Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease

The polarization of CD4+ T cells into distinct T helper cell lineages is essential for protective immunity against infection, but aberrant T cell polarization can cause autoimmunity. The transcription factor T-bet (TBX21) specifies the Th1 lineage and represses alternative T cell fates. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that may be causative for autoimmune diseases. The majority of these polymorphisms are located within non-coding distal regulatory elements. It is considered that these genetic variants contribute to disease by altering the binding of regulatory proteins and thus gene expression, but whether these variants alter the binding of lineage-specifying transcription factors has not been determined. Here, we show that SNPs associated with the mucosal inflammatory diseases Crohn’s disease, ulcerative colitis (UC) and celiac disease, but not rheumatoid arthritis or psoriasis, are enriched at T-bet binding sites. Furthermore, we identify disease-associated variants that alter T-bet binding in vitro and in vivo. ChIP-seq for T-bet in individuals heterozygous for the celiac disease-associated SNPs rs1465321 and rs2058622 and the IBD-associated SNPs rs1551398 and rs1551399, reveals decreased binding to the minor disease-associated alleles. Furthermore, we show that rs1465321 is an expression quantitative trait locus (eQTL) for the neighboring gene IL18RAP, with decreased T-bet binding associated with decreased expression of this gene. These results suggest that genetic polymorphisms may predispose individuals to mucosal autoimmune disease through alterations in T-bet binding. Other disease-associated variants may similarly act by modulating the binding of lineage-specifying transcription factors in a tissue-selective and disease-specific manner

Predicting Distribution of Aedes Aegypti and Culex Pipiens Complex, Potential Vectors of Rift Valley Fever Virus in Relation to Disease Epidemics in East Africa.

The East African region has experienced several Rift Valley fever (RVF) outbreaks since the 1930s. The objective of this study was to identify distributions of potential disease vectors in relation to disease epidemics. Understanding disease vector potential distributions is a major concern for disease transmission dynamics. DIVERSE ECOLOGICAL NICHE MODELLING TECHNIQUES HAVE BEEN DEVELOPED FOR THIS PURPOSE: we present a maximum entropy (Maxent) approach for estimating distributions of potential RVF vectors in un-sampled areas in East Africa. We modelled the distribution of two species of mosquitoes (Aedes aegypti and Culex pipiens complex) responsible for potential maintenance and amplification of the virus, respectively. Predicted distributions of environmentally suitable areas in East Africa were based on the presence-only occurrence data derived from our entomological study in Ngorongoro District in northern Tanzania. Our model predicted potential suitable areas with high success rates of 90.9% for A. aegypti and 91.6% for C. pipiens complex. Model performance was statistically significantly better than random for both species. Most suitable sites for the two vectors were predicted in central and northwestern Tanzania with previous disease epidemics. Other important risk areas include western Lake Victoria, northern parts of Lake Malawi, and the Rift Valley region of Kenya. Findings from this study show distributions of vectors had biological and epidemiological significance in relation to disease outbreak hotspots, and hence provide guidance for the selection of sampling areas for RVF vectors during inter-epidemic periods

Solitary caecal diverticulitis as an unusual cause of a right iliac fossa mass: a case report

Inflammation of a solitary caecal diverticulum is an uncommon pathological condition. Preoperatively the condition is almost indistinguishable from appendicitis, and is often confused with carcinoma of the caecum during operation. The typical patient with this condition is male, Asian, and in the fourth decade of life. This case is unusual in that the patient was a 26-year-old Caucasian man

Optimizing the colour and fabric of targets for the control of the tsetse fly Glossina fuscipes fuscipes

Background: Most cases of human African trypanosomiasis (HAT) start with a bite from one of the subspecies of Glossina fuscipes. Tsetse use a range of olfactory and visual stimuli to locate their hosts and this response can be exploited to lure tsetse to insecticide-treated targets thereby reducing transmission. To provide a rational basis for cost-effective designs of target, we undertook studies to identify the optimal target colour. Methodology/Principal Findings: On the Chamaunga islands of Lake Victoria , Kenya, studies were made of the numbers of G. fuscipes fuscipes attracted to targets consisting of a panel (25 cm square) of various coloured fabrics flanked by a panel (also 25 cm square) of fine black netting. Both panels were covered with an electrocuting grid to catch tsetse as they contacted the target. The reflectances of the 37 different-coloured cloth panels utilised in the study were measured spectrophotometrically. Catch was positively correlated with percentage reflectance at the blue (460 nm) wavelength and negatively correlated with reflectance at UV (360 nm) and green (520 nm) wavelengths. The best target was subjectively blue, with percentage reflectances of 3%, 29%, and 20% at 360 nm, 460 nm and 520 nm respectively. The worst target was also, subjectively, blue, but with high reflectances at UV (35% reflectance at 360 nm) wavelengths as well as blue (36% reflectance at 460 nm); the best low UV-reflecting blue caught 3× more tsetse than the high UV-reflecting blue. Conclusions/Significance: Insecticide-treated targets to control G. f. fuscipes should be blue with low reflectance in both the UV and green bands of the spectrum. Targets that are subjectively blue will perform poorly if they also reflect UV strongly. The selection of fabrics for targets should be guided by spectral analysis of the cloth across both the spectrum visible to humans and the UV region

