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At least 1,423 records · Page 79Linked to original sources
PubMed2000

Diversity of infectious pancreatic necrosis virus strains isolated from fish, shellfish, and other reservoirs in Northwestern Spain.

A comparison was done of 231 strains of birnavirus isolated from fish, shellfish, and other reservoirs in a survey study that began in 1986 in Galicia (northwestern Spain). Reference strains from all of the infectious pancreatic necrosis virus serotypes were included in the comparison, which was done by neutralization tests and agarose and polyacrylamide gel electrophoresis of the viral genome. The neutralization tests with antisera against the West Buxton, Spajarup (Sp), and Abild (Ab) strains showed that most of the Galician isolates were European types Sp and Ab; however, many isolates (30%) could not be typed. Results from agarose gels did not provided information for grouping of the strains, since all were found to have genomic segments of similar sizes. Analysis of polyacrylamide gels, however, allowed six electropherogroups (EGs) to be differentiated on the basis of genome mobility and separation among segments, and a certain relationship between EGs and serotypes was observed. A wide diversity of electropherotypes was observed among the Galician isolates, and as neutralization tests showed, most of the isolates were included in EGs corresponding to European types Ab and Sp. Only 6.5% of the isolates had the electropherotype characteristic of American strains.

Animals↗
PubMed2005

From genome to antivirals: SARS as a test tube.

The severe acute respiratory syndrome (SARS) epidemic brought into the spotlight the need for rapid development of effective anti-viral drugs against newly emerging viruses. Researchers have leveraged the 20-year battle against AIDS into a variety of possible treatments for SARS. Most prominently, based solely on viral genome information, silencers of viral genes, viral-enzyme blockers and viral-entry inhibitors were suggested as potential therapeutic agents for SARS. In particular, inhibitors of viral entry, comprising therapeutic peptides, were based on the recently launched anti-HIV drug enfuvirtide. This could represent one of the most direct routes from genome sequencing to the discovery of antiviral drugs.

Animals↗
PubMed1998

Testing promoter activity in the trypanosome genome: isolation of a metacyclic-type VSG promoter, and unexpected insights into RNA polymerase II transcription.

In trypanosomes, most genes are arranged in polycistronic transcription units. Individual mRNAs are generated by 5'-trans splicing and 3' polyadenylation. Remarkably, no regulation of RNA polymerase II transcription has been detected although many RNAs are differentially expressed during kinetoplastid life cycles. Demonstration of specific class II promoters is complicated by the difficulty in distinguishing between genuine promoter activity and stimulation of trans splicing. Using vectors that were designed to allow the detection of low promoter activities in a transcriptionally silent chromosomal context, we isolated a novel trypanosome RNA polymerase I promoter. We were however unable to detect class II promoter activity in any tested DNA fragment. We also integrated genes which were preceded by a T3 promoter into the genome of cells expressing bacteriophage T3 polymerase: surprisingly, transcription was alpha-amanitin sensitive. One possible interpretation of these results is that in trypanosomes, RNA polymerase II initiation is favored by genomic accessibility and double-strand melting.

Animals↗
PubMed2026

RESCUE: An end-to-end multi-agent LLM system for proactive rare-disease patient screening in the EHR.

BACKGROUND: Rare diseases affect a significant portion of the global population, yet patients often endure a lengthy diagnostic odyssey, frequently missing the opportunity for timely diagnoses with exome or genome sequencing (ES/GS). Existing informatics tools often rely on pre-identified patients or rigid, institution-specific rule sets, failing to address the broader operational question of clinical utility and feasibility. METHODS: We introduce RESCUE (Rare Disease Detection and Escalation Support via a Learning Health System), an end-to-end, multi-agent LLM-powered workflow designed for proactive rare-disease diagnosis across the entire electronic health record (EHR). RESCUE utilizes a team of specialized agents including Ontology, Modeling, Screening, and Review, to automate the screening process to identify candidates for diagnostic testing based on their clinical features. The Ontology Agent classifies clinical data into a four-tier genetic-evidence taxonomy; the Modeling Agent builds a positive-unlabeled (PU) XGBoost classifier to identify potential cases; the Screening Agent applies these models across the EHR population; and the Review Agent evaluates candidates by sampling clinical notes to ensure medical necessity and operational feasibility for genomic testing. RESULTS: Using electronic medical record data from a pediatric hospital, our retrospective evaluation on a holdout set (n=12,591) demonstrates strong discrimination between patients who received diagnostic genomic testing and those who did not (AUC 0.808). Of nearly 500,000 patients in the institutional base, 175,842 met inclusion criteria for screening; among these, RESCUE-flagged candidates were 7.4-fold more likely to receive subsequent genomic assessments compared to controls. Blinded manual chart reviews confirmed that RESCUE identifies previously missed, medically appropriate patients for ES/GS with 80% precision, while simultaneously accounting for prior testing history. CONCLUSIONS: By decoupling expert roles into modular agents, RESCUE offers a flexible, scalable, and adaptable framework for screening patients for rare-disease diagnostic genomic testing. This approach overcomes the limitations of traditional rule-based methods and provides a reproducible, agentic pathway to reduce diagnostic delays and improve patient care at an institutional scale.

