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At least 1,171 records · Page 65Linked to original sources
PubMed1983

Analysis of ambiguity in visual pattern completion.

It is possible to construct an ambiguous line drawing representing several objects partly hidden behind another object. This article deals with two problems: (a) What are the necessary and sufficient conditions for ambiguity to occur? (b) How can the response frequencies of the completions of ambiguous drawings be explained? Whether completions occur or not, the predictions based on the coding theory, better termed the structural information theory, have been discussed in a previous article (Buffart, Leeuwenberg, & Restle, 1981). It is shown here that the theory also specifies the conditions for ambiguity to occur. The theory describes all possible interpretations of a drawing and selects those interpretations or completions to which subjects will respond. A direct relation between the response frequencies and the possible theoretical descriptions of each response is shown to exist. Two one-parameter models describing the behavior of subjects each fit the response frequencies measured in two experiments with 25 drawings. It is argued that the type of ambiguity that is studied in both experiments generally appears during the perceptual process. The character of the theoretical descriptions indicates that guidance of perceptual behavior by interpretations might occur.

Adolescent↗
PubMed1999

Regulation of alternative splicing by RNA editing.

The enzyme ADAR2 is a double-stranded RNA-specific adenosine deaminase which is involved in the editing of mammalian messenger RNAs by the site-specific conversion of adenosine to inosine. Here we identify several rat ADAR2 mRNAs produced as a result of two distinct alternative splicing events. One such splicing event uses a proximal 3' acceptor site, adding 47 nucleotides to the ADAR2 coding region, changing the predicted reading frame of the mature ADAR2 transcript. Nucleotide-sequence analysis of ADAR2 genomic DNA revealed the presence of adenosine-adenosine (AA) and adenosine-guanosine (AG) dinucleotides at these proximal and distal alternative 3' acceptor sites, respectively. Use of the proximal 3' acceptor depends upon the ability of ADAR2 to edit its own pre-mRNA, converting the intronic AA to an adenosine-inosine (AI) dinucleotide which effectively mimics the highly conserved AG sequence normally found at 3' splice junctions. Our observations indicate that RNA editing can serve as a mechanism for regulating alternative splicing and they suggest a novel strategy by which ADAR2 can modulate its own expression.

Adenosine↗
PubMed1997

Regulation of serotonin-2C receptor G-protein coupling by RNA editing.

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) elicits a wide array of physiological effects by binding to several receptor subtypes. The 5-HT2 family of receptors belongs to a large group of seven-transmembrane-spanning G-protein-coupled receptors and includes three receptor subtypes (5-HT2A, 5-HT(2B) and 5-HT(2C)) which are linked to phospholipase C, promoting the hydrolysis of membrane phospholipids and a subsequent increase in the intracellular levels of inositol phosphates and diacylglycerol. Here we show that transcripts encoding the 2C subtype of serotonin receptor (5-HT(2C)R) undergo RNA editing events in which genomically encoded adenosine residues are converted to inosines by the action of double-stranded RNA adenosine deaminase(s). Sequence analysis of complementary DNA isolates from dissected brain regions have indicated the tissue-specific expression of seven major 5-HT(2C) receptor isoforms encoded by eleven distinct RNA species. Editing of 5-HT(2C)R messenger RNAs alters the amino-acid coding potential of the predicted second intracellular loop of the receptor and can lead to a 10-15-fold reduction in the efficacy of the interaction between receptors and their G proteins. These observations indicate that RNA editing is a new mechanism for regulating serotonergic signal transduction and suggest that this post-transcriptional modification may be critical for modulating the different cellular functions that are mediated by other members of the G-protein-coupled receptor superfamily.

3T3 Cells↗
PubMed2002

Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast.

In eukaryotes, the DNA of the genome is packaged with histone proteins to form nucleosomal filaments, which are, in turn, folded into a series of less well understood chromatin structures. Post-translational modifications of histone tail domains modulate chromatin structure and gene expression. Of these, histone ubiquitination is poorly understood. Here we show that the ubiquitin-conjugating enzyme Rad6 (Ubc2) mediates methylation of histone H3 at lysine 4 (Lys 4) through ubiquitination of H2B at Lys 123 in yeast (Saccharomyces cerevisiae). Moreover, H3 (Lys 4) methylation is abolished in the H2B-K123R mutant, whereas H3-K4R retains H2B (Lys 123) ubiquitination. These data indicate a unidirectional regulatory pathway in which ubiquitination of H2B (Lys 123) is a prerequisite for H3 (Lys 4) methylation. We also show that an H2B-K123R mutation perturbs silencing at the telomere, providing functional links between Rad6-mediated H2B (Lys 123) ubiquitination, Set1-mediated H3 (Lys 4) methylation, and transcriptional silencing. Thus, these data reveal a pathway leading to gene regulation through concerted histone modifications on distinct histone tails. We refer to this as 'trans-tail' regulation of histone modification, a stated prediction of the histone code hypothesis.

