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At least 271 records · Page 15Linked to original sources
PubMed1998

Dependence of the 16S rRNA decoding region structure on Mg2+, subunit association, and temperature.

The effects of Mg2+ concentration, subunit association, and temperature on the structure of 16S rRNA in the Escherichia coli ribosome were investigated using UV cross-linking and gel electrophoresis analysis. Mg2+ concentrations between 1 and 20 mM and temperatures between 5 and 55 degreesC had little effect on the frequency of 12 of the 14 cross-links in 30S subunits and modest effects on the same cross-links in 70S ribosomes. In contrast, two cross-links, C967 x C1400 and C1402 x C1501, involving rRNA in the decoding region are present in 30S subunits only above 3 mM Mg2+, increase in frequency at higher Mg2+ concentration, and are both more frequent when 50S subunits are included in the reactions. In 70S ribosomes, the cross-link C1402 x C1501 increases but the cross-link C967 x C1400 decreases at higher Mg2+ concentrations. One cross-link, C1397 x U1495, is detected only in 70S ribosomes and decreases in frequency as Mg2+ concentration is increased. An additional cross-link, A1093 x C1182, decreases upon subunit association. The cross-link frequency differences indicate that the arrangement of the decoding region of the 16S rRNA, but not in the rest of the subunit, is readily altered by Mg2+ ions and subunit association.

Base Sequence↗
PubMed2002

The role of neuroscience in the remediation of students with dyslexia.

Dyslexia is a specific learning disability that is neurobiological in origin. It is characterized by difficulties with accurate and/or fluent word recognition, spelling and decoding abilities. Research findings agree that these and other observed behavioral manifestations largely result from a deficit in the phonological component of language. However, conflicting theories on the exact nature of the phonological deficit have given rise to divergent treatment approaches. Recent advances in functional brain imaging and genetics have allowed these theories to be examined more closely. If implemented appropriately, commercial programs can be effective in identifying dyslexia. Treatment of dyslexia has been advanced through neuroscience, yet further study is needed to provide rigorous, reproducible findings that will sustain commercial approaches.

Brain↗
PubMed2026

DNA-aware evaluation and debiasing of sequence-to-function models.

MOTIVATION: Genome sequence-to-function (S2F) models are widely used to interpret base-resolution functional genomics assays. Most S2F models are trained and evaluated against observed counts and profile-shapes using statistical objectives and fidelity metrics. These choices are well motivated, but they are DNA-independent. At the same time, experimental measurements arise from DNA-dependent assays with distinct characteristics. This mismatch motivates a complementary DNA-aware evaluation of S2F-predicted and experimental functional genomic tracks. RESULTS: We study DNA-dependency of experimental and S2F-predicted tracks using track-conditional genome language models (cgLMs). cgLMs predict masked nucleotides from a conditioning track under controlled DNA visibility. Across ATAC-seq and TF ChIP-seq peaks from GM12878 and K562, cgLM-probing reveals a consistent masked DNA-decodability gap between many experimental and S2F-predicted tracks. In particular, single-task (e.g. BPNet) and multi-task (e.g. AlphaGenome) S2F-predicted tracks enabled cgLMs to recover masked nucleotides with significantly higher accuracy and confidence than matched experimental tracks. Analyses of nonpeak and dinucleotide-shuffled sequences show that this gap is not confined to peaks and is not captured by standard DNA-agnostic profile-shape fidelity metrics alone. ChromBPNet Tn5-denoised predictions were an exception and behaved closer to the experimental regime, suggesting that staged training may reduce the gap. We then convert this diagnostic into a critic-derived objective, DNA-dependency matching (DDM), using a frozen multi-headed cgLM critic. We introduce Critic-Guided Profile-Shape Editing (CGPSE), a preliminary post hoc debiasing framework for frozen S2F models. In GM12878 ATAC-seq, CGPSE partially reduces the masked DNA-decodability gap for AlphaGenome and BPNet predictions, while exposing a tradeoff with profile-shape fidelity. AVAILABILITY AND IMPLEMENTATION: https://github.com/li-lab-mcgill/dna-aware-s2f-eval.