The role of clathrin in post-golgi trafficking in toxoplasma gondii

Apicomplexan parasites are single eukaryotic cells with a highly polarised secretory system that contains unique secretory organelles (micronemes and rhoptries) that are required for host cell invasion. In contrast, the role of the endosomal system is poorly understood in these parasites. With many typical endocytic factors missing, we speculated that endocytosis depends exclusively on a clathrin-mediated mechanism. Intriguingly, in Toxoplasma gondii we were only able to observe the endogenous clathrin heavy chain 1 (CHC1) at the Golgi, but not at the parasite surface. For the functional characterisation of Toxoplasma gondii CHC1 we generated parasite mutants conditionally expressing the dominant negative clathrin Hub fragment and demonstrate that CHC1 is essential for vesicle formation at the trans-Golgi network. Consequently, the functional ablation of CHC1 results in Golgi aberrations, a block in the biogenesis of the unique secretory microneme and rhoptry organelles, and of the pellicle. However, we found no morphological evidence for clathrin mediating endocytosis in these parasites and speculate that they remodelled their vesicular trafficking system to adapt to an intracellular lifestyle

Similarities and Differences of the Soleus and Gastrocnemius H-reflexes during Varied Body Postures, Foot Positions, and Muscle Function: Multifactor Designs for Repeated Measures

<p>Abstract</p> <p>Background</p> <p>Although the soleus (Sol), medial gastrocnemius (MG), and lateral gastrocnemius (LG) muscles differ in function, composition, and innervations, it is a common practice is to investigate them as single H-reflex recording. The purpose of this study was to compare H-reflex recordings between these three sections of the triceps surae muscle group of healthy participants while lying and standing during three different ankle positions.</p> <p>Methods</p> <p>The Sol, MG and LG muscles' H-reflexes were recorded from ten participants during prone lying and standing with the ankle in neutral, maximum dorsiflexion, and maximum plantarflexion positions. Four traces were averaged for each combination of conditions. Three-way ANOVAs (posture X ankle position X muscle) with planned comparisons were used for statistical comparisons.</p> <p>Results</p> <p>Although the H-reflex in the three muscle sections differed in latency and amplitude, its dependency on posture and ankle position was similar. The H-reflex amplitudes and maximum H-reflex to M-response (H/M) ratios were significantly 1) lower during standing compared to lying with the ankle in neutral, 2) greater during standing with the ankle in plantarflexion compared to neutral, and 3) less with the ankle in dorsiflexion compared to neutral during lying and standing for all muscles (<it>p </it>≤ .05).</p> <p>Conclusion</p> <p>Varying demands are required for muscles activated during distinctly different postures and ankle movement tasks.</p

Neuroethical issues in pharmacological cognitive enhancement.

This is the published manuscript. It is available online from the Wiley in Wiley Interdisciplinary Reviews: Cognitive Science here: http://onlinelibrary.wiley.com/doi/10.1002/wcs.1306/abstract;jsessionid=05002026F7F8502EFC9A9553EC8CE45C.f03t02.UNLABELLED: Neuroethics is an emerging field that in general deals with the ethics of neuroscience and the neuroscience of ethics. In particular, it is concerned with the ethical issues in the translation of neuroscience to clinical practice and in the public domain. Numerous ethical issues arise when healthy individuals use pharmacological substances known as pharmacological cognitive enhancers (PCEs) for non-medical purposes in order to boost higher-order cognitive processes such as memory, attention, and executive functions. However, information regarding their actual use, benefits, and harms to healthy individuals is currently lacking. Neuroethical issues that arise from their use include the unknown side effects that are associated with these drugs, concerns about the modification of authenticity and personhood, and as a result of inequality of access to these drugs, the lack of distributive justice and competitive fairness that they may cause in society. Healthy individuals might be coerced by social institutions that force them to take these drugs to function better. These drugs might enable or hinder healthy individuals to gain better moral and self-understanding and autonomy. However, how these drugs might achieve this still remains speculative and unknown. Hence, before concrete policy decisions are made, the cognitive effects of these drugs should be determined. The initiation of accurate surveys to determine the actual usage of these drugs by healthy individuals from different sections of the society is proposed. In addition, robust empirical research need to be conducted to delineate not only whether or not these drugs modify complex higher-order cognitive processes but also how they might alter important human virtues such as empathy, moral reasoning, creativity, and motivation in healthy individuals. WIREs Cogn Sci 2014, 5:533-549. doi: 10.1002/wcs.1306 For further resources related to this article, please visit the WIREs website. CONFLICT OF INTEREST: The author has declared no conflicts of interest for this article