Alleles↗
PubMed2007

The SH2B gene is associated with serum leptin and body fat in normal female twins.

Src-homology-2 (SH2)-B, a Janus tyrosine kinase 2-interacting protein, has been identified recently as a key regulator of leptin and insulin sensitivity, glucose homeostasis, and body weight in mice. The aim of this study was to determine whether single-nucleotide polymorphisms (SNPs) in the human SH2B gene are associated with these variables. A tagging SNP (tSNP), Ala484Thr (rs7498665), was selected to represent five common SNPs (minor allele frequency > 0.05) in perfect linkage disequilibrium in a 16-kb region encompassing the SH2B gene. The tSNP was genotyped in 2455 white female twins (mean age, 47.4 +/- 12.6 years) from the St. Thomas' United Kingdom Adult Twin Registry (Twins United Kingdom). Ala484Thr (minor allele frequency, 0.38) was associated with serum leptin, total fat, waist circumference, and body weight (P = 0.02 to 0.04). The coding SNP has no predicted effect on protein structure or function and is likely to be in linkage disequilibrium with an as-yet unidentified functional variant in the SH2B gene. Our results support a role for SH2-B in modulating the regulation of body weight and fat by leptin in this female population. If SH2-B signaling is attenuated in diet-induced obesity, it could become a target for drug-induced leptin sensitization.

Adaptor Proteins, Signal Transducing↗
PubMed2026

Predicting genome-wide functional constraints with GPN-Star.

Genomic language models have emerged as a powerful approach for learning genome-wide functional constraints directly from DNA sequences1. However, standard genomic language models adapted from natural language processing often require large model sizes and computational resources, yet still fall short of classical evolutionary models in predictive tasks2-4. Here we introduce a genomic pretrained network with species tree and alignment representations (GPN-Star), which is a biologically grounded genomic language model featuring a phylogeny-aware architecture that leverages whole-genome alignments and species trees to model evolutionary relationships explicitly. Trained on alignments spanning vertebrate, mammal and primate evolutionary timescales, GPN-Star achieves state-of-the-art performance across a wide range of variant effect prediction tasks in both coding and non-coding regions of the human genome. Analyses across timescales show task-dependent advantages of modelling more recent versus deeper evolution. To demonstrate its potential to advance human genetics, we show that GPN-Star substantially outperforms previous methods in prioritizing pathogenic and fine-mapped genome-wide association study variants, yields strong enrichments of complex trait heritability and improves power in rare variant association testing5. Extending beyond humans, we train GPN-Star for five model organisms-Mus musculus, Gallus gallus, Drosophila melanogaster, Caenorhabditis elegans and Arabidopsis thaliana-demonstrating the robustness and generalizability of the framework. Taken together, these results position GPN-Star as a scalable, powerful and flexible tool for genome interpretation, well suited to leverage the growing abundance of comparative genomics data.

Journal Article↗
PubMed2025

Chromosome-level genome assembly and annotation of Pterygoplichthys pardalis.

Suckermouth catfishes, with their evolved powerful features, have become notorious invasive species, causing significant damage to aquatic ecosystems. However, the lack of high-quality genomes severely restricts research on this group within the field. In this study, we de novo assembled the chromosome-level genome assembly of Pterygoplichthys pardalis using multiple platforms of sequencing data, including Illumina short reads, Nanopore long reads, and Hi-C sequencing reads, resulting in a 1.51 Gb genome assembly. Multiple evaluations, including read mapping ratio (98.52%), transcript mapping ratio (99.61%), conserved BUSCO gene set (98.8%), and N50 score (49.47 Mb), indicated the high continuity and accuracy of the genome assembly we generated. Genome annotation found that 0.97 Gb of genome sequences are repetitive sequences, accounting for 64.47% of the genome assembly. Further, 23,859 protein-coding genes were successfully predicted, 92.92% of which could be annotated in functional databases. This high-quality genome assembly of P. pardalis provides a valuable resource for understanding the genetic underpinnings of P. pardalis's invasive success and offers critical data for future fisheries research and management.