Journal Article↗
PubMed1998

Filamentous bacteriophages of Vibrio parahaemolyticus as a possible clue to genetic transmission.

We have previously reported the isolation and characterization of two filamentous bacteriophages of Vibrio parahaemolyticus, designated Vf12 and Vf33. In this study, to understand the potential of these phages as tools for genetic transmission, we investigated the gene structures of replicative-form (RF) DNAs of their genomes and the distribution of these DNAs on chromosomal and extrachromosomal DNAs. The 7,965-bp nucleotide sequences of Vf12 and Vf33 were determined. An analysis of the overall gene structures revealed that Vf12 and Vf33 had conserved regions and distinctive regions. The gene organization of their conserved regions was similar to that of CTX phage of Vibrio cholerae and coliphage Ff of Escherichia coli, while their distinctive regions were characteristic of Vf12 and Vf33 phage genomes. Southern blot hybridization testing revealed that the filamentous phage genomes integrated into chromosomal DNA of V. parahaemolyticus at the distinctive region of the phage genome and were also distributed on some plasmids of V. parahaemolyticus and total cellular DNAs of one Vibrio damsela and one nonagglutinable Vibrio strain tested. These results strongly suggest the possibilities of genetic interaction among the bacteriophage Vf12 and Vf33 genomes and chromosomal and plasmid-borne DNAs of V. parahaemolyticus strains and of genetic transmission among strains through these filamentous phages.

Bacteriophages↗
PubMed2005

What should we want to know about our future? A Kantian view on predictive genetic testing.

Recent advances in genomic research have led to the development of new diagnostic tools, including tests which make it possible to predict the future occurrence of monogenetic diseases (e.g. Chorea Huntington) or to determine increased susceptibilities to the future development of more complex diseases (e.g. breast cancer). The use of such tests raises a number of ethical, legal and social issues which are usually discussed in terms of rights. However, in the context of predictive genetic tests a key question arises which lies beyond the concept of rights, namely, What should we want to know about our future? In the following I shall discuss this question against the background of Kant's Doctrine of Virtue. It will be demonstrated that the system of duties of virtue that Kant elaborates in the second part of his Metaphysics of Morals offers a theoretical framework for addressing the question of a proper scope of future knowledge as provided by genetic tests. This approach can serve as a source of moral guidance complementary to a justice perspective. It does, however, not rest on the-rather problematic--claim to be able to define what the "good life" is.

Ethical Theory↗
PubMed2025

Molecular insights into the persistence and co-occurrence of two different carbapenem-resistant Pseudomonas aeruginosa lineages within a hospital setting.

UNLABELLED: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) represents a critical-priority pathogen capable of causing life-threatening, multidrug-resistant infections. We performed susceptibility testing, whole-genome sequencing, and bioinformatic analyses on 137 CRPA isolates from a Guangdong hospital. We found that the major specimen types were respiratory specimens (57/137, 41.6%) and bronchoalveolar lavage (42/137, 30.7%). All isolates were carbapenem-resistant but had low resistance to polymyxin B (0.7%, 1/137). IncP-6-positive isolates exhibited &#x2265;2- to 32-fold higher resistance to 9/12 antibiotics (P < 0.05), with no difference to imipenem and meropenem. Fifty-four sequence types and 11 O-serogroups were identified, with ST1971 (6.6%) and O11 (29.9%) being predominant. Temporal and spatial patterns suggest persistent co-occurrence of clade 1 and clade 2 isolates, indicating potential nosocomial outbreak and clonal transmission. IMPORTANCE: The prevalence of carbapenem-resistant Pseudomonas aeruginosa (CRPA) has increased rapidly in recent years, yet few genetic and epidemiological studies on CRPA isolates have been performed. We performed susceptibility testing, whole-genome sequencing, and bioinformatic analyses on hospital isolates to investigate their resistance profiles and molecular epidemiology. These findings may offer new insights for developing effective global strategies to control CRPA and reduce untreatable infections in clinical settings.

