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PubMed1987

Characterization of cell lines derived from enlarged spleens induced in C57BL/6 mice by the variant BSB strain of Friend erythroleukemia virus.

BSB is a variant strain of Friend virus selected for pathogenicity in C57BL/6 mice that are resistant to parental Friend virus strains by virtue of their homozygosity for the recessive Fv-2r allele (Steeves et al., 1970, Int. J. Cancer 5, 346-356). Lines and clones of erythroleukemia cells could readily be established in culture from the enlarged spleens of BSB-infected Fv-2r homozygotes. All lines expressed viral gene products and could be induced to express hemoglobin. Some lines produced infectious virus. In addition to the viral envelope-related proteins (gPr85, gp70, and gp52) detected by precipitation with goat anti-Rauscher gp70 antiserum from tumor cell lines induced by parental Friend virus strains, BSB-induced cell lines also expressed gp80, p52, and gp45 products precipitable with the same antiserum. A rat monoclonal antibody that recognizes an epitope of an amino-terminal region of gp52 (Wolff et al., 1982, J. Virol. 43, 472-481) also precipitated the gp80 and gp45 viral proteins. The data indicate that the BSB strain of Friend virus is oncogenic in Fv-2r homozygotes. Transformation is correlated with the expression of an altered SFFV env-gene product.

Animals↗
PubMed2002

New human sodium/glucose cotransporter gene (KST1): identification, characterization, and mutation analysis in ICCA (infantile convulsions and choreoathetosis) and BFIC (benign familial infantile convulsions) families.

Cotransporters represent a major class of proteins that make use of ion gradients to drive active transport of substrate into cells. A new human gene, KST1, encoding a member of the sodium/glucose cotransporter family, was identified onto human chromosome 16p12-p11. This genomic region contains a major gene responsible for a syndrome of infantile convulsions and paroxysmal dyskinesia (ICCA syndrome), inherited as an autosomal dominant trait, as well as for benign familial infantile convulsions (BFIC). The entire coding sequence of the human KST1 gene was determined using a combination of methods including in silico comparison of its rabbit orthologous DNA complementary to RNA (cDNA) to the corresponding human genomic sequences, reverse transcription-polymerase chain reaction on human brain RNA, 5' and 3' rapid amplification of cDNA ends. The gene is divided into 16 exons and the predicted protein of 675 amino acids contains 14 transmembrane domains. It shares significant homology to the sodium-glucose transporter 1 cotransporter proteins. An alternatively spliced transcript resulting from the skipping of exon 6 led to a predicted protein lacking the 4th transmembrane domain. As ion transporters are good candidates for a large variety of human diseases, including paroxysmal disorders, a mutation search was performed in four families with ICCA or BFIC syndromes. No pathogenic mutation was found, although several polymorphic variants with amino acids exchanges were identified. Due to its broad expression in human tissues, the human KST1 gene could be involved in several other diseases mapped to human chromosome 16p12-p11.

Amino Acid Sequence↗
PubMed2004

Eczema and the spongiotic dermatoses: a histologic and pathogenic update.

The spongiotic dermatoses including eczema and its clinicopathologic variants are capable of presenting in a variety of clinical guises and are pathologically defined by the presence of epithelial intercellular edema that may rarely form blisters. The mechanisms which underlie there pathogensis has only recently begun to be elucidated. Collectively, these disorders comprise an integral facet of dermatology and are the subject of discussion in this article.

Dermatitis, Allergic Contact↗
PubMed2026

Visual Detection and Stratification of Pathogenic mtDNA SNV Heteroplasmy by Balancing FnCas12a Signal Output and Allelic Discrimination.

