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At least 1,261 records · Page 70Linked to original sources
PubMed1987

In vitro growth inhibition of mastitis pathogens by bovine teat skin normal flora.

One factor contributing to differences in the susceptibility of cows to mastitis may be differences in the teat skin normal flora, which could inhibit or enhance the growth of pathogenic bacteria. Using in vitro cross-streaking methods, we found that 25% of the isolates of teat normal flora of non-lactating heifers inhibited the growth of selected mastitis pathogens, but enhancers were not detected. Gram-positive pathogens were inhibited to a greater extent than Gram-negative pathogens. Inhibition was not a characteristic of specific genera or species of normal flora, but rather a property of certain variants within a species. This phenomenon of inhibition of mastitis pathogens in vitro by normal flora may be useful as an in vivo biological control method to reduce the incidence of mastitis.

Acinetobacter↗
PubMed1998

FIV infection of IL-2-dependent and -independent feline lymphocyte lines: host cells range distinctions and specific cytokine upregulation.

We have analyzed the ability of three molecular clones of feline immunodeficiency virus (FIV) and an ex vivo variant to infect nine distinct specific-pathogen-free feline cell lines in tissue culture. The purpose of these studies was to elucidate mechanisms by which host cells regulate the level of virus infection and expression and to assess host cell cytokine responses to virus infection. Cells used for the analyzes included four IL-2-dependent continuous T-cell lines (104-C1, 104-C7, MCH5-4 and DB FeTs) which arose from long-term passage, followed by limiting dilution cloning of peripheral blood mononuclear cells (PBMCs); two IL-2-independent T-cell lines (104-C1DL and MCH5-4DL) which originated from two of the IL-2-dependent lines, 104-C1 and MCH5-4; respectively; Crandell feline kidney cells (CrFK); G355-5 brain-derived glial cells; and the T-cell lymphoma line, 3201. Cells were infected with FIV-PPR, FIV-34TF10, FIV 34TF10orf2rep, and a variant arising from FIV-PPR during ex vivo passage on 104-C1DL cells, termed FIV-PPRglial. Infection of the IL-2-dependent T-cell line, 104-C1, by FIV-PPR resulted in the specific and distinct upregulation of cytokine expression. In particular, these cells doubled their expression of the pleiotropic cytokines, interleukin-4 and interleukin-12 after FIV infection. Interferon-gamma production also increased after infection with FIV whereas, TNFalpha expression remained constant. Also, a marked upregulation of MHC class II expression was noted post infection of MCH5-4 and 104-C1 cells with FIV-PPR. Similar results were obtained after infection with FIV-34TF10orf2rep, indicating that the upregulation of cytokine expression is not an isolate-specific phenomenon. Changes in cytokine and class II expression are similar to various reports for the in vivo cytokine alterations in FIV, SIV and HIV infections. The ex vivo infection of these cell lines offers amanipulable system to examine the mechanism(s) by which lentiviruses alter cytokine expression.

Animals↗
PubMed1979

Characterization of two Chikungunya virus variants.

The stability of virulence and plaque size of two variants of Chikungunya virus (genus Alphavirus) were examined. Mouse pathogenicity did not coincide with infective virus levels in the brain. An increase in the average survival times of mice receiving a lethal dose of the variant which allowed prolonged survival at high doses and harvested late after infection was observed. Studies in Vero cells suggested that the number of infective virus particles produced per cell was lower with the small plaque variant, though these cells were selective for this clone. On the other hand suckling mice or antisera favoured a more virulent large plaque variant.

Animals↗
PubMed2006

Overexpression of GAMT restores GAMT activity in primary GAMT-deficient fibroblasts.

Guanidinoacetate methyltransferase deficiency (MIM 601240) is an autosomal recessive disorder of creatine biosynthesis. Patients present with mental retardation, extrapyramidal symptoms, autistic-like behavior, epilepsy, cerebral creatine deficiency and increased levels of guanidinoacetate. So far 15 mutations have been reported, including six missense variants that are highly likely to be pathogenic mutations. To prove that mutations in the GAMT gene are responsible for GAMT deficiency we overexpressed the GAMT open reading frame in GAMT-deficient fibroblasts by stable transfection. In addition, HeLa cells were transiently transfected with the same expression vector. In contrast to mock transfectants transfection of primary GAMT-deficient fibroblasts with wild-type GAMT results in the restoration of GAMT activity as measured by GC-MS using stable isotope labeled substrates. Moreover, the expression of the GAMT-EGFP fusion protein was analyzed by Western blot, confirming the presence of GAMT fusion protein, both in the stable as well as in the transient transfectants. Here, we prove that mutations in the GAMT gene are responsible for GAMT deficiency, since overexpression of the GAMT open reading frame restores GAMT activity in GAMT-deficient fibroblasts. Furthermore, the transient transfection of HeLa cells will be important for functional analysis of variants of unknown consequence (i.e., missense mutations).

