Y chromosome haplotypes and testicular cancer in the English population.
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Alleles↗
Biomedical subjects
M G Thomas
Publications and source records attributed to M G Thomas.
Mucin gene expression in the ileoanal reservoir is altered and may be relevant to the risk of inflammation and dysplasia.
BACKGROUND: Adaptive colonic phenotypic change of the ileal mucosa is a feature of the ileoanal reservoir (IAR) with time, as described by mucin glycoprotein and histological analysis. Mucin gene expression is altered in colorectal neoplasia and inflammatory bowel disease but little is known of its expression in the IAR. AIMS: To examine the changes in mucin gene expression contributing to mucosal protection of the IAR against a background of known changes occurring in inflammatory disease and colorectal neoplasia. PATIENTS: Paraffin embedded specimens from 29 "W" and 11 "J" ileoanal reservoirs were studied. Colonic and ileal control tissue was obtained from normal resection margins. METHODS: Mucin mRNA was detected by in situ hybridisation using [(35)S]dATP labelled oligonucleotide probes. Mucin core protein was detected by immunohistochemistry. RESULTS: There was no change in mRNA expression of MUC1-4 in the IAR compared with ileal controls but there was a decrease in the protein product of MUC1 and MUC3. No mRNA transcripts of MUC5AC, 5B, or 6 were detected but protein product of MUC5AC and MUC6 was detected. Both cases of MUC6 positivity and 1/5 cases of MUC5AC positivity were confined to the ulcer associated cell lineage. No dysplasia was detected. CONCLUSIONS: There is a change in the pattern of the membrane associated mucins MUC1 and MUC3, part of which is in keeping with changes described in colorectal neoplasia. A small number of cases demonstrated mucin gene changes (MUC5AC) which are seen in early neoplasia and this may provide a valuable monitor for such changes in IAR surveillance.
Child↗
Relationships of metabolic hormones and serum glucose to growth and reproductive development in performance-tested Angus, Brangus, and Brahman bulls.
Understanding mechanisms that regulate growth and reproduction are important for improving selection strategies in cattle. In this study, Angus, Brangus, and Brahman bulls (n = 7 per breed) of similar age were selected from a group of 65 weanlings. Bulls were evaluated after weaning (i.e., approximately 6 mo of age) for 112 d for serum concentrations of metabolic hormones and glucose, growth, and reproductive traits. Performance data and blood sera were collected on d 0, 28, 56, 84, and 112. Sera were also collected in periods from d 50 to 59 (56D) and 103 to 112 (112D). Angus bulls were heavier (P < 0.05) throughout the study than Brahman bulls and were heavier than Brangus bulls on d 56, 84, and 112. Initial and final BW for Angus, Brangus, and Brahman bulls were 292.7, 260.6, and 230.4 and 468.3, 435.6, and 350.7 +/- 12 kg, respectively. Conversely, Brahman bulls had greater hip height (P < 0.05) than Brangus, and Brangus were taller (P < 0.05) than Angus. Angus bulls had the greatest (P < 0.05) scrotal circumference (SC) and Brahman bulls the least. Mean SC across days was 31.5, 29.7, and 25.0 +/- 0.6 cm for the three respective breeds. Serum testosterone was greater (P < 0.01) in Angus and Brangus bulls (10.0 and 8.9 +/- 1.4 ng/mL) than in Brahman bulls (4.0 +/- 1.4 ng/mL) throughout the study. After d 112, 100, 86, and 57% of the Angus, Brangus, and Brahman bulls passed a breeding soundness exam (P = 0.51). Serum concentrations of IGF-I and leptin were greater (P < or = 0.06) in Angus bulls on d 56, 84, and 112 than in Brangus and Brahman bulls. Serum concentrations of GH (P < 0.08) and glucose (P < 0.03) were greater in Brangus bulls than in Angus or Brahman bulls throughout the study. Prediction analyses suggested that serum concentrations of leptin could be used to predict (P < or = 0.08) BW and SC (R2 > 0.82) in the 56D and 112D periods among these breeds. Leptin was also useful in predicting (P < or = 0.09) serum concentrations of GH and testosterone in the 112D period (R2 > 0.32). Residual correlation analyses with the effect of breed removed suggested that leptin was correlated (r > or => 0.53, P < 0.05) with both SC and serum testosterone. Angus and Brahman cattle differ in phenotype, level of adiposity, and rate of sexual development. Data herein suggest that these characteristics could be due to varying mechanisms by which metabolic hormones such as leptin, GH, and(or) IGF-I are regulated.
