A preliminary study of genetic factors that influence susceptibility to bovine tuberculosis in the British cattle herd

Associations between specific host genes and susceptibility to Mycobacterial infections such as tuberculosis have been reported in several species. Bovine tuberculosis (bTB) impacts greatly the UK cattle industry, yet genetic predispositions have yet to be identified. We therefore used a candidate gene approach to study 384 cattle of which 160 had reacted positively to an antigenic skin test (‘reactors’). Our approach was unusual in that it used microsatellite markers, embraced high breed diversity and focused particularly on detecting genes showing heterozygote advantage, a mode of action often overlooked in SNP-based studies. A panel of neutral markers was used to control for population substructure and using a general linear model-based approach we were also able to control for age. We found that substructure was surprisingly weak and identified two genomic regions that were strongly associated with reactor status, identified by markers INRA111 and BMS2753. In general the strength of association detected tended to vary depending on whether age was included in the model. At INRA111 a single genotype appears strongly protective with an overall odds ratio of 2.2, the effect being consistent across nine diverse breeds. Our results suggest that breeding strategies could be devised that would appreciably increase genetic resistance of cattle to bTB (strictly, reduce the frequency of incidence of reactors) with implications for the current debate concerning badger-culling

Determining the neurotransmitter concentration profile at active synapses

Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission

Reconstructing Roma History from Genome-Wide Data

The Roma people, living throughout Europe and West Asia, are a diverse population linked by the Romani language and culture. Previous linguistic and genetic studies have suggested that the Roma migrated into Europe from South Asia about 1,000–1,500 years ago. Genetic inferences about Roma history have mostly focused on the Y chromosome and mitochondrial DNA. To explore what additional information can be learned from genome-wide data, we analyzed data from six Roma groups that we genotyped at hundreds of thousands of single nucleotide polymorphisms (SNPs). We estimate that the Roma harbor about 80% West Eurasian ancestry–derived from a combination of European and South Asian sources–and that the date of admixture of South Asian and European ancestry was about 850 years before present. We provide evidence for Eastern Europe being a major source of European ancestry, and North-west India being a major source of the South Asian ancestry in the Roma. By computing allele sharing as a measure of linkage disequilibrium, we estimate that the migration of Roma out of the Indian subcontinent was accompanied by a severe founder event, which appears to have been followed by a major demographic expansion after the arrival in Europe.Országos Tudományos Kutatási Alapprogramok (OTKA K 103983)Országos Tudományos Kutatási Alapprogramok (OTKA 73430)National Science Foundation (U.S.) (HOMINID grant 1032255)National Institutes of Health (U.S.) (grant GM100233

HIV Risk Profiles Among HIV-Positive, Methamphetamine-Using Men Who Have Sex with Both Men and Women

This study examined demographic characteristics, sexual risk behaviors, sexual beliefs, and substance use patterns in HIV-positive, methamphetamine-using men who have sex with both men and women (MSMW) (n = 50) as compared to men who have sex with men only (MSM) (n = 150). Separate logistic regressions were conducted to predict group membership. In the final model, of 12 variables, eight were independently associated with group membership. Factors independently associated with MSMW were acquiring HIV through injection drug use, being an injection drug user, using hallucinogens, using crack, being less likely to have sex at a bathhouse, being less likely to be the receptive partner when high on methamphetamine, having greater intentions to use condoms for oral sex, and having more negative attitudes about HIV disclosure. These results suggest that, among HIV-positive methamphetamine users, MSMW differ significantly from MSM in terms of their HIV risk behaviors. Studies of gay men and HIV often also include bisexual men, grouping them all together as MSM, which may obscure important differences between MSMW and MSM. It is important that future studies consider MSM and MSMW separately in order to expand our knowledge about differential HIV prevention needs for both groups. This study showed that there were important differences in primary and secondary prevention needs of MSM and MSMW. These findings have implications for both primary and secondary HIV prevention among these high-risk populations

Over-expression of Adenine Nucleotide Translocase 1 (ANT1) Induces Apoptosis and Tumor Regression in vivo

Background: Adenine nucleotide translocase (ANT) is located in the inner mitochondrial membrane and catalyzes the exchange of mitochondrial ATP for cytosolic ADP. ANT has been known to be a major component of the permeability transition pore complex of mitochondria and contributes to mitochondria-mediated apoptosis. Human ANT has four isoforms (ANT1, ANT2, ANT3, and ANT4), and the expression of the ANT isoforms is variable depending on the tissue and cell type, developmental stage, and proliferation status. Among the isoforms, ANT1 is highly expressed in terminally-differentiated tissues, but expressed in low levels in proliferating cells, such as cancer cells. In particular, over-expression of ANT1 induces apoptosis in cultured tumor cells. Methods: We applied an ANT1 gene transfer approach to induce apoptosis and to evaluate the anti-tumor effect of ANT1 in a nude mouse model. Results: We demonstrated that ANT1 transfection induced apoptosis of MDA-MB-231 cells, inactivated NF-κB activity, and increased Bax expression. ANT1-inducing apoptosis was accompanied by the disruption of mitochondrial membrane potential, cytochrome c release and the activation of caspases-9 and -3. Moreover, ANT1 transfection significantly suppressed tumor growth in vivo. Conclusion: Our results suggest that ANT1 transfection may be a useful therapeutic modality for the treatment of cancer

