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PubMed1991

Differences in the two-dimension-gel electrophoresis protein patterns of the lethal K and benign B variants of encephalomyocarditis virus.

Variants of encephalomyocarditis virus (EMCV) are indistinguishable by hyperimmune serum. In spite of their antigenic similarity, they produce different disease syndromes in susceptible strains of mice. To understand the basis for the diversity in pathogenicity, studies have been initiated to characterize each of the virus variants. In this study, two-dimensional gel electrophoresis was used to compare the proteins produced by the benign EMCV-B with those produced by lethal EMCV-K. The data show that (i) the replication cycle of each of the virus variants is characteristic of picornaviruses, (ii) the VP1 of EMCV-K is more basic than that of EMCV-B, and (iii) three proteins, one a major component of VP1, the other two with molecular weight of about 12,000, are present in EMCV-K but not in EMCV-B.

Electrophoresis, Gel, Two-Dimensional↗
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↗
PubMedDate not supplied

[The biological properties and variants of the Japanese encephalitis virus from a Russian collection].

Analysis of 10 strains and 7 variants of Japanese encephalitis virus from the collection of the D. I. Ivanovskiĭ Institute of Virology of the Russian Academy of Medical Sciences revealed marked differences between the populations in the complex of biological properties (pathogenicity, reproductive potential, antigenic activity, etc.). Of the Japanese encephalitis virus variants included in the collection attenuated clones 33 and 43 are practically the most interesting as potential candidates for diagnostic and prophylactic preparations.

Academies and Institutes↗
PubMed1988

The peplomer protein E2 of coronavirus JHM as a determinant of neurovirulence: definition of critical epitopes by variant analysis.

We selected murine coronavirus JHM variants specifically changed in defined antigenic sites of the peplomer protein E2. Variants were isolated from the supernatants of monoclonal antibody hybridoma cell cultures which continued to secrete neutralizing antibodies after being infected with JHM. Comparative antigenic analysis and biological tests were performed in order to refine an operational epitope map and to characterize functional domains important for pathogenicity. The reaction patterns (neutralization, inhibition of cell fusion, immunofluorescence and binding in ELISA) between the variant viruses and the panel of monoclonal antibodies were very similar. Four groups of variants were characterized each of which revealed distinct changes affecting one defined antigenic site. These observations indicated that at least four independently mutable antigenic sites were associated with domains involved in cell fusion, neutralization and pathogenicity (E2-Aa, -Ab, -Ba and -Bb). JHM variants with alterations in the E2-Aa, -Ab or -Bb sites were similar to wild-type virus. These variants caused acute hepatitis and encephalomyelitis in mice. In contrast, JHM variants with changes in site E2-Ba had a strong propensity to induce chronic disease accompanied by demyelination persisting for several months.

Animals↗
PubMedDate not supplied

Escherichia coli serotype O157:H7: novel vehicles of infection and emergence of phenotypic variants.

Escherichia coli serotype O157:H7 was only recognized as a human pathogen a little more than a decade ago, yet it has become a major foodborne pathogen. In the United States, the severity of serotype O157:H7 infections in the young and the elderly has had a tremendous impact on human health, the food industry, and federal regulations regarding food safety. The implication of acidic foods as vehicles of infection has dispelled the concept that low-pH foods are safe. Further, the association of nonbovine products with outbreaks suggests that other vehicles of transmission may exist for this pathogen. In laboratory diagnosis, most microbiologic assays rely on a single phenotype to selectively isolate this pathogen. However, the increasing evidence that phenotypic variations exist among isolates in this serogroup may eventually necessitate modifications in assay procedures to detect them.

Animals↗
PubMed1999

Calpainopathy-a survey of mutations and polymorphisms.