Animals↗
Metabolic characteristics of multiparous Angus and Brahman cows grazing in the Chihuahuan Desert.
Understanding metabolic differences between breeds of cattle is important when selecting for production in semiarid environments. Spring-calving multiparous Angus and Brahman cows (n = 8/breed) grazing in the Chihuahuan Desert were used to evaluate metabolic hormone status in February (i.e., 3rd trimester of pregnancy), May (i.e., early lactation), and September (i.e., late lactation) 2000. Crude protein in ruminal digesta collected from grazing companion ruminally cannulated cows during these months was 5.6, 6.0, and 10.3%, respectively. Angus cows were heavier (P < 0.01) than Brahman cows across months. Body condition scores among breed groups were 4.4, 3.6, and 4.6 in February, May, and September with Brahman cows tending (P < 0.10) to have greater body condition than Angus cows in May. Brahman cows tended to have greater fecal output per 100 kg BW than Angus cows in February (0.9 > 0.7 +/- 0.1, P < 0.10). Brahman cows had greater serum concentrations of leptin than Angus cows in September (1.8 > 0.70 +/- 0.1 ng/mL; P < 0.05), and serum concentrations of insulin were greater (P < 0.01) in Brahman than Angus cows throughout the study. Brahman cows also had greater (P < 0.01) serum concentrations of glucose during February and May than Angus cows. Serum concentrations of triiodothyronine were greatest (P < 0.01) during September and lowest during February and May in both breed groups and were greater (P < 0.01) in Brahman than in Angus cows in February, May, and September. Pregnancy rate and 205-d adjusted weaning weights were similar (P > or = 0.46) among breed groups. Results suggest that Brahman and Angus cows are sensitive to the seasonal dynamics of forage quality in the Chihuahuan Desert. Brahman cattle appear to have greater concentrations of metabolic hormones and metabolites than Angus cows in this environment, but Angus cows experience greater fluctuations in BW.
Animal Feed↗
Armenian Y chromosome haplotypes reveal strong regional structure within a single ethno-national group.
Armenia has been little-studied genetically, even though it is situated in an important area with respect to theories of ancient Middle Eastern population expansion and the spread of Indo-European languages. We screened 734 Armenian males for 11 biallelic and 6 microsatellite Y chromosome markers, segregated them according to paternal grandparental region of birth within or close to Armenia, and compared them with data from other population samples. We found significant regional stratification, on a level greater than that found in some comparisons between different ethno-national identities. A diasporan Armenian sub-sample (collected in London) was not sufficient to describe this stratified haplotype distribution adequately, warning against the use of such samples as surrogates for the non-diasporan population in future studies. The haplotype distribution and pattern of genetic distances suggest a high degree of genetic isolation in the mountainous southern and eastern regions, while in the northern, central and western regions there has been greater admixture with populations from neighbouring Middle Eastern countries. Georgia, to the north of Armenia, also appears genetically more distinct, suggesting that in the past Trans-Caucasia may have acted as a genetic barrier. A Bayesian full-likelihood analysis of the Armenian sample yields a mean estimate for the start of population growth of 4.8 thousand years ago (95% credible interval: 2.0-11.1), consistent with the onset of Neolithic farming. The more isolated southern and eastern regions have high frequencies of a microsatellite defined cluster within haplogroup 1 that is centred on a modal haplotype one step removed from the Atlantic Modal Haplotype, the centre of a cluster found at high frequencies in England, Friesland and Atlantic populations, and which may represent a remnant paternal signal of a Paleolithic migration event.
