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1.
Nucleic Acids Res ; 51(15): 7736-7748, 2023 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-37439359

RESUMO

Nucleic acids not only form the basis of heredity, but are increasingly a source of novel nano-structures, -devices and drugs. This has spurred the development of chemically modified alternatives (xeno nucleic acids (XNAs)) comprising chemical configurations not found in nature to extend their chemical and functional scope. XNAs can be evolved into ligands (XNA aptamers) that bind their targets with high affinity and specificity. However, detailed investigations into structural and functional aspects of XNA aptamers have been limited. Here we describe a detailed structure-function analysis of LYS-S8-19, a 1',5'-anhydrohexitol nucleic acid (HNA) aptamer to hen egg-white lysozyme (HEL). Mapping of the aptamer interaction interface with its cognate HEL target antigen revealed interaction epitopes, affinities, kinetics and hot-spots of binding energy similar to protein ligands such as anti-HEL-nanobodies. Truncation analysis and molecular dynamics (MD) simulations suggest that the HNA aptamer core motif folds into a novel and not previously observed HNA tertiary structure, comprising non-canonical hT-hA-hT/hT-hT-hT triplet and hG4-quadruplex structures, consistent with its recognition by two different G4-specific antibodies.


Assuntos
Aptâmeros de Nucleotídeos , Quadruplex G , Ácidos Nucleicos , Ligantes , Aptâmeros de Nucleotídeos/química , Ácidos Nucleicos/química , Simulação de Dinâmica Molecular , Técnica de Seleção de Aptâmeros
2.
Nucleic Acids Res ; 50(20): 11415-11425, 2022 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-36350642

RESUMO

Xenobiotic nucleic acids (XNAs) offer tremendous potential for synthetic biology, biotechnology, and molecular medicine but their ability to mimic nucleic acids still needs to be explored. Here, to study the ability of XNA oligonucleotides to mimic tRNA, we synthesized three L-Ala-tXNAs analogs. These molecules were used in a non-ribosomal peptide synthesis involving a bacterial Fem transferase. We compared the ability of this enzyme to use amino-acyl tXNAs containing 1',5'-anhydrohexitol (HNA), 2'-fluoro ribose (2'F-RNA) and 2'-fluoro arabinose. L-Ala-tXNA containing HNA or 2'F-RNA were substrates of the Fem enzyme. The synthesis of peptidyl-XNA and the resolution of their structures in complex with the enzyme show the impact of the XNA on protein binding. For the first time we describe functional tXNA in an in vitro assay. These results invite to test tXNA also as substitute for tRNA in translation.


Assuntos
Aminoácidos , RNA de Transferência de Alanina , Ácidos Nucleicos/química , Oligonucleotídeos/química , Peptídeos , RNA de Transferência de Alanina/química
3.
Biochemistry ; 62(19): 2854-2867, 2023 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-37694722

RESUMO

Several efforts are currently directed at the creation and cellular implementation of alternative genetic systems composed of pairing components that are orthogonal to the natural dA/dT and dG/dC base pairs. In an alternative approach, Watson-Crick-type pairing is conserved, but one or all of the four letters of the A, C, G, and T alphabet are substituted by modified components. Thus, all four nucleobases were altered to create halogenated deazanucleic acid (DZA): dA was replaced by 7-deaza-2'-deoxyadenosine (dzA), dG by 7-deaza-2'-deoxyguanosine (dzG), dC by 5-fluoro-2'-deoxycytidine (FdC), and dT by 5-chloro-2'-deoxyuridine (CldU). This base-pairing system was previously shown to retain function in Escherichia coli. Here, we analyze the stability, hydration, structure, and dynamics of a DZA Dickerson-Drew Dodecamer (DDD) of sequence 5'-FdC-dzG-FdC-dzG-dzA-dzA-CldU-CldU-FdC-dzG-FdC-dzG-3'. Contrary to similar stabilities of DDD and DZA-DDD, osmotic stressing revealed a dramatic loss of hydration for the DZA-DDD relative to that for the DDD. The parent DDD 5'-d(CGCGAATTCGCG)-3' features an A-tract, a run of adenosines uninterrupted by a TpA step, and exhibits a hallmark narrow minor groove. Crystal structures─in the presence of RNase H─and MD simulations show increased conformational plasticity ("morphing") of DZA-DDD relative to that of the DDD. The narrow dzA-tract minor groove in one structure widens to resemble that in canonical B-DNA in a second structure. These changes reflect an indirect consequence of altered DZA major groove electrostatics (less negatively polarized compared to that in DNA) and hydration (reduced compared to that in DNA). Therefore, chemical modifications outside the minor groove that lead to collapse of major groove electrostatics and hydration can modulate A-tract geometry.