Animals↗
PubMed1989

Necessary considerations for a theory of form perception: a theoretical and empirical reply to Boselie and Leeuwenberg (1986)

Boselie and Leeuwenberg (1986) recently defended their version of the minimum principle, called structural information theory or SIT, against a varied set of criticisms. Two of the most notable of these criticisms are (i) that perceptual organization can proceed as a piecemeal, rather than as a global, process (as demonstrated by partially-biased Necker cubes and 'impossible' figures), and (ii) that perceptual organization is influenced by subjective variables as well as by stimulus variables (Peterson and Hochberg 1983). The second criticism was acknowledged by Boselie and Leeuwenberg but not addressed. The first criticism was addressed by the introduction of two new variables into SIT in order to argue that the perceived organization of partially-biased Necker cubes and impossible figures can be predicted by a global coding scheme, thereby supporting rather than refuting global minimum principles. It is argued here that the criticisms cannot be dismissed by this rebuttal, which is focused narrowly on single examples rather than on the general principles embodied by the demonstrations. The implications of piecemeal perception and subjective mediation are spelled out, and both old and new data showing that the applicability of global minimum principles must be reexamined, not merely defended, are discussed. Finally, the argument for a richer, more interacting, theory of form perception is presented.

Attention↗
PubMed2003

The substrate specificity-determining amino acid code of 4-coumarate:CoA ligase.

To reveal the structural principles determining substrate specificity of 4-coumarate:CoA ligase (4CL), the crystal structure of the phenylalanine activation domain of gramicidin S synthetase was used as a template for homology modeling. According to our model, 12 amino acid residues lining the Arabidopsis 4CL isoform 2 (At4CL2) substrate binding pocket (SBP) function as a signature motif generally determining 4CL substrate specificity. We used this substrate specificity code to create At4CL2 gain-of-function mutants. By increasing the space within the SBP we generated ferulic- and sinapic acid-activating At4CL2 variants. Increasing the hydrophobicity of the SBP resulted in At4CL2 variants with strongly enhanced conversion of cinnamic acid. These enzyme variants are suitable tools for investigating and influencing metabolic channeling mediated by 4CL. Knowledge of the 4CL specificity code will facilitate the prediction of substrate preference of numerous, still uncharacterized 4CL-like proteins.

Amino Acid Motifs↗
PubMed2000

Genome sequence of Halobacterium species NRC-1.

We report the complete sequence of an extreme halophile, Halobacterium sp. NRC-1, harboring a dynamic 2,571,010-bp genome containing 91 insertion sequences representing 12 families and organized into a large chromosome and 2 related minichromosomes. The Halobacterium NRC-1 genome codes for 2,630 predicted proteins, 36% of which are unrelated to any previously reported. Analysis of the genome sequence shows the presence of pathways for uptake and utilization of amino acids, active sodium-proton antiporter and potassium uptake systems, sophisticated photosensory and signal transduction pathways, and DNA replication, transcription, and translation systems resembling more complex eukaryotic organisms. Whole proteome comparisons show the definite archaeal nature of this halophile with additional similarities to the Gram-positive Bacillus subtilis and other bacteria. The ease of culturing Halobacterium and the availability of methods for its genetic manipulation in the laboratory, including construction of gene knockouts and replacements, indicate this halophile can serve as an excellent model system among the archaea.

Biological Evolution↗
PubMed1982

Human DNA sequence homologous to the transforming gene (mos) of Moloney murine sarcoma virus.

We describe the molecular cloning of a 9-kilo-base-pair BamHI fragment from human placental DNA containing a sequence homologous to the transforming gene (v-mos) of Moloney murine sarcoma virus. The DNA sequence of the homologous region of human DNA (termed humos) was resolved and compared to that of the mouse cellular homolog of v-mos (termed mumos) [Van Beveren, C., van Straaten, F., Galleshaw, J.A. & Verma, I.M. (1981) Cell 27, 97-108]. The humos gene contained an open reading frame of 346 codons that was aligned with the equivalent mumos DNA sequence by the introduction of two gaps of 15 and 3 bases into the mumos DNA and a single gap of 9 bases into the humos DNA. The aligned coding sequences were 77% homologous and terminated at equivalent opal codons. The humos open reading frame initiated at an ATG found internally in the mumos coding sequence. The polypeptides predicted from the DNA sequence to be encoded by humos and mumos also were found to be extensively homologous, and 253 of 337 amino acids were shared between the two polypeptides. The first five NH2-terminal and last two COOH-terminal amino acids of the humos gene product were in common with those of mumos. In addition, near the middle of the polypeptide chains, four regions ranging from 19 to 26 consecutive amino acids were conserved. However, we have not been able to transform mouse cells with transfected humos DNA fragments or with hybrid DNA recombinants containing humos and retroviral long terminal repeat (LTR) sequences.

