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PubMedDate not supplied

Antigenic variation in Trypanosoma equiperdum.

Trypanosoma equiperdum is an African trypanosome that causes dourine in horses. Like the other African trypanosomes, T. equiperdum escapes elimination by the immune system of its host by using an elaborate system of antigenic variant. The trypanosomes are covered by a coat consisting of a single protein called the variable surface glycoprotein (VSG) that acts as the major trypanosome immunogen. As the host responds to one VSG, trypanosomes covered with another VSG become dominant. There is a loose order of appearance of these VSG during the infection. The factors that affect the timing of VSG expression and the effective size of the VSG repertoire in T. equiperdum are reviewed. The VSG genes are generally activated by a process of duplicative transposition involving the duplication of a silent VSG gene and inserting a copy of the gene into an expression site. The order of VSG expression is related to the amount of homology between the silent gene and the expression site. The genes expressed late in infection lack extensive homology with the expression site and depend on homology with the gene in the expression site. The genes coding for VSG expressed late in infection are hybrid genes because of this mode of transfer. This transfer mechanism allows the trypanosome to create complex VSG genes from parts of several different silent genes that are each pseudogenes. Additionally, data are presented showing that only a limited portion of the VSG is actually seen by the host immune system. These factors indicate that the effective VSG repertoire is greater than the number of VSG genes in the trypanosome genome.

Animals↗
PubMed1994

Pathology of livers infected with "silent" hepatitis B virus mutant.

We have discovered that non-A, non-B, non-C, non-D, non-E (so-called type F) acute and chronic hepatitis is caused by a hepatitis B virus (HBV) variant with mutations in the X open reading frame. This silent HBV mutant does not induce immunoserological markers. In the present investigation we attempted to elucidate the putative mechanism of hepatocellular necrosis and expression patterns of hepatitis B surface antigen (HBsAg) and core antigen (HBcAg) in biopsied liver tissue. The subjects consisted of 14 patients with acute hepatitis, 11 with chronic hepatitis and eight with liver cirrhosis, all of whom had been previously diagnosed as having so-called hepatitis F. Nine of the 14, 10 of the 11 and all eight, respectively, of the above patients exhibited significant positive immunostaining for HBsAg within their hepatocellular cytoplasm, diffusely or focally. HBcAg stained in a few hepatocellular nuclei in 24.2% of the patients. Histological features were characterized by necroinflammation, indicating immune-mediated hepatocellular necrosis. Despite the serological-marker negativity, the results of immunostaining for HBsAg and HBcAg support replication and expression of HBV DNA, though weak.

Acute Disease↗
PubMed1994

An ultrashort clock mutation at the period locus of Drosophila melanogaster that reveals some new features of the fly's circadian system.

A rhythm mutant of Drosophila melanogaster was induced by chemical mutagenesis and isolated by testing for locomotor activity rhythms, which in the new variant had periods of approximately 16 hr. The sex-linked mutation responsible for this ultrashort period causes 20-hr rhythms when heterozygous with a normal X. This semidominance notwithstanding, the new mutation was revealed to be an allele of the period (per) gene by noncomplementation with per-null variants, in the sense that females heterozygous for perT (as the ultrafast-clock allele is called) and per- exhibited periods that were much shorter than in the case of perT/+. These tests also revealed in a clearer manner than in previous cases that two "doses" of a fast-clock per mutation lead to appreciably shorter periods than those exhibited by one-dose females whose other per allele is a loss-of-function variant. In light-dark cycles (LD 12:12), flies carrying perT in a genotypic condition leading to free-running periods that are 8 hr faster than normal nevertheless entrained, by phase-shifting that large number of hours each day; the evening peak of locomotor activity was, however, many hours earlier than normal. The use of a newly developed device for monitoring Drosophila eclosion automatically showed that perT exhibits a very marginal emergence rhythm at 25 degrees C, but periodicity of ca. 17-18 hr at 19 degrees. Staining of the per-encoded protein (PER) in sections of perT versus normal pharate adults revealed for the first time that the immunohistochemically detected signal cycles in its intensity in wild-type, in a manner that is similar to the PER rhythm previously demonstrated in adults. The staining cycle in pharate adults expressing perT differed from that of wild-type. Temperature compensation of the adult activity rhythm of perT was found to be faulty, in that periods became appreciably shorter as the flies were heated. However, the mutant exhibited a normal degree of period lengthening when its locomotor activity was monitored in the presence of heavy water. The perT mutation interacted with the long-period Andante allele of the dusky locus in a manner that was anomalous (in comparison to dyAnd interactions with per+ or another short-period per mutation). This and other unique features of perT are discussed from the standpoint of the new mutation's heuristic value, including that which may stimulate a deeper understanding of the period gene's action at the molecular level.