Assuntos
Adenina , DNA , Conformação de Ácido Nucleico , DNA/química , Pareamento de Bases
4.
Chembiochem ; 24(15): e202300191, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37119472

RESUMO

Chemical cell surface modification is a fast-growing field of research, due to its enormous potential in tissue engineering, cell-based immunotherapy, and regenerative medicine. However, engineering of bacterial tissues by chemical cell surface modification has been vastly underexplored and the identification of suitable molecular handles is in dire need. We present here, an orthogonal nucleic acid-protein conjugation strategy to promote artificial bacterial aggregation. This system gathers the high selectivity and stability of linkage to a protein Tag expressed at the cell surface and the modularity and reversibility of aggregation due to oligonucleotide hybridization. For the first time, XNA (xeno nucleic acids in the form of 1,5-anhydrohexitol nucleic acids) were immobilized via covalent, SNAP-tag-mediated interactions on cell surfaces to induce bacterial aggregation.


Assuntos
Escherichia coli , Ácidos Nucleicos , Escherichia coli/genética , DNA/química , Ácidos Nucleicos/química , Hibridização de Ácido Nucleico , Oligonucleotídeos/química
5.
Nucleic Acids Res ; 48(8): 4028-4040, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32170309

RESUMO

In this report, we investigated the hexopyranose chemical modification Altriol Nucleic Acid (ANA) within small interfering RNA (siRNA) duplexes that were otherwise fully modified with the 2'-deoxy-2'-fluoro and 2'-O-methyl pentofuranose chemical modifications. The siRNAs were designed to silence the transthyretin (Ttr) gene and were conjugated to a trivalent N-acetylgalactosamine (GalNAc) ligand for targeted delivery to hepatocytes. Sense and antisense strands of the parent duplex were synthesized with single ANA residues at each position on the strand, and the resulting siRNAs were evaluated for their ability to inhibit Ttr mRNA expression in vitro. Although ANA residues were detrimental at the 5' end of the antisense strand, the siRNAs with ANA at position 6 or 7 in the seed region had activity comparable to the parent. The siRNA with ANA at position 7 in the seed region was active in a mouse model. An Oligonucleotide with ANA at the 5' end was more stable in the presence of 5'-exonuclease than an oligonucleotide of the same sequence and chemical composition without the ANA modification. Modeling studies provide insight into the origins of regiospecific changes in potency of siRNAs and the increased protection against 5'-exonuclease degradation afforded by the ANA modification.


Assuntos
Acetilgalactosamina/química , Carboidratos/química , Interferência de RNA , RNA Interferente Pequeno/química , Álcoois Açúcares/química , Animais , Células COS , Chlorocebus aethiops , Exorribonucleases , Hepatócitos/metabolismo , Camundongos , Conformação de Ácido Nucleico , Pré-Albumina/genética , Ribonucleotídeos/química
6.
Chembiochem ; 22(9): 1638-1645, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33427360

RESUMO

Xenobiology explores synthetic nucleic acid polymers as alternative carriers of genetic information to expand the central dogma. The xylo- and deoxyxylo-nucleic acids (XyNA and dXyNA), containing 3' epimers of riboses and deoxyriboses, are considered to be potential candidates for an orthogonal system. In this study, thermal and spectroscopic analyses show that XyNA and dXyNA form stable hairpins. The dXyNA hairpin structure determined by NMR spectroscopy contains a flexible loop that locks the stem into a stable ladder-like duplex with marginal right-handed helicity. The reduced flexibility of the dXyNA duplex observed in the stem of the hairpin demonstrates that folding of dXyNA yields more stable structures described so far.