Assessment of pathogenic mitochondrial DNA (mtDNA) single-nucleotide variant (SNV) heteroplasmy is important for molecular diagnostics, yet rapid visual profiling remains analytically challenging because an assay must combine single-nucleotide allelic discrimination, mutant-fraction-associated readout, and suitable target access. Herein, we report VISTA (visual identification and stratification of targeted mtDNA alleles), a broad-PAM FnCas12a assay that rebalances trans-cleavage signal output and mutant-wild-type discrimination for visual mtDNA SNV heteroplasmy analysis. VISTA uses unmodified FnCas12a with relaxed TTN PAM recognition and integrates crRNA spacer-length engineering with PEG8000/acBSA reaction tuning to improve the practical signal-discrimination balance without nuclease engineering. At the m.3243A>G model locus, spacer truncation enhanced mutant-wild-type discrimination, while molecular-dynamics simulations identified spacer-dependent differences between matched and mismatched complexes at the crRNA-DNA interface. The optimized assay resolved defined synthetic m.3243A>G heteroplasmy gradients by fluorescence imaging and was further adapted to lateral-flow detection. In locus-specific analyses of a deidentified collection of 74 peripheral-blood samples, fluorescence and lateral-flow readouts achieved ROC AUC values above 0.9 for mutant-allele classification after target-region amplification. Fluorescence supported heteroplasmy-associated profiling, whereas lateral flow provided a visual, semiquantitative readout for relative ranking based on the T/C ratio rather than absolute heteroplasmy measurement. VISTA therefore provides an accessible dual-readout analytical strategy for visual detection and heteroplasmy-associated profiling by tuning the FnCas12a signal output and allelic discrimination.

DNA, Mitochondrial↗
PubMed2004

The periplasmic serine protease inhibitor ecotin protects bacteria against neutrophil elastase.

Ecotin is a dimeric periplasmic protein from Escherichia coli that has been shown to inhibit potently many trypsin-fold serine proteases of widely varying substrate specificity. To help elucidate the physiological function of ecotin, we examined the family of ecotin orthologues, which are present in a subset of Gram-negative bacteria. Phylogenetic analysis suggested that ecotin has an exogenous target, possibly neutrophil elastase. Recombinant protein was expressed and purified from E. coli, Yersinia pestis and Pseudomonas aeruginosa, all species that encounter the mammalian immune system, and also from the plant pathogen Pantoea citrea. Notably, the Pa. citrea variant inhibits neutrophil elastase 1000-fold less potently than the other orthologues. All four orthologues are dimeric proteins that potently inhibit (<10 pM) the pancreatic digestive proteases trypsin and chymotrypsin, while showing more variable inhibition (5 pM to 24 microM) of the blood proteases Factor Xa, thrombin and urokinase-type plasminogen activator. To test whether ecotin does, in fact, protect bacteria from neutrophil elastase, an ecotin-deficient strain was generated in E. coli. This strain is significantly more sensitive in cell-killing assays to human neutrophil elastase, which causes increased permeability of the outer membrane that persists even during renewed bacterial growth. Ecotin affects primarily the ability of E. coli to recover and grow following treatment with neutrophil elastase, rather than the actual rate of killing. This suggests that an important part of the antimicrobial mechanism of neutrophil elastase may be a periplasmic bacteriostatic effect of protease that has translocated across the damaged outer membrane.

Amino Acid Sequence↗
PubMed2001

CDX2 mutations do not account for juvenile polyposis or Peutz-Jeghers syndrome and occur infrequently in sporadic colorectal cancers.

Peutz-Jeghers syndrome (PJS) and juvenile polyposis (JPS) are both characterized by the presence of hamartomatous polyps and increased risk of malignancy in the gastrointestinal tract. Mutations of the LKB1 and SMAD4 genes have been shown recently to cause a number of PJS and JPS cases respectively, but there remains considerable uncharacterized genetic heterogeneity in these syndromes, particularly JPS. The mouse homologue of CDX2 has been shown to give rise to a phenotype which includes hamartomatous-like polyps in the colon and is therefore a good candidate for JPS and PJS cases which are not accounted for by the SMAD4 and LKB1 genes. By analogy with SMAD4, CDX2 is also a candidate for somatic mutation in sporadic colorectal cancer. We have screened 37 JPS families/cases without known SMAD4 mutations, 10 Peutz-Jeghers cases without known LKB1 mutations and 49 sporadic colorectal cancers for mutations in CDX2. Although polymorphic variants and rare variants of unlikely significance were detected, no pathogenic CDX2 mutations were found in any case of JPS or PJS, or in any of the sporadic cancers.

