where each "U" residue is a 2'-O-methyluridine-3’-phosphate. In some embodiments a TDP- 43-binding motif for RNA oligonucleotide sequences includes 5’-GCAUGCAUAAAAUAAAAAAACACUAAAAUGCAUGC-3' (SEQ ID NO: 29) where each "U" residue is a 2'-O-methyluridine-3’-phosphate and all other residues are 2'-O- methyl-ribonucleotides. In another aspect, the instant disclosure provides a method for modifying a DNA aptamer, the method involving a) identifying a DNA aptamer sequence for modification; b) replacing all 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer sequence with 2'-O- methyluridine-3’-phosphate; and c) replacing all remaining deoxyribonucleotide residues of the DNA aptamer with modified ribonucleotides, thereby modifying the DNA aptamer to form an oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues of the oligoribonucleotide. In one embodiment, the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues and modified ribonucleotides at all residues is capable of binding a target polypeptide. In another embodiment, the DNA aptamer is capable of binding a target polypeptide. In a related embodiment, the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues and modified ribonucleotides at all residues is capable of binding the same target polypeptide as the DNA aptamer. In an additional related embodiment, the oligoribonucleotide having 2'-O- methyluridine-3’-phosphate residues and modified ribonucleotides at all residues possesses improved binding properties for the target polypeptide, as compared to the DNA aptamer. In a further related embodiment, the improved binding properties for the target polypeptide include higher predicted and / or measured binding affinity for the target polypeptide and immediate signal generation upon binding to the target polypeptide in a sample. Optionally, Attorney Docket No.: BN00023.0071 the probability of a 3-dimensional structure of the oligoribonucleotide having 2'-O-methyluridine- 3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues binding to the 3-dimensional structure of the target polypeptide is increased. In related embodiments, the sample is a blood sample, a sputum sample, a cerebrospinal fluid (CSF) sample, an aspirate sample, section sample, a biopsy sample or a distinct body fluid sample. Optionally, the sample is a crude sample. In a further related embodiment, the sample is derived from fluids or liquified solids found in the food and beverage industry, from environmental samples and / or from industrial processing fluids. In certain embodiments, the step of identifying the DNA aptamer sequence for modification includes identifying a motif of coaxially stacked stem structures in a quasi- continuous helix ranging between 11-14 base pairs and / or determining a predicted conformational stability of the DNA aptamer sequence when all 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer sequence are replaced with 2'-O-methyluridine-3’-phosphate, and optionally when all other nucleotides of the DNA aptamer are replaced with modified ribonucleotides (e.g., 2'-O-methyl-ribonucleotides). In some embodiments, the method is performed in silico. In a related embodiment, the method further involves synthesizing the oligoribonucleotide having 2'-O-methyluridine-3’- phosphate residues and modified ribonucleotides at all residues. In one embodiment, the DNA aptamer and the oligoribonucleotide having 2'-O- methyluridine-3’-phosphate residues and modified ribonucleotides at all residues each possesses a 5'-terminus and a 3'-terminus. In a related embodiment, the method further involves extending the 5'-terminus, the 3'-terminus, or both termini of the oligoribonucleotide having 2'-O- methyluridine-3’-phosphate residues and modified ribonucleotides at all residues by one or more nucleotides. Optionally, both termini are extended. Optionally, the nucleotides of one terminal extension of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues and modified ribonucleotides at all residues and possessing terminal extensions Watson-Crick base pairs with one or more nucleotides of another terminal extension of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues and modified ribonucleotides at all residues and possessing terminal extensions. In a related embodiment, the terminal extension nucleotides are selected according to their combined free energy (ΔG) in forming a stem structure. Optionally, the stem structure having the terminal extension nucleotides has negative free energy substantially Attorney Docket No.: BN00023.0071 less negative the respective binding of the RNA-aptamer with a target. The initial target value is -10 kcal / mol and a Tmof 37 ℃ or more. Optionally, such values are as determined by the "two state melting hybridisation" mfold algorithm with energy rule settings of RNA, 37 ℃, 215 mM NaCl; 5 mM Mg and 0.00005 µM RNA. (Notably, if the ΔG of the terminal stem is more negative than the binding of the protein to the WRAP or other such probe, it will not bind and the quench will not cease. Also, if the Tmof the terminal stem is too low (i.e., below the assay temperature) it will melt and give a false positive signal. A much higher Tm will usually coincide with a more negative ΔG.) In another embodiment, the 5'-terminus or 3'-terminus of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues that optionally includes one or more nucleotide extension of the 5'-terminus or 3'-terminus further includes a fluorescent moiety, a lanthanide or a quenching moiety. Optionally, the fluorescent moiety, lanthanide or quenching moiety is attached to a terminal nucleotide of the oligoribonucleotide having 2'-O-methyluridine-3’- phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine- 3’-phosphate residues. Optionally, the fluorescent moiety, lanthanide or quenching moiety is covalently attached. In a related embodiment, the oligoribonucleotide having 2'-O-methyluridine- 3’-phosphate residues or the terminally extended oligoribonucleotide having 2'-O-methyluridine- 3’-phosphate residues includes both a fluorescent moiety or a lanthanide and a quenching moiety. In a further related embodiment, the fluorescent moiety or lanthanide is attached to a 5'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues. Alternatively, the fluorescent moiety or lanthanide is attached to a 3'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues. In another embodiment, the quenching moiety is attached to a 5'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues. In one embodiment, the quenching moiety is attached to a 3'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues. Attorney Docket No.: BN00023.0071 In an additional embodiment, the fluorescent moiety or lanthanide is attached to a 5'- terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’- phosphate residues and the quenching moiety is attached to a 3'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues. In another embodiment, the fluorescent moiety or lanthanide is attached to a 3'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues and the quenching moiety is attached to a 5'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues. In some embodiments, the fluorescent moiety is Atto 495, Atto 390, Atto 425, Atto 465, Atto 488, Atto 520, Atto 532, Atto 550, Atto 565, Atto 590, Atto 594, Atto 620, Atto 633, Atto 647N, Atto 655, Atto Rho6G, Atto Rho11, Atto Rho12, Atto Rho101, 5- or 6-carboxyfluorescein (FAM™), VIC™, NED™, fluorescein, fluorescein isothiocyanate (FITC), IRDYE-700 / 800, cyanine dyes, such as CY3™, CY5™, CY3.5™, CY5.5™, Cy7™, xanthen, 6-carboxy- 2',4',7',4,7- hexachlorofluorescein (HEX), 6-carboxy-l,4-dichloro-2',7'-dichloro-fluorescein (TET®), 6- carboxy-4',5'-dichloro-2',7'-dimethodyfluorescein (JOE™), N,N,N',N'-tetramethyl-6- carboxyrhodamine (TAMRA™), 6-carboxy-X-rhodamine (ROX), 5-carboxyrhodamine-6G (R6G5), 6-carboxyrhodamine-6G (RG6), rhodamine, rhodamine green, rhodamine red, rhodamine 110, Rhodamin 6G®, BODIPY dyes, such as BODIPY TMR, Oregon green, coumarines, such as umbelliferone, benzimides, such as Hoechst 33258; phenanthridines, such as Texas Red®, California Red®, Yakima Yellow, Alexa Fluor® 350, Alexa Fluor® 405, Alexa Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 500, Alexa Fluor® 514, Alexa Fluor®532, Alexa Fluor® 546, Alexa Fluor® 555, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 610, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Fluor® 680, Alexa Fluor® 700, Alexa Fluor® 750, PET®, ethidium bromide, acridinium dyes, carbazol dyes, phenoxazine dyes, porphyrine dyes, polymethin dyes, BMN™-5, BMN™-6, BMN™ Q620, CEQ8000 D2, CEQ8000 D3, CEQ8000 D4, DY-480XL, DY-485XL, DY-495, DY-505, DY-510XL, DY- 521XL, DY-521XL, DY-530, DY-547, DY-550, DY- 555, DY-610, DY-615, DY-630, DY-631, Attorney Docket No.: BN00023.0071 DY-633, DY-635, DY-647, DY-651, DY-675, DY-676, DY-680, DY-681, DY-700, DY-701, DY-730, DY-731, DY-732, DY-750, DY-751, DY-776, DY-780, DY-781, DY-782, 6-carboxy- 4',5'-dichloro-2',7'-dimethoxyfluorescein (JOE), TET™, CAL Fluor® Gold 540, CAL Fluor RED 590, CAL Fluor Red 610, CAL Fluor Red 635, IRDye® 700Dx, IRDye® 800CW, Marina Blue®, Pacific Blue®, Yakima Yellow®, 6-(4,7-Dichloro-2',7'-diphenyl-3',6'-dipivaloylfluorescein-6- carboxamido)-hexyl-l-0-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite (SIMA), CAL Fluor® Gold 540, CAL Fluor® Orange 560, CAL Fluor Red 635, Quasar 570, Quasar 670, LIZ, Sunnyvale Red, LC Red® 610, LC Red® 640, LC Red® 670, LC Red® 705 or a squaraine dye (for a description of squarine dyes, see, e.g., Bioconjugate Chem. 2020, 31, 2, 194–213 at doi.org / 10.1021 / acs.bioconjchem.9b00482). In some embodiments, the quenching moiety is TAMRA or a dark quencher. Optionally, the dark quencher is Black Hole Quencher 1, 3' (BHQ1), DQ, dimethylaminoazobenzenesulfonic acid (DABCYL) or Iowa Black® (IWB). In one embodiment, the terminally extended oligoribonucleotide having 2'-O- methyluridine-3’-phosphate residues is capable of binding the same target polypeptide as the DNA aptamer. In a related embodiment, the terminally extended oligoribonucleotide having 2'- O-methyluridine-3’-phosphate residues possesses improved binding properties for the target polypeptide, as compared to the DNA aptamer, as compared to the oligoribonucleotide having 2'- O-methyluridine-3’-phosphate residues in the absence of terminal extension(s), or as compared to both. In a related embodiment, the improved binding properties for the target polypeptide are higher binding affinity for the target polypeptide and / or immediate signal generation upon binding to the target polypeptide in a sample. In one embodiment, the sample is a blood sample, a sputum sample, a cerebrospinal fluid (CSF) sample, an aspirate sample, a section sample, a biopsy sample or a distinct body fluid sample. Optionally, the sample is a crude sample. In some embodiments, the change in Gibbs free energy (ΔG) value(s) associated with the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues binding the target polypeptide is significantly less than the ΔG value(s) associated with the DNA aptamer binding the target polypeptide. In certain embodiments, the target polypeptide is a prion-like protein. Optionally, the prion-like protein is TDP-43, Tau, beta-amyloid, alpha-synuclein, optineurin, prion protein (PrP), Attorney Docket No.: BN00023.0071 or another protein with prion-like domains involved in liquid-liquid phase separation (see A. Louka et al; 11880-11889; NAR 2020,Vol.48,No 21; doi:10.1093 / nar / gkaa822; RNA as the stone quest of protein aggregation). Optionally, the target polypeptide is human Tau. In a related embodiment, the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues selectively binds Tau441 of SEQ ID NO: 1. Optionally, the oligoribonucleotide having 2'-O- methyluridine-3’-phosphate residues or the terminally extended oligoribonucleotide having 2'-O- methyluridine-3’-phosphate residues selectively binds phosphorylated T231 in the Tau441 sequence of SEQ ID NO: 1. Another aspect of the instant disclosure provides a method for generating a RNA affinity probe (RAP), the method involving a) identifying a DNA aptamer sequence having a 5'-terminus and a 3'-terminus, where the DNA aptamer is capable of binding a target polypeptide; b) replacing all 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer sequence with 2'- O-methyluridine-3’-phosphate nucleotide residues; c) replacing all remaining deoxyribonucleotide residues of the DNA aptamer with modified ribonucleotides, thereby forming an oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues and possessing a 5'-terminus and a 3'-terminus; and d) extending the 5'-terminus, the 3'-terminus, or both termini of the oligoribonucleotide having 2'-O- methyluridine-3’-phosphate residues and modified ribonucleotides at all residues by one or more nucleotide residues, thereby forming a terminally extended oligoribonucleotide having 2'-O- methyluridine-3’-phosphate residues and modified ribonucleotides at all residues, where the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues and modified ribonucleotides at all residues further includes a fluorescent moiety, thereby generating a RNA affinity probe (RAP). In one embodiment, the RAP is capable of binding the target polypeptide. In a related embodiment, the RAP possesses improved binding properties for the target polypeptide, as compared to the DNA aptamer. Optionally, the improved binding properties for the target polypeptide include higher predicted binding affinity for the target polypeptide (e.g., via prediction of 3D structure binding by algorithm, such as that found at Attorney Docket No.: BN00023.0071 pridb.gdcb.iastate.edu / RPISeq), higher measured binding affinity for the target polypeptide and / or immediate signal generation upon binding to the target polypeptide in a sample. In one embodiment, the DNA aptamer and corresponding RAP are identified via an iterative process that increases the binding capability of the RAP relative to the DNA aptamer. Optionally, the DNA aptamer is predicted to have multiple conformational options possessing similar free energy levels and the RAP is predicted to form a stable structure (with the combination of replacing all 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer sequence with 2'-O-methyluridine-3’-phosphate nucleotide residues, replacing all remaining nucleotides with modified ribonucleotides, and forming a terminal closed helical stem structure via nucleotide extension helping to form a stable conformation, having a highly negative ΔG value). In some embodiments, the method is performed in silico. In a related embodiment, the method further involves synthesizing the RAP. In certain embodiments, the terminal extension nucleotides are selected according to their combined free energy (ΔG) in forming a stem structure. In one embodiment, the fluorescent moiety is attached to a 5'-terminal nucleotide residue of the RAP. In another embodiment, the fluorescent moiety is attached to a 3'-terminal nucleotide residue of the RAP. In some embodiments, the RAP further includes a quenching moiety. In a related embodiment, the quenching moiety is attached to a 5'-terminal nucleotide residue of the RAP. Alternatively, the quenching moiety is attached to a 3'-terminal nucleotide residue of the RAP. In certain embodiments, the change in Gibbs free energy (ΔG) value(s) associated with the RAP binding the target polypeptide is significantly less than the ΔG value(s) associated with the DNA aptamer binding the target polypeptide. Optionally, binding is assessed in a photovoltaic device. In one embodiment, the RAP selectively binds Tau441 of SEQ ID NO: 1. Optionally, the RAP selectively binds phosphorylated T231 in the Tau441 sequence of SEQ ID NO: 1, as compared to binding of non-phosphorylated Tau441. Another aspect of the instant disclosure provides an array of RAPs as disclosed herein. Optionally, the array of RAPs includes two or more RAPs that bind distinct target polypeptides Attorney Docket No.: BN00023.0071 from one another. Optionally, two or more RAPs include distinct fluorescent moieties and / or quenching moieties from one another. Optionally, the array of RAPs is arranged in a 96-well array or a 384-well array format. An additional aspect of the instant disclosure provides a method for improving one or more target polypeptide binding properties of a DNA aptamer capable of selectively binding a target polypeptide, the method involving replacing all 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer sequence with 2'-O-methyluridine-3’-phosphate residues, thereby forming an oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and possessing one or more improved target polypeptide binding properties as compared to the DNA aptamer. In one embodiment, the one or more target polypeptide binding properties are higher predicted binding affinity for the target polypeptide, higher measured binding affinity for the target polypeptide and / or immediate signal generation upon binding to the target polypeptide in a sample. In certain embodiments, the DNA aptamer and corresponding RAP are identified via an iterative process that increases the binding capability of the RAP relative to the DNA aptamer. Optionally, the DNA aptamer is predicted to have multiple conformational options possessing similar free energy levels and the RAP is predicted to form a stable structure. In some embodiments, the method is performed in silico. Optionally, the method further involves synthesizing the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues. In one embodiment, the DNA aptamer and the oligoribonucleotide having 2'-O- methyluridine-3’-phosphate residues each possesses a 5'-terminus and a 3'-terminus. In a related embodiment, the method further involves extending the 5'-terminus, the 3'-terminus, or both termini of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues by one or more nucleotides. Optionally, both termini are extended. Optionally, the nucleotides of one terminal extension of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues and possessing terminal extensions Watson-Crick base pair with one or more nucleotides of another terminal extension of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues and possessing terminal extensions. In a related embodiment, the terminal extension Attorney Docket No.: BN00023.0071 nucleotides are selected according to their combined free energy (ΔG) in forming a stem structure. Optionally, the stem structure including the terminal extension nucleotides has negative free energy of -10 kcal / mol or less and a Tmof 37 ^ or more. Optionally, such values are as determined by the "two state melting hubridisation" mfold algorithm with energy rule settings of RNA, 37 ^, 215 mM NaCl; 5 mM Mg and 0.00005 µM RNA. In another embodiment, the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and possessing one or more improved target polypeptide binding properties as compared to the DNA aptamer further includes a moiety having electrostatic properties and capable of closing or generating a stem structure in the oligoribonucleotide, disulfide bridges (S-S) capable of closing or generating a stem structure in the oligoribonucleotide, and / or amino acids or short peptides capable of stabilizing a stem structure in the oligoribonucleotide. In certain embodiments, the 5'-terminus or 3'-terminus of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues that optionally includes one or more nucleotide extension of the 5'-terminus or 3'-terminus further includes a fluorescent moiety or a quenching moiety. Optionally, the fluorescent moiety or quenching moiety is attached to a terminal nucleotide of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues. Optionally, the fluorescent moiety or quenching moiety is covalently attached. In a related embodiment, the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues includes both a fluorescent moiety and a quenching moiety. In certain embodiments, the fluorescent moiety is attached to a 5'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues. In some embodiments, the fluorescent moiety is attached to a 3'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues. In one embodiment, the quenching moiety is attached to a 5'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues. Attorney Docket No.: BN00023.0071 In another embodiment, the quenching moiety is attached to a 3'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues. In some embodiments, the fluorescent moiety is attached to a 5'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues and the quenching moiety is attached to a 3'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues. Alternatively, the fluorescent moiety is attached to a 3'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues and the quenching moiety is attached to a 5'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues. In some embodiments, the oligonucleotide is detected using a photovoltaic device. In one embodiment, the change in Gibbs free energy (ΔG) value(s) associated with the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues or the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues binding the target polypeptide is significantly less than the ΔG value(s) associated with the DNA aptamer binding the target polypeptide. A further aspect of the instant disclosure provides a composition including a nucleic acid having a 5'-terminus and a 3'-terminus and having the sequence: CAGCACCGUCAACUGAAUAAGGACUGCUUAGGAUUGCGAUGAUUCAGGGU GAUGCGAUGGAGAUGU (SEQ ID NO: 10), where each "U" residue is a 2'-O-methyluridine- 3’-phosphate. Optionally, all other residues are modified ribonucleotides. Optionally a composition includes a nucleic acid having a 5'-terminus and a 3'-terminus and having the sequence: CAGCACCGUCAACUGAAUAAGGACUGCUUAGGAUUGCGAUGAUUCAGGGU GAUGCGAUGGAGAUGU (SEQ ID NO: 30), where each "U" residue is a 2'-O-methyluridine- 3’-phosphate and all other residues are 2'-O-methyl-ribonucleotides Attorney Docket No.: BN00023.0071 In one embodiment, the composition includes the following the nucleic acid sequence: 5'-ACAUCUCAGCACCGUCAACUGAAUAAGGACUGCUUAGGAUUGCGAUG AUUCAGGGUGAUGCGAUGGAGAUGU-3' (SEQ ID NO: 11), where each "U" residue is a 2'-O-methyluridine-3’-phosphate. Optionally, all other residues of the nucleic acid sequence are modified ribonucleotides. Optionally a composition includes a nucleic acid having a 5'-terminus and a 3'-terminus and having the sequence: 5'-ACAUCUCAGCACCGUCAACUGAAUAAGGACUGCUUAGGAUUGCGAUG AUUCAGGGUGAUGCGAUGGAGAUGU-3' (SEQ ID NO: 31), where each "U" residue is a 2'-O-methyluridine-3’-phosphate and all other residues are 2'-O-methyl-ribonucleotides. In certain embodiments, the 3'-terminus, the 5'-terminus, or both the 3'-terminus and the 5'-terminus is attached to a fluorescent moiety. In another embodiment, the 3'-terminus, the 5'-terminus, or both the 3'-terminus and the 5'-terminus is attached to a quenching moiety. Another aspect of the instant disclosure provides a composition including a nucleic acid having a 5'-terminus and a 3'-terminus and having the sequence: CAGCACCGUCAACUGAAUGGGGAGAGUGGUGGGGCGGGGGCCGGAUCCGUGAUG CGAUGGAGAUGU (SEQ ID NO: 13), where each "U" residue is a 2'-O-methyluridine-3’- phosphate. Optionally, all other residues of the nucleic acid sequence are modified ribonucleotides. Optionally a composition includes a nucleic acid having a 5'-terminus and a 3'- terminus and having the sequence: CAGCACCGUCAACUGAAUGGGGAGAGUGGUGGGGCGGGGGCCGGAUCCGU GAUGCGAUGGAGAUGU (SEQ ID NO: 32), where each "U" residue is a 2'-O-methyluridine- 3’-phosphate and all other residues are 2'-O-methyl-ribonucleotides. In one embodiment, the composition includes the nucleic acid sequence: 5'-ACAUCAGCACCGUCAACUGAAUGGGGAGAGUGGUGGGGCGGGGGCCG GAUCCGUGAUGCGAUGGAGAUGU-3' (SEQ ID NO: 14), where each "U" residue is a 2'-O- methyluridine-3’-phosphate. Optionally, all other residues of the nucleic acid sequence are modified ribonucleotides. Optionally a composition includes a nucleic acid having a 5'-terminus and a 3'-terminus and having the sequence: Attorney Docket No.: BN00023.0071 5'-ACAUCAGCACCGUCAACUGAAUGGGGAGAGUGGUGGGGCGGGGGCCGG AUCCGUGAUGCGAUGGAGAUGU-3' (SEQ ID NO: 33) where each "U" residue is a 2'-O- methyluridine-3’-phosphate and all other residues are 2'-O-methyl-ribonucleotides. In another embodiment, the composition binds both T231 and T231P peptides with high affinity (high affinity is as known in the art and optionally as defined by 1) actively phosphorylating rTAU with glycogen synthase kinase 3β (GSK3β) and 2) using phosphatase (+) and phosphatase (-) human neuroblastoma cell lines to assess). An additional aspect of the instant disclosure provides a composition including a nucleic acid having a 5'-terminus and a 3'-terminus and having the sequence: CAGCACCGUCAACUGAAUGGGUUGGCCGGGCAGCGGGGGGUAGGCUUGGUGAUG CGAUGGAGAUGU (SEQ ID NO: 16), where each "U" residue is a 2'-O-methyluridine-3’- phosphate. Optionally, all other residues of the nucleic acid sequence are modified ribonucleotides. Optionally a composition includes a nucleic acid having a 5'-terminus and a 3'- terminus and having the sequence: CAGCACCGUCAACUGAAUGGGUUGGCCGGGCAGCGGGGGGUAGGCUUGGU GAUGCGAUGGAGAUGU (SEQ ID NO: 34), where each "U" residue is a 2'-O-methyluridine- 3’-phosphate and all other residues are 2'-O-methyl-ribonucleotides. In one embodiment, the composition includes the nucleic acid sequence: 5'-AACACAUCAGCACCGUCAACUGAAUGGGUUGGCCGGGCAGCGGG GGGUAGGCUUGGUGAUGCGAUGGAGAUGUGUU-3' (SEQ ID NO: 17), where each "U" residue is a 2'-O-methyluridine-3’-phosphate. Optionally, all other residues of the nucleic acid sequence are modified ribonucleotides. Optionally a composition includes a nucleic acid having a 5'-terminus and a 3'-terminus and having the sequence: 5'-AACACAUCAGCACCGUCAACUGAAUGGGUUGGCCGGGCAGCGGG GGGUAGGCUUGGUGAUGCGAUGGAGAUGUGUU-3' (SEQ ID NO: 35), where each "U" residue is a 2'-O-methyluridine-3’-phosphate and all other residues are 2'-O-methyl- ribonucleotides. In certain embodiments, the composition selectively binds human Tau polypeptide having a nonphosphorylated T231 residue, as compared to binding of human Tau having a phosphorylated T231 residue. Attorney Docket No.: BN00023.0071 A further aspect of the instant disclosure provides a composition including a nucleic acid having a 5'-terminus and a 3'-terminus and having the sequence: CAGCACCGUCAACUGAAUGGCGGGGGGUCAGGUCGGGGUAAGGUGAGCGU GAUGCGAUGGAGAUGU (SEQ ID NO: 19), where each "U" residue is a 2'-O-methyluridine- 3’-phosphate. Optionally, all other residues of the nucleic acid sequence are modified ribonucleotides. Optionally a composition includes a nucleic acid having a 5'-terminus and a 3'- terminus and having the sequence: CAGCACCGUCAACUGAAUGGCGGGGGGUCAGGUCGGGGUAAGGUGAGCGU GAUGCGAUGGAGAUGU (SEQ ID NO: 36) where each "U" residue is a 2'-O-methyluridine- 3’-phosphate and all other residues are 2'-O-methyl-ribonucleotides. In one embodiment, the composition includes the nucleic acid sequence: 5'- CCACAUCAGCACCGUCAACUGAAUGGCGGGGGGUCAGGUCGGGGUAA GGUGAGCGUUUAUGCGAUGGAGAUGUGG-3' (SEQ ID NO: 20), where each "U" residue is a 2'-O-methyluridine-3’-phosphate. Optionally, all other residues of the nucleic acid sequence are modified ribonucleotides. Optionally a composition includes a nucleic acid having a 5'- terminus and a 3'-terminus and having the sequence: 5'- CCACAUCAGCACCGUCAACUGAAUGGCGGGGGGUCAGGUCGGGGUAA GGUGAGCGUUUAUGCGAUGGAGAUGUGG-3' (SEQ ID NO37), where each "U" residue is a 2'-O-methyluridine-3’-phosphate and all other residues are 2'-O-methyl-ribonucleotides. In another embodiment, the composition is capable of binding Tau441 protein of SEQ ID NO: 1 with a Kd of about 7.6 ± 0.6 nM. Another aspect of the instant disclosure provides an array of nucleic acid compositions including one or more compositions as disclosed herein. Optionally, the array of nucleic acid compositions is arranged in a 96-well array or a 384-well array format. An additional aspect of the instant disclosure includes a kit for detecting the presence or absence of human Tau or of a modified form of human Tau in a sample, the kit including a composition as disclosed herein, and instructions for its use. In one embodiment, human Tau441 of SEQ ID NO: 1 is detected. Attorney Docket No.: BN00023.0071 In another embodiment, a phosphorylated form of the Tau441 sequence of SEQ ID NO: 1 is specifically detected. Optionally, a phosphorylated T231 form of the Tau441 sequence of SEQ ID NO: 1 is specifically detected. Definitions That the present disclosure may be more readily understood, certain terms are first defined. In addition, it should be noted that whenever a value or range of values of a parameter are recited, it is intended that values and ranges intermediate to the recited values are also intended to be part of this disclosure. