The Plasmodium berghei Ca(2+)/H(+) exchanger, PbCAX, is essential for tolerance to environmental Ca(2+) during sexual development.

Ca(2+) contributes to a myriad of important cellular processes in all organisms, including the apicomplexans, Plasmodium and Toxoplasma. Due to its varied and essential roles, free Ca(2+) is tightly regulated by complex mechanisms. These mechanisms are therefore of interest as putative drug targets. One pathway in Ca(2+) homeostatic control in apicomplexans uses a Ca(2+)/H(+) exchanger (a member of the cation exchanger family, CAX). The P. falciparum CAX (PfCAX) has recently been characterised in asexual blood stage parasites. To determine the physiological importance of apicomplexan CAXs, tagging and knock-out strategies were undertaken in the genetically tractable T. gondii and P. berghei parasites. In addition, a yeast heterologous expression system was used to study the function of apicomplexan CAXs. Tagging of T. gondii and P. berghei CAXs (TgCAX and PbCAX) under control of their endogenous promoters could not demonstrate measureable expression of either CAX in tachyzoites and asexual blood stages, respectively. These results were consistent with the ability of parasites to tolerate knock-outs of the genes for TgCAX and PbCAX at these developmental stages. In contrast, PbCAX expression was detectable during sexual stages of development in female gametocytes/gametes, zygotes and ookinetes, where it was dispersed in membranous networks within the cytosol (with minimal mitochondrial localisation). Furthermore, genetically disrupted parasites failed to develop further from "round" form zygotes, suggesting that PbCAX is essential for ookinete development and differentiation. This impeded phenotype could be rescued by removal of extracellular Ca(2+). Therefore, PbCAX provides a mechanism for free living parasites to multiply within the ionic microenvironment of the mosquito midgut. Ca(2+) homeostasis mediated by PbCAX is critical and suggests plasmodial CAXs may be targeted in approaches designed to block parasite transmission

Cooperative Cargo Transport by Several Molecular Motors

The transport of cargo particles which are pulled by several molecular motors in a cooperative manner is studied theoretically. The transport properties depend primarily on the maximal number, $N$, of motor molecules that may pull simultaneously on the cargo particle. Since each motor must unbind from the filament after a finite number of steps but can also rebind to it again, the actual number of pulling motors is not constant but varies with time between zero and $N$. An increase in the maximal number $N$ leads to a strong increase of the average walking distance (or run length) of the cargo particle. If the cargo is pulled by up to $N$ kinesin motors, e.g., the walking distance is estimated to be $5^{N-1}/N$ micrometers which implies that seven or eight kinesin molecules are sufficient to attain an average walking distance in the centimeter range. If the cargo particle is pulled against an external load force, this force is shared between the motors which provides a nontrivial motor-motor coupling and a generic mechanism for nonlinear force-velocity relationships. With increasing load force, the probability distribution of the instantenous velocity is shifted towards smaller values, becomes broader, and develops several peaks. Our theory is consistent with available experimental data and makes quantitative predictions that are accessible to systematic in vitro experiments.Comment: 24 pages, latex, 6 figures, includes Supporting Tex

Predicting cortical bone adaptation to axial loading in the mouse tibia

The development of predictive mathematical models can contribute to a deeper understanding of the specific stages of bone mechanobiology and the process by which bone adapts to mechanical forces. The objective of this work was to predict, with spatial accuracy, cortical bone adaptation to mechanical load, in order to better understand the mechanical cues that might be driving adaptation. The axial tibial loading model was used to trigger cortical bone adaptation in C57BL/6 mice and provide relevant biological and biomechanical information. A method for mapping cortical thickness in the mouse tibia diaphysis was developed, allowing for a thorough spatial description of where bone adaptation occurs. Poroelastic finite-element (FE) models were used to determine the structural response of the tibia upon axial loading and interstitial fluid velocity as the mechanical stimulus. FE models were coupled with mechanobiological governing equations, which accounted for non-static loads and assumed that bone responds instantly to local mechanical cues in an on–off manner. The presented formulation was able to simulate the areas of adaptation and accurately reproduce the distributions of cortical thickening observed in the experimental data with a statistically significant positive correlation (Kendall's τ rank coefficient τ = 0.51, p < 0.001). This work demonstrates that computational models can spatially predict cortical bone mechanoadaptation to a time variant stimulus. Such models could be used in the design of more efficient loading protocols and drug therapies that target the relevant physiological mechanisms

Pattern of adult intestinal obstruction at Tenwek hospital, in south-western Kenya

Introduction: acute mechanical intestinal obstruction (IO) is one of the leading causes of surgical admissions in most emergency departments worldwide. The causes of IO vary significantly depending on geographical location. The aim of this study was to identify the etiology, management and outcomes of patients with acute mechanical IO presenting in south-western Kenya. Methods: a 4 year (November 2009–October 2013) retrospective review of all adult patients admitted with acute mechanical IO at Tenwek Hospital in Bomet, Kenya. Results: a total of 303 male and 142 female patients, presented with acute mechanical IO during the study period. Mean patient age was 40.6 years (range 17-91), with peak  incidence in those aged 31-40 years. The foremost signs and symptoms were abdominal pain (89.4%), abdominal tenderness (81.6%), vomiting (78%), abdominal distension (65.4%) and constipation (50.8%). Sigmoid volvulus (25.6%), adhesions (23.1%), small bowel volvulus (21.3%), and ileo-sigmoid knotting (8.5%) were the leading causes of IO. Laparotomy was undertaken in 361 (81.1%) cases, with bowel gangrene noted in 112 (30.4%). The overall morbidity and mortality rates were 15% and 4.5% respectively. Patients with gangrenous bowel at laparotomy had a higher morbidity rate (22.3% vs 9.6%, P=.001), a higher mortality rate (9.8% vs 3.2%, P=.02) and a longer duration of stay (9.9 days vs 7.6 days,  P=.0001) compared to those with viable bowel. Conclusion: the most common causes of IO in this study were sigmoid volvulus, adhesions, small bowel volvulus and ileo-sigmoid knotting. Presence of bowel gangrene was associated with higher morbidity and mortality rates