Polymorphisms in folate-metabolizing genes, chromosome damage, and risk of Down syndrome in Italian women: identification of key factors using artificial neural networks

<p>Abstract</p> <p>Background</p> <p>Studies in mothers of Down syndrome individuals (MDS) point to a role for polymorphisms in folate metabolic genes in increasing chromosome damage and maternal risk for a Down syndrome (DS) pregnancy, suggesting complex gene-gene interactions. This study aimed to analyze a dataset of genetic and cytogenetic data in an Italian group of MDS and mothers of healthy children (control mothers) to assess the predictive capacity of artificial neural networks assembled in TWIST system in distinguish consistently these two different conditions and to identify the variables expressing the maximal amount of relevant information to the condition of being mother of a DS child.</p> <p>The dataset consisted of the following variables: the frequency of chromosome damage in peripheral lymphocytes (BNMN frequency) and the genotype for 7 common polymorphisms in folate metabolic genes (<it>MTHFR </it>677C>T and 1298A>C, <it>MTRR </it>66A>G, <it>MTR </it>2756A>G, <it>RFC1 </it>80G>A and <it>TYMS </it>28bp repeats and 1494 6bp deletion). Data were analysed using TWIST system in combination with supervised artificial neural networks, and a semantic connectivity map.</p> <p>Results</p> <p>TWIST system selected 6 variables (BNMN frequency, <it>MTHFR </it>677TT, <it>RFC1 </it>80AA, <it>TYMS </it>1494 6bp +/+, <it>TYMS </it>28bp 3R/3R and <it>MTR </it>2756AA genotypes) that were subsequently used to discriminate between MDS and control mothers with 90% accuracy. The semantic connectivity map provided important information on the complex biological connections between the studied variables and the two conditions (being MDS or control mother).</p> <p>Conclusions</p> <p>Overall, the study suggests a link between polymorphisms in folate metabolic genes and DS risk in Italian women.</p

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

A review of elliptical and disc galaxy structure, and modern scaling laws

A century ago, in 1911 and 1913, Plummer and then Reynolds introduced their models to describe the radial distribution of stars in `nebulae'. This article reviews the progress since then, providing both an historical perspective and a contemporary review of the stellar structure of bulges, discs and elliptical galaxies. The quantification of galaxy nuclei, such as central mass deficits and excess nuclear light, plus the structure of dark matter halos and cD galaxy envelopes, are discussed. Issues pertaining to spiral galaxies including dust, bulge-to-disc ratios, bulgeless galaxies, bars and the identification of pseudobulges are also reviewed. An array of modern scaling relations involving sizes, luminosities, surface brightnesses and stellar concentrations are presented, many of which are shown to be curved. These 'redshift zero' relations not only quantify the behavior and nature of galaxies in the Universe today, but are the modern benchmark for evolutionary studies of galaxies, whether based on observations, N-body-simulations or semi-analytical modelling. For example, it is shown that some of the recently discovered compact elliptical galaxies at 1.5 < z < 2.5 may be the bulges of modern disc galaxies.Comment: Condensed version (due to Contract) of an invited review article to appear in "Planets, Stars and Stellar Systems"(www.springer.com/astronomy/book/978-90-481-8818-5). 500+ references incl. many somewhat forgotten, pioneer papers. Original submission to Springer: 07-June-201

Labour intensity of guidelines may have a greater effect on adherence than GPs' workload

Background: Physicians' heavy workload is often thought to jeopardise the quality of care and to be a barrier to improving quality. The relationship between these has, however, rarely been investigated. In this study quality of care is defined as care 'in accordance with professional guidelines'. In this study we investigated whether GPs with a higher workload adhere less to guidelines than those with a lower workload and whether guideline recommendations that require a greater time investment are less adhered to than those that can save time. Methods: Data were used from the Second Dutch National survey of General Practice (DNSGP- 2). This nationwide study was carried out between April 2000 and January 2002. A multilevel logistic-regression analysis was conducted of 170,677 decisions made by GPs, referring to 41 Guideline Adherence Indicators (GAIs), which were derived from 32 different guidelines. Data were used from 130 GPs, working in 83 practices with 98,577 patients. GP-characteristics as well as guideline characteristics were used as independent variables. Measures include workload (number of contacts), hours spent on continuing medical education, satisfaction with available time, practice characteristics and patient characteristics. Outcome measure is an indicator score, which is 1 when a decision is in accordance with professional guidelines or 0 when the decision deviates from guidelines. Results: On average, 66% of the decisions GPs made were in accordance with guidelines. No relationship was found between the objective workload of GPs and their adherence to guidelines. Subjective workload (measured on a five point scale) was negatively related to guideline adherence (OR = 0.95). After controlling for all other variables, the variation between GPs in adherence to guideline recommendations showed a range of less than 10%. 84% of the variation in guideline adherence was located at the GAI-level. Which means that the differences in adherence levels between guidelines are much larger than differences between GPs. Guideline recommendations that require an extra time investment during the same consultation are significantly less adhered to: (OR = 0.46), while those that can save time have much higher adherence levels: OR = 1.55). Recommendations that reduce the likelihood of a follow-up consultation for the same problem are also more often adhered to compared to those that have no influence on this (OR = 3.13). Conclusion: No significant relationship was found between the objective workload of GPs and adherence to guidelines. However, guideline recommendations that require an extra time investment are significantly less well adhered to while those that can save time are significantly more often adhered to.