Assuntos
Ácidos Nucleicos/química , Xilose/química , Aptâmeros de Nucleotídeos/química , Dicroísmo Circular , DNA/química , Simulação de Dinâmica Molecular , Ressonância Magnética Nuclear Biomolecular , Conformação de Ácido Nucleico
7.
Nucleic Acids Res ; 47(13): 7130-7142, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31334814

RESUMO

Xenobiotic nucleic acids (XNA) are nucleic acid analogues not present in nature that can be used for the storage of genetic information. In vivo XNA applications could be developed into novel biocontainment strategies, but are currently limited by the challenge of developing XNA processing enzymes such as polymerases, ligases and nucleases. Here, we present a structure-guided modelling-based strategy for the rational design of those enzymes essential for the development of XNA molecular biology. Docking of protein domains to unbound double-stranded nucleic acids is used to generate a first approximation of the extensive interaction of nucleic acid processing enzymes with their substrate. Molecular dynamics is used to optimise that prediction allowing, for the first time, the accurate prediction of how proteins that form toroidal complexes with nucleic acids interact with their substrate. Using the Chlorella virus DNA ligase as a proof of principle, we recapitulate the ligase's substrate specificity and successfully predict how to convert it into an XNA-templated XNA ligase.


Assuntos
DNA Ligases/metabolismo , Proteínas Virais/metabolismo , Simulação por Computador , DNA Ligases/química , Vírus de DNA/enzimologia , DNA Viral/metabolismo , Desoxirribonuclease BamHI/metabolismo , Modelos Químicos , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Conformação de Ácido Nucleico , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade , Especificidade por Substrato , Moldes Genéticos , Proteínas Virais/química
8.
J Am Chem Soc ; 141(27): 10844-10851, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31251601

RESUMO

A synthetic orthogonal polymer embracing a chiral acyclic-phosphonate backbone [(S)-ZNA] is presented that uniquely adds to the emerging family of xenobiotic nucleic acids (XNAs). (S)-ZNA consists of reiterating six-atom structural units and can be accessed in few synthetic steps from readily available phophonomethylglycerol nucleoside (PMGN) precursors. Comparative thermal stability experiments conducted on homo- and heteroduplexes made of (S)-ZNA are described that evince its high self-hybridization efficiency in contrast to poor binding of natural complements. Although preliminary and not conclusive, circular dichroism data and dynamic modeling computations provide support to a left-handed geometry of double-stranded (S)-ZNA. Nonetheless, PMGN diphosphate monomers were recognized as substrates by Escherichia coli (E. coli) polymerase I as well as being imported into E. coli cells equipped with an algal nucleotide transporter. A further investigation into the in vivo propagation of (S)-ZNA culminated with the demonstration of the first synthetic nucleic acid with an acyclic backbone that can be transliterated to DNA by the E. coli cellular machinery.


Assuntos
Escherichia coli/genética , Ácidos Nucleicos/química , Organofosfonatos/química , Escherichia coli/enzimologia , Escherichia coli/metabolismo , Expressão Gênica , Modelos Moleculares , Conformação de Ácido Nucleico , Hibridização de Ácido Nucleico , Ácidos Nucleicos/genética , Oligonucleotídeos/química , Oligonucleotídeos/genética
9.
J Org Chem ; 84(21): 13394-13409, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31617362

RESUMO

In this report, we present the synthesis of N8-glycosylated 8-aza-2-methylhypoxanthine and 8-aza-6-thiohypoxanthine 2'-deoxynucleosides as well as methylated 2'-deoxynebularine derivatives. In vitro base pairing properties between each modified and canonical nucleobase were studied. As demonstrated by Tm, incorporation of the modified bases in DNA resulted, with few exceptions, in low stability of duplexes. Modified bases studied in this report are preferentially recognized by T (for N8-glycosylated 8-aza-2-methylhypoxanthine and methylated purines) and G (N8-glycosylated 8-aza-2-methylhypoxanthine). The base pair formed between N8-glycosylated 8-aza-6-thiohypoxanthine and N9-glycosylated 2-methyl-6-thiohypoxanthine (X2:X6) showed, to some extent, an orthogonal interaction. Based on Tm studies, the only potential self-pairing system is formed by the N8-glycosylated 8-aza-6-thiohypoxanthine nucleoside (X2) but only in the absence of canonical G and T. This study indicated that the canonical thymine base is the preferential base partner of methylated purine bases.