Armenia↗
Aminoacyl-S-enzyme intermediates in beta-hydroxylations and alpha,beta-desaturations of amino acids in peptide antibiotics.
Many of the alpha-amino acids found in proteins are shunted into microbial secondary metabolism to form peptide antibiotics by specific oxidation, including hydroxylation, at the beta carbon. Examples for the enzymatic hydroxylation of tyrosine and histidine and for desaturation of proline during covalent attachment as aminoacyl-S-pantetheinyl enzyme intermediates suggest a general strategy in peptide antibiotic biosynthesis.
Amino Acids↗
Serum luteinizing hormone, growth hormone and insulin-like growth factor-I after releasing hormone challenge in prepubertal ewe lambs selected for twinning.
Two studies evaluated hormonal markers as indicators of the onset of puberty in Debouillet sheep selected for twinning. In Trial 1, 29 ewe lambs (50 +/- 0.5 kg, 159 to 187 d of age) were given 10 microg GnRH (i.v.) on September 15 and blood was collected at 30 min intervals after the injection for 2 h. Additional samples were taken twice weekly and progesterone (P4) was measured. The day that serum P4 was greater than 1 ng/mL for 2 consecutive sampling days was classified as the day of puberty. Average day of puberty was October 12 (average age at puberty was 199 d) and ewes with values less or greater than the average were classified as early or late, respectively. Average weight at GnRH challenge was 50 kg and ewes weighing less or more were classified as light or heavy, respectively. Early ewes weighed more (P = 0.01) and reached puberty sooner (P = 0.01) than late ewes. Heavy lambs reached puberty earlier, weighed more at GnRH challenge, and had more LH area under the curve (AUC, P < 0.05) than light ewes. In Trial 2, we gave 27 ewe lambs (54 +/- 0.9 kg, 173 to 189 d of age) a single i.v. injection of 10 microg GnRH and 10 microg GHRH on September 17. Average day of puberty was October 13, average weight was 54 kg, and average age at puberty was 208 d. Categories were designated as described for Trial 1. Early lambs reached puberty sooner (P = 0.01) and weighed more (P = 0.01) than late lambs, but the puberty groups had similar LH AUC (P = 0.64) and GH AUC (P = 0.75), whereas IGF-I was greater (P = 0.01) in early puberty ewes than in late puberty ewes. Heavy lambs reached puberty earlier (P = 0.06), weighed more (P = 0.01), and tended (P = 0.11) to have more GH AUC than light ewes. No difference was observed in LH AUC or IGF-I between weight groups (P > 0.15). Results suggest that serum LH after GnRH is not a reliable indicator of the onset of puberty in ewe lambs selected for twinning, but heavier ewes tended to produce more GH after a GHRH challenge and reach puberty earlier than lighter ewe lambs.
Aging↗
Genetic evidence for different male and female roles during cultural transitions in the British Isles.
Human history is punctuated by periods of rapid cultural change. Although archeologists have developed a range of models to describe cultural transitions, in most real examples we do not know whether the processes involved the movement of people or the movement of culture only. With a series of relatively well defined cultural transitions, the British Isles present an ideal opportunity to assess the demographic context of cultural change. Important transitions after the first Paleolithic settlements include the Neolithic, the development of Iron Age cultures, and various historical invasions from continental Europe. Here we show that patterns of Y-chromosome variation indicate that the Neolithic and Iron Age transitions in the British Isles occurred without large-scale male movements. The more recent invasions from Scandinavia, on the other hand, appear to have left a significant paternal genetic legacy. In contrast, patterns of mtDNA and X-chromosome variation indicate that one or more of these pre-Anglo-Saxon cultural revolutions had a major effect on the maternal genetic heritage of the British Isles.
Cultural Evolution↗
The coenzyme b12 analog 5'-deoxyadenosylcobinamide-gdp supports catalysis by methylmalonyl-coa mutase in the absence of trans-ligand coordination.