Activity Cycles↗
PubMed2003

Variants of cyclooxygenase-1 and their roles in medicine.

Acetaminophen (paracetamol) and other analgesic/antipyretic drugs such as dipyrone have been postulated to act centrally through inhibition of cyclooxygenases (COXs). COX activity in lipopolysaccharide-stimulated mammalian leukocytes, microglial cells, and platelets is inhibited by these drugs at physiological concentrations. Yet purified COX enzymes are poorly inhibited by acetaminophen, particularly under conditions of high oxidant tone and elevated substrate levels. This suggests the presence of cell-specific differences that govern COX inhibition by these drugs. COX-3, a variant of COX-1, has been found in canine brain and is inhibited by acetaminophen and dipyrone at physiological concentrations. Additionally, other new COX-1-derived proteins called PCOX have been identified that do not make prostaglandins but apparently bind heme and may have other enzymatic properties. Antibodies specific for these variants detect analogous proteins in human tissues. Expression of COX variants is postulated to be an integral part of the mechanism of action of analgesic/antipyretic drugs.

Acetaminophen↗
PubMedDate not supplied

[Rare erythrocyte phenotypes imitating weak variant of antigen A].

Two phenotypes with defect of sialic acid in the cell membrane of erythrocytes due to some unknown factor, imitating the weak variant of antigen A are reported. One of them found in a healthy candidate for blood donation was called Tn. The second one associated with thrombocytopenia and anaemia differed from all as yet classified ones in that it had simultaneously increased expression of antigen H and lack of reaction with Dolichos biflorus lectin. For demonstrating the diagnostic difficulties differentiation against the weak variant of antigen A approaching A3 is described.

ABO Blood-Group System↗
PubMed2005

Directed evolution, phage display and combination of evolved mutants: a strategy to recover the neutralization properties of the scFv version of BCF2 a neutralizing monoclonal antibody specific to scorpion toxin Cn2.

BCF2, a monoclonal antibody raised against scorpion toxin Cn2, is capable of neutralizing both, the toxin and the whole venom of the Mexican scorpion Centruroides noxius Hoffmann. The single chain antibody fragment (scFv) of BCF2 was constructed and expressed in Escherichia coli. Although its affinity for the Cn2 toxin was shown to be in the nanomolar range, it was non-neutralizing in vivo due to a low stability. In order to recover the neutralizing capacity, the scFv of BCF2 was evolved by error-prone PCR and the variants were panned by phage display. Seven improved mutants were isolated from three different libraries. One of these mutants, called G5 with one mutation at CDR1 and another at CDR2 of the light chain, showed an increased affinity to Cn2, as compared to the parental scFv. A second mutant, called B7 with a single change at framework 2 of heavy chain, also had a higher affinity. Mutants G5 and B7 were also improved in their stability but they were unable to neutralize the toxin. Finally, we constructed a variant containing the changes present in G5 and B7. The purpose of this construction was to combine the increments in affinity and stability borne by these mutants. The result was a triple mutant capable of neutralizing the Cn2 toxin. This variant showed the best affinity constant (KD=7.5x10(-11) M), as determined by surface plasmon resonance (BIAcore). The k(on) and k(off) were improved threefold and fivefold, respectively, leading to 15-fold affinity improvement. Functional stability determinations by ELISA in the presence of different concentrations of guanidinium hydrochloride (Gdn-HCl) revealed that the triple mutant is significantly more stable than the parental scFv. These results suggest that not only improving the affinity but also the stability of our scFv were important for recovering its neutralization capacity. These findings pave the way for the generation of recombinant neutralizing antisera against scorpion stings based on scFvs.

Amino Acid Sequence↗
PubMed2005

Multilocus linkage disequilibrium mapping by the decay of haplotype sharing with samples of related individuals.