10.
Chemistry ; 24(48): 12695-12707, 2018 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-29883012

RESUMO

The synthesis, base pairing properties and in vitro (polymerase) and in vivo (E. coli) recognition of 2'-deoxynucleotides with a 2-amino-6-methyl-8-oxo-7,8-dihydro-purine (X), a 2-methyl-6-thiopurine (Y) and a 6-methyl-4-pyrimidone (Z) base moiety are described. As demonstrated by Tm measurements, the X and Y bases fail to form a self-complementary base pair. Despite this failure, enzymatic incorporation experiments show that selected DNA polymerases recognize the X nucleotide and incorporate this modified nucleotide versus X in the template. In vivo, X is mainly recognized as a A/G or C base; Y is recognized as a G or C base and Z is mostly recognized as T or C. Replacing functional groups in nucleobases normally involved in W-C recognition (6-carbonyl and 2-amino group of purine; 6-carbonyl of pyrimidine) readily leads to orthogonality (absence of base pairing with natural bases).

12.
Chemistry ; 21(13): 5009-22, 2015 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-25684598

RESUMO

The synthesis, base-pairing properties and in vitro and in vivo characteristics of 5-methyl-isocytosine (isoC(Me) ) and isoguanine (isoG) nucleosides, incorporated in an HNA(h) (hexitol nucleic acid)-DNA(d) mosaic backbone, are described. The required h-isoG phosphoramidite was prepared by a selective deamination as a key step. As demonstrated by Tm measurements the hexitol sugar showed slightly better mismatch discrimination against dT. The d-isoG base mispairing follows the order T>G>C while the h-isoG base mispairing follows the order G>C>T. The h- and d-isoC(Me) bases mainly mispair with G. Enzymatic incorporation experiments show that the hexitol backbone has a variable effect on selectivity. In the enzymatic assays, isoG misincorporates mainly with T, and isoC(Me) misincorporates mainly with A. Further analysis in vivo confirmed the patterns of base-pair interpretation for the deoxyribose and hexitol isoC(Me) /isoG bases in a cellular context, through incorporation of the bases into plasmidic DNA. Results in vivo demonstrated that mispairing and misincorporation was dependent on the backbone scaffold of the base, which indicates rational advances towards orthogonality.


Assuntos
5-Metilcitosina/análogos & derivados , Guanina/química , Nucleosídeos/química , 5-Metilcitosina/química , Estrutura Molecular
13.
J Org Chem ; 80(10): 5014-22, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25853790

RESUMO

The synthesis and a preliminary investigation of the base pairing properties of (6' → 4')-linked 1',5'-anhydro-L-ribo-hexitol nucleic acids (α-L-HNA) have herein been reported through the study of a model oligoadenylate system in the mirror image world. Despite its considerable preorganization due to the rigidity of the "all equatorial" pyranyl sugar backbone, α-L-HNA represents a versatile informational biopolymer, in view of its capability to cross-communicate with natural and unnatural complements in both enantiomeric forms. This seems the result of an inherent flexibility of the oligonucleotide system, as witnessed by the singular formation of iso- and heterochiral associations composed of regular, enantiomorphic helical structures. The peculiar properties of α-L-HNA (and most generally of the α-HNA system) provide new elements in our understanding of the structural prerequisites ruling the stereoselectivity of the hybridization processes of nucleic acids.