Limb-girdle muscular dystrophy type 2A (LGMD2A) is an autosomal recessive disorder characterized mainly by symmetrical and selective atrophy of the proximal limb muscles. It derives from defects in the human CAPN3 gene, which encodes the skeletal muscle-specific member of the calpain family. This report represents a compilation of the mutations and variants identified so far in this gene. To date, 97 distinct pathogenic calpain 3 mutations have been identified (4 nonsense mutations, 32 deletions/insertions, 8 splice-site mutations, and 53 missense mutations), 56 of which have not been described previously, together with 12 polymorphisms and 5 nonclassified variants. The mutations are distributed along the entire length of the CAPN3 gene. Thus far, most mutations identified represent private variants, although particular mutations have been found more frequently. Knowledge of the mutation spectrum occurring in the CAPN3 gene may contribute significantly to structure/function and pathogenesis studies. It may also help in the design of efficient mutation-screening strategies for calpainopathies.

Amino Acid Sequence↗
PubMed2000

Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8): epidemiology and pathogenesis.

Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus type 8 (HHV-8), is a gamma2 herpesvirus (rhadinovirus) and the most recently discovered human tumour virus. It is involved in the pathogenesis of Kaposi's sarcoma (KS), primary effusion lymphoma and the plasma cell variant of multicentric Castleman's disease. KSHV is not pathogenic in most otherwise healthy individuals but is highly oncogenic in HIV-1-infected and iatrogenically immunosuppressed individuals. It establishes a latent infection in most KS spindle (endothelial tumour) cells and in the neoplastic B cells of primary effusion lymphomas. The KSHV genome contains several homologues of cellular genes known to regulate cell growth and differentiation. Although some of these have transforming properties in vitro, their precise role in oncogenesis is still under investigation. Other co-factors may be involved in the pathogenesis of KS in HIV-uninfected, immunocompetent individuals, e.g. in African endemic KS, but none have been identified yet. Transmission of KSHV among homosexual men appears to occur through sexual contact, but in endemic countries transmission is frequent in childhood and may occur through close contact within families. Four major variants of KSHV have been defined, on the basis of variability in the K1 gene; they may have co-evolved with certain human populations. In addition, some KSHV strains may have resulted from a recombination event with a related, but not yet identified, gamma2 herpesvirus.

Antiviral Agents↗
PubMed2006

Bacterial contingency loci: the role of simple sequence DNA repeats in bacterial adaptation.

Bacterial pathogens face stringent challenges to their survival because of the many unpredictable, often precipitate, and dynamic changes that occur in the host environment or in the process of transmission from one host to another. Bacterial adaptation to their hosts involves either a mechanism for sensing and responding to external changes or the selection of variants that arise through mutation. Here we review how bacterial pathogens exploit localized hypermutation, through polymerase slippage of simple sequence repeats (SSRs), to generate phenotypic variation and enhanced fitness. These SSRs are located within the reading frame or in the promoter of a subset of genes, often termed contingency loci, whose functions are usually involved in direct interactions with host structures.

Adaptation, Physiological↗
PubMed1994

Evolution of antigen drift/switching: continuously evading pathogens.

Following infection to a host, some pathogens repeatedly alter their antigen expression, and thereby escape the immune defense (antigen drift/switching). This paper examines the evolutionarily stable mutation rate of pathogens which maximizes the stationary pathogen density in a host. Assumptions are: (i) most mutations are deleterious but a minor fraction, p, of mutations can contribute to the alternation of antigenic property of the pathogen; and. (ii) potential antigen types can be indexed in a one-dimensional lattice (the stepping-stone model). The model reveals that: (a) if the mutation rate is higher than a threshold mu(c) = R0/(1-p), where R0 is the per capita growth rate of pathogen before the immune system is activated, pathogens cannot maintain themselves because too many progeny are lost by lethal mutations; (b) if the mutation rate lies between zero and mu(c), the system converges to a traveling wave of antigen variants with a constant wave speed; (c) the evolutionarily stable mutation rate microESS is unexpectedly high: more than 0.25 per genome per replication even if most mutations are lethal. Hence more than a fourth of progeny are born defective in the evolutionarily stable state; (d) the microESS is even higher if multiple infections by pathogens are common. The paper also studies the evolutionarily stable mutation rate if every mutant antigen belongs to a different type (the infinite allele model), and the evolution of antigen switching between a finite number of antigen variants stored in the pathogen genome.

