Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL

Resequencing genes provides the opportunity to assess the full spectrum of variants that influence complex traits. Here we report the first application of resequencing to a large population (n = 3,551) to examine the role of the adipokine ANGPTL4 in lipid metabolism. Nonsynonymous variants in ANGPTL4 were more prevalent in individuals with triglyceride levels in the lowest quartile than in individuals with levels in the highest quartile (P = 0.016). One variant (E40K), present in approximately 3% of European Americans, was associated with significantly lower plasma levels of triglyceride and higher levels of high-density lipoprotein cholesterol in European Americans from the Atherosclerosis Risk in Communities Study and in Danes from the Copenhagen City Heart Study. The ratio of nonsynonymous to synonymous variants was higher in European Americans than in African Americans (4:1 versus 1.3:1), suggesting population-specific relaxation of purifying selection. Thus, resequencing of ANGPTL4 in a multiethnic population allowed analysis of the phenotypic effects of both rare and common variants while taking advantage of genetic variation arising from ethnic differences in population history.     

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.     

物理学与生物学相融合——让不同风格的学科相互沟通

分子生物学家注重冗长的实验数据,而物理学家则习惯于把复杂的系统归结为可有助于了解其全部意义的几个基本原理中。但把这两个学科结合起来并非一件容易的事——     

Energetic landscape of alpha-lytic protease optimizes longevity through kinetic stability.

During the evolution of proteins the pressure to optimize biological activity is moderated by a need for efficient folding. For most proteins, this is accomplished through spontaneous folding to a thermodynamically stable and active native state. However, in the extracellular bacterial alpha-lytic protease (alphaLP) these two processes have become decoupled. The native state of alphaLP is thermodynamically unstable, and when denatured, requires millennia (t1/2 approximately 1,800 years) to refold. Folding is made possible by an attached folding catalyst, the pro-region, which is degraded on completion of folding, leaving alphaLP trapped in its native state by a large kinetic unfolding barrier (t1/2 approximately 1.2 years). alphaLP faces two very different folding landscapes: one in the presence of the pro-region controlling folding, and one in its absence restricting unfolding. Here we demonstrate that this separation of folding and unfolding pathways has removed constraints placed on the folding of thermodynamically stable proteins, and allowed the evolution of a native state having markedly reduced dynamic fluctuations. This, in turn, has led to a significant extension of the functional lifetime of alphaLP by the optimal suppression of proteolytic sensitivity.     

Natural history of a South African insect pollinator assemblage (Insecta: Coleoptera,Diptera, Hymenoptera,Lepidoptera): diagnostic notes,food web analysis and conservation recommendations

We describe activity patterns, relative abundances and pollen transport by insect floral visitors in the Skukuza Ranger District, Kruger National Park, Republic of South Africa, based on field surveys conducted during the early rainy seasons of years 2006 to 2012 (inclusive). Diagnostic notes, illustrations and natural history observations are provided for species in the families Buprestidae, Cerambycidae, Cleridae, Lycidae and Scarabaeidae (Coleoptera), Muscidae, Platystomatidae and Tabanidae (Diptera), Apidae, Halictidae, Megachilidae, Sphecidae and Vespidae (Hymenoptera), and Pieridae and Thyrididae (Lepidoptera) that transported pollen of tree or shrub species. Observations on floral phenology and pollination syndrome are presented for 27 flowering tree or shrub species. To provide a foundation for studies of the effects of drought and climate change on pollination services in the Kruger National Park, we applied methods of food web analysis to characterise this plant-pollinator assemblage. The food web analysis shows moderate levels of redundancy in plant-pollinator interactions (with connectance values averaging 0.19 for plant species and 0.20 for pollinator species), suggesting that pollination services in this system may exhibit some resilience to environmental perturbations. Possible conservation strategies for maintaining pollination services in this ecological system are discussed, including habitat management to conserve larval or nesting areas for social and solitary bees and scarab beetles, as well as further inventories and long-term monitoring of pollinator species.     

Debunking material induction

In this paper, we present an explanatory objection to Norton's material theory of induction, as applied to predictive inferences. According to the objection we present, there is an explanatory disconnect between our beliefs about the future and the relevant future facts. We argue that if we recognize such a disconnect, we are no longer rationally entitled to our future beliefs.     

Neutrophil extracellular traps in cancer progression

Neutrophils are being increasingly recognized as an important element in tumor progression. They have been shown to exert important effects at nearly every stage of tumor progression with a number of studies demonstrating that their presence is critical to tumor development. Novel aspects of neutrophil biology have recently been elucidated and its contribution to tumorigenesis is only beginning to be appreciated. Neutrophil extracellular traps (NETs) are neutrophil-derived structures composed of DNA decorated with antimicrobial peptides. They have been shown to trap and kill microorganisms, playing a critical role in host defense. However, their contribution to tumor development and metastasis has recently been demonstrated in a number of studies highlighting NETs as a potentially important therapeutic target. Here, studies implicating NETs as facilitators of tumor progression and metastasis are reviewed. In addition, potential mechanisms by which NETs may exert these effects are explored. Finally, the ability to target NETs therapeutically in human neoplastic disease is highlighted.     

The origin of spontaneous activity in the developing auditory system

Spontaneous activity in the developing auditory system is required for neuronal survival as well as the refinement and maintenance of tonotopic maps in the brain. However, the mechanisms responsible for initiating auditory nerve firing in the absence of sound have not been determined. Here we show that supporting cells in the developing rat cochlea spontaneously release ATP, which causes nearby inner hair cells to depolarize and release glutamate, triggering discrete bursts of action potentials in primary auditory neurons. This endogenous, ATP-mediated signalling synchronizes the output of neighbouring inner hair cells, which may help refine tonotopic maps in the brain. Spontaneous ATP-dependent signalling rapidly subsides after the onset of hearing, thereby preventing this experience-independent activity from interfering with accurate encoding of sound. These data indicate that supporting cells in the organ of Corti initiate electrical activity in auditory nerves before hearing, pointing to an essential role for peripheral, non-sensory cells in the development of central auditory pathways.