Pseudomonas aeruginosa↗
PubMed1998

Using family history information to distinguish true and false positive model-free linkage results.

Genome scans that test for increased marker identity-by-descent sharing between pairs of affected siblings have become increasingly common. These methods do not specify a priori a genetic model for the disease locus and as such lose the ability to specify the parental source of the disease allele. We propose a method that uses family history information to build a more complete model of disease and marker inheritance, while still avoiding specification of the parameters of the disease model of inheritance. One important use for such a model is to test whether a positive linkage result obtained during the course of a genome scan is a true or false positive result. The key to the new test statistics is the interaction between gender-specific marker identity-by-descent sharing and gender-specific family history of disease. The method is useful when the disease locus of interest has a dominant mode of inheritance and a sufficient number of parents are genotyped at the marker locus. If these conditions are met, the proposed tests have good power to differentiate between true and false positive linkage results.

Genetic Diseases, Inborn↗
PubMed2005

Heterogeneity testing in meta-analysis of genome searches.

Genome searches for identifying susceptibility loci for the same complex disease often give inconclusive or inconsistent results. Genome Search Meta-analysis (GSMA) is an established non-parametric method to identify genetic regions that rank high on average in terms of linkage statistics (e.g., lod scores) across studies. Meta-analysis typically aims not only to obtain average estimates, but also to quantify heterogeneity. However, heterogeneity testing between studies included in GSMA has not been developed yet. Heterogeneity may be produced by differences in study designs, study populations, and chance, and the extent of heterogeneity might influence the conclusions of a meta-analysis. Here, we propose and explore metrics that indicate the extent of heterogeneity for specific loci in GSMA based on Monte Carlo permutation tests. We have also developed software that performs both the GSMA and the heterogeneity testing. To illustrate the concept, the proposed methodology was applied to published data from meta-analyses of rheumatoid arthritis (4 scans) and schizophrenia (20 scans). In the first meta-analysis, we identified 11 bins with statistically low heterogeneity and 8 with statistically high heterogeneity. The respective numbers were 9 and 6 for the schizophrenia meta-analysis. For rheumatoid arthritis, bins 6.2 (the HLA region that is a well-documented susceptibility locus for the disease) and 16.3 (16q12.2-q23.1) had both high average ranks and low between-study heterogeneity. For schizophrenia, this was seen for bin 3.2 (3p25.3-p22.1) and heterogeneity was still significantly low after adjusting for its high average rank. Concordance was high between the proposed metrics and between weighted and unweighted analyses. Data from genome searches should be synthesized and interpreted considering both average ranks and heterogeneity between studies.

Arthritis, Rheumatoid↗
PubMed2001

Antenatal genetic testing and the right to remain in ignorance.

As knowledge increases about the human genome, prenatal genetic testing will become cheaper, safer and more comprehensive. It is likely that there will be a great deal of support for making prenatal testing for a wide range of genetic disorders a routine part of antenatal care. Such routine testing is necessarily coercive in nature and does not involve the same standard of consent as is required in other health care settings. This paper asks whether this level of coercion is ethically justifiable in this case, or whether pregnant women have a right to remain in ignorance of the genetic make-up of the fetus they are carrying. While information gained by genetic testing may be useful for pregnant women when making decisions about their pregnancy, it does not prevent harm to future children. It is argued that as this kind of testing provides information in the interests of the pregnant women and not in the interests of any future child, the same standards of consent that are normally required for genetic testing should be required in this instance.

Coercion↗
PubMed2000

An assessment of gene prediction accuracy in large DNA sequences.

