Differential confounding of rare and common variants in spatially structured populations

Well-powered genome-wide association studies, now made possible through advances in technology and large-scale collaborative projects, promise to characterize the contribution of rare variants to complex traits and disease. However, while population structure is a known confounder of association studies, it remains unknown whether methods developed to control stratification are equally effective for rare variants. Here, we demonstrate that rare variants can show a stratification that is systematically different from, and typically stronger than, common variants, and this is not necessarily corrected by existing methods. We show that the same process leads to inflation for load-based tests and can obscure signals at truly associated variants. Furthermore, we show that populations can display spatial structure in rare variants, even when Wright's fixation index F(ST) is low, but that allele frequency-dependent metrics of allele sharing can reveal localized stratification. These results underscore the importance of collecting and integrating spatial information in the genetic analysis of complex traits.     

Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca<Superscript>2+</Superscript> signalling

Retraction of mesenchymal stromal cells supports the invasion of colorectal cancer cells (CRC) into the adjacent compartment. CRC-secreted 12(S)-HETE enhances the retraction of cancer-associated fibroblasts (CAFs) and therefore, 12(S)-HETE may enforce invasivity of CRC. Understanding the mechanisms of metastatic CRC is crucial for successful intervention. Therefore, we studied pro-invasive contributions of stromal cells in physiologically relevant three-dimensional in vitro assays consisting of CRC spheroids, CAFs, extracellular matrix and endothelial cells, as well as in reductionist models. In order to elucidate how CAFs support CRC invasion, tumour spheroid-induced CAF retraction and free intracellular Ca²⁺ levels were measured and pharmacological- or siRNA-based inhibition of selected signalling cascades was performed. CRC spheroids caused the retraction of CAFs, generating entry gates in the adjacent surrogate stroma. The responsible trigger factor 12(S)-HETE provoked a signal, which was transduced by PLC, IP3, free intracellular Ca²⁺, Ca²⁺-calmodulin-kinase-II, RHO/ROCK and MYLK which led to the activation of myosin light chain 2, and subsequent CAF mobility. RHO activity was observed downstream as well as upstream of Ca²⁺ release. Thus, Ca²⁺ signalling served as central signal amplifier. Treatment with the FDA-approved drugs carbamazepine, cinnarizine, nifedipine and bepridil HCl, which reportedly interfere with cellular calcium availability, inhibited CAF-retraction. The elucidation of signalling pathways and identification of approved inhibitory drugs warrant development of intervention strategies targeting tumour–stroma interaction.     

Are You Receiving Me? A Viable System Model (VSM) Analysis of Purchasing Coordination in a Firm Engaged in Offshoring of Manufacturing Activities

This paper presents an account of the coordination of purchasing activities in a firm that offshored their manufacturing operations that later turned problematic. Empirical data is drawn from a single in-depth case study within a large multinational company which was involved in production offshoring in 2009. The paper draws on the viable systems model (VSM) as the main theoretical lens. First, our findings suggest that purchasing coordination is a loose construct; one in which the role and types of information aggregation in the purchasing process is loosely defined compared to the aggregation of volumes and the effectiveness of sourcing teams. This finding partly explains why many cross-functional sourcing problems occur. Second, that organizational and functional contextual differences can no longer be sidelined in discussions of purchasing coordination because they define how the system’s functions interface and therefore are one of the most essential considerations for better purchasing coordination and ultimately organizational viability.

     

Early microbiota,antibiotics and health

The colonization of the neonatal digestive tract provides a microbial stimulus required for an adequate maturation towards the physiological homeostasis of the host. This colonization, which is affected by several factors, begins with facultative anaerobes and continues with anaerobic genera. Accumulating evidence underlines the key role of the early neonatal period for this microbiota-induced maturation, being a key determinant factor for later health. Therefore, understanding the factors that determine the establishment of the microbiota in the infant is of critical importance. Exposure to antibiotics, either prenatally or postnatally, is common in early life mainly due to the use of intrapartum prophylaxis or to the administration of antibiotics in C-section deliveries. However, we are still far from understanding the impact of early antibiotics and their long-term effects. Increased risk of non-communicable diseases, such as allergies or obesity, has been observed in individuals exposed to antibiotics during early infancy. Moreover, the impact of antibiotics on the establishment of the infant gut resistome, and on the role of the microbiota as a reservoir of resistance genes, should be evaluated in the context of the problems associated with the increasing number of antibiotic resistant pathogenic strains. In this article, we review and discuss the above-mentioned issues with the aim of encouraging debate on the actions needed for understanding the impact of early life antibiotics upon human microbiota and health and for developing strategies aimed at minimizing this impact.     

一种提高视频车速检测精度的方法

通过对基于虚拟线的机动车视频测速方法的精度分析,提出了一种提高测速精度的方法.该方法在车道上定义一个矩形检测区,该检测区在视频图像上呈现出梯形,采用二维图像标定方法将梯形图像区域中任意一点的图像坐标准确地映射为检测区内对应点的地面坐标.通过在车辆经过检测区的视频图像中选取适当的图像帧,可以获得车辆的位移及对应的时间间隔,从而获得较高精度的速度测量结果.     

Translating cancer research into targeted therapeutics

The emphasis in cancer drug development has shifted from cytotoxic, non-specific chemotherapies to molecularly targeted, rationally designed drugs promising greater efficacy and less side effects. Nevertheless, despite some successes drug development remains painfully slow. Here, we highlight the issues involved and suggest ways in which this process can be improved and expedited. We envision an increasing shift to integrated cancer research and biomarker-driven adaptive and hypothesis testing clinical trials. The goal is the development of specific cancer medicines to treat the individual patient, with treatment selection being driven by a detailed understanding of the genetics and biology of the patient and their cancer.     

Friends of Wisdom?

This commentary addresses the question of the meaning of critique in relation to objectivism or dogmatism. Inspired by Kant’s critical philosophy and Husserl’s phenomenology, it defines the first in terms of conditionality, the second in terms of oppositionality. It works out an application on the basis of Salthe’s (Found Sci 15 4(6):357–367, 2010a) paper on development and evolution, where competition is criticized in oppositional, more than in conditional terms.     

A massive, cooling-flow-induced starburst in the core of a luminous cluster of galaxies

In the cores of some clusters of galaxies the hot intracluster plasma is dense enough that it should cool radiatively in the cluster's lifetime, leading to continuous 'cooling flows' of gas sinking towards the cluster centre, yet no such cooling flow has been observed. The low observed star-formation rates and cool gas masses for these 'cool-core' clusters suggest that much of the cooling must be offset by feedback to prevent the formation of a runaway cooling flow. Here we report X-ray, optical and infrared observations of the galaxy cluster SPT-CLJ2344-4243 (ref. 11) at redshift z = 0.596. These observations reveal an exceptionally luminous (8.2?×?10(45)?erg?s(-1)) galaxy cluster that hosts an extremely strong cooling flow (around 3,820 solar masses a year). Further, the central galaxy in this cluster appears to be experiencing a massive starburst (formation of around 740 solar masses a year), which suggests that the feedback source responsible for preventing runaway cooling in nearby cool-core clusters may not yet be fully established in SPT-CLJ2344-4243. This large star-formation rate implies that a significant fraction of the stars in the central galaxy of this cluster may form through accretion of the intracluster medium, rather than (as is currently thought) assembling entirely via mergers.