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element, e.g., a plurality of elements. The term "including" is used herein to mean, and is used interchangeably with, the phrase "including but not limited to". The term "or" is used herein to mean, and is used interchangeably with, the term "and / or," unless context clearly indicates otherwise. The term “about” is used herein to mean within the typical ranges of tolerances in the art. For example, “about” can be understood as about 2 standard deviations from the mean. In certain embodiments, about means ±10%. In certain embodiments, about means ±5%. When about is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range. As used herein, an “aptamer” refers to a nucleic acid that has a specific binding affinity for a target molecule. In certain embodiments, the target molecule is a protein. It is recognized that affinity interactions are a matter of degree; however, in this context, the “specific binding affinity” of an aptamer for its target means that the aptamer binds to its target generally with a much higher degree of affinity than it binds to other components in a test sample. An “aptamer” is a set of copies of one type or species of nucleic acid molecules or peptides that have a particular sequence. An aptamer can include any suitable number of nucleotides, including any number of chemically modified nucleotides or peptide sequences. “Aptamers” refers to more than one such set of molecules. Different aptamers can have either the same or different numbers of nucleotides or amino acids. Peptide aptamers consist of a short variable peptide domain attached to a protein Attorney Docket No.: BN00023.0071 scaffold. Nucleic acid aptamers can be DNA or RNA or chemically modified nucleic acids and can be single stranded, double stranded, or contain double stranded regions, and can include higher ordered structures. A nucleic acid- or peptide aptamer can also be a photoaptamer, where a photoreactive or chemically reactive functional group is included in the aptamer to allow it to be covalently linked to its corresponding target. Any of the aptamer methods disclosed herein can include the use of two or more aptamers that specifically bind the same target molecule. As further described below, an aptamer may include a tag. If an aptamer includes a tag, all copies of the aptamer need not have the same tag. Moreover, if different aptamers each include a tag, these different aptamers can have either the same tag or a different tag. The tags may be combined to only generate a signal when in close proximity to allow e.g., Foerster resonance energy transfer (FRET) to occur. An aptamer can be engineered by artificial combinatorial methodologies of in vitro selection or systematic evolution of ligands by exponential enrichment in iterative processes. In 1990, two laboratories independently developed an in vitro method of systematic evolution of by exponential enrichment (SELEX) to generate ligands towards proteins. Alternative selection methods have recently been developed that increase the efficiency of the selection, and there has been a demonstrated need for improving the selection of a sequence from a randomly assembled set of arbitrarily synthesized oligonucleotides (Nanostructures for Cancer Therapy, 2017). Once identified, an aptamer can be prepared or synthesized in accordance with any known method, including chemical synthetic methods and enzymatic synthetic methods. A "Tau aptamer", as used herein, refers to an aptamer that is capable of binding to a Tau protein. In certain embodiments, a Tau aptamer is capable of binding to a Tau protein at a phosphorylatable site. Tau consists of six isoforms in the human brain with molecular weights of 48 KDa to 67 KDa, depending on isoform. Tau elevation is observed in the cerebrospinal fluid (CSF) of patients with neurodegenerative disease and severe head injuries, suggesting its extracellular release during neuronal damage and a role as a biomarker with specificity for brain injury. In Alzheimer’s disease (AD) and related neurodegenerative diseases, including chronic traumatic encephalopathy, Tau is abnormally phosphorylated and aggregated into bundles of filaments. Phosphorylated Tau is believed to be a more relevant biomarker for AD. Tau phosphorylated at either threonine 181 or 231 have been shown to differentiate AD from healthy controls. It remains unclear which phosphorylation carries the higher differentiation potential. Attorney Docket No.: BN00023.0071 Nonlimiting exemplary human Tau polypeptides include: LOCUS NP_005901 441 aa linear PRI 07-SEP-2021 NAME "Tau441" - microtubule-associated protein Tau isoform 2 [Homo sapiens]. ACCESSION NP_005901 NP_776088 VERSION NP_005901.2 MAEPRQEFEVMEDHAGT[Y18]GLGDRKDQGG[Y29]TMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSE TSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSK DGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPK[T181]PPSSGEPPKSGDRSG[ Y197]SSPG[S202]PGTPGSRSRTPSLP[T217]PPTREPKKVAVVR[T231]PPKSPSSAKSRLQTAP VPMPDLKNVKSKIG[S262]TENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKP VDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENA KAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL (SEQ ID NO: 1), where sites of potential phosphorylation are indicated by brackets and residue numbering. LOCUS NP_001116538 776 aa linear PRI 06-SEP-2021 NAME "Tau776" - microtubule-associated protein Tau isoform 6 [Homo sapiens]. ACCESSION NP_001116538 VERSION NP_001116538.2 MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTP TAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQEPESGKVVQEGFLREP GPPGLSHQLMSGMPGAPLLPEGPREATRQPSGTGPEDTEGGRHAPELLKHQLLGDLHQEGPPLKGAGGKE RPGSKEEVDEDRDVDESSPQDSPPSKASPAQDGRPPQTAAREATSIPGFPAEGAIPLPVDFLSKVSTEIP ASEPDGPSVGRAKGQDAPLEFTFHVEITPNVQKEQAHSEEHLGRAAFPGAPGEGPEARGPSLGEDTKEAD LPEPSEKQPAAAPRGKPVSRVPQLKARMVSKSKDGTGSDDKKAKTSTRSSAKTLKNRPCLSPKHPTPGSS DPLIQPSSPAVCPEPPSSPKYVSSVTSRTGSSGAKEMKLKGADGKTKIATPRGAAPPGQKGQANATRIPA K[T492]PPAPK[T498]PPSSATKQVQRRPPPAGPRSERGEPPKSGDRSGYSSPGSPGTPGSRSRTPSL P[T552]PPTREPKKVAVVR[T566]PPKSPSSAKSRLQTAPVPMPDLKNVKSKIG[S597]TENLKHQP GGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVK SEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSN VSSTGSIDMVDSPQLATLADEVSASLAKQGL (SEQ ID NO: 2), where sites of potential phosphorylation are indicated by brackets and residue numbering. Attorney Docket No.: BN00023.0071 LOCUS NP_001116539 412 aa linear PRI 07-SEP-2021 NAME "Tau412" - microtubule-associated protein Tau isoform 5 [Homo sapiens]. ACCESSION NP_001116539 VERSION NP_001116539.1 MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTP TAEAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANAT RIPAK[T146]PPAPK[T152]PPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVV RTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKH VPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNK KIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQ GL (SEQ ID NO: 3), where sites of potential phosphorylation are indicated by brackets and residue numbering. LOCUS NP_001190180 381 aa linear PRI 06-SEP-2021 NAME "Tau381" - microtubule-associated protein Tau isoform 7 [Homo sapiens]. ACCESSION NP_001190180 XP_003403649 XP_003403650 XP_003403651 XP_003403652 XP_003403653 XP_003403654 XP_003403655 XP_003403656 XP_003403657 VERSION NP_001190180.1 MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTP TAEAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANAT RIPAK[T146]PPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVR[T20 2]PPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIVYKPVDLSKVTSKCGSLGNIHH KPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVS GDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL (SEQ ID NO: 4) LOCUS NP_001190181 410 aa linear PRI 06-SEP-2021 NAME "Tau410" - microtubule-associated protein Tau isoform 8 [Homo sapiens]. ACCESSION NP_001190181 VERSION NP_001190181.1 MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTP TAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDK KAKGADGKTKIATPRGAAPPGQKGQANATRIPAK[T175]PPAPKTPPSSGEPPKSGDRSGYSSPGSPGT PGSRSRTPSLP[T217]PPTREPKKVAVVR[T231]PPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTEN Attorney Docket No.: BN00023.0071 LKHQPGGGKVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGG GNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASL AKQGL (SEQ ID NO: 5), where sites of potential phosphorylation are indicated by brackets and residue numbering. LOCUS NP_058518 383 aa linear PRI 06-SEP-2021 NAME "Tau383" - microtubule-associated protein Tau isoform 3 [Homo sapiens]. ACCESSION NP_058518 VERSION NP_058518.1 MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKAEEAGIGDTPSLEDEAAGHVTQARMV SKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAK[T117]PPAPKTPPSSGEPPKSGD RSGYSSPGSPGTPGSRSRTPSLP[T159]PPTREPKKVAVVR[T173]PPKSPSSAKSRLQTAPVPMPDL KNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCG SLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIV YKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL (SEQ ID NO: 6), where sites of potential phosphorylation are indicated by brackets and residue numbering. Other exemplary versions of Tau protein include the following: LOCUS NP_058519 758 aa linear PRI 07-SEP-2021 NAME "Tau758" - microtubule-associated protein Tau isoform 1 [Homo sapiens]. ACCESSION NP_058519 VERSION NP_058519.3 MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTP TAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQEPESGKVVQEGFLREP GPPGLSHQLMSGMPGAPLLPEGPREATRQPSGTGPEDTEGGRHAPELLKHQLLGDLHQEGPPLKGAGGKE RPGSKEEVDEDRDVDESSPQDSPPSKASPAQDGRPPQTAAREATSIPGFPAEGAIPLPVDFLSKVSTEIP ASEPDGPSVGRAKGQDAPLEFTFHVEITPNVQKEQAHSEEHLGRAAFPGAPGEGPEARGPSLGEDTKEAD LPEPSEKQPAAAPRGKPVSRVPQLKARMVSKSKDGTGSDDKKAKTSTRSSAKTLKNRPCLSPKHPTPGSS DPLIQPSSPAVCPEPPSSPKYVSSVTSRTGSSGAKEMKLKGADGKTKIATPRGAAPPGQKGQANATRIPA K[T492]PPAPK[T498]PPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLP[T534]PPTREPKKVAV VR[T548]PPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGS KDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHV PGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVS Attorney Docket No.: BN00023.0071 ASLAKQGL (SEQ ID NO: 7), where sites of potential phosphorylation are indicated by brackets and residue numbering. LOCUS NP_001364194 833 aa linear PRI 06-SEP-2021 NAME "Tau833" - microtubule-associated protein Tau isoform 9 [Homo sapiens]. ACCESSION NP_001364194 XP_005257421 VERSION NP_001364194.1 MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTP PEAPVPLTASLPQHRPVCPAPPPTGGPQEPSLEWGQKGGDWAEKGPAFPKPATTAYLHTEPESGKVVQEG FLREPGPPGLSHQLMSGMPGAPLLPEGPREATRQPSGTGPEDTEGGRHAPELLKHQLLGDLHQEGPPLKG AGGKERPGSKEEVDEDRDVDESSPQDSPPSKASPAQDGRPPQTAAREATSIPGFPAEGAIPLPVDFLSKV STEIPASEPDGPSVGRAKGQDAPLEFTFHVEITPNVQKEQAHSEEHLGRAAFPGAPGEGPEARGPSLGED TKEADLPEPSEKQPAAAPRGKPVSRVPQLKARMVSKSKDGTGSDDKKAKTSTRSSAKTLKNRPCLSPKHP TPGSSDPLIQPSSPAVCPEPPSSPKYVSSVTSRTGSSGAKEMKLKGADGKTKIATPRGAAPPGQKGQANA TRIPAK[T567]PPAPK[T573]PPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLP[T609]PPTREP KKVAVVR[T623]PPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQ SKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLD NITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATL ADEVSASLAKQGL (SEQ ID NO: 8), where sites of potential phosphorylation are indicated by brackets and residue numbering. In certain embodiments, the reference sequence for sites of Tau phosphorylation and / or numbering of Tau residues is SEQ ID NO: 1. In other embodiments, the reference sequence for sites of Tau phosphorylation and / or numbering of Tau residues is a sequence for any other form of Tau. A reference amino acid sequence for TDP-43 is: LOCUS NP_031401 414 aa linear PRI 25-OCT-2022 DEFINITION TAR DNA-binding protein 43 [Homo sapiens]. ACCESSION NP_031401 NP_112491 VERSION NP_031401.1 MSEYIRVTEDENDEPIEIPSEDDGTVLLSTVTAQFPGACGLRYRNPVSQCMRGVRLVEGILHAPDAGWGN LVYVVNYPKDNKRKMDETDASSAVKVKRAVQKTSDLIVLGLPWKTTEQDLKEYFSTFGEVLMVQVKKDLK Attorney Docket No.: BN00023.0071 TGHSKGFGFVRFTEYETQVKVMSQRHMIDGRWCDCKLPNSKQSQDEPLRSRKVFVGRCTEDMTEDELREF FSQYGDVMDVFIPKPFRAFAFVTFADDQIAQSLCGEDLIIKGISVHISNAEPKHNSNRQLERSGRFGGNP GGFGNQGGFGNSRGGGAGLGNNQGSNMGGGMNFGAFSINPAMMAAAQAALQSSWGMMGMLASQQNQSGPS GNNQNQGNMQREPNQAFGSGNNSYSGSNSGAAIGWGSASNAGSGSGFNGGFGSSMDSKSSGWGM (SEQ ID NO: 25) As will be clear to the skilled artisan, sites (e.g., phosphorylation sites) located in one form of Tau can often be identified via sequence alignment within other forms of Tau (provided that such regions of overlap are not absent from one form of Tau). As used herein, the term "neurodegenerative disease" means and refers to a disorder caused by the deterioration of certain nerve cells (neurons). Changes in these cells cause them to function abnormally, eventually bringing about their death or degeneration. Examples of such diseases include, but not limited to: Alzheimer's disease (including mild or early-stage Alzheimer's disease, mild to moderate Alzheimer's disease, moderate or mid-stage Alzheimer's disease, moderate to severe Alzheimer's disease, moderately severe Alzheimer's disease, severe Alzheimer's disease, Alzheimer's disease with Lewy bodies, (AD)), Parkinson's disease (including Parkinson's disease chemically induced by exposure to environmental agents such as pesticides, insecticides, or herbicides and / or metals such as manganese, aluminum, cadmium, copper, or zinc, SNCA gene- linked Parkinson's disease, sporadic or idiopathic Parkinson's disease, or Parkin- or LRRK2-linked Parkinson's disease (PD)), autosomal-dominant Parkinson's disease, Diffuse Lewy Body Disease (DLBD) also known as Dementia with Lewy Bodies (DLB), Pure Autonomic Failure, Lewy body dysphagia, Incidental LBD, Inherited LBD (e.g., mutations of the alpha-synuclein gene, PARK3 and PARK4), multiple system atrophy (including Olivopontocerebellar Atrophy, Striatonigral Degeneration, Shy-Drager Syndrome (MSA)), combined Alzheimer's and Parkinson disease and / or MSA, Huntington's disease, synucleinopathies, disorders or conditions characterized by the presence of Lewy bodies, multiple sclerosis, Amyotrophic lateral sclerosis (ALS) dementia (including vascular dementia, Lewy body dementia, Parkinson's dementia, frontotemporal dementia), Down syndrome, Psychosis (including agitation caused by a neurodegenerative disease or associated with dopaminergic therapy such as but not limited to Parkinson's disease psychosis, Alzheimer's disease psychosis, Lewy body dementia psychosis), dyskinesia (including agitation caused by a neurodegenerative disease or associated with dopaminergic therapy), agitation (including agitation caused by a neurodegenerative disease or associated with dopaminergic Attorney Docket No.: BN00023.0071 therapy), conditions associated with dopaminergic therapy (including dystonia, myoclonus, or tremor), synucleinopathies, diseases, disorders or conditions associated with abnormal expression, stability, activities and / or cellular processing of a-synuclein, diseases, disorders or conditions characterized by the presence of Lewy bodies, Creutzfeldt- Jakob, cerebral ischemias, epilepsy, neurodegenerative disease caused by traumatic injury, cognitive impairment, and combinations thereof. For purpose of the disclosed invention, the term “domain” or “motif” with respect to a protein refers to a distinct functional or structural unit in the protein. Usually, a protein domain is responsible for a particular function or interaction, contributing to the overall role of a protein. In certain embodiments, a motif may be a combination of structural feature(s) that, as a composite,determine specific protein / nucleic acid interaction sites. Domains or motifs may exist in a variety of biological contexts, where similar domains can be found in proteins with different functions. “G,” “C,” “A,” “T”, and “U” each generally stand for a nucleotide that contains guanine, cytosine, adenine, thymidine, and uracil as a base, respectively in the context of a modified or unmodified nucleotide. However, it will be understood that the term “ribonucleotide” or “nucleotide” can also refer to a modified nucleotide, as further detailed below, or a surrogate replacement moiety. As used herein, the term “modified ribonucleotide” refers to a ribonucleotide having, independently, a modified sugar moiety, a modified internucleotide linkage, or a modified nucleobase. Thus, the term modified ribonucleotide encompasses substitutions, additions or removal of, e.g., a functional group or atom, to internucleoside linkages, sugar moieties, or nucleobases of ribonucleotides. The modifications suitable for use in the agents of the disclosure include all types of modifications disclosed herein or known in the art. In certain embodiments, modified ribonucleotides include, without limitation, 2'-O-alkyl-ribonucleotides (e.g., 2'-O- methyl-ribonucleotides), 2'-deoxy-2'-fluoro-ribonucleotides, 2′-O—N-methylacetamido (2′-O- NMA) ribonucleotides, 2′-O-dimethylaminoethoxyethyl (2′-O-DMAEOE) ribonucleotides, 2′-O- aminopropyl (2′-O-AP) ribonucleotides, or 2′-ara-F ribonucleotides. In some embodiments, modified ribonucleotides of the RNA affinity probes (RAPs) or enwrapping RNA affinity probes (WRAPs) of the instant disclosure include 2'-O-methyluridine-3’-phosphate, 2'-deoxy-2'- fluorouridine-3’-phosphate, 2′-O—N-methylacetamidouridine-3’-phosphate, 2′-O- Attorney Docket No.: BN00023.0071 dimethylaminoethoxyethyluridine-3’-phosphate, 2′-O-aminopropyluridine-3’-phosphate, or 2′- ara-fluorouridine-3’-phosphate. In some embodiments of the instant disclosure, the modified ribonucleotides of the RNA affinity probes (RAPs) of the instant disclosure include 2'-O- methyluridine-3’-phosphate. Optionally, the RNA affinity probes (RAPs) of the instant disclosure include 2'-O-methyluridine-3’-phosphate as ribonucleotides within the RAP oligonucleotide (e.g., where every 2`-deoxythymidine-3`-phosphate nucleotide of an input oligodeoxyribonucleic acid aptamer is replaced with a 2'-O-methyluridine-3’-phosphate in the process of forming a RAP, as disclosed herein). In other embodiments of the instant disclosure, the modified ribonucleotides of the enwrapping RNA affinity probes (WRAPs) of the instant disclosure include 2'-O- methyluridine-3’-phosphate. Optionally, the enwrapping RNA affinity probes (WRAPs) of the instant disclosure include 2'-O-methyl-ribonucleotides within the WRAP oligonucleotide (e.g., optionally where every WRAP nucleotide is a 2'-O-methyl-ribonucleotide). Exemplary modified nucleotides that can be used to substitute unmodified nucleotides within the oligonucleotides described herein include, without limitation, 2'-O-alkyl ribonucleotides (e.g., 2'-O-methyl-ribonucleotide, 2'-O-ethyl-ribonucleotide, etc., occurring at one or more positions of an oligoribonucleotide as described herein including, e.g., occurring at all positions of an oligoribonucleotide as described herein), t-butyl benzyl, C5-methyl-dC, C5-ethyl- dC, C5-methyl-dU, C5-ethyl-dU, 2,6-diaminopurine, C5-propynyl-dC, C5-propynyl-dU, C7- propynyl-dA, C7-propynyl-dG, C5-propargylamino-dC, C5-propargylamino-dU, C7- propargylamino-dA, C7-propargylamino-dG, 7-deaza-2-deoxyxanthosine, pyrazolopyrimidine analog, pseudo-dU, nitro pyrrole, nitro indole, 2′-O-methyl ribo-U, 2′-O-methyl ribo-C, N4-ethyl- dC, N6-methyl-dA, 5-propynyl dU, 5-propynyl dC, 7-deaza-deoxyguanosine (deaza G (u-deaza)) and the like. Many other modified nucleotides that can be substituted in the oligonucleotides of the instant disclosure are referred to herein or are otherwise known in the art. In certain embodiments, modified nucleotide substitutions modify melting temperatures (Tm) of the oligonucleotides relative to the melting temperatures of corresponding unmodified oligonucleotides. Other modified nucleotide substitutions may alter the stability of the oligonucleotide, or provide other desirable features. Oligonucleotides having unmodified nucleotides at one or more positions are also expressly contemplated as within the scope of the instant disclosure. Attorney Docket No.: BN00023.0071 As used herein, a “subject” is an animal, such as a mammal, including a primate (such as a human, a non-human primate, e.g., a monkey, and a chimpanzee), or a non-primate (such as a rat, or a mouse). In a preferred embodiment, the subject is a human, such as a human being treated or assessed for a disease, disorder, or condition; a human at risk for a disease, disorder, or condition; a human having a disease, disorder, or condition; or human being treated for a disease, disorder, or condition as described herein. The term “sample,” as used herein, includes (i) a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject, and / or (ii) other fluids or liquified solids, optionally including those found in the food and beverage industry, environmental samples and / or industrial processing fluids.. Examples of biological fluids include blood, serum and serosal fluids, plasma, cerebrospinal fluid, ocular fluids, lymph, urine, saliva, and the like. Tissue samples may include samples from tissues, organs or localized regions. For example, samples may be derived from particular organs, parts of organs, or fluids or cells within those organs. Modified oligonts, where RNA residues are shown, are also contemplated to have between one and all RNA nts be 2'-O-alkyl (e.g., 2'-O-methly) or other substitution, at one or every RNA nt of the oligont. Without limitation, where "U" nts are shown within an oligont, the instant disclosure primarily contemplates an oligont comprising fully RNA nts (optionally substituted with modified RNA nts, e.g., 2'-O-alkyl nts, e.g., 2'-O-methyl nts), unless otherwise indicated. Similarly, where "T" nts are shown within an oligont, the instant disclosure primarily contemplates an oligont comprising fully DNA nts (optionally substituted with modified nts). However, it is also within the scope of the oligonts contemplated herein to have each residue of an oligont of the disclosure be independently a DNA nt or an RNA nt (optionally substituted at each residue), potentially resulting in oligonts that are mixtures of DNA nts and RNA nts, and still be encompassed within the contemplated scope of the respective oligont sequences set forth herein. Attorney Docket No.: BN00023.0071 BRIEF DESCRIPTION OF THE DRAWINGS The following detailed description, given by way of example, but not intended to limit the disclosure solely to the specific embodiments described, may best be understood in conjunction with the accompanying drawings, in which: FIG. 1 shows a predicted two-dimensional folded sequence for the IT2 RAP of SEQ ID NO: 11, which was identified to possess a highly stable ΔG value of -19.80, with ΔH of -168.50, ΔS of -479.45, and Tm= 78.3 °C. FIGs. 2A and 2B show two-dimensional folded sequences for the IT3 RAP and its stem loop structure. FIG. 2A shows a predicted two-dimensional folded sequence for the IT3 RAP of SEQ ID NO: 14, which was identified to possess a highly stable ΔG value of -19.90, with Tmof 66.7 °C. FIG.2B shows the IT3 RAP stem loop formed via addition of the ACAU sequence to the input sequence. FIG. 3 shows a predicted two-dimensional folded sequence for the IT4 RAP of SEQ ID NO: 17, which was identified to possess a ΔG value of -5.34, with Tmof 49.9 °C. FIGs. 4A to 4D show predicted two-dimensional folded sequences for the IT5 RNA- substituted sequence and for the IT5 RAP. FIG. 4A shows the first of two distinct conformations predicted for the IT5 RNA-substituted sequence of SEQ ID NO: 19, which was identified to possess ΔG of -15.40 and Tm of 74.7 °C. FIG.4B shows the second of two distinct conformations predicted for the IT5 RNA-substituted sequence of SEQ ID NO: 19, which was identified to possess ΔG of -14.80 and Tmof 72.2 °C. FIG. 4C shows a predicted two-dimensional folded sequence for the IT5 RAP of SEQ ID NO: 20, which was identified to possess a ΔG value of - 23.10, ΔH of -221.70, ΔS of -640.34 and a Tmof 73.1 °C. FIG. 4D shows a predicted two- dimensional folded sequence for the stem loop of the IT5 RAP of SEQ ID NO: 20, noting that the complementary CCACAUC and GAUGUGG sequences provide a stem loop having ΔG of -9.1, ΔH of -61.2, ΔS of -168.0 and Tmof 48.2 °C. FIGs. 5A and 5B show binding of the IT5 RAP to human Tau protein in buffer solution. FIG. 5A shows that IT5 RAP signal (produced by Tau binding) increased with time and was generated also at very low concentrations of human Tau protein, noting that the observation of two peaks at two different concentrations indicated that conformational changes were likely occurring in the human Tau protein at different concentrations. FIG.5B shows that IT5 RAP signal increased Attorney Docket No.: BN00023.0071 in a buffer solution containing a fixed concentration of human Tau protein, as the concentration of the IT5 RAP increased. FIGs. 6A to 6D show exemplary design iterations for a Tau-binding RNA affinity probe (RAP). FIG.6A shows the predicted two-dimensional structure of a starting structure used to make a Tau-binding RNA affinity probe. The starting structure, having sequence 5'- CAGCACCGUCAACUGAAUGGCGGGGGGUCAGGUCGGGGUAAGGUGAGCGUUUAU GCGAUGGAGAUGU-3' (SEQ ID NO: 21) has a calculated ΔG value of -15.70, ΔH of -148.50, and a ΔS value of -428. Tmof the starting structure is 73.7 °C. For RNA affinity probes (RAPs), fluorophores with < Rospacing are quenched, whereas fluorophores with > 2Rospacing are not quenched. FIG. 6B shows the predicted two-dimensional structure of a first iteration of stem addition made to the aforementioned starting structure, during the process of making a Tau-binding RNA affinity probe. The first iteration structure, having sequence 5'- acaucucCAGCACCGUCAACUGAAUGGCGGGGGGUCAGGUCGGGGUAAGGUGAGCGU UUAUGCGAUGGAGAUGU-3' (SEQ ID NO: 22) has a calculated ΔG value of -25.50, ΔH of - 235.50, and a ΔS value of -677.09. Tmof the first iteration structure is 74.7 °C. FIG.6C shows the predicted two-dimensional structure of a second iteration of stem addition made to the aforementioned starting structure, during the process of making a Tau-binding RNA affinity probe. The second iteration structure, having sequence 5'- acaucuCAGCACCGUCAACUGAAUGGCGGGGGGUCAGGUCGGGGUAAGGUGAGCGU UUAUGCGAUGGAGAUGU-3' (SEQ ID NO: 23) has a calculated ΔG value of -21.70, ΔH of - 217.10, and a ΔS value of -630.02. Tmof the second iteration structure is 71.4 °C. In isolation, in assessing the strength of the 5'-terminal / 3'-terminal stem structure of this third iteration, the isolated stem structure has a calculated ΔG value of -9.1, ΔH of -61.20, and a ΔS value of -168.0. Tmof the isolated second iteration stem structure is 48.2 °C. FIG. 6D shows the predicted two- dimensional structure of a third iteration of stem addition made to the aforementioned starting structure, during the process of making a Tau-binding RNA affinity probe. The third iteration structure, having sequence 5'- acaucCAGCACCGUCAACUGAAUGGCGGGGGGUCAGGUCGGGGUAAGGUGAGCGUU UAUGCGAUGGAGAUGU-3' (SEQ ID NO: 24) has a calculated ΔG value of -21.70, ΔH of - 217.10, and a ΔS value of -630.02. Tmof the second iteration structure is 71.4 °C. In isolation, in assessing the strength of the 5'-terminal / 3'-terminal stem structure of this third iteration, the Attorney Docket No.: BN00023.0071 isolated stem structure has a calculated ΔG value of -0.3, ΔH of -20.2, and a ΔS value of -64.2. Tmof the isolated third iteration stem structure is -96.0 °C. FIG. 7 shows Gibbs free energy values for individual amino acid-nucleic acid binding interactions, which were used in design of WRAPs. FIG. 8 shows a graphic representation of the TDP-43 polypeptide, aligned to TDP-25 and TDP-35 polypeptides, also identifying functional domains and notable individual amino acid residues throughout the protein. FIGs. 9A to 9E show a spreadsheet-based alignment of TDP-43 amino acid residues, with the most negative Gibbs free energy values and / or optimized number of amino acid-nucleotide interactions per nucleotide (or a combination thereof), of corresponding nucleic acids shown. Under any one of the indicated WRAP nucleotide selection methods, each amino acid has a "preferred" nucleotide base to which it will have the highest affinity, expressed via the amount of free energy generated upon a process of associating (which in the realm of hybridization is termed “kissing”), via the number of amino acid-nucleotide interactions, via a combination thereof, or a Gibbs free energy-based assessment of a consensus sequence derived from such sequences. In performing the Gibbs free energy assessment, one couple of potential binding partners is attracted via electrostatic forces and generates free energy. Should neighboring pairs also generate free energy, more and more partners will join in. The process is called “zipping in”. The more energy that is set free, the stronger the binding affinity, and the probe will enwrap the target sequence. The WRAP sequence is thus set solely by determining one or a combination of (i) the nucleic acid with the lowest free energy for each amino acid of a chosen target, (ii) the most number of interactions between accessible amino acid and potentially selected nucleotide, (iii) an optionally weighted combination of (i) and (ii), and / or a consensus sequence derived from the sequences of (i)-(iii), based upon optimizing total Gibbs free energy value across such consensus sequence. The process used for selection of nucleic acids for the exemplified series of TDP-43-binding WRAPs is also shown. The resulting summed ΔG value for the designed WRAPs (based on respective individual nucleotide-amino acid interactions between the designed WRAP oligonucleotide and the accessible amino acids of the N-terminal domain of human TDP-43) are shown. FIG.9A shows the first five amino acids of the N-terminus of TDP-43, water access values of individual amino acid residues, nucleotide interaction Gibbs free energy values, number of interaction values, and calculated combined scores ("based on ΔG x # interactions"), for each nucleotide aligned against Attorney Docket No.: BN00023.0071 each individual amino acid residue, nucleotide selections, and the selected WRAP sequences. FIG. 9B shows amino acids and corresponding values / interacting nucleotide selections for amino acids 6-19 of the N-terminus of TDP-43. FIG. 9C shows amino acids and corresponding values / interacting nucleotide selections for amino acids 20-34 of the N-terminus of TDP-43. FIG. 9D shows amino acids and corresponding values / interacting nucleotide selections for amino acids 35-45 of the N-terminus of TDP-43. FIGs.10A to 10D show designed TDP-43-binding WRAPs of the instant disclosure. FIG. 10A shows a first TDP-43-binding WRAP sequence (5'- GCATGCATGAAAAAGAGAAAGATGAAAAGCATGC-3', SEQ ID NO: 26), designed solely via optimization of Gibbs free energy values during individual nucleotide selection, shown with a nucleotide stem and a single loop region and having ΔG = -6.50, ΔH = -65.40, ΔS = -189.91, and Tm = 71.2°C. FIG. 10B shows a second TDP-43-binding WRAP sequence (5'- GCATGCTCAACGTAAAACAACACCAAAAATGCATGC-3', SEQ ID NO: 27), designed solely via optimization of number of amino acid-nucleotide interactions during individual nucleotide selection, shown in two different stem and loop region conformations (the first conformation, at left, having ΔG = -6.20, ΔH = -63.70, ΔS = -185.39, and Tm = 70.4°C; the second conformation, at right, having ΔG = -6.10, ΔH = -84.70, ΔS = -253.43, and Tm = 61.1°C). FIG. 10C shows a third TDP-43-binding WRAP sequence (5'- GCAUGCAUGAAAAAGUGAUAGAUGUUAAGCAUGC-3', SEQ ID NO: 28), designed via optimization of multiplied Gibbs free energy x number of amino acid-nucleotide interactions during individual nucleotide selection, shown in two different stem and loop region conformations (the first conformation, at left, having ΔG = -8.40, ΔH = -68.70, ΔS = -194.42, and Tm = 80.2°C; the second conformation, at right, having ΔG = -8.40, ΔH = -88.20, ΔS = -257.29, and Tm = 69.7°C). FIG 10D shows a fourth, consensus TDP-43-binding WRAP sequence (5'- GCAUGCAUAAAAUAAAAAAACACUAAAAUGCAUGC-3', SEQ ID NO: 29), designed by optimizing Gibbs free energy values across a consensus of the preceding sequences of FIGs.10A- 10C, shown with a nucleotide stem and a single loop region, having ΔG = -9.00, ΔH = -75.30, ΔS = -213.77, and Tm = 79.1°C. FIGs. 11A and 11B show performance of one of the designed TDP-43-binding WRAP oligonucleotides of the disclosure. Displayed graphs show the kinetics of the respective bindings of the WRAP to recombinant constructs of TDP-43, including: 1) the complete 414 amino acid Attorney Docket No.: BN00023.0071 long protein commercially available from Origene; 2) the recombinant construct covering the N- terminus, RRM1 and RRM2; and 3) the recombinant construct of RRM 1 & 2. Bovine Serum Albumin was used as a control. Ten measurements were taken at 5 min intervals, which showed increase and saturation of the signal. FIG. 11A shows measured fluorescence of the TDP-43- binding WRAP oligonucleotide across a concentration gradient of the N-terminal domain of TDP- 43, in the presence of MgCl2. FIG. 11B shows measured