We consider the problem of multilocus linkage disequilibrium (LD) mapping of a trait-associated variant from case-control samples in which some individuals may be related. Our method, which we call DHS-R, is an extension of the decay of haplotype sharing (DHS) method of McPeek and Strahs and Strahs and McPeek. The DHS-R method shares the main features of the DHS method: (1) it allows construction of a confidence interval for the location of a trait-associated variant; (2) it allows for missing observations and unphased genotype data, with the uncertainty in the haplotypes taken into account in the analysis; and (3) it allows for heterogeneity, mutation, recombination, and background LD. The main advances of the DHS-R are (1) the ability to include individuals of arbitrary known relationship (including inbreeding) in the case and control samples; (2) an extension to allow partially-phased haplotypes derived from case-parent trio genotype data; and (3) an extension to allow for genotyping error in the model. Our method, which uses a hidden Markov model for likelihood calculation and maximization, has the advantage of being computationally feasible even in a large, complex pedigree. Simulations based on a 13-generation, 1,623-member Hutterite pedigree demonstrate accurate coverage of the confidence intervals for location of the variant. We apply the method to fine-mapping of a susceptibility locus for bronchial hyperresponsiveness (BHR) in the Hutterites. The results confirm the importance of taking into account the relatedness of individuals in LD mapping.

Algorithms↗
PubMed2026

SeqQC-former: A sequence-quality fusion framework for QC-aware review prioritization of candidate somatic SNVs in cancer genomics.

The accurate prioritization of candidate somatic single-nucleotide variants (SNVs) remains a challenge due to the substantial variability in sequencing quality across genomic loci. SeqQC-Former is a sequence-quality fusion framework that integrates the local nucleotide context with read-level quality-control (QC) covariates derived from matched tumor-normal sequencing data. This integration generates QC-aware prioritization scores for the downstream review of candidate variants. Unlike conventional variant callers, SeqQC-Former is designed not to infer biological truth but to support post-calling review and prioritization under heterogeneous sequencing conditions. The framework was trained and evaluated on a SEQC2-derived dataset comprising 89,447 candidate loci, including 1378 positive and 88,069 negative loci. In chromosome-held-out validation, which aims to reduce potential genomic-position leakage, SeqQC-Former demonstrated strong discrimination (AUROC = 0.9479; AUPRC = 0.9448), indicating good generalization to previously unseen chromosomes. Given that the SEQC2-derived labels contain QC-associated information; these results should be interpreted as an evaluation of QC-aware prioritization capability rather than an independent validation of biological variant correctness. Ablation analyses revealed that structured QC covariates provided the dominant predictive signal under the current SEQC2-derived labeling regime. SeqQC-Former achieved a significantly higher AUROC than classical machine-learning baselines, as determined by DeLong's test (p&#x202f;<&#x202f;0.01). Application to 53,164 glioblastoma variants demonstrated that external predictions were sensitive to QC scaling and threshold selection, underscoring that model outputs should be interpreted as QC-dependent prioritization scores rather than calibrated probabilities or definitive biological classifications. Overall, SeqQC-Former offers a reproducible post-calling QC-aware prioritization framework for large-scale somatic SNV review and underscores the importance of explicitly modeling sequencing-quality information when interpreting structured cancer genomics datasets.

Humans↗
PubMed1998

Comparison of CD44 expression in early colorectal carcinomas of the de novo and ex adenoma types.

Small colorectal carcinomas without morphological evidence of origin from an adenoma have been called "de novo" carcinomas. As changes in the expression of the adhesion molecule CD44 and its variants have been described along the adenoma-carcinoma sequence in colorectal carcinoma, we compared patterns of CD44 expression in early de novo and ex-adenoma colorectal carcinomas by staining specimens from a group of early (pT1) colorectal carcinomas by immunohistochemistry for CD44 (standard and variant forms v3, v5, v6, v7, v7/8, v10). We evaluated carcinoma, adenoma (ex-adenoma cases), transitional mucosal areas and apparently nonneoplastic mucosa peripheral to the lesions (when present). A marked increase was seen in numbers and intensity of standard and variant forms of CD44 in carcinomatous areas compared with nonneoplastic mucosa in both groups, with no significant difference between the groups. However, adenoma areas of the ex-adenoma cases and the transitional mucosa of the de novo carcinomas had nearly identical staining patterns. Together with data from other molecular studies, this may be interpreted as evidence for an adenoma-type precursor lesion in so-called de novo colorectal carcinomas.

Adenoma↗
PubMed1990

A variant of calcifying epithelial odontogenic tumor with Langerhans cells.