Amino Acid Metabolism, Inborn Errors↗
PubMed1983

Characterization of an antigenic determinant of the glycoprotein that correlates with pathogenicity of rabies virus.

The pathogenicity of fixed rabies virus strains for adult mice depends on the presence of an antigenic determinant on the viral glycoprotein. Two virus-neutralizing monoclonal antibodies have been used to identify this determinant. All pathogenic strains of fixed rabies virus bind to these antibodies and are neutralized by them, whereas nonpathogenic strains fail to react with these monoclonal antibodies and are not neutralized by them. Antigenic variants of the rabies virus with altered glycoprotein were selected by growing virus in the presence of one monoclonal antibody, 194-2. All variants that lost their ability to react with this antibody and an additional antibody, 248-8, were found to be nonpathogenic for adult mice. Analysis of tryptic peptides of the glycoproteins of pathogenic parent virus and nonpathogenic variants and the amino acid sequence of a specific variant tryptic peptide revealed that the change in pathogenicity corresponded to an amino acid substitution at position 333 of the glycoprotein molecule. The nucleotide sequence of the nonpathogenic variant glycoprotein gene contained a base change that confirmed the single amino acid substitution in the tryptic peptide replacing arginine-333 in the parental glycoprotein. We conclude that arginine-333 is essential for the integrity of an antigenic determinant and for the ability of rabies viruses to produce lethal infection in adult mice.

Amino Acid Sequence↗
PubMed2025

Exploring effector protein dynamics and natural fungicidal potential in rice blast pathogen Magnaporthe oryzae.

Rice blast, caused by Magnaporthe oryzae, is one of the most destructive fungal diseases in rice, resulting in major economic losses worldwide. Genetic and genomic studies have identified key genes and proteins, such as AvrPik variants and MAX proteins, that are crucial for the pathogen's virulence. These effector proteins interact with specific alleles of the Pik gene family on rice chromosome 11, modulating the host's immune response. In this study, we investigated 35 plant-derived metabolites known for their antifungal properties as potential fungicides against M. oryzae. Using molecular docking, we identified Hecogenin and Cucurbitacin E as strong binders to MAX40 and APIKL2A proteins, which are essential for the fungus's immune evasion and pathogenicity. Molecular dynamics simulations further confirmed that these compounds form stable, strong interactions with the target proteins, validating their potential as therapeutic agents. Additionally, the compounds were evaluated based on Lipinski's rule of five and toxicity predictions, indicating their suitability for agricultural use. These results suggest that Hecogenin and Cucurbitacin E could serve as promising lead candidates in the development of novel fungicides for rice blast, offering new strategies for crop protection and sustainable agricultural practices.

Oryza↗
PubMed2006

Recombinant HLA-DP2 binds beryllium and tolerizes beryllium-specific pathogenic CD4+ T cells.

Chronic beryllium disease is a lung disorder caused by beryllium exposure in the workplace and is characterized by granulomatous inflammation and the accumulation of beryllium-specific, HLA-DP2-restricted CD4+ T lymphocytes in the lung that proliferate and secrete Th1-type cytokines. To characterize the interaction among HLA-DP2, beryllium, and CD4+ T cells, we constructed rHLA-DP2 and rHLA-DP4 molecules consisting of the alpha-1 and beta-1 domains of the HLA-DP molecules genetically linked into single polypeptide chains. Peptide binding to rHLA-DP2 and rHLA-DP4 was consistent with previously published peptide-binding motifs for these MHC class II molecules, with peptide binding dominated by aromatic residues in the P1 pocket. 9Be nuclear magnetic resonance spectroscopy showed that beryllium binds to the HLA-DP2-derived molecule, with no binding to the HLA-DP4 molecule that differs from DP2 by four amino acid residues. Using beryllium-specific CD4+ T cell lines derived from the lungs of chronic beryllium disease patients, beryllium presentation to those cells was independent of Ag processing because fixed APCs were capable of presenting BeSO4 and inducing T cell proliferation. Exposure of beryllium-specific CD4+ T cells to BeSO4 -pulsed, plate-bound rHLA-DP2 molecules induced IFN-gamma secretion. In addition, pretreatment of beryllium-specific CD4+ T cells with BeSO4-pulsed, plate-bound HLA-DP2 blocked proliferation and IL-2 secretion upon re-exposure to beryllium presented by APCs. Thus, the rHLA-DP2 molecules described herein provide a template for engineering variants that retain the ability to tolerize pathogenic CD4+ T cells, but do so in the absence of the beryllium Ag.