fluorescence of the TDP-43-binding WRAP oligonucleotide across a concentration gradient of the N-terminal domain of TDP-43, in the absence of MgCl2. FIGs.12A to 12X show a spreadsheet-based alignment of TDP-43 amino acid residues for selection of a WRAP oligonucleotide based upon hydrophilicity, charge, and free Gibbs energy values. FIG. 13 shows measured fluorescence of an rTau-binding WRAP oligonucleotide across a dilution series of rTau polypeptide solutions. The present invention is further illustrated by the following detailed description. DETAILED DESCRIPTION OF THE INVENTION The disclosure provides, at least in part, for design and synthesis of macromolecule-binding oligonucleotides possessing improved target macromolecule binding properties, relative to input macromolecule-binding aptamers. Oligonucleotides of the disclosure specifically possess enhanced binding capabilities (binding affinity, disassociation rate, etc.) and / or when such oligonucleotides are labeled with fluorophores and respective quenchers at the 5’ and 3’terminal nucleotides, provide immediate signal generation on binding, even in crude samples (therefore requiring no washing steps), thereby rendering, e.g., an attractive probe molecule for diagnostic use. The present disclosure therefore provides methods for making and using enhanced probe oligonucleotides, while also providing a series of human Tau protein-binding probe compositions, as well as human TDP-43 protein-binding probe compositions, including associated arrays, kits and diagnostic applications of such probes. The following detailed description discloses how to make and use compositions containing improved protein-binding oligonucleotides, including DNA aptamer-derived compositions including 2’O-methyl RNA that are macromolecule-binding oligonucleotides (RAPs), as well as de novo directedly designed protein-binding modified oligoribonucleotides that possess high Attorney Docket No.: BN00023.0071 affinity for a targeted protein and are modeled to wrap around (enwrap) a targeted protein via a series of individual amino acid-nucleotide interactions. Such directedly designed oligoribonucleotides are, in certain embodiments, optimized by design for the Gibbs free energy value of interaction of each target polypeptide amino acid with a nucleotide to achieve the interaction(s) possessing the most negative free energy. In other embodiments, selection of individual WRAP nucleotides is directed by optimizing numbers of amino acid-nucleotide interactions, optionally in combination with optimizing Gibbs free energy values (e.g., by employing multiplicative, optionally weighted scoring, during such nucleotide selection processes). By any such approach, the target polypeptide amino acid sequence therefore effectively pre-determines the nucleotide sequence. Such directedly designed protein-binding oligoribonucleotides are referred to herein as "EnWrapping RNA Affinity Probes" or "WRAPs". As disclosed herein, both RNA Affinity Probes (RAPs) and WRAPs are primarily employed as molecular diagnostic probes for assessment of, e.g., disease-related biomarkers (particularly of neurodegenerative disease, such as Tauopathies and / or TDP-43 proteinopathies), though other applications, including therapeutic applications, are also contemplated for both the RAPs and WRAPs disclosed herein. Specifically exemplified are RAP-probes binding to human Tau. Probes of the disclosure can be employed for precise measurement of human Tau and / or phosphorylated / non-phosphorylated forms of human Tau, for assessment as a biomarker of neurodegenerative diseases (including, e.g., Alzheimer's Disease). Similarly, specifically exemplified human TDP-43 bespoke-designed protein-binding oligonucleotide probes (WRAPs) of the disclosure can be employed for precise measurement of human TDP-43 protein, as well as potentially for therapeutic use against TDP-43 proteinopathies (as a strong binder of TDP-43 protein). Wrapping RNA Affinity Probes (WRAPs) of the instant disclosure are produced by an approach that is based on the use of proven affinities between biological components to monitor cellular component interactions in vivo or in vitro. WRAPs of the disclosure specifically provide homogeneous test systems that generate signals without (or with minimal) sample preparation (i.e. in crude samples). State-of-the-art signaling techniques can also be employed for the WRAPs of the instant disclosure, to achieve the highest possible sensitivity. It is further contemplated that the currently disclosed WRAP approaches might also be applied to design oligonucleotides capable of Attorney Docket No.: BN00023.0071 binding toxins, non-immunogenic compounds, synthetic macromolecules, etc., as well as assays (e.g., detection assays) associated with such WRAP compositions. The WRAP design process and the exemplary WRAPs disclosed herein advantageously overcome a number of known limitations with antibody-mediated binding of target proteins. For antibodies, a vertebrate immune-system needs to detect a chosen target as antigen to elicit an antibody response. The antigen then needs to be presented appropriately via adjuvants. Adjuvants need to be selected to generate a competent immune response. Both adjuvant and antigen need to be non-toxic to the host. Polyclonal antibodies may have cross-(mixed) reactivity with related proteins. Monoclonal antibodies would generally be preferred, but at times are too specific and can be more difficult / expensive to create, which explains the continued use of polyclonal antibodies in the field. In addition, the respective affinities of antibodies can vary from batch to batch, with each batch of polyclonal antibodies often needing to pass ethical committee approval. Most antibodies are also too large to pass through cellular walls, and many applications of interest that use probes need to detect intra-cellular components. Finally, selected therapeutic antibodies must not elicit a response to themselves. Antibodies also exhibit certain pharmacokinetic delivery problems, which has promoted identification in the art and advancement herein of peptide-binding oligonucleotide design and use. Antibodies specifically commonly encounter the following: slow elimination of monoclonal antibodies from the blood and poor vascular permeability; low and heterogeneous tumour uptake; cross-reactivity with normal tissues; metabolism of monoclonal antibody conjugates; and immunogenicity of murine (or other host) forms in humans. Notably, RNA vaccine technology appears to have overcome the above-described antibody problems. As an alternative to the use of antibodies as targeted protein binding agents, oligonucleotide-based aptamers possess certain properties that tend to make them a viable alternative to antibodies. Aptamers specifically are stable DNA or RNA ligands that bind with high affinity and specificity to targets such as small molecules, peptides, proteins, cells, and tissues. Aptamer products as disclosed herein can be used as research reagents, diagnostics, biosensors, and tools for biomarker or drug discovery, as well as potentially for therapeutics. Aptamers can even be constructed for targets that would otherwise kill a host before any immune response occurred, and can specifically be used for bio-industrial applications and targeted therapeutics. Examples of such other uses that are viable for oligonucleotides that can bind a target Attorney Docket No.: BN00023.0071 with high affinity include, without limitation, endo or exotoxin detection, acting as a therapeutic antitoxin, and acting as a therapeutic antivenom. Also to an aptamer's advantage, aptamers tend to be synthesized chemically, with high reproducibility and at low cost. Traditional aptamers include oligonucleotides that form flexible tRNA-like structures, i.e. they carry multiple stem and loop regions. Single-stranded RNA oligonucleotides can interact with other homogeneous or heterogeneous nucleic acids and form “pseudoknots”, which support secondary structures and in turn present them to interact with targets of choice. The range of viable aptamer targets is very broad: aptamers may interact with all charged or uncharged small active compounds or with sections of large proteins, and single-stranded nucleic acids may interact with polar and / or non-polar amino acids, peptides and / or proteins. Historically, aptamers have been obtained using the Selex aptamer production process, which involves random selection of target peptide-binding oligonucleotides from approximately 1014randomly synthesised oligonucleotides. While 1014seemingly represents a large proportion of compound space for an oligonucleotide, this is actually by definition a severe limitation of the known aptamer selection process. Specifically, synthetic oligonucleotides may be >120 nucleotides long, thereby enabling in excess of 10120different sequence options. The directed / cognate "WRAP" approach to aptamer sequence design / selection disclosed herein removes the above-stated limitations of traditional aptamer sequence selection, thereby revealing a wide array of options. The current WRAP approach specifically takes the protein sequence of a target peptide as determinative for generating a corresponding WRAP sequence capable of high affinity target binding. Specifically, the free energy in the interaction of a nucleotide with an amino acid is quantifiable and provides preferences for selection of specific oligonucleotide residues where such residues are predicted to interact with targeted polypeptide amino acids. In the instant WRAP approach, a multiplicity of amino acids (provided by the target polypeptide sequence) and associated selected nucleotides (chosen on the basis of Gibbs free energy values of amino acid residue–nucleotide residue interactions, or by optimizing numbers of amino acid-nucleotide interactions for each selected nucleotide, or by a combination of both, or by deriving a consensus sequence from such initially designed sequences) provide high specificity for target polypeptide binding, that is not limited to a pre-constructed 1014sequences. In fact, the >10120sequence options provided by a polypeptide of significant length, begin to provide sufficient Attorney Docket No.: BN00023.0071 choice to cover any amino-acid sequence, including all post-translational modifications of such polypeptides. The WRAP cognitive selection technique specifically involves identifying a nucleic acid sequence that is complementary to a target (amino acid) sequence, with exemplary iterations of the instant approach involving: design of oligonucleotide probes in analogy to the design of probes for in situ hybridization (ISH); and design of oligonucleotide probes via a cognitive selection of nucleic acid sequences defined by the respective target (e.g., small molecules, peptides, proteins). WRAP oligonucleotides of the instant disclosure can be designed to enwrap a selected part of a target with a complementary, highly selective nucleic acid sequence (oligonucleotide). It is further contemplated that small molecules and macro-molecules may also be enwrapped by a nucleotide sequence that is complementary to charge and / or polarity of such small molecules. Advantages of the currently disclosed WRAP cognitive selection process include, without limitation, elimination of the random selective process used in the Selex evolutionary process of producing aptamers. In addition, the current WRAP cognitive selection process elevates aptamer technology to a level where WRAP design can potentially access new aptamer sequences, with the potential for creating a target polypeptide-binding oligonucleotide that is significantly more specific to the target in its structures / forms, than polypeptide-binding moieties obtained by other processes. The WRAP cognitive selection technique for identifying a nucleic acid sequence complementary to a target (amino acid) sequence therefore involves utilizing teachings from (t)RNA secondary and tertiary structures and respective protein interactions to find motifs in protein structures that can be targeted by a corresponding WRAP oligonucleotide. WRAP design uses a process analogous to DNA / RNA in-situ hybridization (ISH) probe design techniques, where the (nucleic acid) target is substituted / exchanged by peptide, protein sequence or characteristics of small molecules. WRAP oligonucleotides are then designed to wrap around a motif. Other advantages of the current WRAP design approach include, without limitation, the fact that the WRAP process enables the installation of preserved motifs together with Fluorophore / quenchers using “molecular beacon” technology (as exemplified elsewhere herein); the fact that WRAP enables simple and easy design of a homogeneous assay for small pharmaceutically active compounds; and the fact that WRAP enables simple and easy design of a homogeneous assay for viral proteins (especially in combination with TIP). Attorney Docket No.: BN00023.0071 The currently disclosed WRAP process for peptide-binding oligonucleotide design at core derives from the observation that there are known, previously described interactions between nucleotides and amino acids, as disclosed and tabulated in Hoffman et al. Nucleic Acids Research Vol. 32, Database Issue, AANT: the Amino Acid±Nucleotide Interaction Database. DOI: 10.1093 / nar / gkh128. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of “or” means “and / or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose. Aptamer Selection Candidate input aptamers for the "RAP" approach described herein can be obtained from any source, including, e.g., publications, with selection of specific input aptamers for further development as RAPs involving entry of candidate input aptamer sequences into the Quickfold program (available at www.unafold.org), and DNA-secondary structure(s) prediction. Such prediction of secondary structure tends to result in a multiplicity of conformation options, with very little difference in their respective free energies of internal folding. The multitude of secondary structures reflect the intrinsic instability of most DNA aptamers. Usually, only one or two of the structural options deliver what could resemble a motif. A motif calls for several coaxially stacked stem structures, in which a number of base pairs in a quasi-continuous helix ranging between 11 - 14 base pairs is found. Motifs actively orient a loop or single-strand sequences towards a potential target. In general, single-stranded loop regions may base-pair with nucleotides outside of that loop or find structural options in proteins. These single strands in turn are able to form pseudoknots with other single stranded Attorney Docket No.: BN00023.0071 sequences with close proximity and force a specific three-dimensional structure. Such structures were found in tRNA-like structures that were required for the aminoacylation of viral RNA and functional tRNA (Mans et al. Eur. J. Biochem.201: 303-324). Mans et al. described in detail the structure and function of tRNA with respect to the requirements in conjunction with aminoacylation of RNA and binding to specific enzymes involved in the translational process. However, these teachings did not anticipate the application of these structural principles to find RNA structures with affinities to other protein structures. It was therefore surprising to find that the application of these principles could be successfully applied, with high probability of success, to the development of RNA-substituted sequences possessing specific and high affinity to designated proteins. Adapting and applying principles such as those described in Mans et al. Eur. J. Biochem. 201: 303-324, DNA aptamer sequences are selected based upon their structural features and then used to construct RNA affinity probes. For purpose of RNA affinity probe production, it has been discovered herein that an ideal motif displays 2 to 3 single stranded loops in close vicinity interspersed with the coaxially stacked stem regions forming helical structures. For the current process, the first step is effectively to transform this sequence from DNA to RNA (replacing "T" residues with "2'-O-methyl-U" residues) and to determine its secondary structure using Quickfold. Usually, there are only 1 or 2 stable conformation options. A candidate for an affinity probe is thereby selected and then either the 5’ or 3’ ends are supplemented to form a stable stem structure under physiological conditions. The free energy of the stem sequence alone has been discovered herein to need to be around -10kcal / mol, and stem sequences need to be carefully constructed to achieve this value with minimal base-pairs. These values are determined using the “two state” algorithms on the mfold server (www.bioinfo.rpi.edu / applications / mfold). Synthesis of RAPs RAPs and WRAPs as disclosed herein can be synthesized by any art-recognized means for synthesis of extended, RNA residue-containing oligonucleotide synthesis. In certain embodiments, click chemistry is used to provide oligonucleotides of sufficient quantity and quality for use in the current applications (refer to “A Hitchhiker’s Guide to Click-Chemistry with Nucleic Acids”; Nicolò Zuin Fantoni, Afaf H. El-Sagheer, and Tom Brown; Chemical Reviews 2021121 (12): 7122-7154). Attorney Docket No.: BN00023.0071 While certain exemplified RNA affinity probes of the instant disclosure are prepared to include 2'-O-methyluridine-3’-phosphate, it is contemplated that in certain cases, substitution of a 2`-deoxythymidine-3`-phosphate nucleotide residue of a DNA aptamer might also be performed with another modified RNA residue, including, e.g., other forms of 2'-O-alkyluridine-3'-phosphate (e.g., 2'-O-ethyluridine-3'-phosphate); however, as exemplified herein, use of 2'-O-methyluridine- 3’-phosphate for substitution is preferred to achieve successful target protein binding. Indeed, it is contemplated to synthesize oligo-ribonucleotides solely with 2’-O-methyl-ribonucleotides, or other 2’-O-modifications with the advantage of being resistant to endonucleases. Fluorescent Moieties and Paired Quenchers Electronic energy transfer (EET), Förster (fluorescence) resonance energy transfer (FRET), or resonance energy transfer (RET), is a mechanism describing energy transfer between two chromophores - an excitation chromophore and an acceptor / quencher. An excitation chromophore, also often referred to as donor or donor chromophore, initially in its electronic excited state, may transfer energy to an acceptor chromophore, through non-radiative dipole-dipole coupling. A quencher is a chromophore of which the absorption spectrum overlaps with the emission spectrum of a pairing excitation chromophore. The overall process of excitation, transfer to a second chromophore is called electronic energy transfer (EET) or Förster (fluorescence) resonance energy transfer (FRET). In particular, when an excitation chromophore is excited at a particular wavelength, it is then promoted to an excited state. In the absence of a quencher, the excited chromophore emits light in returning to the ground state. If a quencher chromophore is in the vicinity of an excitation chromophore, then the excited chromophore can return to the ground state by transferring its energy to the quencher, without the emission of light, while the quencher is promoted to its excited state. The excited quencher will later return to the ground state via non-radiative decay pathways, without the emission of light. As such, EET / FRET depends on the ability of the excitation chromophore to transfer energy to the quencher. The efficiency of the energy transfer between an excitation chromophore and a quencher chromophore is inversely proportional to the sixth power of the distance between the two chromophores, which makes FRET highly sensitive to small changes in distance on the level of nanometers. Thus, measurements of FRET efficiency can be Attorney Docket No.: BN00023.0071 used to determine if (donor) chromophore and acceptor are within a certain distance from each other, typically in the range of 1-10 nm. As a powerful tool in molecular biology, EET is frequently used to characterize molecular dynamics in biophysics and biochemistry, especially molecular interaction such as RNA-RNA, DNA-DNA interactions, RNA-protein, DNA-protein interactions, and protein-protein interactions. Oftentimes, various molecules or components within a molecule are labeled chromophores to monitor intermolecular formation of a complex or intra-molecular conformational changes, as reflected by changes in distance between the excitation and the acceptor chromophores. EET in the art-recognized molecular probe assays referred to as TaqMan® assays relies on the utilization of double-labeled TaqMan® probes, which are disclosed in the patents US 5,210,015 and US 5,487,972. Double-labeled TaqMan® probes carry two chromophores on a probe comprising an oligonucleotide sequence that hybridizes to a target nucleic acid. The excitation chromophore is located at the 5’ end, the quencher chromophore at the 3’ end. In certain embodiments, a Lanthanide, optionally Europium, is chelated to a nucleic acid. This allows the setup of time resolved fluorescence (TRF) in combination with FRET (TRF-FRET) and “molecular beacon” technology in a way that the 5’-terminus of a RAP sequence carries a Lanthanide as donor and the 3’-terminus carries a quencher of the Lanthanide emission. Optionally, the quencher is a heat-radiating quencher, such as but not limited to BMN-Q620. As would be clear to one of ordinary skill in the art, it is expressly contemplated that switching of donor and quencher positioning between 3’ and 5’ ends would in principle generate the same result. Upon binding of the RAP to a protein, the RAP will unfold and form a dimer with the protein. The unfolding will separate the quencher from the fluor (e.g., Europium) and only the unfolded probe bound to the protein will emit visible fluorescent energy. The combination of TRF-FRET and the quenching modulation QM (TRF-FRET-QM) allows the set-up of a homogeneous assay for blood or body-fluid based samples with high autofluorescence, without sample purification. As an example, a TRF-FRET-based assay for TDP-43 in serum has recently been established, which called for an extension of the delayed reading from 60 µseconds to 500µs. Although the TDP-43 assay is not a RAP assay, the same principles are likely to be applicable to a RAP. Attorney Docket No.: BN00023.0071 Some of the well-known commercially available excitation chromophores for EET techniques include but are not limited to: 5- or 6-carboxyfluorescein (FAM™), VIC™, NED™, fluorescein, fluorescein isothiocyanate (FITC), IRDYE-700 / 800, cyanine dyes, such as CY3™, CY5™, CY3.5™, CY5.5™, Cy7™, xanthen, 6-carboxy-2',4',7',4,7- hexachlorofluorescein (HEX), 6-carboxy-l,4-dichloro-2',7'-dichloro-fluorescein (TET®), 6- carboxy-4',5'-dichloro-2',7'- dimethodyfluorescein (JOE™), N,N,N',N'-tetramethyl-6- carboxyrhodamine (TAMRA™), 6- carboxy-X-rhodamine (ROX), 5-carboxyrhodamine-6G (R6G5), 6-carboxyrhodamine-6G (RG6), rhodamine, rhodamine green, rhodamine red, rhodamine 110, Rhodamin 6G®, BODIPY dyes, such as BODIPY TMR, Oregon green, coumarines, such as umbelliferone, benzimides, such as Hoechst 33258; phenanthridines, such as Texas Red®, California Red®, Yakima Yellow, Alexa Fluor® 350, Alexa Fluor® 405, Alexa Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 500, Alexa Fluor® 514, Alexa Fluor®532, Alexa Fluor® 546, Alexa Fluor® 555, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 610, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Fluor® 680, Alexa Fluor® 700, Alexa Fluor® 750, PET®, ethidium bromide, acridinium dyes, carbazol dyes, phenoxazine dyes, porphyrine dyes, polymethin dyes, Atto 390, Atto 425, Atto 465, Atto 488, Atto 495, Atto 520, Atto 532, Atto 550, Atto 565, Atto 590, Atto 594, Atto 620, Atto 633, Atto 647N, Atto 655, Atto Rho6G, Atto Rho11, Atto Rho12, Atto Rho101, BMN™-5, BMN™-6, BMN™ Q620, CEQ8000 D2, CEQ8000 D3, CEQ8000 D4, DY-480XL, DY-485XL, DY-495, DY-505, DY-510XL, DY-521XL, DY-521XL, DY-530, DY-547, DY-550, DY- 555, DY-610, DY-615, DY-630, DY-631, DY-633, DY-635, DY-647, DY-651, DY-675, DY-676, DY- 680, DY-681, DY-700, DY-701, DY-730, DY-731, DY-732, DY-750, DY-751, DY-776, DY-780, DY-781, DY-782, 6-carboxy-4',5'-dichloro-2',7'-dimethoxyfluorescein (JOE), TET™, CAL Fluor® Gold 540, CAL Fluor RED 590, CAL Fluor Red 610, CAL Fluor Red 635, IRDye® 700Dx, IRDye® 800CW, Marina Blue®, Pacific Blue®, Yakima Yellow®, 6-(4,7-Dichloro-2',7'- diphenyl-3',6'-dipivaloylfluorescein-6-carboxamido)-hexyl-l-0-(2-cyanoethyl)-(N,N- diisopropyl)-phosphoramidite (SIMA), CAL Fluor® Gold 540, CAL Fluor® Orange 560, CAL Fluor Red 635, Quasar 570, Quasar 670, LIZ, Sunnyvale Red, LC Red® 610, LC Red® 640, LC Red® 670, and LC Red® 705. Well-known commercially available non-fluorescent quenchers include but not are limited to, Black Hole Quencher® (BHQ®), DQ, dimethylaminoazobenzenesulfonic acid (DABCYL), Iowa Black® (IWB), and TAMRA. Further discussion of these molecules is provided by Attorney Docket No.: BN00023.0071 Johansson, M. K, et al, J. Am. Chem., Soc., (2002). These and similar non-fluorescent quenchers improve the sensitivity of probes by suppressing background fluorescence, thereby increasing the signal gain following enzymatic cleavage of the probe. In certain applications, such as time-resolved fluorometry (TRF), lanthanides can be employed. TRF combined with fluorescence resonance energy transfer (FRET) offers a powerful tool: Time-Resolved Fluorescence Resonance Energy Transfer or TR-FRET. TR-FRET combines the low background aspect of TRF with the homogeneous assay format of FRET. The resulting assay provides an increase in flexibility, reliability and sensitivity in addition to higher throughput and fewer false positive / false negative results. This method involves two fluorophores: a donor and an acceptor. Excitation of the donor fluorophore (in this case, the lanthanide ion complex) by an energy source (e.g., flash lamp or laser) produces an energy transfer to the acceptor fluorophore if they are within a given proximity to each other (known as the Förster's radius). The acceptor fluorophore in turn emits light at its characteristic wavelength. Lanthanides are the members of the 15 naturally occurring metallic chemical elements, whose atomic numbers fall between 57 (Lanthanum) and 71 (Lutetium). These elements have their 4f sublevel filled. The specific lanthanides are lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium and lutetium. The two most commonly used lanthanides in life science assays are europium and terbium, often paired with respective acceptor molecules of allophycocyanin and phycoerythrin. It is known to those of skill in the art that, for FRET to occur, the emission spectrum of the excitation chromophore and the absorption spectrum of the quencher chromophore typically need to overlap. And such a person is able to ascertain suitable combinations of an excitation chromophore and a quencher. Examples of some of the commonly used paring chromophores for EET-based techniques include but are not limited to: FAM / TAMRA, VIC / BHQl, HEX / BHQ2, Cy3 / BHQ1, Cy5 / BHQ1, and TET / DHQ and the like. Examples of guidelines and protocols of selecting suitable chromophores combinations and making necessary adjustments include Lee et al. (New energy transfer dyes for DNA sequencing Nucleic Acids Research 25:2816) and Bajar et al. (A Guide to Fluorescent Protein FRET Pairs Sensors (Basel, Switzerland) vol. 16,91488). It will be readily apparent to those of ordinary skill in the art in light of the teachings herein that Attorney Docket No.: BN00023.0071 certain changes and modifications may be made thereto without departing from the spirit and scope of the disclosure. Prediction of RAP Target Protein Binding Capabilities Predicted RAP target protein binding capability is assessed by entering a candidate RAP sequence into a RPISeq database (pridb.gdcb.iastate.edu / RPISeq), with the site then used to calculate the probability of the respective 3D-stuctures binding target protein. The probability value is given between 0 and 1. Good input DNA aptamers tend to achieve a value just under 0.5. Without wishing to be bound by theory, preferred RAPs achieve values around 0.6. RAP values are not higher, apparently attributable to the limitations of the algorithm. Notably, the algorithm is currently based upon the 3D structure of some 100 proteins, with the algorithm reasonably expected to improve as additional elements are added to the database. RAP Target Proteins It is contemplated that RAPs can be designed and used to detect and / or measure levels of any macromolecule to which a DNA aptamer has been selected to bind, including, e.g., any protein of potential future diagnostic or therapeutic value. In certain exemplified aspects of the current disclosure, wherein the target polypeptide is human Tau. Certain preferred groups of proteins for RAP design include “prion-like” proteins, which can be used, e.g., as biomarker for neurodegenerative diseases. "Prion-like" proteins specifically include TDP-43, Tau, beta- amyloids, alpha-synuclein, optineurin, prion protein (PrP), and other proteins with prion-like domains involved in liquid-liquid phase separation. (see Louka et al. NAR 48: 11880-11889; doi:10.1093 / nar / gkaa822). Such "prion-like" proteins are proteins capable of aggregation and forming prion-like structures widely regarded as harmful in playing a pathogenic role in neurodegenerative diseases. While the principles of RAP design and implementation disclosed herein may be applied to any protein of diagnostic value, exemplary neurodegenerative disease - associated RAP targets are listed in Table 1 below. Attorney Docket No.: BN00023.0071 Table 1. RAP / WRAP Targeting of Select Neurodegenerative Diseases Disease Main neuropathology Protein Main anatomic vulnerability aggregate(s) Amyloidoses Creutzfeldt–Jakob disease (genetic, Spongiform changes PrP Cerebral cortex variant, sporadic, iatrogenic) Prion protein (PrP) Neostriatum accumulation Thalamus Cerebellum Gerstmann–Sträussler–Scheinker disease Spongiform change PrP Cerebral cortex Multicentric PrP Cerebellum plaques Familial British dementia Amyloid angiopathy ABRI Cerebral cortex Parenchymal amyloid Cerebellum plaques Alzheimer’s disease Neurofibrillary tangles Aβ Basal forebrain (NFTs) Neuropil threads 3R + 4R Tau Frontal and temporal lobes Neuritic and amyloid Limbic structures plaques Amyloid angiopathy Locus coeruleus Olfactory bulb Tauopathies Chronic traumatic encephalopathy Astrocytic Tau tangles 3R + 4R Tau Frontal, temporal, and parietal Neuropil threads lobesDepth of sulci and NFTs surrounding vasculature Primary age-related Tauopathy NFTs 3R + 4R Tau Basal forebrain Brainstem Medial temporal lobe Olfactory bulb Pick’s disease Pick bodies 3R Tau Basal forebrain