DNA↗
PubMed2026

Towards efficient perturbation for the noncoding genome.

Deciphering the functionality of the noncoding genome, which includes important cis-regulatory elements (CREs) and transcribed noncoding RNA genes, remains technically challenging. Here, using massively parallel genetic screening, we systematically benchmark the performance of five representative loss-of-function perturbation tools, including single-guide RNA (gRNA) mediated SpCas9 cleavage or CRISPR interference, and paired gRNA (pgRNA) involved dual-SpCas9, Big Papi (paired SpCas9 and SaCas9) or dual-enAsCas12a fragment deletion methods, in decoding the roles of the noncoding genome. For targeting CREs such as enhancers, dual-SpCas9 outperforms other methods with superior efficiency in destroying functional genomic regions. For perturbing noncoding RNA genes, in addition to dual-SpCas9, other RNA-targeting methods such as RNA interference are recommended to discriminate transcript-dependent or -independent roles. A deep learning model, DeepDC, with an associated web server, is built to facilitate optimal dual-SpCas9 pgRNA design for efficiently deleting a genomic fragment. Together, our work provides practical guidance on selecting appropriate loss-of-function tools to resolve the functional complexity of the noncoding genome.

CRISPR-Cas Systems↗
PubMed1998

The Human Genome Project: applications in the diagnosis and treatment of neurologic disease.

The Human Genome Project (HGP), an international program to decode the entire DNA sequence of the human genome in 15 years, represents the largest biological experiment ever conducted. This set of information will contain the blueprint for the construction and operation of a human being. While the primary driving force behind the genome project is the potential to vastly expand the amount of genetic information available for biomedical research, the ramifications for other fields of study in biological research, the biotechnology and pharmaceutical industry, our understanding of evolution, effects on agriculture, and implications for bioethics are likely to be profound.

Brain Diseases↗
PubMed1989

Suppression of a -1 frameshift mutation by a recessive tRNA suppressor which causes doublet decoding.

sufS was found to suppress the only known suppressible-1 frameshift mutation, trpE91, at a site identified as GGA and mapped within the single gene of the only tRNA that can decode GGA in Escherichia coli. It mapped to the same gene in Salmonella typhimurium. sufS alleles were recessive, and dominant alleles could not be isolated. This is in contrast to all other tRNA structural gene mutations identified thus far that cause frameshift suppression. The recessiveness implies that all sufS alleles are poor competitors against their wild-type tRNA(Gly2) counterparts. The base G immediately 5' of the GGA suppression site influenced the level but was not critical for suppression by sufS601. From this result, it is inferred that sufS601 causes frameshifting by doublet decoding.

Alleles↗
PubMed1998

Rabbit beta-globin is extended beyond its UGA stop codon by multiple suppressions and translational reading gaps.

Translational reading gaps occur when genetic information encoded in mRNA is not translated during the normal course of protein synthesis. This phenomenon has been observed thus far only in prokaryotes and is a mechanism for extending the reading frame by circumventing the normal stop codon. Reading frames of proteins may also be extended by suppression of the stop codon mediated by a suppressor tRNA. The rabbit beta-globin read-through protein, the only known, naturally occurring read-through protein in eukaryotes, was sequenced by ion trap mass spectrometry to determine how the reading frame is extended. Seven different proteolytic peptide fragments decoded by the same sequence that spans the UGA stop codon of rabbit beta-globin mRNA were detected. Three of these peptides contain translational reading gaps of one to three amino acids that correspond to the UGA stop codon site and/or one or two of the immediate downstream codons. To our knowledge, this is the first reported example of the occurrence of reading gaps in protein synthesis in eukaryotes. This event is unique in that it is associated with bypasses involving staggered lengths of untranslated information. Four of the seven peptides contain serine, tryptophan, cysteine, and arginine decoded by UGA and thus arise by suppression. Serine is donated by selenocysteine tRNA, and it, like the other tRNAs, has previously been shown to suppress UGA in vitro in mammals, but not in vivo.