Alleles↗
PubMed1999

Transfusion-transmitted diseases: risks, prevention and perspectives.

During the past decades major improvements in blood safety have been achieved, both in developed and developing countries. The introduction of donor counseling and screening for different pathogens has made blood a very safe product, especially in developed countries. However, even in these countries, there is still a residual risk for the transmission of several pathogens. For viruses such as the human immunodeficiency virus (HIV), and the hepatitis viruses B and C, this is due mainly to window-period donations. Furthermore, the threat of newly emerging pathogens which can affect blood safety is always present. For example, the implications of the agent causing new variant Creutzfeld-Jakob disease for transfusion practice are not yet clear. Finally, there are several pathogens, e.g. CMV and parvo B19, which are common in the general donor population, and might pose a serious threat in selected groups of immunosuppressed patients. In the future, further improvements in blood safety are expected from the introduction of polymerase chain reaction for testing and from the implementation of photochemical decontamination for cellular blood products. The situation in transfusion medicine in the developing world is much less favorable, due mainly to a higher incidence and prevalence of infectious diseases.

Bacterial Infections↗
PubMed1999

Identification of JC virus variants in multiple tissues of pediatric and adult PML patients.

The transcriptional control region (TCR) of JC virus (JCV), the causative agent of progressive multifocal leukoencephalopathy (PML), undergoes rearrangement during replication of the virus in its human host. The mechanism by which viral promoter/enhancer sequences are deleted and duplicated within the TCR of the archetype form of JCV is not understood, but it is hypothesized that the generation of JCV variants with rearranged TCRs contributes to the virus's pathogenic potential. In a recent study of a pediatric PML patient, we detected extensive rearrangement of the JCV TCR in multiple tissues, and the archetype TCR was amplified from sites other than the kidney. These findings differed from those of previous studies that had examined tissues from adult PML patients. Since exposure to JCV usually occurs early in life, it is likely that some pediatric cases of PML arise as the result of a primary infection, whereas adult cases of PML are thought to result from the reactivation of an infection suffered as an immunocompetent child. To investigate further whether rearrangement of the JCV TCR is affected by the host's age and immune status at the time of exposure, a second pediatric patient and two adult PML patients were examined. As in our first study, multiple tissues were found to contain JCV DNA; however, fewer rearranged variants were detected. In one adult patient, related rearranged variants were detected in the brain, while archetype JCV was found in the other tissues. Based on differences in their VP1 sequences, these two forms represented different JCV genotypes, indicating that this patient had suffered a dual infection. The relevance of these findings to the rearrangement process that alters the JCV TCR is discussed.

Capsid↗
PubMed2004

Emerging infections in transfusion medicine.

The risk of transfusion-transmitted infectious diseases (TTIDs) has declined dramatically in high-income nations over the past 2 decades, primarily because of extraordinary success in preventing HIV and other established transfusion-transmitted viruses from entering the blood supply. Despite this achievement, TTIDs remain a public health concern, and attention is refocusing on new and emerging pathogens, such as West Nile virus, infectious proteins (the presumed cause of variant Creutzfeldt-Jakob disease), and other transmissible organisms such as bacteria and parasites. In this article the authors concentrate on this heterogeneous group of infectious agents, describe individual pathogens and the risks they pose to transfusion recipients, and comment on existing and evolving procedures that are designed to protect the blood supply from this threat.

Blood-Borne Pathogens↗
PubMed2002

Diversity within inc genes of clinical Chlamydia trachomatis variant isolates that occupy non-fusogenic inclusions.