[0002] Attorney Docket No.: BN00023.0071 Pick cells / ballooned Frontal and temporal lobes neurons Limbic structures Striatum Progressive supranuclear palsy Globose NFTs 4R Tau Subthalamic nucleus Tufted astrocytes Substantia nigra Oligodendroglial coiled Superior colliculus bodies Neuropil threads Cerebellar dentate Corticobasal degeneration Pretangles 4R Tau Frontoparietal association cortices Astrocytic plaques Neostriatum Neuropil threads Substantia nigra Ballooned neurons Argyrophilic grain disease Argyrophilic grains 4R Tau Limbic structures Ballooned neurons Coiled bodies Ramified astrocytes Aging-related Tau astrogliopathy Thorn-shaped 4R Tau Subpial and perivascular astrocytes spaces Granular astrocytes Mediobasal forebrain Amygdala Synucleinopathies Lewy body disorders Lewy bodies α-Synuclein Amygdala Lewy neurites Cerebral cortex Dorsal motor nucleus Hippocampus (CA2) Locus coeruleus Olfactory bulb Substantia nigra Multiple system atrophy Glial cytoplasmic α-Synuclein Putamen inclusions Substantia nigra

[0003] Attorney Docket No.: BN00023.0071 Pontine nuclei Medulla (inferior olivary nucleus) Cerebellum TDP-43 Proteinopathies Frontotemporal lobar degeneration Neuronal cytoplasmic TDP-43 Frontal and temporal cortices inclusions Neuronal nuclear Basal ganglia inclusions Dystrophic neurites Substantia nigra Amyotrophic lateral sclerosis Upper and lower motor TDP-43 Motor cortex neuron loss Bunina bodies Brainstem motor neurons Neuronal inclusions Spinal cord motor neurons Astrocytic hyaline inclusions Primary lateral sclerosis Upper motor neuron TDP-43 Motor cortex loss Corticospinal tract Corticospinal tracts degeneration Progressive muscular atrophy Lower motor neuron TDP-43 Brainstem motor neurons loss Swollen motor neurons Spinal cord motor neurons