Amino Acid Sequence↗
PubMed2001

A one-bead, one-stock solution approach to chemical genetics: part 1.

BACKGROUND: In chemical genetics, small molecules instead of genetic mutations are used to modulate the functions of proteins rapidly and conditionally, thereby allowing many biological processes to be explored. This approach requires the identification of compounds that regulate pathways and bind to proteins with high specificity. Structurally complex and diverse small molecules can be prepared using diversity-oriented synthesis, and the split-pool strategy allows their spatial segregation on individual polymer beads, but typically in quantities that limit their usefulness. RESULTS: We report full details of the first phase of our platform development, including the synthesis of a high-capacity solid-phase bead/linker system, the development of a reliable library encoding strategy, and the design of compound decoding methods both from macrobeads and stock solutions. This phase was validated by the analysis of an enantioselective, diversity-oriented synthesis resulting in an encoded 4320-member library of structurally complex dihydropyrancarboxamides. CONCLUSIONS: An efficient and accessible approach to split-pool, diversity-oriented synthesis using high-capacity macrobeads as individual microreactors has been developed. Each macrobead contains sufficient compound to generate a stock solution amenable to many biological assays, and reliable library encoding allows for rapid compound structure elucidation post-synthesis. This 'one-bead, one-stock solution' strategy is a central element of a technology platform aimed at advancing chemical genetics.

Combinatorial Chemistry Techniques↗
PubMed1991

UGA can be decoded as tryptophan at low efficiency in Bacillus subtilis.

Replacement of cat-86 codon 7 or 144 with the UGA codon permitted the gene to confer chloramphenicol resistance in wild-type Bacillus subtilis. UAA replacements of the same codons resulted in a chloramphenicol-sensitive phenotype in wild-type B. subtilis and a chloramphenicol-resistant phenotype in suppressor-positive strains. N-terminal sequencing showed that UGA at codon 7 was decoded as tryptophan in wild-type cells, at an efficiency of about 6%.

Bacillus subtilis↗
PubMed2003

Triple decoding of hepatitis C virus RNA by programmed translational frameshifting.

Ribosomes can be programmed to shift from one reading frame to another during translation. Hepatitis C virus (HCV) uses such a mechanism to produce F protein from the -2/+1 reading frame. We now report that the HCV frameshift signal can mediate the synthesis of the core protein of the zero frame, the F protein of the -2/+1 frame, and a 1.5-kDa protein of the -1/+2 frame. This triple decoding function does not require sequences flanking the frameshift signal and is apparently independent of membranes and the synthesis of the HCV polyprotein. Two consensus -1 frameshift sequences in the HCV type 1 frameshift signal facilitate ribosomal frameshifts into both overlapping reading frames. A sequence which is located immediately downstream of the frameshift signal and has the potential to form a double stem-loop structure can significantly enhance translational frameshifting in the presence of the peptidyl-transferase inhibitor puromycin. Based on these results, a model is proposed to explain the triple decoding activities of the HCV ribosomal frameshift signal.

Amino Acid Sequence↗
PubMed2026

Rab9 depletion enhances human adenovirus type 26 transduction efficiency through increased internalization and reduced late endosomal/lysosomal retention.

Understanding intracellular trafficking is central to decoding viral pathogenesis and engineering optimized viral vectors. How a virus or vector is routed through the endocytic pathway directly dictates its genome release, immune sensing, and overall transduction efficiency. Human adenovirus type 26 (HAdV-D26) presents a promising platform for vector design due to its low preexisting immunity, potent immune stimulation, scalable production, and versatile genetic engineering capacity. Although increasingly significant, the fundamental mechanisms governing HAdV-D26 intracellular trafficking are still not fully understood. Our study demonstrates that compared to well-described human adenovirus type 5 (HAdV-C5), HAdV-D26 undergoes prolonged intracellular trafficking, transiently localizing to early endosomes before residing in late endosomes/lysosomes for up to four hours post-infection. Inhibition of lysosomal acidification modestly enhances HAdV-D26 transduction efficiency, whereas blocking transport from early to late endosomes/lysosomes does not. Strikingly, Rab9 knockdown reduces HAdV-D26 late endosomal/lysosomal localization while increasing both virus internalization and genome delivery to the host cell nucleus. These findings indicate that late endosomal sorting pathways actively influence HAdV-D26 infection outcomes. By identifying a previously unappreciated role for Rab9 in adenovirus transduction, our results provide new mechanistic insight into HAdV-D26 intracellular trafficking, highlight serotype-specific differences in adenovirus entry pathways, and identify endosomal trafficking steps that may be targeted to improve adenoviral vector performance.