AMP-Activated Protein Kinase Kinases↗
PubMed2000

Acinetobacter calcoaceticus pneumonia and the formation of pneumatoceles.

Pneumatoceles are cystic lesions of the lungs often seen in children with staphylococcal pneumonia and positive-pressure ventilation. Acinetobacter calcoaceticus is an aerobic, short immobile gram-negative rod, or coccobacillus, which is an omnipresent saprophyte. The variant anitratus is the most clinically significant pathogen in this family, usually presenting as a lower respiratory tract infection. Acinetobacter has been demonstrated to be one of the most common organisms found in the ICU. We present three critically ill surgery patients with Acinetobacter pneumonia, high inspiratory pressures, and the subsequent development of pneumatoceles. One of these patients died from a ruptured pneumatocele, resulting in tension pneumothorax. Treatment of pneumatoceles should center on appropriate intravenous antimicrobial therapy. This should be culture directed but is most often accomplished with Imipenem. Percutaneous, computed tomographic-guided catheter placement or direct tube thoracostomy decompression of the pneumatocele may prevent subsequent rupture and potentially lethal tension pneumothorax.

Acinetobacter Infections↗
PubMed1999

Optic atrophy and chronic acquired polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic, multifocal disorder usually defined as limited to the peripheral nervous system. Multifocal motor neuropathy, an acquired demyelinating neuropathy with conduction block affecting motor neurons only, may be a pathogenically distinct syndrome or a predominantly motor variant of chronic inflammatory demyelinating polyneuropathy. Central nervous system demyelination including optic neuropathy has been reported uncommonly previously in these entities. We report two cases and review the literature on the possible association of optic neuropathy and chronic acquired polyneuropathy.

Chronic Disease↗
PubMed2000

Major histocompatibility complex variation in the Arabian oryx.

In the 1960s, the Arabian oryx was one of the most endangered species in the world, extinct in the wild and surviving in only a few captive herds. The present day population of over 2000 descends from a small number of founders and may have restricted genetic variation for important adaptive genes. We have examined the amount of genetic variation for a class II gene in the major histocompatibility complex thought to be the most important genetic basis for pathogen resistance in vertebrates. We found three very divergent alleles, which on average, differed by 24 nucleotides and 15 amino acids in the 236-bp fragment we examined. Using single-strand conformation polymorphism, we found that in a sample of 57 animals, the alleles were in Hardy-Weinberg proportions, although one allele was found only in four heterozygous individuals. The average heterozygosity for the 22 amino acid positions involved in antigen binding was 0.165, three times as high as that for the 56 amino acids not involved with antigen binding. Because the three alleles have such divergent sequences, it is likely that they may recognize peptides from quite different pathogens. As a result, maintenance of these variants should be considered as a goal in the captive breeding program of the Arabian oryx.

Adaptation, Physiological↗
PubMed1989

Immunogenicity of Mycoplasma gallisepticum.

The serological response and protective immunity elicited in the chicken by the pathogenic Ap3AS strain and the moderately pathogenic 80083 strain of Mycoplasma gallisepticum and variants of strain 80083 attenuated by repeated passage in mycoplasma broth were investigated. Strain 80083 elicited a substantial serum antibody response after administration either in drinking water or by conjunctival sac instillation to 7-week-old SPF chickens. No vaccinated chickens developed air sac lesions when challenged by intra-abdominal (IA) injection with the virulent Ap3AS strain. Chickens vaccinated with strain 80083M (50 broth passages) showed only a weak serological response but were substantially protected when challenged 4 weeks after vaccination. Chickens vaccinated with 80083H (100 broth passages) were serologically negative 4 weeks after vaccination and developed severe air sac lesions after challenge. Thirty-seven-week-old hens vaccinated 6 months previously with strain 80083 had high serum antibody levels and were completely protected against IA challenge with the homologous strain. However, 4/6 showed mild air sac lesions when challenged intra-abdominally with strain Ap3AS. Another group showed high M. gallisepticum serum antibody levels 6 months after vaccination with strain Ap3AS but 4/6 and 2/6 showed mild lesions after IA challenge with strains Ap3AS or 80083, respectively. Strains 80083 or 80083M were administered by conjunctival sac instillation to susceptible 11-week-old commercial pullets at the time of fowl pox vaccination. The concurrent use of both vaccines had no apparent adverse effect on the health of the chickens. Similar protection against IA challenge with strain Ap3AS was produced with the M. gallisepticum vaccines whether used alone or in combination with fowl pox.