[0004] Attorney Docket No.: BN00023.0071 WRAP Design Wrapping RNA Affinity Probe (WRAP) design as disclosed herein is performed using a set of tools based on nucleic acid structural “base and base pair” features. Structural features of oligonucleotides are used to position pseudoknots or present an amino acids sequence towards a peptide / protein: • Helical sense right-handed • Rotation 34.3° • Base pairs per helical turn 11 • Inclination of base pairs with respect to axis 19° • Rise / bp along axis 0.23 Å (2.83nm) • Pitch / turn of helix 28.2 Å • Sugar pucker C3’endo • Diameter 23 Å (2.3nm) Complementary components during WRAP design are the amino acids of a target polypeptide. The WRAP design process is specifically exemplified below. Target Protein Binding Assays Affinity probe-based assays are designed to be applicable in both in vitro and in situ environments. The in vitro application of RAPs (and WRAPs) disclosed herein allows for detection and quantification of proteins in body fluids such as serum, CSF, aspirates, biopsies and other body fluids, performed optionally in microtiter format. The simplicity of the assays is achieved by designing them to be intrinsically homogeneous. Samples and the RAPs / WRAPs are brought together in a defined salt and buffer environment, incubated at tightly controlled temperatures and measured directly in one step. Nucleic acid- protein interactions are highly dependent upon pH and salt interactions and therefore such conditions are expected to have a pivotal impact on the functioning of the affinity probes disclosed herein (Goh et al. Journal of Chemical Theory and Computation. 8: 36-46; Pullman, A., & Pullman, B. (1981). Molecular electrostatic potential of the nucleic acids. Attorney Docket No.: BN00023.0071 Quarterly Reviews of Biophysics. 14: 289-380). pH values for the assays disclosed herein have been selected to deprotonate nucleotide bases and corresponding amino acids, thereby favoring specific hydrogen bonding between nucleic acids and proteins. Typically, selected pH values are between pH 7 and pH 9.5. More favored pH values are between pH 8 and pH 9. In certain embodiments, the selected pH is between pH 8.3 and pH 8.5. Salt and magnesium concentrations are preferably set at physiological conditions. These mild conditions are chosen to avoid conformational changes of respective proteins due to denaturing compounds or solvents and under standard conditions, to avoid competing with hydrogen bonding in the broadest sense. However, for certain assays investigating prion-like proteins it is contemplated that it might be advantageous to add denaturing salts (e.g., high molar urea or guanidine hydrochloride) to specifically modulate three dimensional structures or aggregations. For non-denaturing assays, the sum of the ionic strengths of the components is also designed to be near physiological conditions, ranging between about 120 and about 215mM. Optionally, the combined ionic strength is targeted to about 140mM to about 170mM. In certain embodiments, the ionic strength is between about 145 and about 155mM. Body fluids also contain inherent buffer concentrations. In certain embodiments, buffer concentrations are chosen to be between about 10mM and about 50mM. Optionally, buffer concentration is between about 15mM and about 30mM. In some embodiments, buffer concentration is about 20mM. Exemplary buffers are shown in Table 2, noting primarily variations in pH and denaturing agents. Table 2. Buffer Solutions for Protein Binding Assays Buffer B pH7.5 50ml Final Molarity Tris-HCL 1M pH 7.5 1mL 20mM MgCl2100mM 2.5mL 5mM NaCl 5M 2.15mL 215mM Buffer water 44.35mL N / A Buffer D pH7.5 50ml Final Molarity Tris 1M pH 7.5 1mL 20mM MgCl2100mM 2.5mL 5mM NaCl 5M 2.15mL 215mM Urea 8M 25mL 4M Attorney Docket No.: BN00023.0071 Buffer water 19.35mL N / A Buffer E pH7.5 50ml Final Molarity Tris 1M pH 7.5 1mL 20mM MgCl2100mM 2.5mL 5mM NaCl 5M 2.15mL 215mM Guanidine HCl 8M 25mL 4M Buffer water 19.35mL N / A Buffer B pH 8.3 50ml Final Molarity Tris-HCl 1M pH 8.3 1mL 20mM MgCl2100mM 2.5mL 5mM NaCl 5M 2.15mL 215mM Buffer water 44.35mL N / A Buffer D pH 8.3 50ml Final Molarity Tris-HCl 1M pH 8.3 1mL 20mM MgCl2100mM 2.5mL 5mM NaCl 5M 2.15mL 215mM Urea 8M 25mL 4M Buffer water 19.35mL N / A Buffer E pH 8.3 50ml Final Molarity Tris-HCl 1M pH 8.3 1mL 20mM MgCl2100mM 2.5mL 5mM NaCl 5M 2.15mL 215mM Guanidine HCl 8M 25mL 4M Buffer water 19.35mL N / A The above-described identification of nucleic acid-peptide interactions functioning best in conditions of deprotonating pH unexpectedly aided the transition of the current oligonucleotide- Attorney Docket No.: BN00023.0071 peptide interaction assays from in situ hybridization conditions to an assay in microtiter format. The microtiter format specifically encompasses not only the above-noted salt and pH conditions (see Table 2 above) but also features temperature control. Such conditions are important to establish and measure for nucleic acid–protein interaction assays, such as those for the affinity probes of the instant disclosure and for aptamers in microtiter format, as rigorous control of the temperature of such assays, even beyond standard temperature control specifications, can be advantageous. In the microtiter format, temperature control can be achieved by adding an additional heat plate below the microtiter plate and sealing each microtiter well with a non- fluorescent polymer thermal seal (e.g., ThermalSeal RTSTM, Excel Scientific Inc. USA). The thermal seal ensures that there is no fluctuation in temperature due to evaporation. Moreover, the sealing also eliminates changes in molar concentrations of respective components within the well due to evaporation during incubation and measurement. The combination of such measures thereby allows for rigorous control of reaction conditions within each plate that makes performance of nucleic acid-protein assays in microtiter format advantageous. Affinity Probe-Mediated Target Protein Detection in Samples Investigation of unknown clinical samples with affinity probes of the instant disclosure is performed similar to immune assays that are well known in the art. E.g., standardized concentrations of pure recombinant proteins, both in a synthetic and matrix-based environment, are used to create a standard curve, which enables the determination of concentrations of targeted proteins (and / or peptide subdomains thereof) in clinical samples. The practice of the present disclosure employs, unless otherwise indicated, conventional techniques of chemistry, molecular biology, microbiology, recombinant DNA, genetics, immunology, cell biology, cell culture and transgenic biology, which are within the skill of the art. See, e.g., Maniatis et al., 1982, Molecular Cloning (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.); Sambrook et al., 1989, Molecular Cloning, 2nd Ed. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.); Sambrook and Russell, 2001, Molecular Cloning, 3rd Ed. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.); Ausubel et al., 1992), Current Protocols in Molecular Biology (John Wiley & Sons, including periodic updates); Glover, 1985, DNA Cloning (IRL Press, Oxford); Anand, 1992; Guthrie and Fink, 1991; Harlow and Lane, 1988, Antibodies, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.); Jakoby and Attorney Docket No.: BN00023.0071 Pastan, 1979; Nucleic Acid Hybridization (B. D. Hames & S. J. Higgins eds.1984); Transcription And Translation (B. D. Hames & S. J. Higgins eds.1984); Culture Of Animal Cells (R. I. Freshney, Alan R. Liss, Inc., 1987); Immobilized Cells And Enzymes (IRL Press, 1986); B. Perbal, A Practical Guide To Molecular Cloning (1984); the treatise, Methods In Enzymology (Academic Press, Inc., N.Y.); Gene Transfer Vectors For Mammalian Cells (J. H. Miller and M. P. Calos eds., 1987, Cold Spring Harbor Laboratory); Methods In Enzymology, Vols. 154 and 155 (Wu et al. eds.), Immunochemical Methods In Cell And Molecular Biology (Mayer and Walker, eds., Academic Press, London, 1987); Handbook Of Experimental Immunology, Volumes I- IV (D. M. Weir and C. C. Blackwell, eds., 1986); Riott, Essential Immunology, 6th Edition, Blackwell Scientific Publications, Oxford, 1988; Hogan et al., Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986); Westerfield, M., The zebrafish book. A guide for the laboratory use of zebrafish (Danio rerio), (4th Ed., Univ. of Oregon Press, Eugene, 2000). Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Reference will now be made in detail to exemplary embodiments of the disclosure. While the disclosure will be described in conjunction with the exemplary embodiments, it will be understood that it is not intended to limit the disclosure to those embodiments. To the contrary, it is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the disclosure as defined by the appended claims. Standard techniques well known in the art or the techniques specifically described below were utilized. Attorney Docket No.: BN00023.0071 EXAMPLES Example 1: Materials and Methods Aptamer Selection Suitable aptamers for adaptation were initially selected from published data. Exemplified input aptamers of the instant disclosure (Tau IT2, IT3, IT4 and IT5 aptamers) were initially selected from I-Ting Teng et al. J Am Chem Soc.2018 October 31; 140(43): 14314–14323. Each of Tau aptamers IT2, IT3, IT4 and IT5 displayed high binding affinities toward Tau441, with Kd values ranging from 5.5 nM to 68 nM. Respective published aptamer DNA sequences were entered into the Quickfold program (available at www.unafold.org), and DNA-secondary structure(s) were predicted. Such prediction of secondary structure tends to result in a multiplicity of conformation options, with very little difference in their respective free energies of internal folding. The multitude of secondary structures reflected the intrinsic instability of DNA-aptamers. Usually, only one or two of the structural options deliver what could resemble a motif. A motif calls for several coaxially stacked stem structures, in which a number of base pairs in a quasi-continuous helix ranging between 11 - 14 base pairs is found. Motifs actively orient a loop or single-strand sequences towards a potential target. In general, single-stranded loop regions may base-pair with nucleotides outside of that loop or find structural options in proteins. These single strands in turn are able to form pseudoknots with other single stranded sequences with close proximity and force a specific three-dimensional structure. Such structures were found in tRNA-like structures that were required for the aminoacylation of viral RNA and functional tRNA (Mans et al. Eur. J. Biochem. 201: 303-324). Mans et al. described in detail the structure and function of tRNA with respect to the requirements in conjunction with aminoacylation of RNA and binding to specific enzymes involved in the translational process. However, these teachings did not anticipate the application of these structural principles to find RNA structures with affinities to other protein structures. It was therefore surprising to find that the application of these principles could be successfully applied, with high probability of success, to the development of RNA-substituted sequences possessing specific and high affinity to designated proteins. It was even more surprising to detect the impact of deprotonation of the designed probes with respect to their binding to protein. A shift in pH from pH 7.5 to pH 8.3 increase the signal from background noise to 105fluorescent counts. Attorney Docket No.: BN00023.0071 Adapting and applying principles such as those described in Mans et al. Eur. J. Biochem. 201: 303-324, Tau aptamer sequences were selected based upon their structural features and were used to construct RNA affinity probes. For purpose of RNA affinity probe production, it was discovered that an ideal motif displays 2 to 3 single stranded loops in close vicinity interspersed with the coaxially stacked stem regions forming helical structures. For the current process, the first step was effectively to transform this sequence from DNA to RNA and to determine its secondary structure using Quickfold. Usually, there were only 1 to 2 stable conformation options. A candidate for an affinity probe was chosen and then either the 5’ or 3’ ends were supplemented to form a stable stem under physiological conditions. The free energy of the stem sequence alone was identified as needing to be around -10kcal / mol, and stem sequences needed to be carefully constructed to achieve this value with minimal base-pairs. These values were determined using the “two state” algorithms on the mfold server (www.bioinfo.rpi.edu / applications / mfold). Accordingly, it was discovered herein that preparation of an RNA affinity probe can be most readily performed where an input aptamer possesses a stable (few or no conformational options) secondary / tertiary structure with alternating coaxially stacked stem and single stranded sequences, together with single stranded sequences having affinity to a selected protein. Identifying an aptamer sequence specific for a selected protein that fulfills all criteria, containing such structures and determining an effective motif, therefore involves an active search for both structures and sequences to construct a RNA affinity probe having high affinity (specificity) to a protein of interest, and is therefore a process that is unique relative to previously described processes. RAP Synthesis The transformation of a chosen DNA aptamer sequence into a RNA affinity probe (RAP) begins with the substitution of all thymidine nucleotides with uracil nucleotides and the analysis of the secondary structure with Quickfold with RNA rules. This provides a structure with a motif and single-stranded 5’ and 3’ ends. The 5’ and 3’ ends need to be forced into a helical stem structure. The objective of this exercise is to bring the 5’ and 3’ ends into very close proximity for quenching to take place, as is well known in the art of molecular beacon technology. On the other hand, the free energy exerted by this newly-formed stem alone needs to be less negative than the free energy set free upon the binding of the nucleic acid to form a binary oligonucleotide-protein complex. This will differ for each binary pair. Moreover, the free energy Attorney Docket No.: BN00023.0071 set free should be as small as possible, so that said complex formation is not prohibited by free energy-driven preferences. A further aspect regarding optimal length of an oligonucleotide is that each base-pair saved reduces the production cost and increases the yield for a commercial substrate. The optimization of each RAP is a process that differs for each RAP sequence. For example, there may be more than one RAP option considered as a final choice for a lead agent, which can be made by swapping positions. Fine tuning may be made by modulating A / U versus G / C content, also taking the quenching effect a G can have in the proximity-terminal nucleotides into account. Additional facets of the RAP synthesis process (and of the WRAP synthesis process) are considered in further detail in the following Examples. Example 2: Identification of RAPs as Robust Target Protein-Binding Oligonucleotide Probes A published series of Tau-binding DNA aptamers were identified by the above-described selection criteria of Example 1, as providing input DNA aptamers potentially capable of successful conversion to RAPs that would possess enhanced target binding and other properties, as compared to input DNA aptamers. Tau-binding DNA aptamers disclosed in Mans et al. (Eur. J. Biochem. 201: 303-324) displayed high binding affinities toward Tau441, with Kdvalues ranging from 5.5 nM to 68 nM, and specifically included the following, identified herein as RAP candidates (by using teachings from (t)RNA secondary and tertiary structures and respective protein interactions to find motifs in published aptamers with similar structures): IT2, which possessed the best binding (lowest Kd) characteristics for the T231 phosphorylation site (T231-P, noting numbering based upon the Tau 441 fragment) of all Tau- binding DNA aptamers of Mans et al. IT2 recognized not only both T231 and T231P, but it also bound to S202. (1.067 ± 0.018) × 104M−1s−1was detected for IT2 binding to Tau441. IT2 also demonstrated an extremely slow off-rate (koff) ((5.9 ± 1.2) × 10−5s−1) for Tau441, exhibiting the lowest Kd(5.5 ± 1.1 nM) for Tau441 protein among all aptamers. IT2a, the truncation of IT2 in Mans et al., appeared to benefit its recognition of T231P; however, overall, the binding affinity of IT2a was weakened by the truncation; IT3, which possessed undifferentiated binding affinity to T231 and T231-P. IT3 appeared to have bypassed the phosphorylated site and bound to both T231 and T231P peptides; Attorney Docket No.: BN00023.0071 IT4, which was identified to provide a good RAP candidate for binding of Tau 441. IT4 appears only to have detected the presence of non-phosphorylated T231 residue; and IT5, which also was identified to provide a good RAP candidate for binding of Tau 441. IT5 exhibited the second lowest Kd (7.6 ± 0.6 nM) for Tau441 protein. Notably, IT1 and other Tau-binding DNA aptamers disclosed in Mans et al. were excluded from further consideration as viable candidates for RAP conversion / formation: specifically, the IT1 DNA aptamer was identified to have FAST binding characteristics, and whereas the IT1 DNA aptamer provided a good DNA motif, the corresponding RNA motif was identified as variable and therefore sub-optimal for proceeding with RAP synthesis. Five of the Mans et al. aptamers (IT1, IT4, IT5, IT6, and IT9) were reported to possess strong and specific binding to the phosphorylation site (T231 peptide). Surprisingly, the SELEX process to generate an aptamer towards the T181 peptide failed. Each of the selected IT2, IT3, IT4 and IT5 input DNA aptamers was identified to exhibit conformational instability as DNA aptamers, in view of the presence within each DNA aptamer of various conformational states of DNA motifs possessing very close Gibbs free energy (ΔG) values. For IT2, instability of the DNA aptamer was first identified. The Tau-binding IT216.2 23.5 DNA aptamer, formed via a genetic selection from a large random sequence pool via in vitro selection or by SELEX (systematic evolution of ligands by exponential enrichment), has the following sequence: CAGCACCGTCAACTGAATAAGGACTGCTTAGGATTGCGATGATTCAGGGTGATGCG ATGGAGATGT (SEQ ID NO: 9). The IT2 16.2 23.5 aptamer is a variable DNA motif with very close free energy (ΔG) values (these close ΔG values therefore define the IT2 aptamer as a variable DNA motif). In particular, a first conformation of the IT2 aptamer was identified to possess ΔG of -3.03, ΔH of - 76.80, ΔS of -237.85, and Tmof 49.7°C. Meanwhile, a second conformation of the IT2 aptamer was identified to possess ΔG of -2.88, ΔH of -91.00, ΔS of -284.12, and Tmof 47.1°C. A third conformation of the IT2 aptamer was identified to possess ΔG of -2.43, ΔH of -94.80, ΔS of - 297.82, and Tmof 45.2°C. A fourth conformation of the IT2 aptamer was identified to possess ΔG of -2.27, ΔH of -75.90, ΔS of -237.40, and Tmof 46.6°C. Attorney Docket No.: BN00023.0071 Substitution of 2`-deoxythymidine-3`-phosphate nucleotide residues with 2'-O- methyluridine-3’-phosphate throughout the IT2 aptamer produced the following RNA-substituted sequence directly corresponding to IT2: CAGCACCGUCAACUGAAUAAGGACUGCUUAGGAUUGCGAUGAUUCAGGGUGAUG CGAUGGAGAUGU (SEQ ID NO: 10), where each "U" residue is a 2'-O-methyluridine-3’- phosphate. The above RNA-substituted oligonucleotide was identified to have only two clear conformations, each having a much lower (and therefore more stable) ΔG value than any of the four conformations modeled above for the original IT2 DNA aptamer. In particular, a first conformation of the initial IT2 RNA-substituted sequence of SEQ ID NO: 10 was identified to possess ΔG of -10.70, ΔH of -118.50, ΔS of -347.57, and Tm of 67.8°C. Meanwhile, a second conformation of the initial IT2 RNA-substituted sequence of SEQ ID NO: 10 was identified to possess ΔG of -9.90, ΔH of -106.00, ΔS of -309.85, and Tmof 69.0°C. Substitution of each 2`-deoxythymidine-3`-phosphate nucleotide residue of the IT2 DNA aptamer sequence with a 2'-O-methyluridine-3’-phosphate therefore stabilized the IT2 motif. Further stabilization of the first conformation identified for the IT2 RNA-substituted sequence of SEQ ID NO: 10 was then achieved via addition of a 5'-terminal tail sequence, which not only promoted annealing of terminal residues to form a stem, but also allowed for addition of terminal quencher and fluorescent moieties in proximity to one another. This final, stabilized IT2 RAP had the following sequence: ACAUCUCAGCACCGUCAACUGAAUAAGGACUGCUUAGGAUUGCGAUGAUUCAGG GUGAUGCGAUGGAGAUGU (SEQ ID NO: 11), where a 5'-terminal ACAUCU was added to stabilize and align quenched fluorescent moieties. The predicted two-state result of adding the above-noted stem sequence (ACAUCU) to the initial IT2 RNA-substituted sequence of SEQ ID NO: 10 was a further lowered ΔG of -7.7, ΔH of -57.9, ΔS of -161.9, and Tmof 0.3°C. Moreover, the final IT2 RAP of SEQ ID NO: 11, for which a two-dimensional folded sequence is shown in FIG. 1, was identified to possess a highly stable ΔG value of -19.80, with ΔH of -168.50, ΔS of -479.45, and Tm= 78.3°C. Interaction probabilities of IT2 and IT2-derived sequences were modeled on RNA protein interaction prediction software of Iowa State University. Specifically, prediction was performed using a RF classifier value of 0.6 and a SVM classifier value of 0.58. Attorney Docket No.: BN00023.0071 For IT3, instability of the DNA aptamer was first identified. The Tau-binding IT315.9 11.9 DNA aptamer, formed via a genetic selection from a large random sequence pool via in vitro selection or by SELEX (systematic evolution of ligands by exponential enrichment), has the following sequence: CAGCACCGTCAACTGAATGGGGAGAGTGGTGGGGCGGGGGCCGGATCCGTGATGC GATGGAGATGT (SEQ ID NO: 12). The IT3 15.9 11.9 aptamer is a variable DNA motif with very close free energy (ΔG) values (these close ΔG values therefore define the IT3 aptamer as a variable DNA motif). In particular, a first conformation of the IT3 aptamer was identified to possess ΔG of -3.85 and Tmof 51.5°C. Meanwhile, a second conformation of the IT3 aptamer was identified to possess ΔG of -3.84 and Tm of 53.9°C. A third conformation of the IT3 aptamer was identified to possess ΔG of -3.59 and Tmof 50.3°C. A fourth conformation of the IT3 aptamer was identified to possess ΔG of -3.57 and Tmof 47.9°C. A fifth conformation of the IT3 aptamer was identified to possess ΔG of -3.27 and Tmof 53.0°C. A sixth conformation of the IT3 aptamer was identified to possess ΔG of -3.13 and Tmof 49.7°C. The IT3 DNA aptamer motifs were therefore identified as highly variable in conformation, meaning that there was high wobble of IT3 motifs. Tau binding of the IT3 aptamer was identified to bypass the phosphorylated site and bind both T231 and T231P peptides (with amino acid residues numbered based upon Tau 441). Substitution of 2`-deoxythymidine-3`-phosphate nucleotide residues with 2'-O- methyluridine-3’-phosphate throughout the IT3 aptamer produced the following RNA-substituted sequence directly corresponding to IT3: CAGCACCGUCAACUGAAUGGGGAGAGUGGUGGGGCGGGGGCCGGAUCCGUGAUG CGAUGGAGAUGU (SEQ ID NO: 13), where each "U" residue is a 2'-O-methyluridine-3’- phosphate. The above RNA-substituted oligonucleotide was identified to have one clear conformation possessing a much lower (and therefore more stable) ΔG value than any of the six conformations identified above for the original IT3 DNA aptamer. In particular, the initial IT3 RNA-substituted sequence of SEQ ID NO: 13 was identified to possess ΔG of -18.30, ΔH of - 175.40, ΔS of -506.53 and Tmof 73.1°C. Substitution of each 2`-deoxythymidine-3`-phosphate nucleotide residue of the IT3 DNA aptamer sequence with a 2'-O-methyluridine-3’-phosphate therefore stabilized the IT3 motif. Attorney Docket No.: BN00023.0071 Further stabilization of the one conformation identified for the IT3 RNA-substituted sequence of SEQ ID NO: 13 was then achieved via addition of a 5'-terminal tail sequence, which not only promoted annealing of terminal residues to form a stem, but also allowed for addition of terminal quencher and fluorescent moieties in proximity to one another. This final, stabilized IT3 RAP had the following sequence: ACAUCAGCACCGUCAACUGAAUGGGGAGAGUGGUGGGGCGGGGGCCGGAUCCGU GAUGCGAUGGAGAUGU (SEQ ID NO: 14), where a 5'-terminal ACAU was added to stabilize and align quenched fluorescent moieties. The predicted two-state result of adding the above-noted stem sequence (ACAU) to the initial IT3 RNA-substituted sequence of SEQ ID NO: 13 was a further lowered ΔG of -2.7, with Tm of -55.9 °C. Moreover, the final IT3 RAP of SEQ ID NO: 14, for which a two-dimensional folded sequence is shown in FIG. 2A, was identified to possess a highly stable ΔG value of - 19.90, with Tmof 66.7°C. The stem loop formed via addition of the ACAU sequence is also shown in FIG.2B. Interaction probabilities of IT3 and IT3-derived sequences were modeled on RNA protein interaction prediction software of Iowa State University. Specifically, prediction was performed using a RF classifier value of 0.55 and a SVM classifier value of 0.66. The IT3 RAP was therefore identified to possess a high binding probability for Tau protein. To make a RAP perform on samples taken from a complex matrix such as human serum or plasma, a routinely working RAP will likely need to be further refined. Human blood derived samples inherently carry a large number of proteins with a high auto-fluorescent signal. The preferred way to remove autofluorescence is to integrate and apply time-resolved fluorescence technology to the RAP construct. This was achieved by labeling the 5’end of the RAP sequence with biotin and further extending the 3’end to incorporate a target sequence for a hairpin loop in analogy to the approach described in PCT / GB2022 / 050153 (Target Dependent Polymerisation of Oligonucleotides). TIP signal generation relied upon DNA oligonucleotides, whereas the RAP technology of the instant disclosure implements 2’O-methyl modified ribonucleotides. While the combination of DNA with RNA may be technically feasible, use of 2’O-methyl ribonucleotides only is preferred for the RAPs of the instant disclosure. To achieve this with TIP chain loops would involve a transformation to RNA sequences, which would also account for the differing Attorney Docket No.: BN00023.0071 thermodynamic characteristics of RAPs of the instant disclosure as compared to TIP DNA oligonucleotides. For IT4, instability of the DNA aptamer was first identified. The Tau-binding IT4 DNA aptamer, formed via a genetic selection from a large random sequence pool via in vitro selection or by SELEX (systematic evolution of ligands by exponential enrichment), has the following sequence: CAGCACCGTCAACTGAATGGGTTGGCCGGGCAGCGGGGGGTAGGCTTGGTGATGC GATGGAGATGT (SEQ ID NO: 15). The IT4 aptamer is a variable DNA motif with very close free energy (ΔG) values (these close ΔG values therefore define the IT4 aptamer as a variable DNA motif). In particular, a first conformation of the IT4 aptamer was identified to possess ΔG of -4.36 and Tm of 57.0°C. Meanwhile, a second conformation of the IT4 aptamer was identified to possess ΔG of -4.17 and Tmof 58.4°C. A third conformation of the IT4 aptamer was identified to possess ΔG of -4.02 and Tmof 51.9°C. A fourth conformation of the IT4 aptamer was identified to possess ΔG of -3.90 and Tmof 52.0°C. A fifth conformation of the IT4 aptamer was identified to possess ΔG of -3.44 and Tmof 50.3°C. The IT4 DNA aptamer motifs were therefore identified as highly variable in conformation, meaning that there was high wobble of IT4 motifs. Upon binding to Tau, the IT4 aptamer was predicted to inhibit Tau phosphorylation. Substitution of 2`-deoxythymidine-3`-phosphate nucleotide residues with 2'-O- methyluridine-3’-phosphate throughout the IT4 aptamer produced the following RNA-substituted sequence directly corresponding to IT4: CAGCACCGUCAACUGAAUGGGUUGGCCGGGCAGCGGGGGGUAGGCUUGGUGAUG CGAUGGAGAUGU (SEQ ID NO: 16), where each "U" residue is a 2'-O-methyluridine-3’- phosphate. The above RNA-substituted oligonucleotide was identified to have three distinct conformations, each possessing a much lower (and therefore more stable) ΔG value than any of the five conformations identified above for the original IT4 DNA aptamer. In particular, the first conformation of the initial IT4 RNA-substituted sequence of SEQ ID NO: 16 was identified to possess ΔG of -17.50 and Tmof 73.9°C. The second conformation of the initial IT4 RNA- substituted sequence of SEQ ID NO: 16 was identified to possess ΔG of -16.70 and Tmof 73.5°C. Attorney Docket No.: BN00023.0071 The third conformation of the initial IT4 RNA-substituted sequence of SEQ ID NO: 16 was identified to possess ΔG of -16.60 and Tmof 86.8°C. Substitution of each 2`-deoxythymidine-3`-phosphate nucleotide residue of the IT4 DNA aptamer sequence with a 2'-O-methyluridine-3’-phosphate therefore stabilized the IT4 motif. While the DNA motif was variable, the RNA-substituted motif was more stable. A single conformation of the IT4 RNA-substituted sequence of SEQ ID NO: 16 was then achieved via addition of both a 5'-terminal tail sequence and a 3'-terminal tail sequence, which not only promoted annealing of terminal residues to form a stem, but also allowed for addition of terminal quencher and fluorescent moieties in proximity to one another. This final IT4 RAP had the following sequence: AACACAUCAGCACCGUCAACUGAAUGGGUUGGCCGGGCAGCGGGGGGUAGGCUU GGUGAUGCGAUGGAGAUGUGUU (SEQ ID NO: 17), where a 5'-terminal AACACAU and a 3' GUU were added to align quenched fluorescent moieties. The final IT4 RAP of SEQ ID NO: 17, for which a two-dimensional folded sequence is shown in FIG.3, was identified to possess a ΔG value of -5.34, with Tmof 49.9°C. Interaction probabilities of IT4 and IT4-derived sequences were modeled on RNA protein interaction prediction software of Iowa State University. Specifically, prediction was performed using a RF classifier value of 0.45 and a SVM classifier value of 0.55. The IT4 RAP was therefore identified to as a candidate for lower binding probability for Tau protein. For IT5, the DNA aptamer was first identified. The Tau-binding IT5 DNA aptamer, formed via a genetic selection from a large random sequence pool via in vitro selection or by SELEX (systematic evolution of ligands by exponential enrichment), has the following sequence (66 nt): CAGCACCGTCAACTGAATGGCGGGGGGTCAGGTCGGGGTAAGGTGAGCGTGATGC GATGGAGATGT (SEQ ID NO: 18). The IT5 aptamer is a DNA motif with a primary conformation free energy (ΔG) value of -4.75 and a Tmof 61.9°C. The IT5 aptamer was specifically described to inhibit Tau phosphorylation when bound. Substitution of 2`-deoxythymidine-3`-phosphate nucleotide residues with 2'-O-methyluridine-3’- phosphate throughout the IT5 aptamer produced the following RNA-substituted sequence directly corresponding to IT5: Attorney Docket No.: BN00023.0071 CAGCACCGUCAACUGAAUGGCGGGGGGUCAGGUCGGGGUAAGGUGAGCGUGAUG CGAUGGAGAUGU (SEQ ID NO: 19), where each "U" residue is a 2'-O-methyluridine-3’- phosphate. The above RNA-substituted oligonucleotide was identified to have two distinct conformations, each possessing a much lower (and therefore more stable) ΔG value than the original IT5 DNA aptamer. In particular, the first conformation (FIG.4A) of the initial IT5 RNA- substituted sequence of SEQ ID NO: 19 was identified to possess ΔG of -15.40 and Tmof 74.7°C. The second conformation (FIG.4B) of the initial IT5 RNA-substituted sequence of SEQ ID NO: 19 was identified to possess ΔG of -14.80 and Tmof 72.2°C. Substitution of each 2`-deoxythymidine-3`-phosphate nucleotide residue of the IT5 DNA aptamer sequence with a 2'-O-methyluridine-3’-phosphate therefore enhanced the IT5 motif. A single conformation of the IT5 RNA-substituted sequence of SEQ ID NO: 19 was then achieved via addition of both a 5'-terminal tail sequence (CCACAU) and a 3'-terminal tail sequence (GG), which not only promoted annealing of terminal residues to form a stem, but also allowed for addition of terminal quencher and fluorescent moieties in proximity to one another. This final IT5 RAP had the following sequence: CCACAUCAGCACCGUCAACUGAAUGGCGGGGGGUCAGGUCGGGGUAAGGUGAGC GUUUAUGCGAUGGAGAUGUGG (SEQ ID NO: 20), where a 5'-terminal CCACAU and a 3' GG were added to align quenched fluorescent moieties. The final IT5 RAP of SEQ ID NO: 20, for which a two-dimensional folded sequence is shown in FIG.4C, was identified to possess a ΔG value of -23.10, ΔH of -221.70, ΔS of -640.34 and a Tmof 73.1°C. The stem loop of this RAP is also shown in FIG. 4D, noting that the complementary CCACAUC and GAUGUGG sequences provide a stem loop having ΔG of -9.1, ΔH of -61.2, ΔS of -168.0 and Tmof 48.2°C Interaction probabilities of IT5 and IT5-derived sequences were modeled on RNA protein interaction prediction software of Iowa State University. Specifically, prediction was performed using a RF classifier value of 0.55 and a SVM classifier value of 0.62. The IT5 RAP was then assessed for its Tau binding profile. The IT5 RAP was labelled with Atto495 and BHQ1 as respective fluorescent and quenching moieties, and binding to human Tau was first assessed in a simple buffer (20mMTris / HCl pH 7.5, 215mM NaCl and 5mM MgCl2) in serial dilutions while incubating at 37 °C. Time points were taken within 30 minutes, and Attorney Docket No.: BN00023.0071 averages of three independent runs of the assay are shown in FIG. 5A. IT5 RAP signal increases with time and is generated also at very low concentrations of human Tau protein. Interestingly, two peaks were observed, at two different concentrations, which indicated that conformational changes were likely occurring in the human Tau protein at different concentrations. When levels of human Tau protein were maintained at a constant concentration while levels of the IT5 RAP probe were varied, the observed signal level was dependent upon the concentration of the IT5 RAP probe (FIG.5B). Example 3: Production of Lead RAPs Via an Iterative Design Process Arriving at a final RAP sequence is achieved by an iterative process where either the 5’ or 3’ ends are extended to be mutually complementary (FIGs. 6A-6D), with the objective being to have minimum total length, while the terminal stem sequence needs to have a Tmvalue above the designed assay temperature. The first iteration was to extend the 5’ end with nucleotides complementary to the 3’end (FIG.6B). The additions to the stem generate a decreased total ΔG to -25.5 kcal / mol. This was deemed to be too stringent to enable a flexible oligonucleotide-protein annealing interaction. Two other iterations of stem design were therefore attempted, where the stem was successively shortened in steps of one base pair (FIGs.6C and 6D). While still having a negative ΔG, the Tmin the third iteration (FIG. 6D) is -96.0°C, which would let the stem melt and generate a false positive signal. The stem in the second iteration will only melt above assay temperature (as Tm = 48.2°C), and any signal generated is therefore deemed to be due to the RAP oligonucleotide-protein annealing interaction. Furthermore, the negative free energy is higher (ΔG = -9.1) than the anticipated free energy generated upon annealing. The second iteration (FIG. 6C) was therefore deemed to be the most promising candidate for a lead RAP. At least in view of the above results, design and implementation of a homogenous and sensitive assay for human Tau, even in crude samples, is contemplated, which can optionally be run, e.g., in parallel with a TDP-43 biomarker assay. Certain of the above-identified human Tau- binding RAPs (i.e., the IT4 and IT5 RAPs) are also predicted to allow for differentiation of phosphorylated and non-phosphorylated forms of human Tau in a test sample. In summary, RAPs as disclosed herein turn unstable DNA aptamer sequences into stable RNA-containing affinity probes having defined secondary and tertiary structures, which are capable of acting as signal generators (when labeled) and that remarkably possess higher binding Attorney Docket No.: BN00023.0071 affinity than aptamer technology, particularly when stabilizing terminal stem loops are integrated. RAPs not only possess high binding affinity, but also immediate signal generation upon binding to target macromolecule, therefore likely requiring no washing steps for most applications and providing a diagnostic probe technology applicable even to crude (unfractionated, unpurified, etc.) samples. Exemplified RAPs were designed and installed herein to maintain DNA aptamer motifs and were labelled with fluorophore / quencher pairs (i.e., beacon technology). Example 4: Enwrapping RNA Affinity Probe (WRAP) Design and Efficacy In certain aspects, the instant disclosure provides a process for designing a peptide- binding oligonucleotide, where the process specifically allows for directed design of a high affinity peptide-binding oligonucleotide, based upon selection of individual nucleotides of the oligonucleotide in a manner that is directly informed by the Gibbs free energy values for nucleic acid-amino acid binding, the total number of amino acid-nucleotide interactions described for a given amino acid-nucleotide relationship (derived, e.g., from Hoffmann et al, NAR, 2004, Vol. 32, Database issue, D174 – D181, AANT: the Amino Acid-Nucleotide Interaction Database), or from some combination of the preceding (including, e.g., nucleotide selections based upon optionally weighted multiplications of number of interactions and Gibbs free energy values), to arrive at a selected WRAP nucleotide, for each accessible amino acid of the targeted peptide. The Gibbs free energy value of the interaction between a given amino acid of a target peptide and a corresponding nucleotide of the affinity probe is shown in FIG. 7 (derived from de Ruiter A, Zagrovic B. Absolute binding-free energies between standard RNA / DNA nucleobases and amino-acid sidechain analogs in different environments. Nucleic Acids Res. 2015 Jan;43(2):708- 18), which is used to inform the nucleotide selections of the target peptide-binding oligonucleotide of the current Example. The WRAP design process of the instant disclosure integrates three-dimensional polypeptide structural information and such individual amino acid- nucleotide interaction data, to achieve a peptide-binding oligonucleotide possessing high affinity and target specificity. Design of exemplary human TDP-43-binding WRAPs involved the following steps. First, a three-dimensional structure for the targeted human TDP-43 protein was obtained from the NCBI database (specifically, the crystal structure of the N-terminal domain of human TDP-43 at 2.55 Å resolution can be found at NCBI PDB structure 6T4B; three- dimensional peptide structures can also be obtained from DNAstar or other sources). In the three- dimensional structure for human TDP-43, the amino acids shown by the structure to be accessible Attorney Docket No.: BN00023.0071 to water were identified throughout the N-terminus of the TDP-43 protein (the N-terminus of TDP-43 has been identified to function in dimerization and / or oligomerization of TDP-43, with activity in mRNA splicing, FIG. 8). Next, the N-terminal domain TDP-43 amino acid residues were individually assessed for accessibility to water and for optimal nucleotide-amino acid interactions and one or more of the following: associated Gibbs free energy values, associated numbers of interactions, a weighted combination of associated Gibbs free energy values and associated numbers of interactions, and a consensus sequence based upon optimizing Gibbs free energy values across such alternative oligonucleotide sequences provided by the prior three optimized selections (refer to spreadsheet of FIGs.9A-9D). Three-dimensional protein structural information (and optionally projection of three-dimensional oligonucleotide structure when wrapping around a target protein) was also used to identify where to locate bridging (non-binding) nucleotides within the TDP-43-binding WRAP structure. (It is expressly contemplated that such bridging / non-binding nucleotides can be as few as one or two nucleotides between respective binding nucleotides, or can be of longer length, optionally even including a stem (double- stranded) region and / or attached loop sequence region as a component of such bridging nucleotides. For water-accessible amino acid residues of the N-terminus of TDP-43, Gibbs free energy values for interactions between various nucleotides and the individual amino acid residues were evaluated (via VLOOKUP of the free energy value between each amino acid residue and nucleotide residue for all nucleotides), or total number of interactions were evaluated for all potential nucleotide-amino acid interactions (via VLOOKUP of the total number of interactions between each amino acid residue and nucleotide residue for all nucleotides), or a combination of the preceding two was approaches was used, via VLOOKUP of the free energy x # interactions between each amino acid residue and nucleotide residue for all nucleotides, or a consensus sequence optimizing Gibbs free energy values for binding derived therefrom was obtained / derived from the preceding sequences. △G [kcal / mol] was then multiplied across the full number of interactions modeled between the oligonucleotide and the TDP-43 polypeptide. Using such Gibbs free energy, number of interactions, and structural information, a selection of polynucleotides having the highest probability of binding to the targeted TDP-43 polypeptide was determined (FIG. 9E; FIGs. 10A to 10D). Additional assessments of the emerging WRAP sequences were then performed based on the 3D structure, to determine whether a wobble base or Watson / Crick base pairs needed to be inserted to bridge a gap in the TDP-43-binding WRAP. Attorney Docket No.: BN00023.0071 An arbitrary stem nucleotide sequence was then also added, for attachment of fluorophore and quencher moieties. The target value for the added stem nucleotide sequence was △G=-5-6 [kcal / mol]. In the final stage of WRAP design, △G values and / or number of interaction values were determined for each match / mismatch and the designed WRAP was checked for cross- reactivity by comparing △G values and / or interaction values. One of the designed TDP-43- binding WRAPs was then assessed for fluorescence over time in association with the N-terminus of TDP-43, both in the presence of MgCl2and in the absence of MgCl2, at 30 °C (FIGs.11A and 11B). A selection of WRAPs having high affinity and specificity for binding and detection of human TDP-43 was thereby designed, synthesized and evaluated for activity. Example 5: WRAP Sequence Selection Using Linear Polypeptide Sequence and Hydrophilicity / Hydrophobicity The instant disclosure also provides a process for selecting a WRAP sequence with an optimized probability of working (binding its target polypeptide with high affinity), that employs a more limited structural representation of a polypeptide sequence (e.g., a linear structural representation and / or a two-dimensional structural representation of the polypeptide), together with assessing hydrophilicity / hydrophobicity, charge, and / or free Gibbs energy, at individual residues and / or using a scanning window of such values across multiple residues to arrive at local selections (e.g., where a window of 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 or more residues is evaluated to arrive at a value for a given residue, used to guide a corresponding WRAP nucleotide selection at an individual amino acid residue). The current Example therefore shows an additional WRAP oligonucleotide design process that assesses and uses hydrophilicity / hydrophobicity, charge, and free Gibbs energy values obtained across a linear peptide sequence, to achieve WRAP oligonucleotide design. The design process specifically involves: I) Selection of a primary polypeptide (amino acid) sequence, shown in an accompanying spreadsheet (FIGs.12A-12X) as one amino acid to one cell. II) Preselection of a nucleotide according to algorithm (ΔG of base - aa interaction × frequency of interactions). III) Projection of a final nucleotide sequence, where amino acid residues modeled to have no interaction with nucleotides (see below) are substituted with "X", having no impact on binding (ΔG=0). Here equal amounts of all 4 nucleotides are inserted (effectively creating a fully Attorney Docket No.: BN00023.0071 degenerate nucleotide position). This allows implementation of a “Darwinian" selection approach for each WRAP, to find the best possible fit. IV) Each cell shows the respective hydrophilicity calculated for each respective amino acid. V) A rolling sum of charge is also calculated for the following 25 amino acids, starting at each respective residue assessed. This allows / helps to select a region for oligonucleotide design. VII) The calculated free energy value of each base binding to an amino acid / base pair is also calculated and used for optimized WRAP oligonucleotide design. One nucleotide base is assigned for each amino acid. VIII) Rolling combined ΔG values are also calculated for 25mers, as well as for 40mers, and for 50mers. Such rolling averages enhance site selection for WRAP oligonucleotide design and help to optimize respective nucleotide-amino acid residue interactions. The compilation and evaluation of hydrophilicity, charge, and free Gibbs energy along a target polypeptide ultimately enables selection of a WRAP oligonucleotide sequence possessing the highest probability of working (binding a target polypeptide sequence with high affinity; FIGs.12A-12X). Thus, using only a linear structural representation of a peptide, in combination with calculated hydrophilicity / hydrophobicity, charge, and free Gibbs energy values, an optimized WRAP oligonucleotide was designed. Example 6: A High Affinity Tau-Binding WRAP Oligonucleotide Exhibited Remarkable Detection of Tau Across a Wide Dynamic Range A Tau-binding WRAP designed by the current process was assessed for Tau binding across a wide dilution series of Tau peptide, measured via detection of fluorescence over time in association with Tau (FIG.13). A WRAP oligonucleotide having high affinity and specificity for Tau binding and detection was thereby designed, synthesized, and identified to function with high efficacy, across a wide dynamic range of detection. Attorney Docket No.: BN00023.0071 SEQCOMMENTID NO: 1 MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ Amino acid TPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGT TAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKI ATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSP GTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKN VKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSV QIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSL DNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHL SNVSSTGSIDMVDSPQLATLADEVSASLAKQGL 2 MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ Amino acid TPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGT TAEEAGIGDTPSLEDEAAGHVTQEPESGKVVQEGFLREPGPPGLSHQLMSG MPGAPLLPEGPREATRQPSGTGPEDTEGGRHAPELLKHQLLGDLHQEGPPL KGAGGKERPGSKEEVDEDRDVDESSPQDSPPSKASPAQDGRPPQTAAREAT SIPGFPAEGAIPLPVDFLSKVSTEIPASEPDGPSVGRAKGQDAPLEFTFHVEIT PNVQKEQAHSEEHLGRAAFPGAPGEGPEARGPSLGEDTKEADLPEPSEKQP AAAPRGKPVSRVPQLKARMVSKSKDGTGSDDKKAKTSTRSSAKTLKNRPC LSPKHPTPGSSDPLIQPSSPAVCPEPPSSPKYVSSVTSRTGSSGAKEMKLKGA DGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSATKQVQRRPPPA GPRSERGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTP PKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDL SNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGG QVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKT DHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAK QGL 3 MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ Amino acid TPTEDGSEEPGSETSDAKSTPTAEAEEAGIGDTPSLEDEAAGHVTQARMVSK SKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKT PPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKS PSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNV QSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVE VKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHG AEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL 4 MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ Amino acid TPTEDGSEEPGSETSDAKSTPTAEAEEAGIGDTPSLEDEAAGHVTQARMVSK SKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKT PPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKS PSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIVYKPVDLSK VTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGN KKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMV DSPQLATLADEVSASLAKQGL 5 MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ Amino acid TPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGT TAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKI ATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSP GTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKN Attorney Docket No.: BN00023.0071 VKSKIGSTENLKHQPGGGKVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQV EVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDH GAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQG L MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKAEEA Amino acid GIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRG AAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSR SRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGS TENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPV DLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVP GGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTG SIDMVDSPQLATLADEVSASLAKQGL MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ Amino acid TPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGT TAEEAGIGDTPSLEDEAAGHVTQEPESGKVVQEGFLREPGPPGLSHQLMSG MPGAPLLPEGPREATRQPSGTGPEDTEGGRHAPELLKHQLLGDLHQEGPPL KGAGGKERPGSKEEVDEDRDVDESSPQDSPPSKASPAQDGRPPQTAAREAT SIPGFPAEGAIPLPVDFLSKVSTEIPASEPDGPSVGRAKGQDAPLEFTFHVEIT PNVQKEQAHSEEHLGRAAFPGAPGEGPEARGPSLGEDTKEADLPEPSEKQP AAAPRGKPVSRVPQLKARMVSKSKDGTGSDDKKAKTSTRSSAKTLKNRPC LSPKHPTPGSSDPLIQPSSPAVCPEPPSSPKYVSSVTSRTGSSGAKEMKLKGA DGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGY SSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPM PDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVP GGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQS KIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTS PRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ Amino acid TPTEDGSEEPGSETSDAKSTPTAEAEEAGIGDTPSLEDEAAGHVTQEELRVP GRQRKAPERPLANEISAHVQPGPCGEASGVSGPCLGEKEPEAPVPLTASLPQ HRPVCPAPPPTGGPQEPSLEWGQKGGDWAEKGPAFPKPATTAYLHTEPESG KVVQEGFLREPGPPGLSHQLMSGMPGAPLLPEGPREATRQPSGTGPEDTEG GRHAPELLKHQLLGDLHQEGPPLKGAGGKERPGSKEEVDEDRDVDESSPQ DSPPSKASPAQDGRPPQTAAREATSIPGFPAEGAIPLPVDFLSKVSTEIPASEP DGPSVGRAKGQDAPLEFTFHVEITPNVQKEQAHSEEHLGRAAFPGAPGEGP EARGPSLGEDTKEADLPEPSEKQPAAAPRGKPVSRVPQLKARMVSKSKDGT GSDDKKAKTSTRSSAKTLKNRPCLSPKHPTPGSSDPLIQPSSPAVCPEPPSSP KYVSSVTSRTGSSGAKEMKLKGADGKTKIATPRGAAPPGQKGQANATRIPA KTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVA VVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIIN KKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHH KPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFREN AKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEV SASLAKQGLCAGCACCGTCAACTGAATAAGGACTGCTTAGGATTGCGATGATTCDNA AGGGTGATGCGATGGAGATGTCAGCACCGNCAACNGAANAAGGACNGCNNAGGANNGCGANGANDNA + modified NCAGGGNGANGCGANGGAGANGN RNA NracilsACANCNCAGCACCGNCAACNGAANAAGGACNGCNNAGGANNGCDNA + modified GANGANNCAGGGNGANGCGANGGAGANGN RNA Nracils Attorney Docket No.: BN00023.0071CAGCACCGTCAACTGAATGGGGAGAGTGGTGGGGCGGGGGCCGGDNA ATCCGTGATGCGATGGAGATGTCAGCACCGNCAACNGAANGGGGAGAGNGGNGGGGCGGGGGCCGDNA + modified GANCCGNGANGCGANGGAGANGN RNA NracilsACANCAGCACCGNCAACNGAANGGGGAGAGNGGNGGGGCGGGGDNA + modified GCCGGANCCGNGANGCGANGGAGANGN RNA NracilsCAGCACCGTCAACTGAATGGGTTGGCCGGGCAGCGGGGGGTAGGDNA CTTGGTGATGCGATGGAGATGTCAGCACCGNCAACNGAANGGGNNGGCCGGGCAGCGGGGGGNAGDNA + modified GCNNGGNGANGCGANGGAGANGN RNA NracilsAACACANCAGCACCGNCAACNGAANGGGNNGGCCGGGCAGCGGDNA + modified GGGGNAGGCNNGGNGANGCGANGGAGANGNGNN RNA NracilsCAGCACCGTCAACTGAATGGCGGGGGGTCAGGTCGGGGTAAGGTDNA GAGCGTGATGCGATGGAGATGTCAGCACCGNCAACNGAANGGCGGGGGGNCAGGNCGGGGNAAGGDNA + modified NGAGCGNGANGCGANGGAGANGN RNA NracilsCCACANCAGCACCGNCAACNGAANGGCGGGGGGNCAGGNCGGGDNA + modified GNAAGGNGAGCGNNNANGCGANGGAGANGNGG RNA NracilsCAGCACCGNCAACNGAANGGCGGGGGGNCAGGNCGGGGNAAGGRNA NGAGCGNNNANGCGANGGAGANGNacaNcNcCAGCACCGNCAACNGAANGGCGGGGGGNCAGGNCGGGGRNA NAAGGNGAGCGNNNANGCGANGGAGANGNacaNcNCAGCACCGNCAACNGAANGGCGGGGGGNCAGGNCGGGGNRNA AAGGNGAGCGNNNANGCGANGGAGANGNacaNcCAGCACCGNCAACNGAANGGCGGGGGGNCAGGNCGGGGNARNA AGGNGAGCGNNNANGCGANGGAGANGN MSEYIRVTEDENDEPIEIPSEDDGTVLLSTVTAQFPGACGLRYRNPVSQCMR Amino acid GVRLVEGILHAPDAGWGNLVYVVNYPKDNKRKMDETDASSAVKVKRAV QKTSDLIVLGLPWKTTEQDLKEYFSTFGEVLMVQVKKDLKTGHSKGFGFV RFTEYETQVKVMSQRHMIDGRWCDCKLPNSKQSQDEPLRSRKVFVGRCTE DMTEDELREFFSQYGDVMDVFIPKPFRAFAFVTFADDQIAQSLCGEDLIIKGI SVHISNAEPKHNSNRQLERSGRFGGNPGGFGNQGGFGNSRGGGAGLGNNQ GSNMGGGMNFGAFSINPAMMAAAQAALQSSWGMMGMLASQQNQSGPSG NNQNQGNMQREPNQAFGSGNNSYSGSNSGAAIGWGSASNAGSGSGFNGGF GSSMDSKSSGWGMGCATGCATGAAAAAGAGAAAGATGAAAAGCATGCDNAGCATGCTCAACGTAAAACAACACCAAAAATGCATGCDNAGCANGCANGAAAAAGNGANAGANGNNAAGCANGCRNAGCANGCANAAAANAAAAAAACACNAAAANGCANGCRNACAGCACCGNCAACNGAANAAGGACNGCNNAGGANNGCGANGANModified RNA NCAGGGNGANGCGANGGAGANGNACANCNCAGCACCGNCAACNGAANAAGGACNGCNNAGGANNGCModified RNA GANGANNCAGGGNGANGCGANGGAGANGNCAGCACCGNCAACNGAANGGGGAGAGNGGNGGGGCGGGGGCCGModified RNA GANCCGNGANGCGANGGAGANGN Attorney Docket No.: BN00023.0071 ACANCAGCACCGNCAACNGAANGGGGAGAGNGGNGGGGCGGGGModified RNA GCCGGANCCGNGANGCGANGGAGANGN CAGCACCGNCAACNGAANGGGNNGGCCGGGCAGCGGGGGGNAGModified RNA GCNNGGNGANGCGANGGAGANGN AACACANCAGCACCGNCAACNGAANGGGNNGGCCGGGCAGCGGModified RNA GGGGNAGGCNNGGNGANGCGANGGAGANGNGNN CAGCACCGNCAACNGAANGGCGGGGGGNCAGGNCGGGGNAAGGModified RNA NGAGCGNGANGCGANGGAGANGN CCACANCAGCACCGNCAACNGAANGGCGGGGGGNCAGGNCGGGModified RNA GNAAGGNGAGCGNNNANGCGANGGAGANGNGG `