Animals↗
PubMed1988

B29: a member of the immunoglobulin gene superfamily exclusively expressed on beta-lineage cells.

A number of the glycoproteins identified on the surfaces of cells of the immune response belong to the immunoglobulin superfamily. We have isolated and characterized cDNA clones and the complete genomic gene encoding a B-cell-specific member of the immunoglobulin superfamily called "B29." This isolate is expressed at all stages in B-cell development beginning with the earliest precursor B cells undergoing immunoglobulin heavy chain gene diversity region----joining region gene (DH----JH) rearrangements. The protein sequence predicted by the B29 coding region contains a leader sequence and a single extracellular immunoglobulin-like domain, followed by a hydrophobic transmembrane segment and a charged intracytoplasmic domain. The immunoglobulin-like domain contains cysteines and other conserved amino acids characteristic of light chain variable and joining regions, but overall the sequence is only distantly related to immunoglobulins. Each of these domains is encoded in separate exons in the B29 gene, in analogy to other members of the immunoglobulin superfamily. The conserved structural features of the immunoglobulin-like domain in the B29 gene product resemble those of other members of the immunoglobulin superfamily involved in cell recognition and adhesion.

Amino Acid Sequence↗
PubMed1992

Unusually high conservation of untranslated sequences in cDNAs for Trimeresurus flavoviridis phospholipase A2 isozymes.

As a step toward understanding the structure and function of phospholipases A2 (PLA2s), we isolated and sequenced several cDNAs encoding Trimeresurus flavoviridis venom PLA2 isozymes including two [Lys49]PLA2s called basic proteins I and II, [Thr37]PLA2, and PLX'-PLA2. Comparison of the nucleotide sequences of these cDNAs with the previously isolated [Asp49]PLA2 cDNA revealed some interesting findings from the viewpoint of evolution. First, the homologies of the 5' and 3' untranslated regions (98% and 89%, respectively) were much higher than that of the protein-coding regions (67%). The predicted secondary structure showed the characteristic stem-loop structures for both the untranslated regions of the mRNAs, suggesting that these regions play some functional role(s) in translation or stability of mRNAs. Second, base substitutions appeared to have occurred at similar rates for the three positions of codons among these PLA2s. The results are discussed in terms of evolution of PLA2s. Northern blot analysis showed that these PLA2s are specific to venom gland.

Amino Acid Sequence↗
PubMed1994

A yeast system for expression of human cystathionine beta-synthase: structural and functional conservation of the human and yeast genes.

Human cystathionine beta-synthase (CBS; EC 4.2.1.22) deficiency results in a recessive genetic disorder whose clinical and biochemical manifestations vary greatly among affected individuals. In an effort to identify and analyze mutations in the human CBS gene, we have developed a yeast expression system for human CBS. We have cloned and sequenced a human cDNA that codes for CBS and have expressed the human CBS protein in yeast cells lacking endogenous CBS. The human enzyme produced in yeast is functional both in vitro and in vivo. We have also cloned and sequenced the yeast gene, CYS4, that codes for CBS. The predicted human and yeast CBS proteins are 38% identical and 72% similar to each other, as well as sharing significant similarity with bacterial cysteine synthase. These results demonstrate the evolutionary conservation of CBS and establish the utility of a yeast expression system for studying human CBS.

Animals↗
PubMed1995

High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas.

Malignant mesotheliomas (MMs) are aggressive tumors that develop most frequently in the pleura of patients exposed to asbestos. In contrast to many other cancers, relatively few molecular alterations have been described in MMs. The most frequent numerical cytogenetic abnormality in MMs is loss of chromosome 22. The neurofibromatosis type 2 gene (NF2) is a tumor suppressor gene assigned to chromosome 22q which plays an important role in the development of familial and spontaneous tumors of neuroectodermal origin. Although MMs have a different histogenic derivation, the frequent abnormalities of chromosome 22 warranted an investigation of the NF2 gene in these tumors. Both cDNAs from 15 MM cell lines and genomic DNAs from 7 matched primary tumors were analyzed for mutations within the NF2 coding region. NF2 mutations predicting either interstitial in-frame deletions or truncation of the NF2-encoded protein (merlin) were detected in eight cell lines (53%), six of which were confirmed in primary tumor DNAs. In two samples that showed NF2 gene transcript alterations, no genomic DNA mutations were detected, suggesting that aberrant splicing may constitute an additional mechanism for merlin inactivation. These findings implicate NF2 in the oncogenesis of primary MMs and provide evidence that this gene can be involved in the development of tumors other than nervous system neoplasms characteristic of the NF2 disorder. In addition, unlike NF2-related tumors, MM derives from the mesoderm; malignancies of this origin have not previously been associated with frequent alterations of the NF2 gene.