A variant of calcifying epithelial odontogenic tumor (CEOT) with Langerhans cells is reported. Compared to a typical CEOT, the tumor islands of this case were thin and composed of a small number of polyhedral epithelial cells. Almost no calcification of homogeneous eosinophilic materials was observed. In addition, clear cells which structurally corresponded to Langerhans cell were intermingled in the epithelial islands. These cells stain positively for S-100 protein, lysozome, MT 1, LN-3 and OKT 6 antibodies, but not for keratin antibody. Electronmicroscopic examination revealed the rod-shaped and racket-shaped structures called Birbeck's granules in the cytoplasm of these clear cells. Our observations indicate a variant case of CEOT with Langerhans cells in tumor nests.

Adult↗
PubMed1979

Plant histone 2 from wheat germ, a family of histone H2a variants. Partial amino acid sequences.

1. The 0.5 M perchloric acid extract prepared from chromatin of wheat germ, Triticum aestivum, contains a group of histones formerly called plant histones. These can be resolved by gel filtration on Bio-Gel P-60 with subsequent CM-cellulose ion-exchange chromatography into five histone fractions containing families of histones H2A and H2B. 2. The partial amino acid sequences of histone H2A variants H2A(1)Triticum, H2A(2)Triticum and H2A(3)Triticum are presented. Extensive sequence homology exists between calf thymus histone H2A and wheat embryo H2A histones. Differences are largely due to conservative amino acid substitutions and in two of the variants, viz. H2A(2) and H2A(3) to N-terminal extensions of the polypeptide chains.

Amino Acid Sequence↗
PubMed1993

Characterization of a variant of the polysaccharide acetan produced by a mutant of Acetobacter xylinum strain CR1/4.

Acetobacter xylinum NRRL B42 (NCIB 40123) produces both cellulose and a complex anionic branched heteropolysaccharide called acetan. Chemical mutagenesis was used to isolate stable cellulose-minus Acetobacter xylinum mutants. Further chemical mutagenesis of these cellulose-minus A. xylinum bacteria was used to select mutants which secrete polysaccharides which are variants of the acetan structure. Preparation, purification and characterization of these polysaccharides are described. Methylation analysis of the polysaccharide structure CR1/4 suggests that the polysaccharide has an acetan structure with a truncated sidechain terminating in glucuronic acid.

Carbohydrate Conformation↗
PubMed1980

Ovarian neoplasms resembling sex cord tumors with annular tubules.

A clinicopathologic analysis of 6 patients with ovarian neoplasms resembling sex cord tumors with annular tubules (SCTAT) was performed. The patients' ages ranged from 20 to 43 years. Most had signs and symptoms of estrogenic hormonal imbalance; none had evidence of the Peutz-Jeghers syndrome. The tumors were unilateral in all cases and, except for one lesion of microscopic size, were from 3 to 18 cm in greatest dimension. One tumor was combined with a germinoma. Surgery alone was the primary mode of therapy in all cases. Lymph nodal metastases developed in 2 patients 7.5 and 10.5 years postoperatively. They are the first documented examples of malignant behavior recorded. At the time of last known contact, all patients were alive without demonstrable tumor for intervals from 1.5 to 16.3 years (mean, 7.8 years) after initial treatment. While the annular patterns of growth have often been attributed to Sertoli cell differentiation, histologic and cytologic features of granulosa cell tumor were observed in areas of the primary tumors and in metastatic lesions. True lumen formation was never observed in the so-called tubules. We propose classification of SCTAT as a distinctive annular and membranous variant of granulosa cell tumor in view of the morphologic similarities and comparable clinical behavior of these two neoplasms.

Adult↗
PubMedDate not supplied

Histogenesis of microscopic adenoma and hyperplastic (metaplastic) gland in nonpolyposis coli.

Histogenesis of microscopic adenoma in nonpolypoid colons (those not included in the special disease group of familial polyposis coli) was investigated using complete serial sections with the following results: Adenoma arises from basal cells in the deep layer of the mucosa; and two types of basal cells found were 1) those which had already undergone changes to adenoma and 2) those which are in their transitional stage to adenomas. Early-phase growth of adenoma is brought about by branching. Individual hyperplastic (metaplastic) glands constituting so-called hyperplastic (metaplastic) polyps are considered to be only an expression of one variant in the growing process of adenomas and the glands showing these changes most characteristically have a serrated pattern. Based on these findings, the histogenesis of adenoma in nonpolypoid colons is shown schematically.

Adenoma↗
PubMed2004

Dual surface selection methodology for the identification of thrombin binding epitopes from hotspot biased phage-display libraries.