Methylmalonyl-CoA mutase is an 5'-adenosylcobalamin (AdoCbl)-dependent enzyme that catalyzes the rearrangement of methylmalonyl-CoA to succinyl-CoA. The crystal structure of this protein revealed that binding of the cofactor is accompanied by a significant conformational change in which dimethylbenzimidazole, the lower axial ligand to cobalt in solution, is replaced by His(610) donated by the active site. The role of the lower axial ligand in the trillion-fold labilization of the upper axial cobalt-carbon bond has been the subject of enduring debate in the model inorganic literature. In this study, we have used a cofactor analog, 5'deoxyadenosylcobinamide GDP (AdoCbi-GDP), which reconstitutes the enzyme in a "histidine-off" form and which allows us to evaluate the contribution of the lower axial ligand to catalysis. The k(cat) for the enzyme in the presence of AdoCbi-GDP is reduced by a factor of 4 compared with the native cofactor AdoCbl. The overall deuterium isotope effect in the presence of AdoCbi-GDP ((D)V = 7.2 +/- 0.8) is comparable with that observed in the presence of AdoCbl (5.0 +/- 0.6) and indicates that the hydrogen transfer steps in this reaction are not significantly affected by the change in coordination state of the bound cofactor. These surprising results are in marked contrast to the effects ascribed to the corresponding lower axial histidine ligands in the cobalamin-dependent enzymes glutamate mutase and methionine synthase.
Binding Sites↗
Differential expression of the chromosome 11 mucin genes in colorectal cancer.
The four secretory mucin genes clustered on chromosome 11, MUC2, MUC5AC, MUC5B and MUC6, were screened in 37 patients with cancers in the left hemi-colon or rectum and 10 normal rectal controls. The mucin genes were detected by in situ hybridization using oligonucleotide probes to the variable number tandem repeat (VNTR) sequences, while the proteins were stained with non-VNTR (MUC2, MUC5AC and MUC5B) or VNTR (MUC6) antibodies. Low levels of MUC2 mRNA were detected in non-mucinous adenocarcinomas (5/27) while a higher proportion of mucinous carcinomas (4/9) was positive. All 25 cases of adjacent normal tissue expressed MUC2 mRNA. No transcripts for MUC5AC, MUC5B or MUC 6 were detected in any of these specimens. MUC2 protein product was detected immunohistochemically in 34/36 carcinoma specimens, with no change from normal controls. There was de novo expression of MUC5AC in 23/36 carcinomas. No MUC5B or MUC6 protein was detected. No difference in MUC2 and MUC5AC protein was found between mucinous and non-mucinous carcinomas. The level of MUC2 was increased in moderately differentiated cancers compared with normal controls and decreased in the poorly differentiated group. Decreased MUC2 was found in poorly differentiated compared with moderately differentiated tumours. More MUC5AC protein was detected in well and moderately differentiated tumours than in poorly differentiated tumours and in all tumours relative to controls. The pattern of MUC2 staining in cancers was different from control tissue, with strong staining in the perinuclear region and none in goblet cell vesicles. MUC5AC staining was mainly detected in the cytoplasm. Poor detection of MUC2 and MUC5AC mRNA and associated strong staining for the total protein suggests altered biosynthesis and processing, leading to the characteristic subcellular distribution. Hence, change in the synthesis of MUC2 and the de novo appearance of MUC5AC in colorectal carcinomas may be significant events in the adenoma-carcinoma sequence, with possible implications for tumour prognosis.
Adenocarcinoma↗
Population genetic structure of variable drug response.
Geographic patterns of genetic variation, including variation at drug metabolizing enzyme (DME) loci and drug targets, indicate that geographic structuring of inter-individual variation in drug response may occur frequently. This raises two questions: how to represent human population genetic structure in the evaluation of drug safety and efficacy, and how to relate this structure to drug response. We address these by (i) inferring the genetic structure present in a heterogeneous sample and (ii) comparing the distribution of DME variants across the inferred genetic clusters of individuals. We find that commonly used ethnic labels are both insufficient and inaccurate representations of the inferred genetic clusters, and that drug-metabolizing profiles, defined by the distribution of DME variants, differ significantly among the clusters. We note, however, that the complexity of human demographic history means that there is no obvious natural clustering scheme, nor an obvious appropriate degree of resolution. Our comparison of drug-metabolizing profiles across the inferred clusters establishes a framework for assessing the appropriate level of resolution in relating genetic structure to drug response.
