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PubMed1958

Enzymatic variants of influenza virus. II. Effect of environmental factors on enzymatic characteristics of a variant of influenza B virus.

The rate of elution of the variant virus from chicken RBC is progressively decreased as the temperature of incubation is increased above 25 degrees C. The activity of the parent virus, on the other hand, is increased as the temperature is increased up to 40 degrees C. The major cause of the decreased activity of the variant at temperatures above 2S degrees C. is an inhibition of the variant enzyme rather than its inactivation. The activity of the variant enzyme is stimulated in the presence of strontium, calcium, and barium ions. Manganese has only a slight effect, and magnesium has no stimulatory effect on the elution of the variant virus. Elution of the variant at 37 degrees C. is progressively inhibited at pH values above 7, while the parent virus is still active at pH 8. In the absence of calcium the variant enzyme, hemagglutinin, and infectivity are more heat labile than those of the parent virus. The addition of calcium increases the heat stability of all three properties of the variant, and in the presence of calcium the infectivity of the variant is as stable as that of the parent virus.

Calcium↗

PubMed2019

Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE): a cloud-based platform for curating and classifying germline variants.

Variant interpretation in the era of massively parallel sequencing is challenging. Although many resources and guidelines are available to assist with this task, few integrated end-to-end tools exist. Here, we present the Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE), a web- and cloud-based platform for annotation, identification, and classification of variations in known or putative disease genes. Starting from a set of variants in variant call format (VCF), variants are annotated, ranked by putative pathogenicity, and presented for formal classification using a decision-support interface based on published guidelines from the American College of Medical Genetics and Genomics (ACMG). The system can accept files containing millions of variants and handle single-nucleotide variants (SNVs), simple insertions/deletions (indels), multiple-nucleotide variants (MNVs), and complex substitutions. PeCanPIE has been applied to classify variant pathogenicity in cancer predisposition genes in two large-scale investigations involving >4000 pediatric cancer patients and serves as a repository for the expert-reviewed results. PeCanPIE was originally developed for pediatric cancer but can be easily extended for use for nonpediatric cancers and noncancer genetic diseases. Although PeCanPIE's web-based interface was designed to be accessible to non-bioinformaticians, its back-end pipelines may also be run independently on the cloud, facilitating direct integration and broader adoption. PeCanPIE is publicly available and free for research use.

Child↗

PubMed2001

Comparative results of coronary intervention in patients with variant angina versus those with non-variant angina.

Coronary angioplasty is reported to be feasible and safe in patients with coronary spasm and fixed stenosis. However, the long-term results are not positive. We compared the results of coronary angioplasty in 20 patients with variant angina versus 17 patients with non-variant angina among 231 consecutive patients with vasospastic angina. Coronary angioplasty was performed successfully in all 37 patients without any complications. Stenting for coronary dissection or recoil was performed in 8 patients, directional coronary atherectomy was selected for ostial lesion of left anterior descending coronary artery stenosis in 2 patients, and standard balloon angioplasty was performed in 27 patients. There were no clinical differences between the two groups. The restensois rate in patients with variant angina was similar to that in patients with non-variant angina (30% vs 29%, ns). There was no relationship between the provoked spasm and restenosis. During the follow-up period, no major complications were observed in patients with variant angina or those with non-variant angina. In conclusion, full medication with calcium channel antagonists and isosorbide dinitrate, and treatment by coronary angioplasty including the use of new devices, were useful treatments for patients with coronary vasospasm and significant organic stenosis. There was no difference concerning the results of coronary intervention between the patients with variant angina and those with non-variant angina.

Aged↗

PubMed1981

Defining the locus of origin of a genetically determined electrophoretic variant of a multilocus enzyme system; the Calcutta-1 of human LDH system is a B-locus variant.

Six (four Hindus, one Sikh, and one Muslim) outr of 213 individuals originating from different parts of the Indian subcontinent (namely, Andhra Pradesh, Maharashtra, Uttar Pradesh, East Punjab, and West Punjab) were found to be Calcutta-1 (CAL1) variants of lactate dehydrogenase (LDH). The CAL1 variant was originally described (and thus, generally believed at present) as an allelic variant at the LDHA locus in chromosome 11. By using an improved Cellogel electrophoretic procedure the isozyme patterns observed in the erythrocytes and leukocytes of the variant have indicated that the CAL1 is not variant of LDHA but that of LDHB, a chromosome 12 marker. The suggestion was supported by the isozyme patterns of LDH in a set of segregating clones of man-mouse somatic cell hybrids with the variant as human partner. Moreover, the variant cosegregated consistently with the human chromosome 12 and with the markers firmly assigned to the latter but not with human chromosome 11 or its markers in these hybrids. These results confirmed that the CAL1 is an LDHB variant.