Animals↗
PubMed1993

Nuclear Ribosomal DNA as a Probe for Genetic Variability in the Japanese Pear Pathotype of Alternaria alternata.

A restriction fragment length polymorphism analysis of nuclear ribosomal RNA genes (rDNA) was used to measure the amount and distribution of genetic variability in populations of the Japanese pear pathotype of Alternaria alternata on both micro- and macrogeographical scales. A total of 322 isolates were obtained from 13 areas in Aichi, Gifu, and Tottori Prefectures in central and western Japan. The restriction fragment length polymorphism analysis revealed that the pathogen populations contained at least eight rDNA variants. The eight variant types differed in the lengths and in the presence of the restriction sites in spacer DNA outside the coding regions for rRNAs. A total of 271 isolates were classified into the eight types. The remaining 51 isolates were determined to have mixed rDNA types. Single pear fields typically contained two to five types of rDNA variants. The frequencies of rDNA variants in 11 populations in Tottori Prefecture were compared; in this prefecture orchards containing the susceptible pear are common. Except for one collection site, there were no significant differences in the composition of the rDNA variants among the populations. This suggests that dispersal of inocula has occurred frequently in Tottori Prefecture. In contrast, significantly different distributions were observed in the three prefectures, indicating that gene flow between prefectures might be limited by geographical isolation. DNA fingerprints resulting from hybridization with a moderately repetitive DNA sequence of the fungus revealed greater genetic variability and geographical differences in genetic population structure even within the same rDNA type.

Journal Article↗
PubMed1999

Green fluorescent protein as a marker in Rickettsia typhi transformation.

Transformation of rickettsiae is a recent accomplishment, but utility of this technique is limited due to the paucity of selectable markers suitable for use in this intracellular pathogen. We chose a green fluorescent protein variant optimized for fluorescence under UV lights (GFPUV) as a fluorometric marker and transformed Rickettsia typhi with an rpoB-GFPUV fusion construct. The rickettsiae were subsequently grown in Vero cells, and cultures were screened by PCR and restriction fragment length polymorphism (RFLP) to confirm incorporation of the rpoB-GFPUV construct. Cultures were then analyzed by flow cytometry for detection of GFPUV expression, and transformed R. typhi were isolated in a fluorescence-activated cell sorter. This is the first report of transformation of rickettsiae with a nonrickettsial (GFPUV) gene.

Biomarkers↗
PubMed2026

Healthcare-facility-based SARS-CoV-2 genomic surveillance in Brazil: experience from the global action in healthcare network.