Humans↗
PubMed1998

Post-transcriptional gene regulatory mechanisms in eukaryotes: an overview.

Expression of a gene can be controlled at many levels, including transcription, mRNA splicing, mRNA stability, translation and post-translational events such as protein stability and modification. The majority of studies to date have focused on transcriptional control mechanisms, but the importance of post-transcriptional mechanisms in regulating gene expression in eukaryotes is becoming increasingly clear. In this short review, selected examples of post-transcriptional gene regulatory mechanisms operating in both lower and higher eukaryotes will be used to highlight the plethora of such mechanisms already identified. The underlying theme is that post-transcriptional gene regulation relies on specific RNA-protein interactions that either result in the targeted degradation of the mRNA or prevent access of the ribosome to the translation start codon. Such interactions can occur in the 5' or 3' untranslated regions of an mRNA or within the decoded portion of the molecule. The importance of these regulatory mechanisms in a range of biological systems is also illustrated.

Animals↗
PubMed2001

Forty years of decoding the silence in X-chromosome inactivation.

In 1961, Mary Lyon first put forth the hypothesis that one X chromosome is inactivated in each cell of the female mammal. As we enter the new millennium and complete 40 years of study, the field of X-inactivation is rich with ideas and many contrasting viewpoints. This review will focus on the random form of X-inactivation and present the latest views on its mechanism. Much attention has been focused on the genetic parsing of X-chromosome counting, choice, silencing and maintenance. It is now known that counting is functionally distinct from choice and that initiation and establishment of silencing are distinct from maintenance. Since Xist's seminal discovery 10 years ago, significant progress has been made towards understanding its function. Required only for initiation and establishment, Xist must act within a narrow developmental window, but its precise mode of action remains elusive. The ongoing search for Xist RNA-binding factors and effector proteins for silencing has led to members of the macroH2A family of histone variants. Finally, the recent discovery of Tsix implicates regulation of Xist expression by an antisense mechanism. Required for choice but not counting, Tsix blocks Xist RNA accumulation and hence blocks initiation of silencing on the future active X.

Animals↗
PubMed1999

The Candida albicans CUG-decoding ser-tRNA has an atypical anticodon stem-loop structure.

In many Candida species, the leucine CUG codon is decoded by a tRNA with two unusual properties: it is a ser-tRNA and, uniquely, has guanosine at position 33 (G33). Using a combination of enzymatic (V1 RNase, RnI nuclease) and chemical (Pb(2+), imidazole) probing of the native Candida albicans ser-tRNACAG, we demonstrate that the overall tertiary structure of this tRNA resembles that of a ser-tRNA rather than a leu-tRNA, except within the anticodon arm where there is considerable disruption of the anticodon stem. Using non-modified in vitro transcripts of the C. albicans ser-tRNACAG carrying G, C, U or A at position 33, we demonstrate that it is specifically a G residue at this position that induces the atypical anticodon stem structure. Further quantitative evidence for an unusual structure in the anticodon arm of the G33-tRNA is provided by the observed change in kinetics of methylation of the G at position 37, by purified Escherichia coli m(1)G37 methyltransferase. We conclude that the anticodon arm distortion, induced by a guanosine base at position 33 in the anticodon loop of this novel tRNA, results in reduced decoding ability which has facilitated the evolution of this tRNA without extinction of the species encoding it.

Anticodon↗
PubMed1996

Characterization of a B. subtilis minor isoleucine tRNA deduced from tDNA having a methionine anticodon CAT.