Animals↗

PubMedDate not supplied

Mutagen-induced Imm+ variants: the need for viable and cloned Imm+ variants for effective protection against a primary murine tumor and its metastases.

Immunogenic variants (Imm+) generated after the treatment of murine tumor cells with the mutagen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) can produce a strong protective response against non-mutagenized parent tumor cells. The use of this methodology to treat human tumors is currently thwarted by technological difficulties in applying the findings obtained with murine models to human disease. Two of these difficulties are described in this study. The first is that Imm+ variants lose most of their immunogenicity after treatment with X-irradiation or mitomycin C. The second is that mutagen-treated tumor cells must be cloned so as to select for Imm+ variants, for the presence of as few as 0.001 per cent tumorigenic cells within the bulk population will result in the failure of the protective effect of the Imm+ variants. Because of these and other difficulties with mutagen-induced Imm+ variants, we have developed a different approach to producing such variants using transfection of tumor cells with foreign genes. In contrast to mutagen induced Imm+ variants, these variants have been shown to retain their immunogenicity after X-irradiation.

Animals↗

PubMed1991

High-performance anion-exchange chromatographic study of desialylated human alpha 1-acid glycoprotein variants. Development of a fractionation method for the protein slow variants.

The three main desialylated variants (F1, S and A) of human alpha 1-acid glycoprotein (AAG), a serum acute-phase reactant, were analysed by high-performance anion-exchange chromatography in order to determine their optimum separation conditions. The analysis consisted of three steps, as follows: (1) A desialylated commercial AAG was separated into one "fast"- and one "slow"-migrating fraction by preparative isoelectrofocusing. The "fast" and "slow" fractions were shown to contain the F1 variant and a mixture of the S and A variants, respectively. (2) The pH titration curves of these two fractions were then measured by strong anion-exchange chromatography with several buffer systems of increasing pH. From the data obtained, it was not possible to select the optimum conditions to separate the "fast" variant F1 from the "slow" variants A and S. However, the S and A variants were shown to ionize very differently. (3) The specific fractionation of the S and A variants was therefore carried out by anion-exchange chromatography under operating conditions based on the data obtained from the study of their pH titration curves. This was performed both with the "slow"-migrating fraction obtained by preparative isoelectrofocusing of commercial AAG and with an AAG (containing only variants S and A) purified from an individual serum on immobilized Cibacron Blue F3G-A. Identification of the fractionated proteins was achieved by analytical isoelectrofocusing.

Chromatography, Ion Exchange↗

PubMed1996

Improved determination of variant erythrocytes at the glycophorin A (GPA) locus and variant frequency in patients treated with radioiodine for thyroid cancer.

Red blood cells from individuals with the blood group MN express each form of the allelic GPA protein (GPAM and GPAN) on their cell surface. Variant cells have lost one form of the protein. Their frequency is about 10(-5) in blood from unexposed persons. The BR6 assay is currently the most widely used assay to determine variant frequency (VF) by immunolabelling and flow cytometry. The precision of the BR6 assay is mainly limited by the Poisson error because only small numbers of variant cells are detected in each assay. The BR6 assay has been improved by magnetic cell separation (MACS) of variant erythrocytes prior to their determination by this assay. This new version of the assay is named 'MACS-BR6'. It allows enumeration of variant cells from 2 x 10(8) or more blood cells instead of 5 x 10(6) in the BR6 assay with a precision which is about 5 times higher than that of the BR6 assay. The MACS-BR6 assay was used to determine the VF of GPAN/0 and GPAN/N variant cells in 12 healthy adults and 11 patients treated with radioiodine for thyroid cancer 2 to 16 years before. The average red bone marrow dose was 347 mGy. In healthy adults the mean VF of GPAN/0 and GPAN/N variant cells was 16.1 x 10(6) and 5.3 x 10(-6) respectively. In patients the corresponding mean VF was 25.4 x 10(6) and 11.9 x 10(-6), respectively. The patients GPAN/0 VF was significantly higher than that of controls. In patients VF increases linearly with the dose. The linear regression parameters of VF were 16.6 x 10(-6) (intercept), 23.7 x 10(-6) GY-1 (slope) and 6.3 x 10(-6) (intercept), 12.9 x 10(-6) Gy-1 (slope) for GPAN/0 and GPAN/N variant cells, respectively.

Adult↗

PubMed1999

Lymphoproliferative responses to human herpesvirus-6 variant A and variant B in healthy adults.