One of the first useful products from the human genome will be a set of predicted genes. Besides its intrinsic scientific interest, the accuracy and completeness of this data set is of considerable importance for human health and medicine. Though progress has been made on computational gene identification in terms of both methods and accuracy evaluation measures, most of the sequence sets in which the programs are tested are short genomic sequences, and there is concern that these accuracy measures may not extrapolate well to larger, more challenging data sets. Given the absence of experimentally verified large genomic data sets, we constructed a semiartificial test set comprising a number of short single-gene genomic sequences with randomly generated intergenic regions. This test set, which should still present an easier problem than real human genomic sequence, mimics the approximately 200kb long BACs being sequenced. In our experiments with these longer genomic sequences, the accuracy of GENSCAN, one of the most accurate ab initio gene prediction programs, dropped significantly, although its sensitivity remained high. Conversely, the accuracy of similarity-based programs, such as GENEWISE, PROCRUSTES, and BLASTX was not affected significantly by the presence of random intergenic sequence, but depended on the strength of the similarity to the protein homolog. As expected, the accuracy dropped if the models were built using more distant homologs, and we were able to quantitatively estimate this decline. However, the specificities of these techniques are still rather good even when the similarity is weak, which is a desirable characteristic for driving expensive follow-up experiments. Our experiments suggest that though gene prediction will improve with every new protein that is discovered and through improvements in the current set of tools, we still have a long way to go before we can decipher the precise exonic structure of every gene in the human genome using purely computational methodology.

Base Composition↗
PubMed2006

Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome.

Genomic disorders are characterized by the presence of flanking segmental duplications that predispose these regions to recurrent rearrangement. Based on the duplication architecture of the genome, we investigated 130 regions that we hypothesized as candidates for previously undescribed genomic disorders. We tested 290 individuals with mental retardation by BAC array comparative genomic hybridization and identified 16 pathogenic rearrangements, including de novo microdeletions of 17q21.31 found in four individuals. Using oligonucleotide arrays, we refined the breakpoints of this microdeletion, defining a 478-kb critical region containing six genes that were deleted in all four individuals. We mapped the breakpoints of this deletion and of four other pathogenic rearrangements in 1q21.1, 15q13, 15q24 and 17q12 to flanking segmental duplications, suggesting that these are also sites of recurrent rearrangement. In common with the 17q21.31 deletion, these breakpoint regions are sites of copy number polymorphism in controls, indicating that these may be inherently unstable genomic regions.

Chromosome Breakage↗
PubMed2026

Designing an optimized strategy for extracellular expression of recombinant human TNF-&#x3b1; in Escherichia coli.

Extracellular protein expression in Escherichia coli is an elegant solution that addresses the complex issue of protein misfolding while simultaneously simplifying downstream processing steps. Human TNF-&#x3b1; was chosen as the target protein for export since it is a therapeutically important cytokine. Different genomic knockouts were tested for the ability to sustain and enhance protein expression, and BW25113 &#x394;(elaA + cysW) knockout was found to give a sustained and high level of expression. To improve secretion, various tags were tested, and the MBP tag at the N-terminal end was found to give maximum enhancement in the export of hTNF-&#x3b1;. Even the linker peptide was found to play a critical role in export, with the Ek linker giving the highest extracellular secretion, while the intein sequence completely blocked export. The co-expression of pSecAB, which is involved in protein transport to the periplasm, was also found to be helpful in enhancing extracellular protein titers. Interestingly, pelB performed poorly as compared to the native signal sequence of MBP, which gave better results. Culture conditions were optimized, and it was observed that growing cells in TB medium at a temperature of 25&#xa0;&#xb0;C, coupled with a pulse of concentrated nutrients at 24&#xa0;h, led to a very high extracellular accumulation of &#x223c;1.3&#xa0;g/L of MBP-hTNF-&#x3b1; in shake flask culture. The protein was purified and tested using L929 cells for bioactivity. Thus, a combination of genomic and bioprocess strategies allowed us to obtain high levels of soluble and active extracellular expression of hTNF-&#x3b1;, making this a very attractive strategy for protein production.

E. coli↗
PubMed1995

Genomic mismatch scanning: current progress and potential applications.

Genomic mismatch scanning (GMS) is a new method of genetic mapping which attempts to purify and map the regions of identity between two complex genomes in a single test. Identical DNA fragments from two genomic sources are enriched in two steps: (i) after reannealing of the two genomes, heterohybrids are purified by using a combination of a restriction methylase and methylation-sensitive endonucleases, (ii) heterohybrids that contain mismatches are nicked in vitro by the E. coli MutHLS mismatch repair system and are eliminated subsequently from the pool, leaving only mismatch-free heterohybrids. The genomic origin of this selected pool of DNA fragments is then mapped in a single hybridization step onto metaphase chromosomes or ordered DNA arrays. The principal advantages of GMS are (i) it approaches the theoretical limit of mapping power and resolution offered by an arbitrarily dense set of completely informative polymorphic markers and (ii) it results in a great increase in the effective number of informative markers without a corresponding increase in the number of individual tests. Thus, it should provide an efficient method for affected-relative-pair linkage mapping and for linkage disequilibrium mapping. In addition, a variation of GMS may allow rapid genomic scanning for regions of homozygosity-by-descent or somatic loss-of-heterozygosity. The feasibility of GMS has been validated in the 15 mb genome of Saccharomyces cerevisiae. This article discusses the principles of GMS, the application to more complex genomes, and the possible uses of GMS.