Amino Acid Sequence↗
PubMed2026

Genetic associations in sepsis and ARDS.

Critical illness syndromes, such as sepsis and acute respiratory distress syndrome (ARDS), are characterized by substantial clinical heterogeneity and remain major causes of morbidity and mortality worldwide. Increasing evidence suggests that genetic variation contributes to susceptibility, disease severity, and clinical outcomes in critically ill patients. However, the molecular mechanisms linking genetic predisposition to the pathophysiology of sepsis and ARDS remain incompletely understood. In this review, we evaluated genetic associations reported in sepsis and ARDS, including 13 genome-wide studies identifying 19 unique single-nucleotide polymorphisms (SNPs) across 17 distinct genomic loci, as well as 21 meta-analyses of candidate-gene studies identifying 21 SNPs across 16 genes. The identified variants were primarily associated with pathways involved in pathogen recognition, immune and inflammatory signaling, leukocyte recruitment, and endothelial dysfunction. Collectively, these findings support a polygenic basis for susceptibility to critical illness and highlight several biologically relevant pathways that may contribute to sepsis and ARDS pathogenesis. Improved understanding of the functional consequences of these variants may facilitate the identification of potential therapeutic targets and support the development of precision-guided approaches to critical care.

ARDS↗
PubMed1989

Mouse hepatitis virus 3 pathogenicity expressed by a lytic viral infection in bone marrow 14.8+ mu+ B lymphocyte subpopulations.

Mouse hepatitis virus type 3 (MHV3) provides an excellent model for studying viral-B lymphocyte interaction in the immune system, which plays an important role in the outcome of an acute disease. Bone marrow B lymphocyte subpopulations, at various times postinfection, were studied in genetically C57BL/6 and resistant A/J mice, infected with pathogenic L2-MHV3 and its nonpathogenic variant, YAC-MHV3. B lineage cell subpopulations were identified by double immunofluorescence assays using mAb of terminal deoxynucleotidyl transferase, 14.8 and cytoplasmic (cu) or surface (su) Ig mu-chains. Results revealed diminished percentage and absolute number in the bone marrow 14.8+ mu+ B lymphocyte subpopulations, including pre-B (cu+ su-) and B (cu+ su+) cells of L2-MHV3-infected susceptible C57BL/6 mice; whereas, slight or no increase was evident in the cell subpopulations of L2-MHV3 infected resistant A/J mice or in YAC-MHV3 infected in both strains of mice. Abnormal large-sized forms of the 14.8+ mu+ cells occurred, at 48-h postinfection, in L2-MHV3-infected susceptible C57BL/6 mice only. In contrast, no change in the percentage and absolute number of precursor cells (terminal deoxynucleotidyl transferase positive) and pre pre-B cells (14.8+ mu-) were detected in all infected mice. In vitro L2-MHV3 infection of C57BL/6 bone marrow purified B lineage cell subpopulations showed that pre-B (cu+ su-) and B (cu+ su+) cells became abnormally large in size and depleted in number as a result of a productive and lytic viral replication. Low L2-MHV3 viral replication occurred in these cell subpopulations of A/J mice but no YAC-MHV3 virus was produced in the cells of both strains of mice. Pre pre-B (14.8+ mu-) cells in both strains were not permissive to L2-MHV3 or YAC-MHV3 viral replication. These results are discussed with regard to the role of humoral immunodeficiency in the pathogenic process.

Acute Disease↗
PubMed1996

Analysis of the fim cluster of an avian O2 strain of Escherichia coli: serogroup-specific sites within fimA and nucleotide sequence of fimI.

Escherichia coli MT78, an avian pathogenic strain of serogroup 02, produces a variant form of type 1 fimbriae with distinct antigenic properties and apparent mol. wt of the major subunit. The fim gene cluster of strain MT78 was cloned and its sequence was determined in a region spanning upstream of fimB to the beginning of fimD. Whereas most genes were well conserved relative to fim genes previously described, comparison of the fimA gene from strain MT78 with homologous sequences from other strains of E. coli and Klebsiella pneumoniae revealed that most differences were clustered in four well defined regions. A PCR assay, based upon these variable sequences, allowed amplification of a fragment of gene fimA which is specific for most 02 strains. In addition, the sequence of the previously uncharacterised gene fimI, which is located between genes fimA and fimC, was determined.