Bacillus subtilis, which belongs to Gram-positive eubacteria, has been predicted to have a minor isoleucine tRNA transcribed from the gene possessing the CAT anticodon, which corresponds to methionine. We isolated this tRNA and determined its sequence including modified nucleotides. Modified nucleotide analyses using TLC, UV, and FAB mass spectroscopy revealed that the first letter of the anticodon is modified to lysidine [4-amino-2-(N6-lysino)-1-beta-d-ribofuranosyl pyrimidine]. As a result, this tRNA agrees with the minor one predicted from the DNA sequence and is thought to decode the isoleucine codon AUA.

Acylation↗
PubMed1984

The sup8 tRNALeu gene of Schizosaccharomyces pombe has an unusual intervening sequence and reduced pairing in the anticodon stem.

We have cloned and sequenced the wild-type and suppressor alleles of the S. pombe sup8 tRNA gene. The wild-type allele has a leucine UAA anticodon and the suppressor (sup8-e) carries the opal suppressor anticodon UCA. The gene has a 16 base pair intervening sequence that, in the RNA, is predicted to form a secondary structure which involves base pairing to the 5', rather than the usual 3' side of the 5' splice site. When incubated in Saccharomyces cerevisiae cell-free extracts both alleles are efficiently transcribed, the 5' leader and 3' trailer sequences are removed and CCA is added to the 3' processed end; however, the intervening sequence is not excised. This finding implies that the structural requirements of the splicing endonucleases in the two yeasts have diverged. No other tRNA genes with related sequences were detected in S. pombe DNA by hybridization, suggesting that other UUA isoacceptors may be structurally dissimilar to sup8 or that the UUA codon may be decoded by a UUG leucine isoacceptor.

Alleles↗
PubMedDate not supplied

[Genomic polymorphism in the resolution of the fundamental and applied problems of microbiology and epidemiology].

As shown in this work, the methods of genomic fingerprinting make it possible to study genotypic links between strains, closely related phenotypically and genotypically, but having different epidemiological significance, to decode the mechanisms of the appearance and formation of epidemic strains, as well as to determine areas of their spread. The application principles of the methods of the study of genomic polymorphism for solving a number of fundamental problems of microbiology and epidemiology, as well as for carrying out effective retrospective and operative epidemiological analysis, are presented. Schemes for the genetic typing of a number of causative agents of bacterial infections are given. As an example, the optimum scheme of the identification and typing of Mycobacterium tuberculosis strains on the basis of polymerase chain reaction is presented and its advantages in comparison with the routine methods of laboratory diagnostics and typing are shown.

Animals↗
PubMed2000

Pseudouridine in RNA: what, where, how, and why.

Pseudouridine (5-ribosyluracil) is a ubiquitous yet enigmatic constituent of structural RNAs (transfer, ribosomal, small nuclear, and small nucleolar). Although pseudouridine (psi) was the first modified nucleoside to be discovered in RNA, and is the most abundant, its biosynthesis and biological roles have remained poorly understood since its identification as a "fifth nucleoside" in RNA. Recently, a combination of biochemical, biophysical, and genetic approaches has helped to illuminate the structural consequences of psi in polyribonucleotides, the biochemical mechanism of U-->psi isomerization in RNA, and the role of modification enzymes (psi synthases) and box H/ACA snoRNAs, a class of eukaryotic small nucleolar RNAs, in the site-specific biosynthesis of psi. Through its unique ability to coordinate a structural water molecule via its free N1-H, psi exerts a subtle but significant "rigidifying" influence on the nearby sugar-phosphate backbone and also enhances base stacking. These effects may underlie the biological role of most (but perhaps not all) of the psi residues in RNA. Certain genetic mutants lacking specific psi residues in tRNA or rRNA exhibit difficulties in translation, display slow growth rates, and fail to compete effectively with wild-type strains in mixed culture. In particular, normal growth is severely compromised in an Escherichia coli mutant deficient in a pseudouridine synthase responsible for the formation of three closely spaced psi residues in the mRNA decoding region of the 23S rRNA. Such studies demonstrate that pseudouridylation of RNA confers an important selective advantage in a natural biological context.

Animals↗