Human herpesvirus-6 (HHV-6) isolates can be classified into variants A and B, and over 95% of people older than 2 years of age are seropositive for either or both variants. However, the prevalence of the two HHV-6 variants is still not defined since the serological methods used at present cannot discriminate one variant from the other. Lymphoproliferative responses to glycine extracted cellular antigens from human herpes-virus-6 (HHV-6) GS strain (variant A)- and Z 29 strain (variant B)-infected T-lymphoid cell lines were examined in healthy Swedish and Japanese adults. Nine of 36 (25%) persons had responses to the GS antigen, while 21/36 (58%) had responses to the Z 29 antigen (P=0.008). Individuals with low anti-HHV-6 IgG titers (< or = 320) were more likely to respond to the Z 29 antigen than to the GS antigen (P=0.006), while there was no difference in those with high anti-HHV-6 IgG titers (> or =1280). Three of 7 Japanese adults had lymphoproliferative responses to the GS antigen compared with 6/29 Swedes (not significant), and 7/7 Japanese had lymphoproliferative responses to the Z 29 antigen compared with 14/29 Swedes (P=0.03). Lymphoproliferative responses were neither related with the presence of HHV-6 DNA nor related with the presence of HHV-7 DNA in peripheral blood cells. These results suggest a higher prevalence of HHV-6 variant B than variant A in both Swedes and Japanese adults, and possibly a difference in either the HHV-6 virus strains and/or the nature of immune response of Swede and Japanese.

Adult↗

PubMed1999

Cytopathology of high-grade papillary thyroid carcinomas: tall-cell variant, diffuse sclerosing variant, and poorly differentiated papillary carcinoma.

Cytologic reports of the aggressive tall-cell and diffuse sclerosing variants of papillary carcinoma have emphasized features such as tall and large cells, increased nuclear size, nuclear pleomorphism, intranuclear pseudoinclusions, three-dimensional tissue fragments, squamous-like cells, and dense inflammatory background as characteristic features. However, the specificity of these features in identifying the particular variants and distinguishing them from other poorly differentiated papillary carcinomas and typical low-grade forms of papillary carcinoma has not been established. The objective of this study was to assess the predictive value of these reported cytologic features. Fourteen cases of high-grade papillary carcinoma consisting of the aggressive variants (tall-cell variant (tcv) and diffuse sclerosing variant (dsv)) and poorly differentiated papillary carcinomas (pdpc) were compared to 18 cases of low-grade papillary carcinoma. Seven cytologic features consisting of the presence of tall and large cells, architectural disorganization, nuclear enlargement, prominent intranuclear pseudoinclusions, nuclear pleomorphism, lymphocytic infiltrate, and squamoid appearance of the neoplastic cells were evaluated. Cytology samples from tcv, dsv, and pdpc consistently demonstrated 3 of the 7 cytologic features (architectural disorganization, nuclear enlargement, and pleomorphism). In contrast, only two of the samples from low-grade cases demonstrated these 3 features. The recognition of these 3 cytologic features had a positive predictive value of 88% and a negative predictive value of 100% for identifying tcv, dsv, and pdpc. The remaining cytologic features were not a consistent feature in the variants, and by cytology alone, distinction between the aggressive variants (dsv and tcv) and pdpc could not be made.

Adenocarcinoma↗

PubMed1991

Biochemical characteristics of glucose-6-phosphate dehydrogenase variants among the Malays of Singapore with report of a new non-deficient (GdSingapore) and three deficient variants.

Biochemical characteristics of one non-deficient fast G6PD variant (GdSingapore) and six different deficient variants (three new, two Mahidol, one each of Indonesian and Mediterranean) were studied among the Malays of Singapore. The GdSingapore variant had normal enzyme activity (82%) and fast electrophoretic mobilities (140% in TEB buffer, 160% in phosphate and 140% in Tris-HCl buffer systems respectively). This variant is further characterized by normal Km for G6P; utilization of analogues (Gal6P, 2dG6P; dAmNADP), heat stability and pH optimum. The other six deficient G6PD variants had normal electrophoretic mobility in TEB buffer with enzyme activities ranging from 1 to 12% of GdB+. The biochemical characteristics identity them to be 2 Mahidol, 1 Indonesian and 1 Mediterranean variants and three new deficient variants.

Electrophoresis↗

PubMed2000

Variant detection at the delta opioid receptor (OPRD1) locus and population genetics of a novel variant affecting protein sequence.