Adhesins, Escherichia coli↗
PubMed1994

Alterations in major histocompatibility complex association of myocarditis induced by coxsackievirus B3 mutants selected with monoclonal antibodies to group A streptococci.

Three monoclonal antibodies (mAbs), 49.8.9, 36.2.2, and 54.2.8, made to the group A streptococcus M5 serotype identify crossreactive epitopes in cardiac tissues and also neutralize a highly myocarditic variant of coxsackievirus B3 (H3). Mutants of H3 were selected with these mAbs and evaluated for pathogenicity compared with the wild-type virus. H3 and the mutant variants selected with mAbs 36.2.2 (H3-36) and 54.2.8 (H3-54) induced severe myocarditis in DBA/2 (H-2d) and A/J (H-2a) male mice, whereas CBA (H-2k) mice were disease resistant. The virus variant isolated with mAb 49.8.9 (H3-49) was strikingly different and caused disease in CBA and A/J mice but not in DBA/2 animals, suggesting that the major histocompatibility complex association of the disease had been altered. This hypothesis was confirmed by using B10 congenic mice. In addition, T lymphocytes from the H3 and H3-49 virus-infected mice responded to distinctly different peptides in the streptococcal M protein, suggesting that certain epitopes of infectious agents which are shared with host tissues may be critical in determining disease susceptibility in genetically distinct individuals.

Amino Acid Sequence↗
PubMed1999

Serological evidence for swine hepatitis E virus infection in Australian pig herds.

Hepatitis E virus (HEV) is an enterically transmitted human pathogen, with some similarities to caliciviruses. A variant of HEV was recently identified in pigs in the USA, infecting almost 100% of animals in commercial herds. Phylogenetic analysis suggests that this is a true 'swine HEV' distinct from the human virus, but the swine virus may also infect man. Using an in-house ELISA based on a highly conserved, recombinant HEV protein, we have examined collections of sera from Australian pigs for evidence of HEV infection in local pig herds. Sera from one research herd (n = 32) were uniformly non-reactive, and this was used to establish an assay cut-off (= mean + 3 SD of reference pig serum reactivities). Screening of sera from other herds demonstrates that swine HEV is present in Australia, with reactivity observed in 30% (12/40) of random samples from two piggeries, 92-95% of pigs by the age of 16 weeks in two other piggeries (n = 45), and 17% (15/59) of wild-caught pigs. Further studies are required to examine whether HEV causes disease in pigs and to determine the risk of swine HEV transmission to man.

Age Factors↗
PubMed1958

Antigenic variants of influenza A virus (PR8 strain). V. Virulence, antigenic potency, and cross-protection tests in mice of the original and second series.

Two series of variants of influenza PR8-S virus have been described. While all retain the same degree of pathogenicity for mice and fertile eggs, there was a progressive loss in the ability of the variants to provoke antibody following vaccination or infection of mice and ferrets. The immunogenicity of the variants was, therefore, less than that of the original strain. Although little or no serological relationship could be demonstrated between some of the variants and the PR8-S virus a considerable degree of cross-immunity could be demonstrated in the cross-protection tests with these viruses if observations were based solely on death or survival of the mice. By employing the occurrence of lesions in the lung and the titer of virus in the lung 48 hours after challenge, the amount of cross-protection in mice could be related to the amount of serological cross-reaction. In general mice vaccinated with PR8-S virus were less resistant to infection with the variant viruses than mice vaccinated with variants and challenged with the PR8-S parent virus. The role of the immune environment of the host in the production of the variant influenza viruses with their serological differences, decreasing antigenicity, and persisting pathogenicity as well as the epidemiological implications of these findings with respect to epidemic influenza in man are discussed.

Animals↗
PubMed2000

Linkage exclusion in French families with probable Parkinson' s disease.

We analyzed the segregation of genetic markers spanning chromosomal regions 2p13, 4p14-15, 4q21-23, 6q25-27, and 17q21 in nine French families affected by autosomal-dominant probable Parkinson's disease. These regions have been linked or associated with familial Parkinson's disease. Multipoint linkage and haplotype analyses excluded 2p13 and 4p14-15 loci in five of nine families. For three families, which were equivocal for two-point linkage at D4S405, the ubiquitin carboxy-terminal hydrolase gene (UCH-L1) was sequenced. In one family, a novel UCH-L1 M124L mutation that did not segregate with early-onset disease was identified. This suggests that rare variants in this gene may not be pathogenic. In seven of nine families, it could be inferred that affected individuals did not share 4q21-23 (alpha-synuclein) haplotypes. All families were unequivocally excluded by haplotype analysis from the parkin locus on 6q25-27. Finally, the 17q21 region was excluded in four of nine families, and no mutation in the tau gene was identified in the five remaining families. Findings from this study confirm genetic heterogeneity within familial parkinsonism.