The obligately intracellular chlamydiae are bacterial pathogens that occupy intracellular vacuoles, termed inclusions, as they develop and multiply. Typical Chlamydia trachomatis isolates occupy inclusions that fuse with other C. trachomatis inclusions within cells infected with multiple elementary bodies (wild-type phenotype). The authors of this study have recently described C. trachomatis isolates that form multiply-lobed, non-fusogenic inclusions within single cells infected with multiple elementary bodies (variant phenotype). Inclusions formed by these isolates uniformly lacked the protein IncA on the inclusion membrane (IM). In the present work, the study of the C. trachomatis inclusion phenotype has been expanded to include 27 variant and 13 wild-type isolates. Twenty-four of the 27 variant isolates were IncA-negative, as detected by fluorescence microscopy and immunoblotting, but three variants localized IncA to the IM. The IncA-positive variants formed inclusions that fused, at a reduced rate, with those occupied by wild-type isolates and with inclusions formed by other IncA-positive variants. Nucleotide-sequence analysis of the incA sequences from the variant isolates identified a variety of distinct sequence polymorphisms relative to incA from wild-type strains. The authors also demonstrate that a second Inc protein, CT223p, is not found in the IM in selected C. trachomatis isolates. No change in the structure or the fusogenicity of the inclusions was associated with the presence or absence of CT223p.

Bacterial Proteins↗
PubMed2004

Molecular characterization of Porcine circovirus type 2 isolates from post-weaning multisystemic wasting syndrome-affected and non-affected pigs.

Porcine circovirus type 2 (PCV2) is recognized as a primary cause in post-weaning multisystemic wasting syndrome (PMWS). In this study, both PCV1 and PCV2 types were studied in pigs originating from PMWS-affected (+) and non-affected (-) herds from Brittany. PCV2 was identified by PCR in 100 % of animals from PMWS(+) herds and in 76 % from PMWS(-) herds, while PCV1 was not detected. The complete sequences of 38 PCV2 isolates were determined and 23 new variants were identified, displaying between 94.6 and 99.9 % nucleotide identity with one another. Although highly related to all the PCV2 sequences available in databases, the isolates from France gathered in a distinct subcluster. Compared with the 13 PCV2 from PMWS(+) farms, the 10 PMWS(-) sequences exhibited a slightly higher variability. No viral molecular marker specific to a pathogenic state could be identified, even by including other PCV2 variants isolated from PMWS-suffering animals from other countries. We concluded that the PMWS outbreaks in Brittany are most likely not due to the emergence of a new genotype of circovirus.

Animals↗
PubMed2001

Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer.

Mutations of the BRCA1 or BRCA2 genes have been shown to strongly predispose towards the development of contralateral breast cancer in patients from large multi-case families. In order to test the hypothesis that BRCA1 and BRCA2 mutations are more frequent in patients with bilateral breast cancer, we have investigated a hospital-based series of 75 consecutive patients with bilateral breast cancer and a comparison group of 75 patients with unilateral breast cancer, pairwise matched by age and family history, for mutations in the BRCA1 and BRCA2 genes. Five frameshift deletions (517delGT in BRCA1; 4772delA, 5946delCT, 6174delT and 8138del5 in BRCA2) were identified in patients with bilateral disease. No further mutations, apart from polymorphisms and 3 rare unclassified variants, were found after scanning the whole BRCA1 and BRCA2 coding sequence. Three pathogenic BRCA1 mutations (Cys61Gly, 3814del5, 5382insC) were identified in the group of patients with unilateral breast cancer. The frequencies of common BRCA1 and BRCA2 missense variants were not different between the 2 groups. In summary, we did not find a significantly increased prevalence of BRCA1 and BRCA2 mutations in a hospital-based cohort of German patients with bilateral breast cancer. We conclude that bilaterality of breast cancer on its own is not strongly associated with BRCA1 and BRCA2 mutations when adjusted for age and family history. The high frequency of bilateral disease in multi-case breast cancer families may be due to a familial aggregation of additional susceptibility factors modifying the penetrance of BRCA1 and BRCA2 mutations.