The three opioid receptor genes, and in particular the mu and delta loci (OPRM1 and OPRD1, respectively), are compelling candidates to influence risk for substance dependence. Previous study of a variant at the OPRD1 locus, T921C, has shown association with opioid dependence. This variant does not alter protein sequence, and could not be directly responsible for a physiologic effect. We sequenced the OPRD1 coding region in six individuals with differing T921C alleles, to identify new common variants more likely to explain the association with phenotype. We identified one novel variant in exon 1, 80T-->G, which predicts a change in amino acid sequence from phenylalanine (80T) to cysteine (80G) (F27C). We present here basic population genetics of this variant, and population genetic data for the T921C variant. We found significant differences in allele frequency between populations, and a maximum frequency of the 80G allele of 9%, in each of two European populations. This variant could contribute to the previously reported association results.

Alleles↗

PubMed1982

Immunogenic variants obtained by mutagenesis of mouse Lewis lung carcinoma. Recognition of variant-specific antigens by cytolytic T lymphocytes.

By mutagenesis of a cell line derived from Lewis lung carcinoma (3LL), it is possible to obtain at high frequency stable tumor cell variants (tum-) that are rejected by syngeneic mice. The possibility of obtaining a cytolytic T cell (CTL) response directed specifically against these tum- variants was examined. With the four variants that were analysed, a significant cytolytic activity was obtained with peritoneal cells from immune mice collected shortly after an intraperitoneal boost and also with spleen cells after a secondary stimulation in vitro. The CTL populations preferentially lysed the immunizing tum- variant, while also showing a cross-reactive lysis against the other variants and the original 3LL cells. Highly active CTL clones could be isolated from limiting dilution microcultures of these CTL populations. The clonal analysis clearly showed the existence of two distinct CTL populations, one directed exclusively against the immunizing variant and another that lysed all 3LL targets equally. This CTL specificity analysis therefore demonstrates directly the presence of new antigens on the 3LL tum- cell variants.

Animals↗

PubMed2025

Polygenic variants in DNA repair genes are associated with neurodevelopmental disorders, regression and increased burdens of somatic variants and short tandem repeat expansions.

PURPOSE: Developmental regression, characterized by the loss of acquired milestones, occurs in some individuals with neurodevelopmental disorders (NDDs); yet, its molecular basis remains unclear. Studies suggest that DNA damage repair (DDR) genes, such as FAN1, may protect against neurological dysfunction by modulating the somatic stability of short tandem repeats (STRs). This study explores the contribution of DDR gene variants in NDD cases presenting with regression. METHODS: We analyzed 1087 NDD patients, focusing on those carrying variants in DDR genes and presenting regression. We assessed the sensitivity to DNA damage using mitomycin C on lymphoblastoid cells. Somatic variants and STR expansions were evaluated through high-depth short-read genome sequencing. To further investigate the pathogenetic role of STR expansions, we performed long-read genome sequencing on the most severely affected proband. RESULTS: Probands with regression carried multiple DDR gene variants, several within the Fanconi anemia pathway. Their lymphoblastoid cells showed increased sensitivity to mitomycin C-induced cytotoxicity compared with parental and control samples. Probands with severe phenotypes and regression exhibited an accumulation of somatic variants and STR instability, enriched in neurodevelopmental genes. CONCLUSION: Our findings suggest that polygenic DDR gene variants may contribute to developmental regression in NDDs by promoting the accumulation of somatic variants and STR expansions.

Humans↗

PubMed2002

Cloning and characterization of a novel human 5-HT4 receptor variant that lacks the alternatively spliced carboxy terminal exon. RT-PCR distribution in human brain and periphery of multiple 5-HT4 receptor variants.

We have cloned a novel C-terminal splice variant of serotonin 5-HT4 receptors from human hippocampus. The deduced protein extends only one aminoacid past the splicing point. We propose to call the novel variant h5-HT4(n) since it contains none of the C-terminal exons alternatively spliced in other variants. The pharmacological profile of h5-HT4(n) stably expressed in HeLa cells is in agreement with other reported variants. Stably transfected cells showed increased basal levels of intracellular cAMP in absence of agonist, indicating constitutive activity of the expressed receptors. 5-HT induced robust increases of intracellular cAMP. The 5-HT4 receptor antagonist GR 113808 blocked the effects of 5-HT and brought intracellular cAMP below basal constitutive levels, indicating inverse agonism of this compound in this system. The RT-PCR distribution of all known human C-terminal splice variants in human brain regions and periphery showed complex patterns of variant expression, with the novel variant h5-HT4(n) being widely and abundantly expressed.

Alternative Splicing↗

PubMed1998

Persistence of human herpesvirus 6 according to site and variant: possible greater neurotropism of variant A.