Chi-Square Distribution↗
TT virus infection in patients with primary hypogammaglobulinaemia: natural history and relationship to liver disease in the immunocompromised host.
BACKGROUND: TT virus (TTV) is a recently discovered human DNA virus with worldwide distribution, but with no clear disease association. The possibility of an enhanced TTV virulence in patients with immunodeficiencies has not yet been investigated but is of particular interest because other viruses have been demonstrated to cause severe and rapid liver disease in such patients. Here we analysed the characteristics of TTV infection in a large cohort of patients with primary hypogammaglobulinaemia (PHG) and whether TTV has a role in the frequently observed cryptogenic liver disease in these patients. METHODS: 83 Norwegian patients with PHG (serum immunoglobulin G < 2 g/L), receiving substitution treatment with immunoglobulins, were followed regularly for median 10.2 years (range 2-30). TTV DNA was sought in serum samples and three immunoglobulin preparations by polymerase chain reaction; TTV DNA quantitation, DNA sequencing and phylogenetic analysis were performed in selected samples. RESULTS: TTV DNA was detected in 27 of 83 (32.5%) patients and was not associated with a particular type of PHG. The prevalence of TTV infection was dependent on intravenous immunoglobulin administration, duration of therapy and patient's age. TTV DNA was found in two of three currently used immunoglobulin preparations. In the longitudinal study, whether TTV was cleared or newly acquired had no impact on liver function tests and no particular TTV strain was found in patients with more severe liver disease. CONCLUSIONS: TTV infection is common in patients with PHG. Treatment with immunoglobulins has a role in the transmission of TTV in these patients. However, we found no evidence of TTV-induced liver disease in this group of immunocompromised patients.
Adult↗
Prospective study of 424 cases of Staphylococcus aureus bacteraemia: determination of factors affecting incidence and mortality.
BACKGROUND: Staphylococcus aureus bacteraemia (SAB) is a common complication of S. aureus infection and is associated with a high mortality. AIMS: To document prospectively the pattern of illness associated with SAB in New Zealand and, by recording patient demographic factors and clinical features, to identify risk factors associated with a poor outcome. METHODS: From 1 July 1996 to 31 December 1997, adults with SAB were prospectively studied in six tertiary care hospitals. All information obtained from patients' records was recorded on worksheets and transferred to a computerized spreadsheet for analysis. RESULTS: There were 424 patients with SAB. Maori (relative risk (RR)= 1.8, 95% confidence interval (CI) = 1.3-2.6) and Pacific Island people (RR = 4.0, 95% CI = 3.1-5.3) were significantly more likely than people of European descent to acquire SAB, but not to die from the infection. Fifty per cent of cases were community acquired. A source was identified for 85%: intravenous catheter (31%), primarily hospital acquired, and skin/soft tissue (22%), primarily community acquired, were the most common foci. The 30-day mortality was 19%, 83% of whom died within 2 weeks. Risk factors for a poor outcome were: increasing age above 60, female sex (RR = 1.4, 95% CI = 1.0-2.1), diabetes mellitus (RR = 1.5, 95% CI = 1.0-2.4), immunosuppression (RR = 1.5, 95% CI = 1.0-2.4), pre-existing renal impairment (RR = 1.8, 95% CI = 1.2-2.7), malignancy (RR= 2.2, 95% CI = 1.4-3.5), lung as a source (RR = 2.8, 95% CI = 1.9-4.2) and unknown source (RR = 2.3, 95% CI = 1.5-3.3). Mortality was also accurately predicted by two multifactor scoring systems. There was a low rate of methicillin resistance (5%). CONCLUSIONS: Staphylococcus aureus bacteraemia is more likely to occur in certain ethnic groups, while mortality is associated with other identifiable risk factors and continues to be high. Intravenous catheters remain the most common and most preventable cause of SAB.
Adolescent↗
Long-term DNA survival in ethanol-preserved archival material.