[0005] Attorney Docket No.: BN00023.0071 EQUIVALENTS Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the following claims.

Claims

Attorney Docket No.: BN00023.0071 I claim:

1. A method for making an oligonucleotide capable of binding a reference amino acid sequence with high affinity, the method comprising: a) obtaining a structural representation of the reference amino acid sequence; b) designing an oligonucleotide sequence corresponding to the reference amino acid sequence, wherein said designing comprises optimizing Gibbs free energy (ΔG) values, number of amino acid-nucleotide interactions, or a combination thereof, across a series of two or more individual amino acid-nucleotide interactions between two or more water-accessible amino acid residues of the reference amino acid sequence and a corresponding two or more nucleotides of the oligonucleotide, wherein the corresponding two or more nucleotides of the oligonucleotide are modeled to be the respective individual nucleotides in closest physical proximity to each of the respective two or more water-accessible amino acid residues of the reference amino acid sequence; and c) synthesizing the oligonucleotide, thereby making an oligonucleotide capable of binding a reference amino acid sequence with high affinity.

2. The method of claim 1, wherein the structural representation of the reference amino acid sequence is selected from the group consisting of an X-ray crystallography structure, a NMR structure, an in silico structural model of the reference amino acid sequence, and a two-dimensional structural representation or linear polypeptide sequence, optionally wherein the structural representation of the reference amino acid sequence is obtained from a public database.

3. The method of claim 1 or claim 2, wherein the reference amino acid sequence is of 500 amino acids or less in length, optionally of 50 amino acids or less in length.

4. The method of any one of the preceding claims, wherein the corresponding two or more nucleotides of the oligonucleotide are modeled using oligonucleotide structure modeling software, optionally wherein the oligonucleotide structure modeling software is UNAFold.Attorney Docket No.: BN00023.0071 5. The method of any one of the preceding claims, wherein the reference amino acid sequence comprises at least five accessible amino acid residues in an aqueous solution, optionally at least ten accessible amino acid residues in an aqueous solution, optionally at least 15 accessible amino acid residues in an aqueous solution, optionally at least 20 accessible amino acid residues in an aqueous solution.

6. The method of claim 1, wherein step (b) comprises one or more of the following: (i) optimizing Gibbs free energy (ΔG) values across a series of three or more individual amino acid- nucleotide interactions, optionally across four or more individual amino acid-nucleotide interactions, optionally across five or more individual amino acid-nucleotide interactions, optionally across six or more individual amino acid-nucleotide interactions, optionally across seven or more individual amino acid-nucleotide interactions, optionally across eight or more individual amino acid-nucleotide interactions, optionally across nine or more individual amino acid-nucleotide interactions, optionally across ten or more individual amino acid-nucleotide interactions, optionally across eleven or more individual amino acid-nucleotide interactions, optionally across twelve or more individual amino acid-nucleotide interactions, optionally across thirteen or more individual amino acid-nucleotide interactions, optionally across fourteen or more individual amino acid-nucleotide interactions, optionally across fifteen or more individual amino acid-nucleotide interactions, optionally across sixteen or more individual amino acid-nucleotide interactions, optionally across seventeen or more individual amino acid-nucleotide interactions, optionally across eighteen or more individual amino acid-nucleotide interactions, optionally across nineteen or more individual amino acid-nucleotide interactions, optionally across twenty or more individual amino acid-nucleotide interactions; (ii) optimizing number of amino acid-nucleotide interactions across a series of three or more individual amino acid-nucleotide interactions, optionally across four or more individual amino acid-nucleotide interactions, optionally across five or more individual amino acid-nucleotide interactions, optionally across six or more individual amino acid-nucleotide interactions, optionally across seven or more individual amino acid- nucleotide interactions, optionally across eight or more individual amino acid-nucleotide interactions, optionally across nine or more individual amino acid-nucleotide interactions, optionally across ten or more individual amino acid-nucleotide interactions, optionally across eleven or more individual amino acid-nucleotide interactions, optionally across twelve or more individual amino acid-nucleotide interactions, optionally across thirteen or more individual aminoAttorney Docket No.: BN00023.0071 acid-nucleotide interactions, optionally across fourteen or more individual amino acid-nucleotide interactions, optionally across fifteen or more individual amino acid-nucleotide interactions, optionally across sixteen or more individual amino acid-nucleotide interactions, optionally across seventeen or more individual amino acid-nucleotide interactions, optionally across eighteen or more individual amino acid-nucleotide interactions, optionally across nineteen or more individual amino acid-nucleotide interactions, optionally across twenty or more individual amino acid- nucleotide interactions; or ; (iii) optimizing a combination of Gibbs free energy (ΔG) values and number of amino acid-nucleotide interactions across a series of three or more individual amino acid-nucleotide interactions, optionally across four or more individual amino acid-nucleotide interactions, optionally across five or more individual amino acid-nucleotide interactions, optionally across six or more individual amino acid-nucleotide interactions, optionally across seven or more individual amino acid-nucleotide interactions, optionally across eight or more individual amino acid-nucleotide interactions, optionally across nine or more individual amino acid-nucleotide interactions, optionally across ten or more individual amino acid-nucleotide interactions, optionally across eleven or more individual amino acid-nucleotide interactions, optionally across twelve or more individual amino acid-nucleotide interactions, optionally across thirteen or more individual amino acid-nucleotide interactions, optionally across fourteen or more individual amino acid-nucleotide interactions, optionally across fifteen or more individual amino acid-nucleotide interactions, optionally across sixteen or more individual amino acid-nucleotide interactions, optionally across seventeen or more individual amino acid-nucleotide interactions, optionally across eighteen or more individual amino acid-nucleotide interactions, optionally across nineteen or more individual amino acid-nucleotide interactions, optionally across twenty or more individual amino acid-nucleotide interactions.

7. The method of claim 1, wherein step (b): further comprises adding a 5'-terminal sequence, a 3'-terminal sequence, or a 5'-terminal sequence and a 3'-terminal sequence to the oligonucleotide, wherein the 5'-terminal sequence, the 3'-terminal sequence, or the 5'-terminal sequence and the 3'- terminal sequence are capable of forming a double-stranded stem region, optionally in annealing with an end region of the oligonucleotide sequence corresponding to the reference amino acid sequence, under conditions sufficient for hybridization to occur, thereby forming an oligonucleotide comprising a double-stranded stem region, a 5'-terminus and a 3'-terminus; and / or further comprises generating a consensus nucleic acid sequence from a series of initial sequencesAttorney Docket No.: BN00023.0071 of step (b) optimized for Gibbs free energy (ΔG) values, number of amino acid-nucleotide interactions, and / or a combination thereof, optionally by optimizing for summed Gibbs free energy values across the consensus sequence.

8. The method of claim 7, wherein the double-stranded stem region: has a negative free energy value of -15 kcal / mol or less, optionally -20 kcal / mol or less; has a negative free energy value that is substantially less negative than the free energy generated when the oligonucleotide having the double-stranded stem region binds to the reference amino acid sequence; and / or has a Tmof 37 ℃ or more.

9. The method of claim 7 or claim 8, wherein the 5'-terminus or the 3'-terminus comprises a fluorescent moiety, a lanthanide or a quenching moiety, optionally wherein the fluorescent moiety, lanthanide or quenching moiety is attached to a terminal nucleotide of the oligonucleotide, optionally wherein the fluorescent moiety, lanthanide or quenching moiety is covalently attached.

10. The method of any one of claims 7-9, wherein the oligonucleotide comprising a double- stranded stem region, a 5'-terminus and a 3'-terminus comprises both a fluorescent moiety or a lanthanide and a quenching moiety.

11. The method of claim 9 or claim 10, wherein the fluorescent moiety or lanthanide is attached to a 5'-terminal nucleotide residue of the oligonucleotide comprising a double-stranded stem region, a 5'-terminus and a 3'-terminus.

12. The method of claim 9 or claim 10, wherein the fluorescent moiety or lanthanide is attached to a 3'-terminal nucleotide residue of the oligonucleotide comprising a double-stranded stem region, a 5'-terminus and a 3'-terminus.

13. The method of claim 9 or claim 10, wherein the quenching moiety is attached to a 5'- terminal nucleotide residue of the oligonucleotide comprising a double-stranded stem region, a 5'-terminus and a 3'-terminus.Attorney Docket No.: BN00023.0071 14. The method of claim 9 or claim 10, wherein the quenching moiety is attached to a 3'- terminal nucleotide residue of the oligonucleotide comprising a double-stranded stem region, a 5'-terminus and a 3'-terminus.

15. The method of claim 7 or claim 8, wherein a fluorescent moiety or lanthanide is attached to a 5'-terminal nucleotide residue of the oligonucleotide comprising a double-stranded stem region, a 5'-terminus and a 3'-terminus, and a quenching moiety is attached to a 3'-terminal nucleotide residue of the oligonucleotide comprising a double-stranded stem region, a 5'-terminus and a 3'-terminus.

16. The method of claim 7 or claim 8, wherein a fluorescent moiety or lanthanide is attached to a 3'-terminal nucleotide residue of the oligonucleotide comprising a double-stranded stem region, a 5'-terminus and a 3'-terminus, and a quenching moiety is attached to a 5'-terminal nucleotide residue of the oligonucleotide comprising a double-stranded stem region, a 5'-terminus and a 3'-terminus.

17. The method of any one of claims 9-16, wherein the fluorescent moiety is selected from the group consisting of Atto 495, Atto 390, Atto 425, Atto 465, Atto 488, Atto 520, Atto 532, Atto 550, Atto 565, Atto 590, Atto 594, Atto 620, Atto 633, Atto 647N, Atto 655, Atto RhoG6, Atto Rholl, Atto Rhol2, Atto RholOl, 5- or 6-carboxyfluorescein (FAM™), VIC™, NED™, fluorescein, fluorescein isothiocyanate (FITC), IRDYE-700 / 800, cyanine dyes, such as CY3™, CY5™, CY3.5™, CY5.5™, Cy7™, xanthen, 6-carboxy-2',4',7',4,7- hexachlorofluorescein (HEX), 6-carboxy-l,4-dichloro-2',7'-dichloro-fluorescein (TET®), 6- carboxy-4',5'-dichloro-2',7'- dimethodyfluorescein (JOE™), N,N,N',N'-tetramethyl-6- carboxyrhodamine (TAMRA™), 6- carboxy-X-rhodamine (ROX), 5-carboxyrhodamine-6G (R6G5), 6-carboxyrhodamine-6G (RG6), rhodamine, rhodamine green, rhodamine red, rhodamine 110, Rhodamin 6G®, BODIPY dyes, such as BODIPY TMR, Oregon green, coumarines, such as umbelliferone, benzimides, such as Hoechst 33258; phenanthridines, such as Texas Red®, California Red®, Yakima Yellow, Alexa Fluor® 350, Alexa Fluor® 405, Alexa Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 500, Alexa Fluor® 514, Alexa Fluor®532, Alexa Fluor® 546, Alexa Fluor® 555, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 610, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Fluor® 680, Alexa Fluor® 700, Alexa Fluor® 750, PET®, ethidium bromide, acridiniumAttorney Docket No.: BN00023.0071 dyes, carbazol dyes, phenoxazine dyes, porphyrine dyes, polymethin dyes, BMN™-5, BMN™- 6, CEQ8000 D2, CEQ8000 D3, CEQ8000 D4, DY-480XL, DY-485XL, DY-495, DY-505, DY- 510XL, DY-521XL, DY-521XL, DY-530, DY-547, DY-550, DY- 555, DY-610, DY-615, DY- 630, DY-631, DY-633, DY-635, DY-647, DY-651, DY-675, DY-676, DY-680, DY-681, DY- 700, DY-701, DY-730, DY-731, DY-732, DY-750, DY-751, DY-776, DY-780, DY-781, DY- 782, 6-carboxy-4',5'-dichloro-2',7'-dimethoxyfluorescein (JOE), TET™, CAL Fluor® Gold 540, CAL Fluor RED 590, CAL Fluor Red 610, CAL Fluor Red 635, IRDye® 700Dx, IRDye® 800CW, Marina Blue®, Pacific Blue®, Yakima Yellow®, 6-(4,7-Dichloro-2',7'-diphenyl-3',6'- dipivaloylfluorescein-6-carboxamido)-hexyl-l-0-(2-cyanoethyl)-(N,N-diisopropyl)- phosphoramidite (SIMA), CAL Fluor® Gold 540, CAL Fluor® Orange 560, CAL Fluor Red 635, Quasar 570, Quasar 670, LIZ, Sunnyvale Red, LC Red® 610, LC Red® 640, LC Red® 670, LC Red® 705 and a squaraine dye.

18. The method of any one of claims 9-17, wherein the quenching moiety is selected from the group consisting of TAMRA and a dark quencher, optionally wherein the dark quencher is selected from the group consisting of Black Hole Quencher 1, 3' (BHQ1), DQ, dimethylaminoazobenzenesulfonic acid (DABCYL) and Iowa Black® (IWB).

19. The method of any one of claims 7-18, wherein the oligonucleotide comprising a double- stranded stem region, a 5'-terminus and a 3'-terminus is capable of binding the reference amino acid sequence with high affinity, optionally with an equilibrium binding constant (Kd) of less than 100 nM, optionally from about 0.01 nM to about 50 nM.

20. The method of any one of the preceding claims, wherein the oligonucleotide sequence corresponding to the reference amino acid sequence is capable of binding the reference amino acid sequence with an equilibrium binding constant (Kd) of less than 100 nM, optionally from about 0.01 nM to about 50 nM.

21. The method of any one of the preceding claims, wherein the oligonucleotide sequence corresponding to the reference amino acid sequence is capable of binding the reference amino acid sequence in a sample, optionally in a sample without prior purification, optionally wherein binding of the reference amino acid sequence in a sample causes immediate signal generation upon binding to the reference amino acid sequence in the sample.Attorney Docket No.: BN00023.0071 22. The method of claim 21, wherein the sample: is selected from the group consisting of a blood sample, a sputum sample, a cerebrospinal fluid (CSF) sample, an aspirate sample, section sample, a biopsy sample and a distinct body fluid sample, optionally wherein the sample is a crude sample; and / or is obtained from fluids or liquified solids found in the food and beverage industry, from environmental samples, and / or from industrial processing fluids.

23. The method of any one of the preceding claims, wherein at least one of the nucleotides of the oligonucleotide sequence corresponding to the reference amino acid sequence is a 2'-O- methyl-ribonucleotide, optionally wherein multiple nucleotides of the oligonucleotide sequence corresponding to the reference amino acid sequence are 2'-O-methyl-ribonucleotide nucleotides, optionally wherein all nucleotides of the oligonucleotide sequence corresponding to the reference amino acid sequence are 2'-O-methyl-ribonucleotides.

24. The method of any one of the preceding claims, wherein the structural representation of the reference amino acid sequence is a two-dimensional structural representation or linear polypeptide sequence, optionally wherein said designing comprises evaluating hydrophilicity / hydrophobicity values at individual residues of the polypeptide, optionally employing a scanning window of hydrophilicity / hydrophobicity values and / or Gibbs free energy (ΔG) values across a range of amino acid residues for evaluation of individual amino acid residues and assignment of a corresponding nucleotide residue, optionally wherein the scanning window range of amino acid residues is 10 or more amino acid residues, 20 or more amino acid residues, 25 or more amino acid residues, 30 or more amino acid residues, 35 or more amino acid residues, 40 or more amino acid residues, 45 or more amino acid residues, or 50 or more amino acid residues.