Assuntos
Adenina/síntese química , Ácidos Nucleicos/síntese química , Oligonucleotídeos/síntese química , Álcoois Açúcares/síntese química , Adenina/química , Pareamento de Bases , Modelos Moleculares , Conformação de Ácido Nucleico , Ácidos Nucleicos/química , Oligonucleotídeos/química , RNA/química , Estereoisomerismo , Álcoois Açúcares/química
14.
Org Biomol Chem ; 13(39): 10041-9, 2015 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-26293202

RESUMO

The synthesis and a preliminary evaluation of the pairing properties of ribo-cyclohexanyl nucleic acids (r-CNA) is herein reported. Incorporation of a single r-CNA nucleotide into natural duplexes did not enhance their stability, while a very high pairing selectivity for RNA was found. As deduced by comparative analysis of Tm and NMR data, a relationship between pairing selectivity and conformational preferences of the "sugar" moiety of r-CNA (and more generally of six-membered nucleic acids) was suggested.


Assuntos
Pareamento de Bases , Oligonucleotídeos/química , RNA/química , Ribonucleosídeos/química , Ribose/análogos & derivados , Sequência de Bases , Configuração de Carboidratos , Conformação de Ácido Nucleico , Estabilidade de RNA
15.
Molecules ; 20(3): 4020-41, 2015 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-25741897

RESUMO

In further study of our series of six-membered ring-containing nucleic acids, different 1',3'-di-O-methyl altropyranoside nucleoside analogs (DMANA) were synthesized comprising all four base moieties, adenine, cytosine, uracil and guanine. Following assembly into oligonucleotides (ONs), their affinity for natural oligonucleotides was evaluated by thermal denaturation of the respective duplexes. Data were compared with results obtained previously for both anhydrohexitol (HNAs) and 3'-O-methylated altrohexitol modified ONs (MANAs). We hereby demonstrate that ONs modified with DMANA monomers, unlike some of our previously described analogues with constrained 6-membered hexitol rings, did not improve thermodynamic stability of dsRNA complexes, most probably in view of an energetic penalty when forced in the required 1C4 pairing conformation. Overall, a single incorporation was more or less tolerated or even positive for the adenine congener, but incorporation of a second modification afforded a slight destabilization (except for A), while a fully modified sequence displayed a thermal stability of -0.3 °C per modification. The selectivity of pairing remained very high, and the new modification upon incorporation into a DNA strand, strongly destabilized the corresponding DNA duplexes. Unfortunately, this new modification does not bring any advantage to be further evaluated for antisense or siRNA applications.


Assuntos
Hibridização de Ácido Nucleico/genética , Ácidos Nucleicos/química , Adenina/química , Citosina/química , DNA/química , DNA/genética , Guanina/química , Desnaturação de Ácido Nucleico/genética , Oligonucleotídeos/química , RNA Interferente Pequeno/genética , Álcoois Açúcares/química , Termodinâmica , Uracila/química
16.
Chembiochem ; 15(15): 2255-8, 2014 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-25158283

RESUMO

The templating potential of anhydrohexitol oligonucleotides bearing ambiguous bases was studied in vivo, by using a selection screen for mosaic heteroduplex plasmids in Escherichia coli. 1,5-Anhydro-2,3-dideoxy-2-(5-nitroindazol-1-yl)-D-arabino-hexitol showed the greatest ambiguity among the three nucleosides tested. At most two successive ambiguous bases could be tolerated on hexitol templates read in bacterial cells. Hexitol nucleosides bearing simplified heterocycles thus stand as promising monomers for generating random DNA sequences in vivo from defined synthetic oligonucleotides.


Assuntos
Pareamento de Bases , Ácidos Nucleicos/genética , Oligonucleotídeos/química , Álcoois Açúcares/química , Transformação Genética/genética , Estrutura Molecular , Ácidos Nucleicos/química , Oligonucleotídeos/síntese química , Moldes Genéticos
17.
Chembiochem ; 10(7): 1175-85, 2009 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-19373795