UNLABELLED: Genomic sequencing is essential to effectively monitor the SARS-CoV-2 evolution and spread of its lineages. Healthcare-facility-based SARS-CoV-2 genomic surveillance has been proposed as a valuable strategy, considering the characteristics of its target population. As part of the Centers for Disease Control and Prevention's Global Action in Healthcare Network program, this study aimed to describe the distribution and frequency of SARS-CoV-2 lineages in two tertiary-care hospitals in Brazil, where the genomic sequencing capacity is limited. Whole-genome sequencing of SARS-CoV-2 samples obtained from 993 healthcare workers (75.4%) and inpatients (24.6%) was analyzed between February 2023 and August 2024. In total, 113 distinct lineages were identified. Notably, we observed a temporal replacement of predominant lineages corresponding to three distinct epidemic waves: the first wave dominated by XBB.1.5 and XBB.2.3 (February 2023 to June 2023), the second by GK.1.1 and JD.1.1 (September 2023 to December 2023), and the third by JN.1 and JN.1.9 (January 2024 to April 2024). JN.1.9 was the only lineage with a significantly higher prevalence among healthcare workers compared to inpatients. Additionally, we identified cases of co-infection with genetically distinct variants, underscoring the potential for healthcare-based monitoring to capture events relevant to viral evolution. Overall, our findings were consistent with those observed across Brazil, suggesting that this strategy may be valuable for SARS-CoV-2 genomic surveillance. They also indicate a clear temporal pattern of lineage replacement, reflecting successive waves driven by emerging variants and rapid global dissemination. IMPORTANCE: Genomic surveillance of SARS-CoV-2 remains essential for identifying emerging variants with increased transmissibility, immune escape, or pathogenicity. While most genomic surveillance efforts focus on community-based sampling, a healthcare-facility-based strategy may offer a complementary approach. In this study, we describe SARS-CoV-2 lineage dynamics over an 18-month period among healthcare workers and hospitalized patients in southern Brazil. Our findings align closely with regional and national trends, supporting the value of healthcare-facility-based SARS-CoV-2 genomic surveillance for documenting the local genomic landscape and demonstrating the feasibility and value of this approach in settings with limited genome sequencing capacity. Additionally, this approach may be applicable to other respiratory viruses in healthcare settings; however, further studies would be needed to confirm this.

Humans↗
PubMed2004

Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation.

The MutLalpha heterodimer formed by mismatch repair (MMR) proteins MLH1 and PMS2 is a major component of the MMR complex, yet mutations in the PMS2 gene are rare in the etiology of hereditary nonpolyposis colorectal cancer. Evidence from five published cases suggested that contrary to the Knudson principle, PMS2 mutations cause hereditary nonpolyposis colorectal cancer or Turcot syndrome only when they are biallelic in the germline or abnormally expressed. As candidates for PMS2 mutations, we selected seven patients whose colon tumors stained negative for PMS2 and positive for MLH1 by immunohistochemistry. After conversion to haploidy, truncating germline mutations of PMS2 were found in two patients (2192delTAACT and deletion of exon 8). These mutations abrogated PMS2 protein in germline cells by Western analysis. In two additional patients, PMS2 protein from one allele also was abrogated. Novel or previously described missense variants of PMS2 were detected, but their pathogenicity is undetermined. We detected and characterized a new transcript, PMS2CL, showing 98% sequence identity with exons 9 and 11-15 of PMS2 and emanating from a locus close to PMS2 in chromosome 7p. Its predicted protein product was not detected. Thus, in addition to several previously described PMS2-related genes resembling the 5' end of PMS2, at least one related gene resembles the 3' end of PMS2. In conclusion, both detectable and presently undefined germline mutations are deleterious and produce susceptibility to cancer by the two-hit mechanism. Paralogous genes interfere with mutation detection, resulting in underdiagnosis of PMS2 mutations. Mutation detection in PMS2 requires haploid DNA.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Cellular response to gene expression profiles of different hepatitis C virus core proteins in the Huh-7 cell line with microarray analysis.

In the current investigation, we constructed recombinants of expression of HCV genotype 1b, 2a, and 4d whole core proteins and established a human hepatoma (Huh-7) cell line which expressed different core proteins constitutively. In the Affymetrix human gene chip, the HG-U133 A and B were employed for identification of variant core protein gene expression in the Huh-7 cell line. In data analysis, we applied a threshold that eliminated all genes that were not increased or decreased by at least a 3-fold change in a comparison between transfected cells and control cells. All of these genes were annotated by using NetAffx analysis through the Affymetrix website and categorized on the basis of their biological processes. The microarray analysis result suggested that the gene expression profiles caused by three kinds of core proteins were mainly shown in metabolism, signal transduction, protease activity, immune responses, etc. and that some pathogenesis/oncogenesis, apoptosis, or anti-apoptosis gene expression were up/down-regulated simultaneously in the Huh-7 cell line. In conclusion, the gene expression profiles of variant core proteins were implicated in HCV replication, pathogenesis, or oncogenesis in the Huh-7 cell line, which is useful for our understanding of HCV variant core protein biological function and its pathogenic mechanism.

Carcinoma, Hepatocellular↗
PubMed2002

Level of galactosylation determines cryoglobulin activity of murine IgG3 monoclonal rheumatoid factor.