25. An oligonucleotide capable of binding TDP-43 and possessing an equilibrium binding constant (Kd) of less than 100 nM, optionally from about 0.01 nM to about 50 nM.

26. An oligonucleotide sequence comprising a sequence selected from the group consisting of SEQ ID NO: 26 (5'-GCATGCATGAAAAAGAGAAAGATGAAAAGCATGC-3'), SEQ ID NO: 27 (5'-GCATGCTCAACGTAAAACAACACCAAAAATGCATGC-3'),Attorney Docket No.: BN00023.0071 SEQ ID NO: 28 (5'-GCAUGCAUGAAAAAGUGAUAGAUGUUAAGCAUGC-3') and SEQ ID NO: 29 (5'-GCAUGCAUAAAAUAAAAAAACACUAAAAUGCAUGC-3').

27. A method for modifying a DNA aptamer, the method comprising: a) identifying a DNA aptamer sequence for modification; b) replacing all 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer sequence with 2'-O-methyluridine-3’-phosphate; and c) replacing all remaining deoxyribonucleotide residues of the DNA aptamer with modified ribonucleotides, thereby modifying the DNA aptamer to form an oligoribonucleotide having 2'-O- methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues of the oligoribonucleotide.

28. The method of claim 27, wherein the oligoribonucleotide having 2'-O-methyluridine-3’- phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues is capable of binding a target polypeptide.

29. The method of claim 27, wherein the DNA aptamer is capable of binding a target polypeptide.

30. The method of claim 29, wherein the oligoribonucleotide having 2'-O-methyluridine-3’- phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues is capable of binding the same target polypeptide as the DNA aptamer, optionally wherein the oligoribonucleotide having 2'-O- methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues possesses improved binding properties for the target polypeptide, as compared to the DNA aptamer.

31. The method of claim 27, wherein the modified ribonucleotides are selected from the group consisting of 2'-O-alkyl-ribonucleotides (e.g., 2'-O-methyl-ribonucleotides), 2'-deoxy-2'-fluoro- ribonucleotides, 2′-O—N-methylacetamido (2′-O-NMA) ribonucleotides, 2′-O- dimethylaminoethoxyethyl (2′-O-DMAEOE) ribonucleotides, 2′-O-aminopropyl (2′-O-Attorney Docket No.: BN00023.0071 AP) ribonucleotides, and 2′-ara-F ribonucleotides, optionally wherein the modified ribonucleotides comprise 2'-O-methyl-ribonucleotides, optionally wherein the modified ribonucleotides consist of 2'-O-methyl-ribonucleotides.

32. The method of claim 30, wherein the improved binding properties for the target polypeptide are selected from the group consisting of higher binding affinity for the target polypeptide and immediate signal generation upon binding to the target polypeptide in a sample, optionally wherein the probability of a 3-dimensional structure of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues binding to the 3-dimensional structure of the target polypeptide is increased.

33. The method of claim 32, wherein the sample is selected from the group consisting of a blood sample, a sputum sample, a cerebrospinal fluid (CSF) sample, an aspirate sample, section sample, a biopsy sample and a distinct body fluid sample, optionally wherein the sample is a crude sample.

34. The method of claim 27, wherein the step of identifying the DNA aptamer sequence for modification comprises identifying a motif of coaxially stacked stem structures in a quasi- continuous helix ranging between 11-14 base pairs and / or determining a predicted conformational stability of the DNA aptamer sequence when all 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer sequence are replaced with 2'-O-methyluridine-3’-phosphate.

35. The method of any one of claims 27-34, wherein the method is performed in silico.

36. The method of claim 35, further comprising synthesizing the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues.

37. The method of any one of claims 27-36, wherein the DNA aptamer and the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues each possesses a 5'-terminus and a 3'-terminus.Attorney Docket No.: BN00023.0071 38. The method of claim 37, further comprising extending the 5'-terminus, the 3'-terminus, or both termini of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues by one or more nucleotides, optionally wherein both termini are extended, optionally wherein the nucleotides of one terminal extension of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues and possessing terminal extensions form Watson-Crick base pairs with one or more nucleotides of another terminal extension of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues and possessing terminal extensions.

39. The method of claim 38, wherein the terminal extension nucleotides are selected according to their combined free energy (ΔG) in forming a stem structure, optionally wherein the stem structure having the terminal extension nucleotides has negative free energy substantially less negative than the respective binding of the oligoribonucleotide having 2'-O-methyluridine- 3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues with a target and / or optionally wherein the stem structure comprising the terminal extension nucleotides has negative free energy of -10 kcal / mol or less and a Tmof 37 ℃ or more, optionally as determined by the "two state melting hybridisation" mfold algorithm with energy rule settings of RNA, 37 ℃, 215 mM NaCl; 5 mM Mg and 0.00005 µM RNA.

40. The method of any one of claims 37-39, wherein the 5'-terminus or 3'-terminus of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues that optionally comprises one or more nucleotide extension of the 5'-terminus or 3'-terminus further comprises a fluorescent moiety, a lanthanide or a quenching moiety, optionally wherein the fluorescent moiety, lanthanide or quenching moiety is attached to a terminal nucleotide of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of the terminally extended oligoribonucleotide havingAttorney Docket No.: BN00023.0071 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues, optionally wherein the fluorescent moiety, lanthanide or quenching moiety is covalently attached.

41. The method of claim 40, wherein the oligoribonucleotide having 2'-O-methyluridine-3’- phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues comprises both a fluorescent moiety or a lanthanide and a quenching moiety.

42. The method of claim 40 or claim 41, wherein the fluorescent moiety or lanthanide is attached to a 5'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine- 3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues.

43. The method of claim 40 or claim 41, wherein the fluorescent moiety or lanthanide is attached to a 3'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine- 3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues.

44. The method of claim 40 or claim 41, wherein the quenching moiety is attached to a 5'- terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of the terminally extended oligoribonucleotideAttorney Docket No.: BN00023.0071 having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues.

45. The method of claim 40 or claim 41, wherein the quenching moiety is attached to a 3'- terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues.

46. The method of claim 41, wherein the fluorescent moiety or lanthanide is attached to a 5'- terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues and the quenching moiety is attached to a 3'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues.

47. The method of claim 41, wherein the fluorescent moiety or lanthanide is attached to a 3'- terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues and the quenching moiety is attached to a 5'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of theAttorney Docket No.: BN00023.0071 terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues.

48. The method of any one of claims 40-47, wherein the fluorescent moiety is selected from the group consisting of Atto 495, Atto 390, Atto 425, Atto 465, Atto 488, Atto 520, Atto 532, Atto 550, Atto 565, Atto 590, Atto 594, Atto 620, Atto 633, Atto 647N, Atto 655, Atto RhoG6, Atto Rholl, Atto Rhol2, Atto RholOl, 5- or 6-carboxyfluorescein (FAM™), VIC™, NED™, fluorescein, fluorescein isothiocyanate (FITC), IRDYE-700 / 800, cyanine dyes, such as CY3™, CY5™, CY3.5™, CY5.5™, Cy7™, xanthen, 6-carboxy-2',4',7',4,7- hexachlorofluorescein (HEX), 6-carboxy-l,4-dichloro-2',7'-dichloro-fluorescein (TET®), 6- carboxy-4',5'-dichloro-2',7'- dimethodyfluorescein (JOE™), N,N,N',N'-tetramethyl-6- carboxyrhodamine (TAMRA™), 6- carboxy-X-rhodamine (ROX), 5-carboxyrhodamine-6G (R6G5), 6-carboxyrhodamine-6G (RG6), rhodamine, rhodamine green, rhodamine red, rhodamine 110, Rhodamin 6G®, BODIPY dyes, such as BODIPY TMR, Oregon green, coumarines, such as umbelliferone, benzimides, such as Hoechst 33258; phenanthridines, such as Texas Red®, California Red®, Yakima Yellow, Alexa Fluor® 350, Alexa Fluor® 405, Alexa Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 500, Alexa Fluor® 514, Alexa Fluor®532, Alexa Fluor® 546, Alexa Fluor® 555, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 610, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Fluor® 680, Alexa Fluor® 700, Alexa Fluor® 750, PET®, ethidium bromide, acridinium dyes, carbazol dyes, phenoxazine dyes, porphyrine dyes, polymethin dyes, BMN™-5, BMN™- 6, BMN™ Q620, CEQ8000 D2, CEQ8000 D3, CEQ8000 D4, DY-480XL, DY-485XL, DY-495, DY-505, DY-510XL, DY-521XL, DY-521XL, DY-530, DY-547, DY-550, DY- 555, DY-610, DY-615, DY-630, DY-631, DY-633, DY-635, DY-647, DY-651, DY-675, DY-676, DY-680, DY-681, DY-700, DY-701, DY-730, DY-731, DY-732, DY-750, DY-751, DY-776, DY-780, DY-781, DY-782, 6-carboxy-4',5'-dichloro-2',7'-dimethoxyfluorescein (JOE), TET™, CAL Fluor® Gold 540, CAL Fluor RED 590, CAL Fluor Red 610, CAL Fluor Red 635, IRDye® 700Dx, IRDye® 800CW, Marina Blue®, Pacific Blue®, Yakima Yellow®, 6-(4,7-Dichloro-2',7'- diphenyl-3',6'-dipivaloylfluorescein-6-carboxamido)-hexyl-l-0-(2-cyanoethyl)-(N,N- diisopropyl)-phosphoramidite (SIMA), CAL Fluor® Gold 540, CAL Fluor® Orange 560, CAL Fluor Red 635, Quasar 570, Quasar 670, LIZ, Sunnyvale Red, LC Red® 610, LC Red® 640, LC Red® 670, LC Red® 705 and a squaraine dye.Attorney Docket No.: BN00023.0071 49. The method of any one of claims 40-48, wherein the quenching moiety is selected from the group consisting of TAMRA and a dark quencher, optionally wherein the dark quencher is selected from the group consisting of Black Hole Quencher 1, 3' (BHQ1), DQ, dimethylaminoazobenzenesulfonic acid (DABCYL) and Iowa Black® (IWB).

50. The method of any one of claims 38-49, wherein the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues is capable of binding the same target polypeptide as the DNA aptamer.

51. The method of claim 50, wherein the terminally extended oligoribonucleotide having 2'- O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues possesses improved binding properties for the target polypeptide, as compared to the DNA aptamer, as compared to the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues in the absence of terminal extension(s), or as compared to both.

52. The method of claim 51, wherein the improved binding properties for the target polypeptide are selected from the group consisting of higher binding affinity for the target polypeptide and immediate signal generation upon binding to the target polypeptide in a sample.

53. The method of claim 52, wherein the sample is selected from the group consisting of a blood sample, a sputum sample, a cerebrospinal fluid (CSF) sample, an aspirate sample, section sample, a biopsy sample and a distinct body fluid sample, optionally wherein the sample is a crude sample.

54. The method of any one of claims 28-53, wherein the change in Gibbs free energy (ΔG) value(s) associated with the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphateAttorney Docket No.: BN00023.0071 nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues binding the target polypeptide is significantly less than the ΔG value(s) associated with the DNA aptamer binding the target polypeptide.

55. The method of any one of claims 28-54, wherein the target polypeptide is a prion-like protein, optionally wherein the prion-like protein is selected from the group consisting of TDP- 43, Tau, beta-amyloid, alpha-synuclein, optineurin, prion protein (PrP), and other proteins with prion-like domains involved in liquid-liquid phase separation, optionally wherein the target polypeptide is human Tau.

56. The method of claim 55, wherein the oligoribonucleotide having 2'-O-methyluridine-3’- phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues selectively binds Tau441 of SEQ ID NO: 1, optionally wherein the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or the terminally extended oligoribonucleotide having 2'-O- methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues selectively binds phosphorylated T231 in the Tau441 sequence of SEQ ID NO:

1.

57. A method for generating a RNA affinity probe (RAP), the method comprising: a) identifying a DNA aptamer sequence having a 5'-terminus and a 3'-terminus, wherein the DNA aptamer is capable of binding a target polypeptide; b) replacing all 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer sequence with 2'-O-methyluridine-3’-phosphate nucleotide residues; c) replacing all remaining deoxyribonucleotide residues of the DNA aptamer with modified ribonucleotides, thereby forming an oligoribonucleotide having 2'-O-methyluridine-3’- phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNAAttorney Docket No.: BN00023.0071 aptamer and modified ribonucleotides at all residues and possessing a 5'-terminus and a 3'- terminus; d) extending the 5'-terminus, the 3'-terminus, or both termini of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues by one or more nucleotide residues, thereby forming a terminally extended oligoribonucleotide having 2'- O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues, wherein the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues further comprises a fluorescent moiety, thereby generating a RNA affinity probe (RAP).

58. The method of claim 57, wherein the RAP is capable of binding the target polypeptide.

59. The method of claim 58, wherein the RAP possesses improved binding properties for the target polypeptide, as compared to the DNA aptamer.

60. The method of claim 59, wherein the improved binding properties for the target polypeptide are selected from the group consisting of higher predicted binding affinity for the target polypeptide, higher measured binding affinity for the target polypeptide and immediate signal generation upon binding to the target polypeptide in a sample.

61. The method of claim 60, wherein the sample is selected from the group consisting of a blood sample, a sputum sample, a cerebrospinal fluid (CSF) sample, an aspirate sample, section sample, a biopsy sample and a distinct body fluid sample, optionally wherein the sample is a crude sample.

62. The method of claim 57, wherein the DNA aptamer and corresponding RAP are identified via an iterative process that increases the binding capability of the RAP relative to the DNA aptamer, optionally wherein the DNA aptamer is predicted to have multiple conformational options possessing similar free energy levels and the RAP is predicted to form a stable structure.

63. The method of any one of claims 57-62, wherein the method is performed in silico.Attorney Docket No.: BN00023.0071 64. The method of claim 63, further comprising synthesizing the RAP.

65. The method of claim 57, wherein the terminal extension nucleotides are selected according to their combined free energy (ΔG) in forming a stem structure, optionally wherein the stem structure having the terminal extension nucleotides has negative free energy substantially less negative than the respective binding of the oligoribonucleotide having 2'-O-methyluridine- 3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues with a target and / or optionally wherein the stem structure comprising the terminal extension nucleotides has negative free energy of -10 kcal / mol or less and a Tmof 37 ℃ or more, optionally as determined by the "two state melting hybridisation" mfold algorithm with energy rule settings of RNA, 37 ℃, 215 mM NaCl; 5 mM Mg and 0.00005 µM RNA.

66. The method of any one of claims 57-65, wherein the fluorescent moiety is attached to a 5'-terminal nucleotide residue of the RAP.

67. The method of any one of claims 57-65, wherein the fluorescent moiety is attached to a 3'-terminal nucleotide residue of the RAP.

68. The method of any one of claims 57-67, wherein the RAP further comprises a quenching moiety.

69. The method of claim 68, wherein the quenching moiety is attached to a 5'-terminal nucleotide residue of the RAP.

70. The method of claim 68, wherein the quenching moiety is attached to a 3'-terminal nucleotide residue of the RAP.

71. The method of any one of claims 57-70, wherein the fluorescent moiety is selected from the group consisting of Atto 495, Atto 390, Atto 425, Atto 465, Atto 488, Atto 520, Atto 532, Atto 550, Atto 565, Atto 590, Atto 594, Atto 620, Atto 633, Atto 647N, Atto 655, Atto RhoG6, Atto Rholl, Atto Rhol2, Atto RholOl, 5- or 6-carboxyfluorescein (FAM™), VIC™, NED™, fluorescein, fluorescein isothiocyanate (FITC), IRDYE-700 / 800, cyanine dyes, such as CY3™, CY5™, CY3.5™, CY5.5™, Cy7™, xanthen, 6-carboxy-2',4',7',4,7- hexachlorofluoresceinAttorney Docket No.: BN00023.0071 (HEX), 6-carboxy-l,4-dichloro-2',7'-dichloro-fluorescein (TET®), 6- carboxy-4',5'-dichloro-2',7'- dimethodyfluorescein (JOE™), N,N,N',N'-tetramethyl-6- carboxyrhodamine (TAMRA™), 6- carboxy-X-rhodamine (ROX), 5-carboxyrhodamine-6G (R6G5), 6-carboxyrhodamine-6G (RG6), rhodamine, rhodamine green, rhodamine red, rhodamine 110, Rhodamin 6G®, BODIPY dyes, such as BODIPY TMR, Oregon green, coumarines, such as umbelliferone, benzimides, such as Hoechst 33258; phenanthridines, such as Texas Red®, California Red®, Yakima Yellow, Alexa Fluor® 350, Alexa Fluor® 405, Alexa Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 500, Alexa Fluor® 514, Alexa Fluor®532, Alexa Fluor® 546, Alexa Fluor® 555, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 610, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Fluor® 680, Alexa Fluor® 700, Alexa Fluor® 750, PET®, ethidium bromide, acridinium dyes, carbazol dyes, phenoxazine dyes, porphyrine dyes, polymethin dyes, BMN™-5, BMN™- 6, BMN™ Q620, CEQ8000 D2, CEQ8000 D3, CEQ8000 D4, DY-480XL, DY-485XL, DY-495, DY-505, DY-510XL, DY-521XL, DY-521XL, DY-530, DY-547, DY-550, DY- 555, DY-610, DY-615, DY-630, DY-631, DY-633, DY-635, DY-647, DY-651, DY-675, DY-676, DY-680, DY-681, DY-700, DY-701, DY-730, DY-731, DY-732, DY-750, DY-751, DY-776, DY-780, DY-781, DY-782, 6-carboxy-4',5'-dichloro-2',7'-dimethoxyfluorescein (JOE), TET™, CAL Fluor® Gold 540, CAL Fluor RED 590, CAL Fluor Red 610, CAL Fluor Red 635, IRDye® 700Dx, IRDye® 800CW, Marina Blue®, Pacific Blue®, Yakima Yellow®, 6-(4,7-Dichloro-2',7'- diphenyl-3',6'-dipivaloylfluorescein-6-carboxamido)-hexyl-l-0-(2-cyanoethyl)-(N,N- diisopropyl)-phosphoramidite (SIMA), CAL Fluor® Gold 540, CAL Fluor® Orange 560, CAL Fluor Red 635, Quasar 570, Quasar 670, LIZ, Sunnyvale Red, LC Red® 610, LC Red® 640, LC Red® 670, LC Red® 705 and a squaraine dye.

72. The method of any one of claims 68-71, wherein the quenching moiety is selected from the group consisting of TAMRA and a dark quencher, optionally wherein the dark quencher is selected from the group consisting of Black Hole Quencher 1, 3' (BHQ1), DQ, dimethylaminoazobenzenesulfonic acid (DABCYL) and Iowa Black® (IWB).

73. The method of any one of claims 68-72, wherein the change in Gibbs free energy (ΔG) value(s) associated with the RAP binding the target polypeptide is significantly less than the ΔG value(s) associated with the DNA aptamer binding the target polypeptide.Attorney Docket No.: BN00023.0071 74. The method of any one of claims 68-73, wherein the target polypeptide is a prion-like protein, optionally wherein the prion-like protein is selected from the group consisting of TDP- 43, Tau, beta-amyloid, alpha-synuclein, optineurin, prion protein (PrP), and other proteins with prion-like domains involved in liquid-liquid phase separation, optionally wherein the target polypeptide is human Tau.

75. The method of any one of claims 68-74, wherein the RAP selectively binds Tau441 of SEQ ID NO: 1, optionally wherein the RAP selectively binds phosphorylated T231 in the Tau441 sequence of SEQ ID NO: 1, as compared to binding of non-phosphorylated Tau441.

76. An array of RAPs generated by the method of claim 68, optionally wherein the array of RAPs comprises two or more RAPs that bind distinct target polypeptides from one another, optionally wherein two or more RAPs comprise distinct fluorescent moieties and / or quenching moieties from one another, optionally wherein the array of RAPs is arranged in a 96-well array or a 384-well array format.

77. A method for improving one or more target polypeptide binding properties of a DNA aptamer capable of selectively binding a target polypeptide, the method comprising replacing all 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer sequence with 2'-O- methyluridine-3’-phosphate residues and all remaining nucleotide residues with modified ribonucleotides, thereby forming an oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified oligoribonucleotides at all residues and possessing one or more improved target polypeptide binding properties as compared to the DNA aptamer.

78. The method of claim 77, wherein the one or more target polypeptide binding properties are selected from the group consisting of higher predicted binding affinity for the target polypeptide, higher measured binding affinity for the target polypeptide and immediate signal generation upon binding to the target polypeptide in a sample.

79. The method of claim 78, wherein the sample is selected from the group consisting of a blood sample, a sputum sample, a cerebrospinal fluid (CSF) sample, an aspirate sample, sectionAttorney Docket No.: BN00023.0071 sample, a biopsy sample and a distinct body fluid sample, optionally wherein the sample is a crude sample.

80. The method of claim 77, wherein the DNA aptamer and corresponding RAP are identified via an iterative process that increases the binding capability of the RAP relative to the DNA aptamer, optionally wherein the DNA aptamer is predicted to have multiple conformational options possessing similar free energy levels and the RAP is predicted to form a stable structure.

81. The method of any one of claims 77-80, wherein the method is performed in silico.

82. The method of claim any one of claims 77-81, further comprising synthesizing the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues and modified ribonucleotides at all residues.

83. The method of any one of claims 77-82, wherein the DNA aptamer and the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues each possesses a 5'-terminus and a 3'-terminus.

84. The method of claim 83, further comprising extending the 5'-terminus, the 3'-terminus, or both termini of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues by one or more nucleotides, optionally wherein both termini are extended, optionally wherein the nucleotides of one terminal extension of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues and possessing terminal extensions Watson-Crick base pair with one or more nucleotides of another terminal extension of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues and possessing terminal extensions.

85. The method of claim 84, wherein the terminal extension nucleotides are selected according to their combined free energy (ΔG) in forming a stem structure, optionally wherein the stem structure comprising the terminal extension nucleotides has negative free energy of -10 kcal / molAttorney Docket No.: BN00023.0071 or less and a Tmof 37 ^ or more, optionally as determined by the "two state melting hybridisation" mfold algorithm with energy rule settings of RNA, 37 ^, 215 mM NaCl; 5 mM Mg and 0.00005 µM RNA.

86. The method of claim 77, wherein the oligoribonucleotide having 2'-O-methyluridine-3’- phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues and possessing one or more improved target polypeptide binding properties as compared to the DNA aptamer further comprises a moiety selected from the group consisting of a moiety having electrostatic properties and capable of closing or generating a stem structure in the oligoribonucleotide, disulfide bridges (S-S) capable of closing or generating a stem structure in the oligoribonucleotide, and amino acids or short peptides capable of stabilizing a stem structure in the oligoribonucleotide.

87. The method of any one of claims 84-86, wherein the 5'-terminus or 3'-terminus of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues that optionally comprises one or more nucleotide extension of the 5'-terminus or 3'-terminus further comprises a fluorescent moiety or a quenching moiety, optionally wherein the fluorescent moiety or quenching moiety is attached to a terminal nucleotide of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of the terminally extended oligoribonucleotide having 2'-O- methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues, optionally wherein the fluorescent moiety or quenching moiety is covalently attached.

88. The method of claim 87, wherein the oligoribonucleotide having 2'-O-methyluridine-3’- phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues comprises both a fluorescent moiety and a quenching moiety.Attorney Docket No.: BN00023.0071 89. The method of claim 87 or claim 88, wherein the fluorescent moiety is attached to a 5'- terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues.

90. The method of claim 87 or claim 88, wherein the fluorescent moiety is attached to a 3'- terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues.

91. The method of claim 87 or claim 88, wherein the quenching moiety is attached to a 5'- terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues.

92. The method of claim 87 or claim 88, wherein the quenching moiety is attached to a 3'- terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues.

93. The method of claim 88, wherein the fluorescent moiety is attached to a 5'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphateAttorney Docket No.: BN00023.0071 nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues and the quenching moiety is attached to a 3'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues.

94. The method of claim 88, wherein the fluorescent moiety is attached to a 3'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues and the quenching moiety is attached to a 5'-terminal nucleotide residue of the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or of the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues.

95. The method of any one of claims 87-94, wherein the fluorescent moiety is selected from the group consisting of Atto 495, Atto 390, Atto 425, Atto 465, Atto 488, Atto 520, Atto 532, Atto 550, Atto 565, Atto 590, Atto 594, Atto 620, Atto 633, Atto 647N, Atto 655, Atto RhoG6, Atto Rholl, Atto Rhol2, Atto RholOl, 5- or 6-carboxyfluorescein (FAM™), VIC™, NED™, fluorescein, fluorescein isothiocyanate (FITC), IRDYE-700 / 800, cyanine dyes, such as CY3™, CY5™, CY3.5™, CY5.5™, Cy7™, xanthen, 6-carboxy-2',4',7',4,7- hexachlorofluorescein (HEX), 6-carboxy-l,4-dichloro-2',7'-dichloro-fluorescein (TET®), 6- carboxy-4',5'-dichloro-2',7'- dimethodyfluorescein (JOE™), N,N,N',N'-tetramethyl-6- carboxyrhodamine (TAMRA™), 6- carboxy-X-rhodamine (ROX), 5-carboxyrhodamine-6G (R6G5), 6-carboxyrhodamine-6G (RG6), rhodamine, rhodamine green, rhodamine red, rhodamine 110, Rhodamin 6G®, BODIPY dyes, such as BODIPY TMR, Oregon green, coumarines, such as umbelliferone, benzimides,Attorney Docket No.: BN00023.0071 such as Hoechst 33258; phenanthridines, such as Texas Red®, California Red®, Yakima Yellow, Alexa Fluor® 350, Alexa Fluor® 405, Alexa Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 500, Alexa Fluor® 514, Alexa Fluor®532, Alexa Fluor® 546, Alexa Fluor® 555, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 610, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Fluor® 680, Alexa Fluor® 700, Alexa Fluor® 750, PET®, ethidium bromide, acridinium dyes, carbazol dyes, phenoxazine dyes, porphyrine dyes, polymethin dyes, BMN™-5, BMN™- 6, BMN™ Q620, CEQ8000 D2, CEQ8000 D3, CEQ8000 D4, DY-480XL, DY-485XL, DY-495, DY-505, DY-510XL, DY-521XL, DY-521XL, DY-530, DY-547, DY-550, DY- 555, DY-610, DY-615, DY-630, DY-631, DY-633, DY-635, DY-647, DY-651, DY-675, DY-676, DY-680, DY-681, DY-700, DY-701, DY-730, DY-731, DY-732, DY-750, DY-751, DY-776, DY-780, DY-781, DY-782, 6-carboxy-4',5'-dichloro-2',7'-dimethoxyfluorescein (JOE), TET™, CAL Fluor® Gold 540, CAL Fluor RED 590, CAL Fluor Red 610, CAL Fluor Red 635, IRDye® 700Dx, IRDye® 800CW, Marina Blue®, Pacific Blue®, Yakima Yellow®, 6-(4,7-Dichloro-2',7'- diphenyl-3',6'-dipivaloylfluorescein-6-carboxamido)-hexyl-l-0-(2-cyanoethyl)-(N,N- diisopropyl)-phosphoramidite (SIMA), CAL Fluor® Gold 540, CAL Fluor® Orange 560, CAL Fluor Red 635, Quasar 570, Quasar 670, LIZ, Sunnyvale Red, LC Red® 610, LC Red® 640, LC Red® 670, LC Red® 705 and a squaraine dye.

