Ranking non-synonymous single nucleotide polymorphisms based on disease concepts

As the number of non-synonymous single nucleotide polymorphisms (nsSNPs) identified through whole-exome/whole-genome sequencing programs increases, researchers and clinicians are becoming increasingly reliant upon computational prediction algorithms designed to prioritize potential functional variants for further study. A large proportion of existing prediction algorithms are ‘disease agnostic’ but are nevertheless quite capable of predicting when a mutation is likely to be deleterious. However, most clinical and research applications of these algorithms relate to specific diseases and would therefore benefit from an approach that discriminates between functional variants specifically related to that disease from those which are not. In a whole-exome/whole-genome sequencing context, such an approach could substantially reduce the number of false positive candidate mutations. Here, we test this postulate by incorporating a disease-specific weighting scheme into the Functional Analysis through Hidden Markov Models (FATHMM) algorithm. When compared to traditional prediction algorithms, we observed an overall reduction in the number of false positives identified using a disease-specific approach to functional prediction across 17 distinct disease concepts/categories. Our results illustrate the potential benefits of making disease-specific predictions when prioritizing candidate variants in relation to specific diseases. A web-based implementation of our algorithm is available at http://fathmm.biocompute.org.uk.     

Reciprocal regulation of fat content and flight activity in male tsetse flies (Glossina palpalis)

Abstract. To disentangle cause and effect in previously observed relationships between fat content and flight activity in male tsetse ( Glossina spp.), three groups of flies were fed at different intervals to raise their fat content to different levels before their flight activity was recorded. The greater the mean daily blood intake, the higher the fat content and the greater the subsequent spontaneous flight activity, thereby using up almost all of the fat reserves before the next blood meal. It is proposed that although male flies would benefit from maximum food intake to permit maximum flight associated with mate-seeking, they do not in fact feed as often as possible either in the field or the laboratory. This is explicable if energy acquisition is constrained by an additional mortality risk associated with feeding.     

Purine Nucleoside and Nucleobase Cell Membrane Transport in Giardia lamblia

ABSTRACT. Giardia lamblia is dependent on the salvage of preformed purines and pyrimidines. This study investigated purine nucleoside and nucleobase transport utilizing rapid uptake determinations. Nucleoside substrate/velocity curves exhibited the hyperbolic kinetics of a saturable carrier-mediated system. Deoxynucleosides exhibited a much lower affinity for the transporter. Inhibition studies confirmed the relative camer affinities of these ribonucleosides and deoxyribonucleosides. The nucleobase adenine did not exhibit saturation lunetics at a comparable substrate range, and did not inhibit nucleoside transport. Dipyridamole markedly inhibited nucleoside but not nucleobase transport, confirming the separate entry pathways. When cells were depleted of ATP, the velocity of nucleoside and nucleobase transport was unchanged, indicating that it is a non-energy-dependent process. Three nucleoside analogs, formycin A, adenine arabinoside and 7–deazaadenosine, were studied. Transport kinetics ranged widely among this group and could not completely account for their cytotoxic effect. When the apparent Km and Vmax of the nucleosides were compared, an approximately linear relationship (r²= 0.95) was noted. This suggests that a high affinity of the nucleoside permease for the substrate retards disassociation of the substrate-carrier complex, slowing net influx.     

Teachers' Expectations and Sense of Responsibility for Student Learning: The Importance of Race, Class, and Organizational Habitus

This article examines how the concentration of low-income African American students in urban elementary schools is deeply coupled with a leveling of teachers' expectations of students and a reduction in their sense of responsibility for student learning. We argue that this process is rooted in school-based organizational habitus through which expectations of students become embedded in schools. We show that this process can be mediated if school leaders engage in practices designed to increase teachers' sense of responsibility for student learning. [organizational habitus, race, class, teacher expectations]     

Effect of host odours on trap catch composition of Glossina pallidipes in Kenya

The effect of odour attractants on the composition of samples of Glossina pallidipes Austen was investigated by comparing the age and nutritional status of flies caught in unbaited biconical traps with those caught in traps baited with cow urine and acetone. For both male and female flies, baited traps caught more flies with significantly higher fat content than did unbaited traps. Thus the samples from baited traps were more representative of the population as a whole: males showed a fuller range of the fat/haematin conditions known to occur in the field and proportionately more females were in later stages of the pregnancy cycle, than from unbaited traps.     

Abiotic and biotic determinants of the seasonal dynamics of the tick Rhipicephalus appendiculatus in South Africa

Abstract. The creation of a generic population model for the tick Rhipicephalus appendiculatus requires a detailed, quantified understanding of the interactions of these ticks with their biotic and abiotic environment in the different parts of their range, from the tropical regions of East Africa to the temperate regions of South Africa. The much greater seasonal variation in climatic conditions, particularly temperature, further from the equator introduces variable development rates and diapause into the life cycle. Estimates of natural temperature-dependent interstadial development periods, derived from a combination of published laboratory and field data, were applied to published data on the seasonal abundance of R.appendiculatus on three farms in the Eastern Cape Province of South Africa. This enabled an assessment of which ticks of one stage give rise to which ticks of the next stage, from which (a) the onset and duration of diapause in unfed adults, and (b) seasonal interstadial mortality indices in the form of fc-values, could be estimated. The contribution of biotic (tick density) and abiotic (climatic) factors as predictors of mortality at each life stage was investigated by step-wise multiple regression. Density-independent mortality at the female-to-larval stage is correlated with geographically variable climatic factors, minimum temperature at two farms and minimum relative humidity at the third. The other two stages are governed by density-dependent mortality, which, it is argued, may be caused largely by the hosts' acquired resistance to ticks. As expected on theoretical grounds, this density dependence is weaker nearer to the edge of the tick's range and for the more vulnerable immature stages.