Autoantibodies of the cryoprecipitating IgG3 isotype have been shown to play a significant role in the development of murine lupus-like autoimmune syndrome. At present, the structural basis of IgG3 cryoprecipitation and its role in autoantibody pathogenicity remain to be defined. Using molecular variants of an IgG3 monoclonal rheumatoid factor, 6-19, derived from an autoimmune MRL-Fas(lpr) mouse, we have investigated the implication of charged residues in the heavy-chain variable (VH) region, potential CH3-linked oligosaccharides, and galactosylation of CH2-linked oligosaccharides in its cryoglobulin activity. The cryoglobulin activity of the IgG3 6-19 mutant bearing more negatively charged residues at VH 6 and 23 was found to be reduced but still highly significant, whereas that of the mutant lacking a potential CH3 glycosylation site remained unchanged. In marked contrast, IgG3 6-19 variants obtained from 6-19 heavy-chain transgenic mice displayed barely detectable cryoglobulin activity associated with an increased level of galactosylation in the CH2 oligosaccharide side chains. Thus, our data strongly suggest that the cryoglobulin activity of IgG3 6-19 autoantibody is critically determined by levels of galactosylation in the CH2 oligosaccharide side chains, whereas VH residues play a secondary role in 6-19 IgG3 cryoglobulin activity.

Animals↗
PubMed1995

Thyroid cytotoxic antibodies in atrophic and goitrous autoimmune thyroiditis.

It is unknown whether in chronic lymphocytic thyroiditis the goitrous (Hashimoto's thyroiditis) and atrophic forms (primary myxedema) are variants of the same disease or different pathogenic entities. Conventional thyroid-related autoimmune parameters are unable to separate both diseases serologically. It is assumed that cellular and humoral cytotoxic events induce gland atrophy and thus should be detectable more often in non-goitrous than goitrous autoimmune thyroiditis. We determined antibody-dependent cell-mediated cytotoxicity in 67 patients with autoimmune thyroiditis, using a 51chromium-release assay against human thyroid cells. Thyroid volume had been measured by ultrasonography. Other thyroid-specific antibodies, like TSH binding-inhibiting antibodies, TSH function-blocking antibodies, thyroglobulin antibodies and thyroid peroxidase antibodies, were determined. Cytotoxic antibody activity was 20.5% (median, range 0-54.5%) in patients with autoimmune thyroiditis and 8.3% (median, range 0-18.4%) in controls (p < 0.0001). Analysis of cytotoxicity regarding thyroid size showed a high incidence of cytotoxic antibodies in atrophic disease (median thyroid volume 6 ml), where cytotoxic antibodies were detectable in 80% versus 39% (x2 = 9.6; p < 0.0001) in goitrous disease (median thyroid volume 36 ml). The specific lysis of 30% (median; 95% confidence limit 23.9-32.9) in non-goitrous thyroiditis patients was significantly higher than in goitrous patients (16.9%; 95% confidence limit 13.2-20.4) (p = 0.0006).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2003

Integrating microarrays into disease-gene identification strategies.

Positional cloning represents one of the most successful paradigm shifts in identifying the underlying patho-mechanisms in human disease. While traditional discovery tools focused on identifying defects at the tissue or cellular level, positional cloning identifies the damaged region of the genome as the preliminary step. While a large number of inherited single gene disorders have been mapped using this approach, a bottleneck still exists in combing through the genomic interval, often millions of nucleotides in length, to identify the nucleotide changes which result in a defective protein and subsequent disease. Along with the recent unravelling of the human genetic code, the development of massively parallel tools, such as microarrays, represent an equally important step forward in unraveling pathogenic genome dysfunctions. There are many emerging variants on microarray technology, such as expression arrays, exon arrays, array-based comparative genomic hybridization and sequencing arrays. Several of these platforms, if used properly, can accelerate the positional cloning process. The proper use of the platform is driven by knowledge of the underlying molecular defect being searched for and the operating characteristics of the array. The resultant insight forms the basis for improved molecular diagnostics and novel therapeutic targets.

Computational Biology↗