Electron transport and band structure in phosphorus-doped polycrystalline silicon films

We study transport mechanisms, effective mass, and band structure by measuring the resistivity, Hall, and Seebeck and Nernst coefficients in heavily phosphorus-doped polycrystalline silicon films made by thermal crystallization of amorphous silicon. We observe a change in transport mechanism which results in an increase in electron mobility from 10% to 80% of the single-crystal silicon mobility as the carrier concentration increases from 1019 to 1020 cm-3. Our measurements of effective mass at the Fermi level indicate that as the carrier concentration increases, there is a shift from impurity-band transport to conduction-band transport, and that the electron effective mass is lower in the impurity band than in the conduction band of Si. The shift to conduction-band transport improves electron mobility with carrier density by improving intragrain carrier mean free path lengths and relaxation times. © 2009 American Institute of Physics.published_or_final_versio

Efficient Computation of Squarefree Separator Polynomials

Given a finite set of distinct points, a separator family is a set of polynomials, each one corresponding to a point of the given set, such that each of them takes value one at the corresponding point, whereas it vanishes at any other point of the set. Separator polynomials are fundamental building blocks for polynomial interpolation and they can be employed in several practical applications. Ceria and Mora recently developed a new algorithm for squarefree separator polynomials. The algorithm employs as a tool the point trie structure, first defined by Felszeghy-R\ue1th-R\uf3nyai in their Lex game algorithm, which gives a compact representation of the relations among the points\u2019 coordinates. In this paper, we propose a fast implementation in C of the aforementioned algorithm, based on an efficient storing and visiting of the point trie. We complete the implementation with tests on some sets of points, giving different configurations of the corresponding tries

‘20 tins of Stella for a fiver’: The making of class through Labour and Coalition government alcohol policy

Alcohol use in the UK has been a key concern to both the Labour and Coalition governments, and commands considerable attention in the media and academic discussions. This article analyses how recent government policy discussions have defined particular forms of drinking as problematic, and how these definitions and associated policy initiatives can be seen as part of a wider symbolic economy through which people come to be valued differently, incorporating ideas of economic, cultural and social capital. Therefore, I argue that government policies and discussions of drinking are a key way in which class is constituted in contemporary Britain

Notch signaling in serous ovarian cancer

Ovarian cancer is the most lethal of all gynecologic malignancies because women commonly present with advanced stage disease and develop chemotherapy refractory tumors. While cytoreductive surgery followed by platinum based chemotherapy are initially effective, ovarian tumors have a high propensity to recur highlighting the distinct need for novel therapeutics to improve outcomes for affected women. The Notch signaling pathway plays an established role in embryologic development and deregulation of this signaling cascade has been linked to many cancers. Recent genomic profiling of serous ovarian carcinoma revealed that Notch pathway alterations are among the most prevalent detected genomic changes. A growing body of scientific literature has confirmed heightened Notch signaling activity in ovarian carcinoma, and has utilized in vitro and in vivo models to suggest that targeting this pathway with gamma secretase inhibitors (GSIs) leads to anti-tumor effects. While it is currently unknown if Notch pathway inhibition can offer clinical benefit to women with ovarian cancer, several GSIs are currently in phase I and II trials across many disease sites including ovary. This review will provide background on Notch pathway function and will focus on the pre-clinical literature that links altered Notch signaling to ovarian cancer progression

Linking the subcultures of physics: Virtual empiricism and the bonding role of trust

This article draws on empirical material concerning the communication and use of knowledge in experimental physics and their relations to the culture of theoretical physics. The role that trust plays in these interactions is used to create a model of social distance between interacting theoretical and experimental cultures. This article thus seeks to reintroduce trust as a fundamental element in answering the problem of disunity in the sociology of knowledge

Tackling concentrated worklessness: integrating governance and policy across and within spatial scales

Spatial concentrations of worklessness remained a key characteristic of labour markets in advanced industrial economies, even during the period of decline in aggregate levels of unemployment and economic inactivity evident from the late 1990s to the economic downturn in 2008. The failure of certain localities to benefit from wider improvements in regional and national labour markets points to a lack of effectiveness in adopted policy approaches, not least in relation to the governance arrangements and policy delivery mechanisms that seek to integrate residents of deprived areas into wider local labour markets. Through analysis of practice in the British context, we explore the difficulties of integrating economic and social policy agendas within and across spatial scales to tackle problems of concentrated worklessness. We present analysis of a number of selected case studies aimed at reducing localised worklessness and identify the possibilities and constraints for effective action given existing governance arrangements and policy priorities to promote economic competitiveness and inclusion