96. The method of any one of claims 87-95, wherein the quenching moiety is selected from the group consisting of TAMRA and a dark quencher, optionally wherein the dark quencher is selected from the group consisting of Black Hole Quencher 1, 3' (BHQ1), DQ, dimethylaminoazobenzenesulfonic acid (DABCYL) and Iowa Black® (IWB).

97. The method of any one of claims 87-96, wherein the oligonucleotide is detected using a photovoltaic device.

98. The method of any one of claims 77-97, wherein the change in Gibbs free energy (ΔG) value(s) associated with the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues binding theAttorney Docket No.: BN00023.0071 target polypeptide is significantly less than the ΔG value(s) associated with the DNA aptamer binding the target polypeptide.

99. The method of any one of claims 77-98, wherein the target polypeptide is a prion-like protein, optionally wherein the prion-like protein is selected from the group consisting of TDP- 43, Tau, beta-amyloid, alpha-synuclein, optineurin, prion protein (PrP), and other proteins with prion-like domains involved in liquid-liquid phase separation, optionally wherein the target polypeptide is human Tau.

100. The method of claim 99, wherein the oligoribonucleotide having 2'-O-methyluridine-3’- phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or the terminally extended oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues selectively binds Tau441 of SEQ ID NO: 1, optionally wherein the oligoribonucleotide having 2'-O-methyluridine-3’-phosphate residues at all former 2`- deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues or the terminally extended oligoribonucleotide having 2'-O- methyluridine-3’-phosphate residues at all former 2`-deoxythymidine-3`-phosphate nucleotide residues of the DNA aptamer and modified ribonucleotides at all residues selectively binds phosphorylated T231 in the Tau441 sequence of SEQ ID NO: 1, as compared to binding of non- phosphorylated Tau441.

101. A composition comprising a nucleic acid having a 5'-terminus and a 3'-terminus and comprising the sequence: CAGCACCGUCAACUGAAUAAGGACUGCUUAGGAUUGCGAUGAUUCAGGGUGAUG CGAUGGAGAUGU (SEQ ID NO: 10), wherein each "U" residue is a 2'-O-methyluridine-3’- phosphate or CAGCACCGUCAACUGAAUAAGGACUGCUUAGGAUUGCGAUGAU UCAGGGUGAUGCGAUGGAGAUGU (SEQ ID NO: 30), wherein each "U" residue is a 2'-O- methyluridine-3’-phosphate and all other residues are 2’-O-methyl ribonucleotides 102. The composition of claim 101, comprising the nucleic acid sequence:Attorney Docket No.: BN00023.0071 5'- ACAUCUCAGCACCGUCAACUGAAUAAGGACUGCUUAGGAUUGCGAUGAUUCAGG GUGAUGCGAUGGAGAUGU-3' (SEQ ID NO: 11), wherein each "U" residue is a 2'-O- methyluridine-3’-phosphate or 5'-ACAUCUCAGCACCGUCAACUGAAUAAGGACUGCUUAGGAUUGCGAUGAUU CAGGGUGAUGCGAUGGAGAUGU-3' (SEQ ID NO: 31), wherein each "U" residue is a 2'-O- methyluridine-3’-phosphate and all other residues are 2’-O-methyl ribonucleotides.

103. The composition of claim 101 or claim 102, wherein the 3'-terminus, the 5'-terminus, or both the 3'-terminus and the 5'-terminus is attached to a fluorescent moiety, optionally wherein the fluorescent moiety is selected from the group consisting of Atto 495, Atto 390, Atto 425, Atto 465, Atto 488, Atto 520, Atto 532, Atto 550, Atto 565, Atto 590, Atto 594, Atto 620, Atto 633, Atto 647N, Atto 655, Atto RhoG6, Atto Rholl, Atto Rhol2, Atto RholOl, 5- or 6- carboxyfluorescein (FAM™), VIC™, NED™, fluorescein, fluorescein isothiocyanate (FITC), IRDYE-700 / 800, cyanine dyes, such as CY3™, CY5™, CY3.5™, CY5.5™, Cy7™, xanthen, 6- carboxy-2',4',7',4,7- hexachlorofluorescein (HEX), 6-carboxy-l,4-dichloro-2',7'-dichloro- fluorescein (TET®), 6- carboxy-4',5'-dichloro-2',7'-dimethodyfluorescein (JOE™), N,N,N',N'- tetramethyl-6- carboxyrhodamine (TAMRA™), 6-carboxy-X-rhodamine (ROX), 5- carboxyrhodamine-6G (R6G5), 6-carboxyrhodamine-6G (RG6), rhodamine, rhodamine green, rhodamine red, rhodamine 110, Rhodamin 6G®, BODIPY dyes, such as BODIPY TMR, Oregon green, coumarines, such as umbelliferone, benzimides, such as Hoechst 33258; phenanthridines, such as Texas Red®, California Red®, Yakima Yellow, Alexa Fluor® 350, Alexa Fluor® 405, Alexa Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 500, Alexa Fluor® 514, Alexa Fluor®532, Alexa Fluor® 546, Alexa Fluor® 555, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 610, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Fluor® 680, Alexa Fluor® 700, Alexa Fluor® 750, PET®, ethidium bromide, acridinium dyes, carbazol dyes, phenoxazine dyes, porphyrine dyes, polymethin dyes, BMN™-5, BMN™-6, BMN™ Q620, CEQ8000 D2, CEQ8000 D3, CEQ8000 D4, DY-480XL, DY-485XL, DY-495, DY-505, DY-510XL, DY- 521XL, DY-521XL, DY-530, DY-547, DY-550, DY- 555, DY-610, DY-615, DY-630, DY-631, DY-633, DY-635, DY-647, DY-651, DY-675, DY-676, DY-680, DY-681, DY-700, DY-701, DY-730, DY-731, DY-732, DY-750, DY-751, DY-776, DY-780, DY-781, DY-782, 6-carboxy- 4',5'-dichloro-2',7'-dimethoxyfluorescein (JOE), TET™, CAL Fluor® Gold 540, CAL Fluor REDAttorney Docket No.: BN00023.0071 590, CAL Fluor Red 610, CAL Fluor Red 635, IRDye® 700Dx, IRDye® 800CW, Marina Blue®, Pacific Blue®, Yakima Yellow®, 6-(4,7-Dichloro-2',7'-diphenyl-3',6'-dipivaloylfluorescein-6- carboxamido)-hexyl-l-0-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite (SIMA), CAL Fluor® Gold 540, CAL Fluor® Orange 560, CAL Fluor Red 635, Quasar 570, Quasar 670, LIZ, Sunnyvale Red, LC Red® 610, LC Red® 640, LC Red® 670, LC Red® 705 and a squaraine dye.

104. The composition of any one of claims 101-103, wherein the 3'-terminus, the 5'-terminus, or both the 3'-terminus and the 5'-terminus is attached to a quenching moiety, optionally wherein the quenching moiety is selected from the group consisting of TAMRA and a dark quencher, optionally wherein the dark quencher is selected from the group consisting of Black Hole Quencher 1, 3' (BHQ1), DQ, dimethylaminoazobenzenesulfonic acid (DABCYL) and Iowa Black® (IWB).

105. A composition comprising a nucleic acid having a 5'-terminus and a 3'-terminus and comprising the sequence: 5’-CAGCACCGUCAACUGAAUGGGGAGAGUGGUGGGGCGGGGGCCGGAUCCGUGA UGCGAUGGAGAUGU-3’ (SEQ ID NO: 13), wherein each "U" residue is a 2'-O-methyluridine- 3’-phosphate or CAGCACCGUCAACUGAAUGGGGAGAGUGGUGGGGCGGGGGCCGG AUCCGUGAUGCGAUGGAGAUGU (SEQ ID NO: 13), wherein each "U" residue is a 2'-O- methyluridine-3’-phosphate and all other residues are 2’-O-methyl ribonucleotides.

106. The composition of claim 105, comprising the nucleic acid sequence: 5'-ACAUCAGCACCGUCAACUGAAUGGGGAGAGUGGUGGGGCGGGGGCCGGAUC CGUGAUGCGAUGGAGAUGU-3' (SEQ ID NO: 14), wherein each "U" residue is a 2'-O- methyluridine-3’-phosphate or 5'-ACAUCAGCACCGUCAACUGAAUGGGGAGAGUGG UGGGGCGGGGGCCGGAUC CGUGAUGCGAUGGAGAUGU-3' (SEQ ID NO: 33), wherein each "U" residue is a 2'-O-methyluridine-3’-phosphate and all other residues are 2’-O-methyl ribonucleotides.

107. The composition of claim 105 or claim 106, wherein the 3'-terminus, the 5'-terminus, or both the 3'-terminus and the 5'-terminus is attached to a fluorescent moiety, optionally wherein the fluorescent moiety is selected from the group consisting of Atto 495, Atto 390, Atto 425, Atto 465, Atto 488, Atto 520, Atto 532, Atto 550, Atto 565, Atto 590, Atto 594, Atto 620, Atto 633,Attorney Docket No.: BN00023.0071 Atto 647N, Atto 655, Atto RhoG6, Atto Rholl, Atto Rhol2, Atto RholOl, 5- or 6- carboxyfluorescein (FAM™), VIC™, NED™, fluorescein, fluorescein isothiocyanate (FITC), IRDYE-700 / 800, cyanine dyes, such as CY3™, CY5™, CY3.5™, CY5.5™, Cy7™, xanthen, 6- carboxy-2',4',7',4,7- hexachlorofluorescein (HEX), 6-carboxy-l,4-dichloro-2',7'-dichloro- fluorescein (TET®), 6- carboxy-4',5'-dichloro-2',7'-dimethodyfluorescein (JOE™), N,N,N',N'- tetramethyl-6- carboxyrhodamine (TAMRA™), 6-carboxy-X-rhodamine (ROX), 5- carboxyrhodamine-6G (R6G5), 6-carboxyrhodamine-6G (RG6), rhodamine, rhodamine green, rhodamine red, rhodamine 110, Rhodamin 6G®, BODIPY dyes, such as BODIPY TMR, Oregon green, coumarines, such as umbelliferone, benzimides, such as Hoechst 33258; phenanthridines, such as Texas Red®, California Red®, Yakima Yellow, Alexa Fluor® 350, Alexa Fluor® 405, Alexa Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 500, Alexa Fluor® 514, Alexa Fluor®532, Alexa Fluor® 546, Alexa Fluor® 555, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 610, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Fluor® 680, Alexa Fluor® 700, Alexa Fluor® 750, PET®, ethidium bromide, acridinium dyes, carbazol dyes, phenoxazine dyes, porphyrine dyes, polymethin dyes, BMN™-5, BMN™-6, BMN™ Q620, CEQ8000 D2, CEQ8000 D3, CEQ8000 D4, DY-480XL, DY-485XL, DY-495, DY-505, DY-510XL, DY- 521XL, DY-521XL, DY-530, DY-547, DY-550, DY- 555, DY-610, DY-615, DY-630, DY-631, DY-633, DY-635, DY-647, DY-651, DY-675, DY-676, DY-680, DY-681, DY-700, DY-701, DY-730, DY-731, DY-732, DY-750, DY-751, DY-776, DY-780, DY-781, DY-782, 6-carboxy- 4',5'-dichloro-2',7'-dimethoxyfluorescein (JOE), TET™, CAL Fluor® Gold 540, CAL Fluor RED 590, CAL Fluor Red 610, CAL Fluor Red 635, IRDye® 700Dx, IRDye® 800CW, Marina Blue®, Pacific Blue®, Yakima Yellow®, 6-(4,7-Dichloro-2',7'-diphenyl-3',6'-dipivaloylfluorescein-6- carboxamido)-hexyl-l-0-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite (SIMA), CAL Fluor® Gold 540, CAL Fluor® Orange 560, CAL Fluor Red 635, Quasar 570, Quasar 670, LIZ, Sunnyvale Red, LC Red® 610, LC Red® 640, LC Red® 670, LC Red® 705 and a squaraine dye.

108. The composition of any one of claims 105-107, wherein the 3'-terminus, the 5'-terminus, or both the 3'-terminus and the 5'-terminus is attached to a quenching moiety, optionally wherein the quenching moiety is selected from the group consisting of TAMRA and a dark quencher, optionally wherein the dark quencher is selected from the group consisting of Black Hole Quencher 1, 3' (BHQ1), DQ, dimethylaminoazobenzenesulfonic acid (DABCYL) and Iowa Black® (IWB).Attorney Docket No.: BN00023.0071 109. The composition of any one of claims 105-108, wherein the composition binds both T231 and T231P peptides with high affinity.

110. A composition comprising a nucleic acid having a 5'-terminus and a 3'-terminus and comprising the sequence: CAGCACCGUCAACUGAAUGGGUUGGCCGGGCAGCGGGGGGUAGGCUUGGUGAUG CGAUGGAGAUGU (SEQ ID NO: 16), wherein each "U" residue is a 2'-O-methyluridine-3’- phosphate, or or or CAGCACCGUCAACUGAAUGGGUUGGCCGGGCAGCGGGGGGUAGGCUUGGUGAUG CGAUGGAGAUGU (SEQ ID NO: 16), wherein each "U" residue is a 2'-O-methyluridine-3’- phosphate and all other residues are modified ribonucleotides, or CAGCACCGUCAACUGAAUGGGUUGGCCGGGCAGCGGGGGGUAGGCUUGGUGA UGCGAUGGAGAUGU (SEQ ID NO: 34), wherein each "U" residue is a 2'-O-methyluridine- 3’-phosphate and all other residues are 2’-O-methyl ribonucleotides.

111. The composition of claim 110, comprising the nucleic acid sequence: 5'-AACACAUCAGCACCGUCAACUGAAUGGGUUGGCCGGGCAGCGGG GGGUAGGCUUGGUGAUGCGAUGGAGAUGUGUU-3' (SEQ ID NO: 17), wherein each "U" residue is a 2'-O-methyluridine-3’-phosphate, or 5'-AACACAUCAGCACCGUCAACUGAA UGGGUUGGCCGGGCAGCGGGGGGUAGGCUUGGUGAUGCGAUGGAGAUGUGUU-3' (SEQ ID NO: 17), wherein each "U" residue is a 2'-O-methyluridine-3’-phosphate and all other residues are modified ribonucleotides, or 5'-AACACAUCAGCACCGUCAACUGAA UGGGUUGGCCGGGCAGCGGGGGGUAGGCUUGGUGAUGCGAUGGAGAUGUGUU-3' (SEQ ID NO: 35), wherein each "U" residue is a 2'-O-methyluridine-3’-phosphate.

112. The composition of claim 110 or claim 111, wherein the 3'-terminus, the 5'-terminus, or both the 3'-terminus and the 5'-terminus is attached to a fluorescent moiety, optionally wherein the fluorescent moiety is selected from the group consisting of Atto 495, Atto 390, Atto 425, Atto 465, Atto 488, Atto 520, Atto 532, Atto 550, Atto 565, Atto 590, Atto 594, Atto 620, Atto 633, Atto 647N, Atto 655, Atto RhoG6, Atto Rholl, Atto Rhol2, Atto RholOl, 5- or 6- carboxyfluorescein (FAM™), VIC™, NED™, fluorescein, fluorescein isothiocyanate (FITC), IRDYE-700 / 800, cyanine dyes, such as CY3™, CY5™, CY3.5™, CY5.5™, Cy7™, xanthen, 6-Attorney Docket No.: BN00023.0071 carboxy-2',4',7',4,7- hexachlorofluorescein (HEX), 6-carboxy-l,4-dichloro-2',7'-dichloro- fluorescein (TET®), 6- carboxy-4',5'-dichloro-2',7'-dimethodyfluorescein (JOE™), N,N,N',N'- tetramethyl-6- carboxyrhodamine (TAMRA™), 6-carboxy-X-rhodamine (ROX), 5- carboxyrhodamine-6G (R6G5), 6-carboxyrhodamine-6G (RG6), rhodamine, rhodamine green, rhodamine red, rhodamine 110, Rhodamin 6G®, BODIPY dyes, such as BODIPY TMR, Oregon green, coumarines, such as umbelliferone, benzimides, such as Hoechst 33258; phenanthridines, such as Texas Red®, California Red®, Yakima Yellow, Alexa Fluor® 350, Alexa Fluor® 405, Alexa Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 500, Alexa Fluor® 514, Alexa Fluor®532, Alexa Fluor® 546, Alexa Fluor® 555, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 610, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Fluor® 680, Alexa Fluor® 700, Alexa Fluor® 750, PET®, ethidium bromide, acridinium dyes, carbazol dyes, phenoxazine dyes, porphyrine dyes, polymethin dyes, BMN™-5, BMN™-6, BMN™ Q620, CEQ8000 D2, CEQ8000 D3, CEQ8000 D4, DY-480XL, DY-485XL, DY-495, DY-505, DY-510XL, DY- 521XL, DY-521XL, DY-530, DY-547, DY-550, DY- 555, DY-610, DY-615, DY-630, DY-631, DY-633, DY-635, DY-647, DY-651, DY-675, DY-676, DY-680, DY-681, DY-700, DY-701, DY-730, DY-731, DY-732, DY-750, DY-751, DY-776, DY-780, DY-781, DY-782, 6-carboxy- 4',5'-dichloro-2',7'-dimethoxyfluorescein (JOE), TET™, CAL Fluor® Gold 540, CAL Fluor RED 590, CAL Fluor Red 610, CAL Fluor Red 635, IRDye® 700Dx, IRDye® 800CW, Marina Blue®, Pacific Blue®, Yakima Yellow®, 6-(4,7-Dichloro-2',7'-diphenyl-3',6'-dipivaloylfluorescein-6- carboxamido)-hexyl-l-0-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite (SIMA), CAL Fluor® Gold 540, CAL Fluor® Orange 560, CAL Fluor Red 635, Quasar 570, Quasar 670, LIZ, Sunnyvale Red, LC Red® 610, LC Red® 640, LC Red® 670, LC Red® 705 and a squaraine dye.

113. The composition of any one of claims 110-112, wherein the 3'-terminus, the 5'-terminus, or both the 3'-terminus and the 5'-terminus is attached to a quenching moiety, optionally wherein the quenching moiety is selected from the group consisting of TAMRA and a dark quencher, optionally wherein the dark quencher is selected from the group consisting of Black Hole Quencher 1, 3' (BHQ1), DQ, dimethylaminoazobenzenesulfonic acid (DABCYL) and Iowa Black® (IWB).Attorney Docket No.: BN00023.0071 114. The composition of any one of claims 110-113, wherein the composition selectively binds human Tau polypeptide having a nonphosphorylated T231 residue, as compared to binding of human Tau having a phosphorylated T231 residue.

115. A composition comprising a nucleic acid having a 5'-terminus and a 3'-terminus and comprising the sequence: CAGCACCGUCAACUGAAUGGCGGGGGGUCAGGUCGGGGUAAGGUGAGCGUG AUGCGAUGGAGAUGU (SEQ ID NO: 19), wherein each "U" residue is a 2'-O-methyluridine- 3’-phosphate, or CAGCACCGUCAACUGAAUGGCGGGGGGUCAGGUCGGGGUA AGGUGAGCGUGAUGCGAUGGAGAUGU (SEQ ID NO: 36), wherein each "U" residue is a 2'-O-methyluridine-3’-phosphate and all other residues are 2’-O-methyl ribonucleotides.

116. The composition of claim 115, comprising the nucleic acid sequence: 5'- CCACAUCAGCACCGUCAACUGAAUGGCGGGGGGUCAGGUCGGGGUAAGGUG AGCGUUUAUGCGAUGGAGAUGUGG-3' (SEQ ID NO: 20), wherein each "U" residue is a 2'-O-methyluridine-3’-phosphate, or 5'- CCACAUCAGCACCGUCAACUGAAUGGCGGGGG GUCAGGUCGGGGUAAGGUGAGCGUUUAUGCGAUGGAGAUGUGG-3' (SEQ ID NO: 37), wherein each "U" residue is a 2'-O-methyluridine-3’-phosphate and all other residues are 2’- O-methyl ribonucleotides.

117. The composition of claim 115 or claim 116, wherein the 3'-terminus, the 5'-terminus, or both the 3'-terminus and the 5'-terminus is attached to a fluorescent moiety, optionally wherein the fluorescent moiety is selected from the group consisting of Atto 495, Atto 390, Atto 425, Atto 465, Atto 488, Atto 520, Atto 532, Atto 550, Atto 565, Atto 590, Atto 594, Atto 620, Atto 633, Atto 647N, Atto 655, Atto RhoG6, Atto Rholl, Atto Rhol2, Atto RholOl, 5- or 6- carboxyfluorescein (FAM™), VIC™, NED™, fluorescein, fluorescein isothiocyanate (FITC), IRDYE-700 / 800, cyanine dyes, such as CY3™, CY5™, CY3.5™, CY5.5™, Cy7™, xanthen, 6- carboxy-2',4',7',4,7- hexachlorofluorescein (HEX), 6-carboxy-l,4-dichloro-2',7'-dichloro- fluorescein (TET®), 6- carboxy-4',5'-dichloro-2',7'-dimethodyfluorescein (JOE™), N,N,N',N'- tetramethyl-6- carboxyrhodamine (TAMRA™), 6-carboxy-X-rhodamine (ROX), 5- carboxyrhodamine-6G (R6G5), 6-carboxyrhodamine-6G (RG6), rhodamine, rhodamine green,Attorney Docket No.: BN00023.0071 rhodamine red, rhodamine 110, Rhodamin 6G®, BODIPY dyes, such as BODIPY TMR, Oregon green, coumarines, such as umbelliferone, benzimides, such as Hoechst 33258; phenanthridines, such as Texas Red®, California Red®, Yakima Yellow, Alexa Fluor® 350, Alexa Fluor® 405, Alexa Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 500, Alexa Fluor® 514, Alexa Fluor®532, Alexa Fluor® 546, Alexa Fluor® 555, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 610, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Fluor® 680, Alexa Fluor® 700, Alexa Fluor® 750, PET®, ethidium bromide, acridinium dyes, carbazol dyes, phenoxazine dyes, porphyrine dyes, polymethin dyes, BMN™-5, BMN™-6, BMN™ Q620, CEQ8000 D2, CEQ8000 D3, CEQ8000 D4, DY-480XL, DY-485XL, DY-495, DY-505, DY-510XL, DY- 521XL, DY-521XL, DY-530, DY-547, DY-550, DY- 555, DY-610, DY-615, DY-630, DY-631, DY-633, DY-635, DY-647, DY-651, DY-675, DY-676, DY-680, DY-681, DY-700, DY-701, DY-730, DY-731, DY-732, DY-750, DY-751, DY-776, DY-780, DY-781, DY-782, 6-carboxy- 4',5'-dichloro-2',7'-dimethoxyfluorescein (JOE), TET™, CAL Fluor® Gold 540, CAL Fluor RED 590, CAL Fluor Red 610, CAL Fluor Red 635, IRDye® 700Dx, IRDye® 800CW, Marina Blue®, Pacific Blue®, Yakima Yellow®, 6-(4,7-Dichloro-2',7'-diphenyl-3',6'-dipivaloylfluorescein-6- carboxamido)-hexyl-l-0-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite (SIMA), CAL Fluor® Gold 540, CAL Fluor® Orange 560, CAL Fluor Red 635, Quasar 570, Quasar 670, LIZ, Sunnyvale Red, LC Red® 610, LC Red® 640, LC Red® 670, LC Red® 705 and a squaraine dye.

118. The composition of any one of claims 115-117, wherein the 3'-terminus, the 5'-terminus, or both the 3'-terminus and the 5'-terminus is attached to a quenching moiety, optionally wherein the quenching moiety is selected from the group consisting of TAMRA and a dark quencher, optionally wherein the dark quencher is selected from the group consisting of Black Hole Quencher 1, 3' (BHQ1), DQ, dimethylaminoazobenzenesulfonic acid (DABCYL) and Iowa Black® (IWB).

119. The composition of any one of claims 115-118, wherein the composition is capable of binding Tau441 protein of SEQ ID NO: 1 with a Kd of about 7.6 ± 0.6 nM.

120. An array of nucleic acid compositions comprising one or more compositions of any one of claims 101-119, optionally wherein the array of nucleic acid compositions is arranged in a 96- well array or a 384-well array format.Attorney Docket No.: BN00023.0071 121. A kit for detecting the presence or absence of human Tau or of a modified form of human Tau in a sample, the kit comprising a composition of any one of claims 101-119, and instructions for its use.

122. The kit of claim 121, wherein the sample is selected from the group consisting of a blood sample, a sputum sample, a cerebrospinal fluid (CSF) sample, an aspirate sample, section sample, a biopsy sample and a distinct body fluid sample, optionally wherein the sample is a crude sample.

123. The kit of claim 121 or claim 122, wherein human Tau441 of SEQ ID NO: 1 is detected.

124. The kit of any one of claims 121-123, wherein a phosphorylated form of the Tau441 sequence of SEQ ID NO: 1 is specifically detected, optionally wherein a phosphorylated T231 form of the Tau441 sequence of SEQ ID NO: 1 is specifically detected.

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