Animals↗
PubMed1979

Murine cytomegalovirus infects spermatogenic cells.

Murine cytomegalovirus replicated in reproductive tissue of male mice infected with the virus. We examined three strains of mice latently infected by injection at birth with 100 plaque-forming units of the virus. As adults, these mice contained within their testes 4--6 viral genomic equivalents per 100 cells, as tested by hybridization between mouse DNA and cytomegalovirus DNA. Acutely infected male adult CBA mice homozygous for the nude gene (athymic: nude/nude) produced infectious virus in their testes, the amounts of which varied according to the animal's age at the time of infection. Heterozygous (nude/+) litter mates contained significantly less virus than nude/nude mice. At the peak of virus replication hybridization between virus DNA and mouse DNA indicated the presence of 3.3 viral genome equivalents per testicular cell. Both in situ hybridization studies and phenol emulsion reassociation of virus DNA to DNA from purified spermatozoa localized this viral DNA to immature and mature sperm cells. Hence, murine cytomegalovirus can be harbored in testes during both acute and latent infections and can replicate in male germ-line cells.

Animals↗
PubMed1990

Construction of a facsimile data set for large genome sequence analysis.

A test was devised for exploring the question of whether it will be possible to identify genes in large-scale genome studies solely by sequence comparison with current sequence collections. To this end, a facsimile data set was constructed by dividing GenBank Release 56 randomly into two halves, one to serve as a reference set and the other intended to simulate raw data anticipated from large genome sequence projects. All supplementary information and identifying marks were removed from the test set after assignment of random identification numbers to each entry and their encryption. Because noncoding intervening sequences (introns) are underrepresented in GenBank, a program that introduced (simulated) introns into mRNA and prokaryotic sequences was devised. In a further attempt to make the problem of identification more realistic, random base substitutions and single-base deletions were also incorporated. The randomly ordered entries were concatenated, along with random intergenic flanking sequences, into a single long "chromosome" 33 Mb in length and then cut into "cosmids" 50-100 kb long. The chopping process was conducted in such a way that terminal overlaps would allow the order of the entries in the chromosome to be reconstituted. Finally, the sequences of a substantial fraction of the cosmids were converted to their complements. Preliminary searching of 10 test cosmids revealed that more than two-thirds of the entries in the test set should be readily identifiable by type of gene product solely on the basis of comparison with the reference set. These preliminary results suggest that existing computer regimens and sequence collections would be able to identify the majority of eukaryotic genes in any new raw data set, the existence of introns not withstanding. Moreover, the analysis can be conducted in pace with the data collection so that the search results and summary identifications will be instantly available to the research community at large.

Animals↗
PubMed1975

Qualitative and quantitative studies of AKR-type murine leukemia virus sequences in mouse DNA.

Utilizing a single-stranded [3H]DNA probe highly representative of AKR viral 70S RNA, we have performed association kinetics experiments with cellular DNA in vast excess from 3 high-, 5 low- and 4 non-virus-yielding mouse strains. Our hybridization studies indicate that in the strains so far tested, the complete genome of the AKR-type MLV is present in the DNA of the embryos of both high- and low-virus-yielding mouse strains, while DNA of non-virus strains contains only a part of the genome. Furthermore, at least two populations of virus-specific DNA sequences can be identified (more abundant and less abundant species) according to their rate of association. Low-virus-yielding mouse strains contain a smaller number (1-2 copies) of the less abundant species, and thus a lower number of complete viral genome than do high-virus strains (3-4 copies). Non-virus-yielding strains are lacking these less abundant sequences in their genome. DNA from wild Mus musculus also contained viral sequences, the sample tested showing association kinetics identical to the non-virus-producing strains. Thus there is a good correlation between completeness of the AKR-type MLV genome in cellular DNA and the capacity of the cells to release AKR-type MLV. Mice of a non-virus-yielding strain made partially congenic for the AKR virus-inducing locus Akv-1 contained the complete virus genome, confirming that this locus consists of structural genes of the virus.

AKR murine leukemia virus↗