Base Sequence↗
PubMed1996

Identification of a c-fos-induced gene that is related to the platelet-derived growth factor/vascular endothelial growth factor family.

Using a mRNA differential screening of fibroblasts differing for the expression of c-fos we isolated a c-fos-induced growth factor (FIGF). The deduced protein sequence predicts that the cDNA codes for a new member of the platelet-derived growth factor/vascular endothelial growth factor (PDGF/VEGF) family. Northern blot analysis shows that FIGF expression is strongly reduced in c-fos-deficient cells. Transfection of exogenous c-fos driven by a constitutive promoter restores the FIGF expression in these cells. In contrast, both PDGF and VEGF expression is unaffected by c-fos. FIGF is a secreted dimeric protein able to stimulate mitogenic activity in fibroblasts. FIGF overexpression induces morphological alterations in fibroblasts. The cells acquire a spindle-shaped morphology, become more refractive, disorganized, and detach from the plate. These results imply that FIGF is a downstream growth and morphogenic effector of c-fos. These results also suggest that the expression of FIGF in response to c-fos activation induces specific differentiation patterns and its aberrant activation contributes to the malignant phenotype of tumors.

Amino Acid Sequence↗
PubMed1995

Characterization of tissue-expressed alpha subunits of the high conductance Ca(2+)-activated K+ channel.

Purified high conductance calcium-activated potassium (maxi-K) channels from tracheal smooth muscle have been shown to consist of a 60-70-kDa alpha subunit, encoded by the slo gene, and a 31-kDa beta subunit. Although the size of the beta subunit is that expected for the product of the gene encoding this protein, the size of the alpha subunit is smaller than that predicted from the slo coding region. To determine the basis for this discrepancy, sequence-directed antibodies have been raised against slo. These antibodies specifically precipitate the in vitro translation product of mslo, which yields an alpha subunit of the expected molecular mass (135 kDa). Immunostaining experiments employing smooth muscle sarcolemma, skeletal muscle T-tubules, as well as membranes derived from GH3 cells reveal the presence of an alpha subunit with an apparent molecular mass of 125 kDa. The difference in size of the alpha subunit as expressed in these membranes and the purified preparations is due to a highly reproducible proteolytic decay that occurs mostly at an advanced stage of the maxi-K channel purification. In the purified maxi-K channel preparations investigated, the full-length alpha subunit, an intermediate size product of 90 kDa, and the 65-kDa polypeptide, as well as other smaller fragments can be detected using appropriate antibodies. Proteolysis occurs exclusively at two distinct positions within the long C-terminal tail of slo. In addition, evidence for the tissue expression of distinct splice variants in membrane-bound as well as purified maxi-K channels is presented.

Amino Acid Sequence↗
PubMed2003

Wolframin expression induces novel ion channel activity in endoplasmic reticulum membranes and increases intracellular calcium.

Wolfram syndrome is an autosomal recessive neuro-degenerative disorder associated with juvenile onset non-autoimmune diabetes mellitus and progressive optic atrophy. The disease has been attributed to mutations in the WFS1 gene, which codes for a protein predicted to possess 9-10 transmembrane segments. Little is known concerning the function of the WFS1 protein (wolframin). Endoglycosidase H digestion, immunocytochemistry, and subcellular fractionation studies all indicated that wolframin is localized to the endoplasmic reticulum in rat brain hippocampus and rat pancreatic islet beta-cells, and after ectopic expression in Xenopus oocytes. Reconstitution of wolframin from oocyte membranes into planar lipid bilayers demonstrated that the protein induced a large cation-selective ion channel that was blocked by Mg2+ or Ca2+. Inositol triphosphate was capable of activating channels in the fused bilayers that were similar to channel components induced by wolframin expression. Expression of wolframin also increased cytosolic calcium levels in oocytes. Wolframin thus appears to be important in the regulation of intracellular Ca2+ homeostasis. Disruption of this function may place cells at risk to suffer inappropriate death decisions, thus accounting for the progressive beta-cell loss and neuronal degeneration associated with the disease.

Animals↗