Adult↗
PubMed2004

High prevalence of V37I genetic variant in the connexin-26 (GJB2) gene among non-syndromic hearing-impaired and control Thai individuals.

Hearing loss is highly prevalent with a worldwide incidence of 1-2 per 1000 newborns. Several previous studies have demonstrated that mutations of connexin 26 (Cx26 or GJB2) are responsible for most cases of the recessive non-syndromic sensorineural hearing loss (NSSHL). Certain mutations have been described frequently among various populations, which include 35delG, 167delT, and 235delC. Recently, a missense mutation, V37I, was reported as a pathogenic change in East Asian affected individuals. To identify genetic variants associated with NSSHL in Thai population, we performed mutation analysis of Cx26 in 166 unrelated probands with NSSHL and 205 controls. We identified seven novel genetic variants in Cx26. We also identified a high prevalence of the V37I mutation among both affected probands (11.1%) and control subjects (8.5%), which suggests that the pathologic role of V37I may be modified by other genes. Our data support previous studies that show heterogeneity in the frequencies and types of mutations in Cx26 within populations and among ethnicities and that before clinical significance and causality can be attributed to a genetic variant, functional characterization is necessary.

Adolescent↗
PubMed2000

Coxiella burnetii exhibits morphological change and delays phagolysosomal fusion after internalization by J774A.1 cells.

Coxiella burnetii, the etiological agent of Q fever, is an obligate intracellular bacterium proliferating within the harsh environment of the phagolysosome. Mechanisms controlling trafficking to, and survival of pathogens within, the phagolysosome are unknown. Two distinct morphological variants have been implicated as playing a role in C. burnetii survival. The dormant small-cell variant (SCV) is resistant to extracellular stresses and the more metabolically active large-cell variant (LCV) is sensitive to environmental stresses. To document changes in the ratio of SCVs to LCVs in response to environment, a protein specific to SCV, ScvA, was quantitated. During the first 2 h after internalization of C. burnetii by J774A.1 cells, the level of ScvA decreased, indicating a change from a population containing primarily SCVs to one containing primarily LCVs. In vitro experiments showed that 2 h of incubation at pH 5.5 caused a significant decrease in ScvA in contrast to incubation at pH 4.5. Measuring in vitro internalization of [(35)S]methionine-[(35)S]cysteine in response to pH, we found the uptake to be optimal at pH 5.5. To explore the possibility that after uptake C. burnetii was able to delay phagolysosomal fusion, we used thorium dioxide and acid phosphatase to label phagolysosomes during infection of J774A.1 cells. We determined that viable C. burnetii was able to delay phagolysosomal fusion. This is the first time that a delay in phagolysosomal fusion has been shown to be a part of the infection process of this pathogenic microorganism.

Animals↗
PubMed2006

The need for continuing vigilance: addressing the threat for transmission of blood-borne infectious disease.

As international travel and human encroachment into previously isolated areas have increased, so too has the potential for the emergence of new infectious diseases. Populations likely to be susceptible to new infectious diseases have also increased in size. The past three decades have seen outbreaks of diseases caused by parvoviruses, Nipah virus, circoviruses, and prions. Infectious pathogens such as these are formidable opponents; they can adapt to new hosts or cause variant diseases within new hosts. Many are also resistant to current inactivation techniques. In order to prevent or contain outbreaks, pathogens that emerge must be identified quickly and efficiently; research and ongoing global surveillance are therefore of primary importance. To effectively protect the blood supply and blood-based therapies, this research should include investigations into improved techniques for detection, screening, and viral inactivation, as well as into ways to reduce patient exposure to infectious pathogens via therapeutic agents. The proactive devotion of appropriate resources to infectious disease containment and prevention prior to an epidemic should be perceived as both essential public health policy and cost effective.

Animals↗