RESUMO

Powerful pyrene probes: Two kinds of pyrene-labeled oligonucleotides (HNA- and RNA-skeleton probes) were explored. The enhanced fluorescence intensity in the monomer region and the disappearance of aggregate/excimer emission in duplexes has been successfully used to detect the hybridization of oligonucleotides. By covalently attaching pyrene chromophores with different linkers onto altritol nucleotides or ribonucleotides, and by varying the number of these pyrene modified altritol nucleotides and ribonucleotides in HNA (hexitol nucleic acid) and RNA, respectively, we have explored the general applicability of pyrene absorbance and especially fluorescence as a probe to monitor RNA hybridization. The results reveal that the backbone of the probes, the number of pyrene units attached and the nature of the tether can all substantially affect the absorbance and fluorescence properties of the probes both in single strand and double strand form. Moreover, the strength of hybridization is also affected. The disappearance of pyrene aggregate/excimer emission and simultaneous increase in monomer emission intensity of the multipyrene-labeled probes has been successfully used to monitor the hybridization of oligonucleotides, including a hairpin structure. Differences in optical response between the HNA- and RNA-skeleton probes upon hybridization indicate that the interaction of pyrene with the nucleobases in both types of duplexes is different.


Assuntos
Sondas de Oligonucleotídeos/química , Pirenos/química , RNA/química , Corantes Fluorescentes/química , Hibridização de Ácido Nucleico , Sondas de Oligonucleotídeos/síntese química , Pirenos/síntese química , Espectrometria de Fluorescência , Temperatura , Temperatura de Transição
18.
Chemistry ; 15(39): 10121-31, 2009 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-19739223

RESUMO

Oligonucleotides composed of 1',5'-anhydro-arabino-hexitol nucleosides belonging to the L series (L-HNA) were prepared and preliminarily studied as a novel potential base-pairing system. Synthesis of enantiopure L-hexitol nucleotide monomers equipped with a 2'-(N(6)-benzoyladenin-9-yl) or a 2'-(thymin-1-yl) moiety was carried out by a de novo approach based on a domino reaction as key step. The L oligonucleotide analogues were evaluated in duplex formation with natural complements as well as with unnatural sugar-modified oligonucleotides. In many cases stable homo- and heterochiral associations were found. Besides T(m) measurements, detection of heterochiral complexes was unambiguously confirmed by LC-MS studies. Interestingly, circular dichroism measurements of the most stable duplexes suggested that L-HNA form left-handed helices with both D and L oligonucleotides.


Assuntos
Arabinose/química , DNA/química , Ácidos Nucleicos/síntese química , Nucleosídeos/síntese química , Nucleosídeos/metabolismo , Oligonucleotídeos/química , Pareamento de Bases , Sequência de Bases , Sítios de Ligação , Modelos Moleculares , Conformação de Ácido Nucleico , Ácidos Nucleicos/metabolismo , Oligonucleotídeos/metabolismo , Estereoisomerismo
19.
Biosens Bioelectron ; 23(11): 1728-32, 2008 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-18378134

RESUMO

DNA microarrays and sensors have become essential tools in the functional analysis of sequence information. Recently we reported that chimeric hexitol (HNA) and altritol (ANA) nucleotide monomers with an anhydrohexitol sugar moiety are easily available and proved their chemistry to be compatible with DNA and RNA synthesis. In this communication we describe a novel analytical platform based on HNA and ANA units to be used as synthetic oligonucleotide arrays on a glass solid support for match/mismatch detection of DNA and RNA targets. Arrays were fabricated by immobilization of diene-modified oligonucleotides on maleimido-activated glass slides. To demonstrate the selectivity and sensitivity of the HNA/ANA arrays and to compare their properties with regular DNA arrays, sequences in the reverse transcriptase gene (codon 74) and the protease gene of HIV-1 (codon 10) were selected. Both, the relative intensity of the signal and match/mismatch discrimination increased up to fivefold for DNA targets and up to 3-3.5-fold for RNA targets applying HNA or ANA arrays (ANA>HNA>DNA). Certainly in the new field of miRNA detection, ANA arrays could prove very beneficial and their properties should be investigated in more detail.


Assuntos
Pareamento Incorreto de Bases/genética , DNA/genética , Análise de Sequência com Séries de Oligonucleotídeos/instrumentação , RNA/genética , Marcadores de Afinidade/química , Desenho de Equipamento , Análise de Falha de Equipamento
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