Little is known of the persistence and pathogenicity of human herpesvirus 6 (HHV-6) after primary infection, including the role of strain variant. Over 2 to 5 years, 2,716 children and 149 families were studied. Peripheral blood mononuclear cell (PBMC), saliva, and cerebrospinal fluid (CSF) specimens were examined for HHV-6 DNA and variant. Ninety-nine percent of isolates causing primary infection were HHV-6 variant B (HHV-6B), which predominated in 95%-98% of the variants persisting in PBMC and saliva specimens from children and adults. Of 668 CSF samples, 13% contained HHV-6 DNA; of 77 children examined after primary infection, 61% had HHV-6 DNA detected only in their CSF and 39% had HHV-6 DNA in both CSF and PBMCs. HHV-6 variant A (HHV-6A) was detected significantly (P = .0001) more frequently in CSF than in PBMCs or saliva. In children for whom HHV-6 was identified in both CSF and PBMCs, PBMCs contained only HHV-6B, while CSF contained HHV-6A or HHV-6B, not both. Thus, in patients with dual infection, only HHV-6A persisted in CSF, which suggests that HHV-6A has greater neurotropism. Findings for adults indicate that dual infection occurs; variant persistence is similar to that for children. The frequency of HHV-6A infection increased little with age, thereby indicating that HHV-6A infection remains uncommon into adulthood. This study suggests that HHV-6 variants have different immunobiologic courses and neurotropism.

Adult↗

PubMed1977

Emergence of variant forms of Staphylococcus aureus after exposure to gentamicin and infectivity of the variants in experimental animals.

Exposure of a large inoculum of Staphylococcus aureus in vitro to concentrations of gentamicin that exceeded the minimal bactericidal concentration regularly resulted in the emergence of aminoglycoside-resistant bacterial variants. Variants lacked typical properties that are associated with S. aureus: they produced small, nonhemolytic colonies that were mostly coagulase-, deoxyribonuclease-, and mannitol-negative. In some instances phage type also differed from that of the parent forms. Animal models of subcutaneous and intravenous infection were studied with use of parent and variant forms of S. aureus. Subcutaneous injection of variants into rats readily produced abscesses, and intravenous inoculation into mice caused pyelonephritis, although in each experimental model in which equivalent bacterial inocula were used, parents produced more extensive disease. These data show that variants of S. aureus cause infection in experimental animals, although these variants appear to be somewhat less virulent than the parents from which they are derived. Preliminary studies in our laboratory have also shown that gentamicin-resistant variants of gram-negative bacilli can be induced by a single in vitro exposure to gentamicin. The virulence of these organisms and their role in antibiotic-susceptibility patterns of hospital flora warrant further investigation.

Animals↗

PubMed1977

Genetic variants of human erythrocyte glucose 6-phosphate dehydrogenase: new variants in West Africa characterized by column chromatography.

Five electrophoretically slow-moving genetic variants of glucose 6-phosphate dehydrogenase are described: four are from Nigeria and one is from Togo. All variants have normal or moderately reduced activity, and they are not associated with adverse clinical or haematological manifestations. Three variants have been fully characterized and are different from all previously described ones. Two variants have been partially characterized and at least one of them is also probably new. The overall population incidence of sporadic variants of G6PD in the Nigerian population is 0-3%. In the course of this study a previously described ion-exchange chromatographic technique for the characterization of G6PD variants has been extensively evaluated. Data are given on ten different variants to demonstrate the high resolving power of this technique.

Chromatography, Ion Exchange↗

PubMed1991

Characterization of glucose-6-phosphate dehydrogenase variants in the Sudan--including GdKhartoum, a hyperactive slow variant.

Erythrocyte glucose-6-phosphate dehydrogenase (G6PD) was characterized in blood samples of 94 male subjects in Sudan having deficient and non-deficient electrophoretic variants. They comprised 44 GdB, 17 GdA, 19 GdB-, 11 GdA- and 3 nondeficient (GdKhartoum) variants. Biochemical characteristics including enzyme activity, electrophoretic mobility, Km for glucose-6-phosphate (G6P) and nicotinamide adenine dinucleotide phosphate (NADP), heat stability and pH optimum of all the common and deficient variants were consistent with the reported characteristics of these variants. The GdKhartoum variant had 90% mobility in TEB buffer and 100% in phosphate buffer, 120% activity, Km of 130 +/- 49 microns for G6P and 0.8 +/- 0.2 microns for NADP, lowered thermostability and an optimum pH of 7.6. This variant was not inhibited by 15 mM maleic acid, 10 mM iodoacetate and dehydro-iso-androsterone. All other variants were inhibited by dehydro-iso-androsterone but uninhibited by maleic acid and iodoacetate.

Alleles↗