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Archives↗
Molecular and morphological evidence on the phylogeny of the Elephantidae.
The African and Asian elephants and the mammoth diverged ca. 4-6 million years ago and their phylogenetic relationship has been controversial. Morphological studies have suggested a mammoth Asian elephant relationship, while molecular studies have produced conflicting results. We obtained cytochrome b sequences of up to 545 base pairs from five mammoths, 14 Asian and eight African elephants. A high degree of polymorphism is detected within species. With a dugong sequence used as the outgroup, parsimony and maximum-likelihood analyses support a mammoth African elephant clade. As the dugong is a very distant outgroup, we employ likelihood analysis to root the tree with a molecular clock, and use bootstrap and Bayesian analyses to quantify the relative support for different topologies. The analyses support the mammoth African elephant relationship, although other trees cannot be rejected. Ancestral polymorphisms may have resulted in gene trees differing from the species phylogeny Examination of morphological data, especially from primitive fossil members, indicates that some supposed synapomorphies between the mammoth and Asian elephant are variable, others convergent or autapomorphous. A mammoth African elephant relationship is not excluded. Our results highlight the need, in both morphological and molecular phylogenetics, for multiple markers and close attention to within-taxon variation and outgroup selection.
Animals↗
Deoxysugars in glycopeptide antibiotics: enzymatic synthesis of TDP-L-epivancosamine in chloroeremomycin biosynthesis.
The 2,3,6-trideoxysugar l-epivancosamine is the terminal sugar added to the aglycone scaffold in chloroeremomycin, a member of the vancomycin family of glycopeptide antibiotics. Five proteins from the chloroeremomycin biosynthetic cluster, ORF14 and ORF23 to ORF26, have been expressed heterologously in Escherichia coli and purified to near homogeneity, and each has been characterized for an enzymatic activity. These five enzymes reconstitute the complete biosynthesis of TDP-l-epivancosamine from TDP-4-keto-6-deoxy-d-glucose. This process involves C-2 deoxygenation, C-3 amination and methylation, C-5 epimerization, and C-4 ketoreduction. Intermediates and the final product of this pathway have been identified by mass spectrometry and NMR. The pathway established here represents the complete in vitro reconstitution of an unusual sugar for an important class of antibiotics and sets the groundwork for future combinatorial biosynthesis for new bioactive compounds.
Anti-Bacterial Agents↗
Analysis of the adenosylcobinamide kinase/adenosylcobinamide-phosphate guanylyltransferase (CobU) enzyme of Salmonella typhimurium LT2. Identification of residue His-46 as the site of guanylylation.
CobU is a bifunctional enzyme involved in adenosylcobalamin (coenzyme B(12)) biosynthesis in Salmonella typhimurium LT2. In this bacterium, CobU is the adenosylcobinamide kinase/adenosylcobinamide-phosphate guanylyltransferase needed to convert cobinamide to adenosylcobinamide-GDP during the late steps of adenosylcobalamin biosynthesis. The guanylyltransferase reaction has been proposed to proceed via a covalently modified CobU-GMP intermediate. Here we show that CobU requires a nucleoside upper ligand on cobinamide for substrate recognition, with the nucleoside base, but not the 2'-OH group of the ribose, being important for this recognition. During the kinase reaction, both the nucleotide base and the 2'-OH group of the ribose are important for gamma-phosphate donor recognition, and GTP is the only nucleotide competent for the complete nucleotidyltransferase reaction. Analysis of the ATP:adenosylcobinamide kinase reaction shows CobU becomes less active during this reaction due to the formation of a covalent CobU-AMP complex that holds CobU in an altered conformation. Characterization of the GTP:adenosylcobinamide-phosphate guanylyltransferase reaction shows the covalent CobU-GMP intermediate is on the reaction pathway for the generation of adenosylcobinamide-GDP. Identification of a modified histidine and analysis of cobU mutants indicate that histidine 46 is the site of guanylylation.
Binding Sites↗
"Just say no"--reducing the use of antibiotics for colds, bronchitis and sinusitis.
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Anti-Bacterial Agents↗