Spatial heterogeneity of habitat suitability for Rift Valley fever occurrence in Tanzania: an ecological niche modelling approach

Despite the long history of Rift Valley fever (RVF) in Tanzania, extent of its suitable habitat in the country remains unclear. In this study we investigated potential effects of temperature, precipitation, elevation, soil type, livestock density, rainfall pattern, proximity to wild animals, protected areas and forest on the habitat suitability for RVF occurrence in Tanzania. Presence-only records of 193 RVF outbreak locations from 1930 to 2007 together with potential predictor variables were used to model and map the suitable habitats for RVF occurrence using ecological niche modelling. Ground-truthing of the model outputs was conducted by comparing the levels of RVF virus specific antibodies in cattle, sheep and goats sampled from locations in Tanzania that presented different predicted habitat suitability values. Habitat suitability values for RVF occurrence were higher in the northern and central-eastern regions of Tanzania than the rest of the regions in the country. Soil type and precipitation of the wettest quarter contributed equally to habitat suitability (32.4% each), followed by livestock density (25.9%) and rainfall pattern (9.3%). Ground-truthing of model outputs revealed that the odds of an animal being seropositive for RVFV when sampled from areas predicted to be most suitable for RVF occurrence were twice the odds of an animal sampled from areas least suitable for RVF occurrence (95% CI: 1.43, 2.76, p < 0.001). The regions in the northern and central-eastern Tanzania were more suitable for RVF occurrence than the rest of the regions in the country. The modelled suitable habitat is characterised by impermeable soils, moderate precipitation in the wettest quarter, high livestock density and a bimodal rainfall pattern. The findings of this study should provide guidance for the design of appropriate RVF surveillance, prevention and control strategies which target areas with these characteristics

Pattern of pesticide storage before pesticide self-poisoning in rural Sri Lanka

<p>Abstract</p> <p>Background</p> <p>Deliberate self-poisoning with agricultural pesticides is the commonest means of suicide in rural Asia. It is mostly impulsive and facilitated by easy access to pesticides. The aim of this large observational study was to investigate the immediate source of pesticides used for self-harm to help inform suicide prevention strategies such as reducing domestic access to pesticides.</p> <p>Methods</p> <p>The study was conducted in a district hospital serving an agricultural region of Sri Lanka. Patients who had self-poisoned with pesticides and were admitted to the adult medical wards were interviewed by study doctors following initial resuscitation to identify the source of pesticides they have ingested.</p> <p>Results</p> <p>Of the 669 patients included in the analysis, 425 (63.5%) were male; the median age was 26 (IQR 20-36). In 511 (76%) cases, the pesticides had been stored either inside or immediately outside the house; among this group only eight patients obtained pesticides that were kept in a locked container. Ten percent (n = 67) of the patients used pesticides stored in the field while 14% (n = 91) purchased pesticides from shops within a few hours of the episode. The most common reasons for choosing the particular pesticide for self-harm were its easy accessibility (n = 311, 46%) or its popularity as a suicide agent in their village (n = 290, 43%).</p> <p>Conclusion</p> <p>Three quarters of people who ingested pesticides in acts of self-harm used products that were available within the home or in close proximity; relatively few patients purchased the pesticide for the act. The study highlights the importance of reducing the accessibility of toxic pesticides in the domestic environment.</p

Do Stacked Species Distribution Models Reflect Altitudinal Diversity Patterns?

The objective of this study was to evaluate the performance of stacked species distribution models in predicting the alpha and gamma species diversity patterns of two important plant clades along elevation in the Andes. We modelled the distribution of the species in the Anthurium genus (53 species) and the Bromeliaceae family (89 species) using six modelling techniques. We combined all of the predictions for the same species in ensemble models based on two different criteria: the average of the rescaled predictions by all techniques and the average of the best techniques. The rescaled predictions were then reclassified into binary predictions (presence/absence). By stacking either the original predictions or binary predictions for both ensemble procedures, we obtained four different species richness models per taxa. The gamma and alpha diversity per elevation band (500 m) was also computed. To evaluate the prediction abilities for the four predictions of species richness and gamma diversity, the models were compared with the real data along an elevation gradient that was independently compiled by specialists. Finally, we also tested whether our richness models performed better than a null model of altitudinal changes of diversity based on the literature. Stacking of the ensemble prediction of the individual species models generated richness models that proved to be well correlated with the observed alpha diversity richness patterns along elevation and with the gamma diversity derived from the literature. Overall, these models tend to overpredict species richness. The use of the ensemble predictions from the species models built with different techniques seems very promising for modelling of species assemblages. Stacking of the binary models reduced the over-prediction, although more research is needed. The randomisation test proved to be a promising method for testing the performance of the stacked models, but other implementations may still be developed