Protein libraries biased towards amino-acid residues found at so-called 'hotspots' were incorporated into the beta-sheet region of the thermostable variant (HTB1) of the B1 domain of the immunoglobulin (IgG) binding protein G and expressed as gene 3 fusions on M13 bacteriophage. The HTB1 library (2.2 x 10(9)) variants with a minimal 12 amino acid basis set were selected for binding IgG, to ensure structural conservation, and subsequently to thrombin to evolve a thrombin-binding function. We believe that this dual surface selection strategy will have great utility in evolving new bi-functional proteins without compromising structure. Furthermore the discrete beta-sheet epitopes identified by our methodology will lend itself to small-molecule mimicry of beta-sheets.

Amino Acid Sequence↗
PubMed1999

Elicited sequential presentation for low vision reading.

This paper reports on a variant of the rapid serial visual presentation (RSVP) technique for low vision reading called elicited sequential presentation (ESP). In both techniques, words are presented sequentially at a constant screen location, but with ESP, the reader elicits presentation of each new word by means of a button press, rather than (as with RSVP) being presented with it automatically at fixed intervals. An experiment comparing reading speeds using, ESP, RSVP and a conventional closed-circuit television (CCTV) reading aid showed that for 15 slow readers who were customary CCTV users with low vision, ESP is superior to RSVP and yields reading speeds averaging 47% faster than RSVP--about the same as CCTV reading speed. The log of the ratio of ESP to RSVP reading speeds was significantly negatively correlated with the log of RSVP reading speed, showing that slower readers benefit more than faster readers; regression predicted no benefit for readers who read with RSVP at 133 wpm or greater. Finally, word length and word presentation duration chosen by subjects reading with ESP were significantly correlated, suggesting that part of the benefit of ESP is due to reader's ability to allocate time based on word length and difficulty.

Audiovisual Aids↗
PubMed1982

A poxvirus antigen associated with pathogenicity for rabbits.

White pock variants of cowpox virus give papular lesions on intradermal inoculation of rabbits, without the necrosis and haemorrhage that are produced by wild type cowpox viruses. Rondle & Dumbell (1962) have shown that white pock variants of cowpox virus fail to produce a specific, precipitating antigen which they called 'd' substance. In this paper it is shown that 'd' is demonstrable in soluble antigen preparations of rabbitpox virus and of neurovirulent strains of vaccinia virus but not in soluble antigens of variola viruses. Two series of recombinant viruses prepared by Dumbell & Bedson (1964) from variola and cowpox and from variola and rabbitpox viruses were tested for the production of 'd' substance. These results were compared with the previously recorded effects of these recombinants when inoculated intradermally in rabbits. It is concluded that functional genes determining the production of 'd' and of rabbit skin pathogenicity are closely linked on the pox virus genome, but that there is insufficient evidence to say that the two functions are interdependent.

Animals↗
PubMed2005

The 2F5 epitope is helical in the HIV-1 entry inhibitor T-20.

The HIV-1 envelope glycoprotein gp41 is responsible for viral fusion with the host cell. The fusion process, as well as the full structure of gp41, is not completely understood. One of the strongest inhibitors of HIV-1 fusion is a 36-residue peptide named T-20, gp41(638-673) (Fuzeon, also called Enfuvirtide or DP-178; residues are numbered according to the HXB2 gp160 variant) now used as an anti HIV-1 drug. This peptide also contains the immunogenic sequences that represent the full or partial recognition epitope for the broadly neutralizing human monoclonal antibodies 2F5 and 4E10, respectively. Due to its hydrophobicity, T-20 tends to aggregate at high concentrations in water, and therefore the structure of this molecule in aqueous solution has not been previously determined. We expressed a uniformly 13C/15N-labeled 42-residue peptide NN-T-20-NITN (gp41(636-677)) and used heteronuclear 2D and 3D NMR methods to determine its structure. Due to the additional gp41-native hydrophilic residues, NN-T-20-NITN dissolved in water, enabling for the first time determination of its secondary structure at near physiological conditions. Our results show that the NN-T-20-NITN peptide is composed of a mostly unstructured N-terminal region and a helical region beginning at the center of T-20 and extending toward the C-terminus. The helical region is found under various conditions and has been observed also in a 13-residue peptide gp41(659-671). We suggest that this helical conformation is maintained in most of the different tertiary structures of the gp41 envelope protein that form during the process of viral fusion. Accordingly, an important element of the immunogenicity of gp41 and the inhibitory properties of Fuzeon may be the propensity of specific sequences in these polypeptides to assume helical structures.

Amino Acid Sequence↗