Adult↗
PubMed2006

Use of FTIR spectroscopy to distinguish between capsular types and capsular quantities in Streptococcus pneumoniae.

Fourier transform infrared (FTIR) spectroscopy has shown remarkable ability in distinguishing between bacterial species and identifying bacterial colony structures, when used in tandem with methods such as cluster analysis, principal component analysis, or linear discriminant analysis. The present work was aimed to evaluate the potential of FTIR-microscopy (FTIR-MSP) to distinguish between different serotypes and capsular quantities of Streptococcus pneumoniae. In general, the results obtained have consistently proven that the spectral information at the region 900-1,185 cm(-1) was sufficient to distinguish between various pneumococcal serotypes. Moreover, the method was able to differentiate between S. pneumoniae phase variants on the basis of their relative carbohydrate content. The unsupervised cluster analysis of the samples showed differences, not only in the carbohydrate content, but also in the region 1,350-1,480 cm(-1), which is dominated by absorptions due to lipids and phospholipids. This approach proved to be useful for the distinction between S. pneumoniae serotypes and between phase variants, which were shown to acquire different pathogenic capacity.

Bacterial Capsules↗
PubMed2001

Axonemal beta heavy chain dynein DNAH9: cDNA sequence, genomic structure, and investigation of its role in primary ciliary dyskinesia.

Dyneins are multisubunit protein complexes that couple ATPase activity with conformational changes. They are involved in the cytoplasmatic movement of organelles (cytoplasmic dyneins) and the bending of cilia and flagella (axonemal dyneins). Here we present the first complete cDNA and genomic sequences of a human axonemal dynein beta heavy chain gene, DNAH9, which maps to 17p12. The 14-kb-long cDNA is divided into 69 exons spread over 390 kb. The cDNA sequence of DNAH9 was determined using a combination of methods including 5' rapid amplification of cDNA ends, RT-PCR, and cDNA library screening. RT-PCR using nasal epithelium and testis RNA revealed several alternatively spliced transcripts. The genomic structure was determined using three overlapping BACs sequenced by the Whitehead Institute/MIT Center for Genome Research. The predicted protein, of 4486 amino acids, is highly homologous to sea urchin axonemal beta heavy chain dyneins (67% identity). It consists of an N-terminal stem and a globular C-terminus containing the four P-loops that constitute the motor domain. Lack of proper ciliary and flagellar movement characterizes primary ciliary dyskinesia (PCD), a genetically heterogeneous autosomal recessive disorder with respiratory tract infections, bronchiectasis, male subfertility, and, in 50% of cases, situs inversus (Kartagener syndrome, KS). Dyneins are excellent candidate genes for PCD and KS because in over 50% of cases the ultrastructural defects of cilia are related to the dynein complex. Genotype analysis was performed in 31 PCD families with two or more affected siblings using a highly informative dinucleotide polymorphism located in intron 26 of DNAH9. Two families with concordant inheritance of DNAH9 alleles in affected individuals were observed. A mutation search was performed in these two "candidate families," but only polymorphic variants were found. In the absence of pathogenic mutations, the DNAH9 gene has been excluded as being responsible for autosomal recessive PCD in these families.

Adenosine Triphosphate↗
PubMed1995

Functional domains in the spike protein of transmissible gastroenteritis virus.

The coronavirus spike protein S is assumed to mediate essential biological functions, including recognition of target cells. Earlier studies from our and other groups identified two regions of the TGEV S (220K) protein possibly implicated in such functions. The first of these corresponds to the 224 amino acid N-terminal region which is deleted in PRCV, the respiratory variant of TGEV. We have examined the pathogenicity for the newborn piglet of a series of neutralization escape mutants encoding an S protein mutated in this region. Several amino acid changes were correlated with a dramatic loss of enterovirulence, thus indicating that crucial determinants are associated with this domain of S. The second region of potential relevance is the major neutralization domain. Baculovirus-vectored expression of 150 to 220 amino acid-long stretches encompassing this region, which is encoded by both TGEV and PRCV, was performed. The resultant recombinant proteins were shown to react with the cognate antibodies and to bind APN specifically, thus localizing the receptor-binding site on the S primary structure. Altogether these data lend support to the view that a domain of S protein structurally distinct from the receptor binding site is required for the virus to express its enteric tropism.

Amino Acid Sequence↗