A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3)

To identify susceptibility loci for classical Hodgkin's lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL, odds ratio (OR) = 1.22, combined P = 1.91 × 10(-8)), 8q24.21 (rs2019960, PVT1, OR = 1.33, combined P = 1.26 × 10(-13)) and 10p14 (rs501764, GATA3, OR = 1.25, combined P = 7.05 × 10(-8)). Furthermore, we confirmed the role of the major histocompatibility complex in disease etiology by revealing a strong human leukocyte antigen (HLA) association (rs6903608, OR = 1.70, combined P = 2.84 × 10(-50)). These data provide new insight into the pathogenesis of cHL.     

Synthetic alpha-synuclein fibrils cause mitochondrial impairment and selective dopamine neurodegeneration in part via iNOS-mediated nitric oxide production

Intracellular accumulation of α-synuclein (α-syn) are hallmarks of synucleinopathies, including Parkinson’s disease (PD). Exogenous addition of preformed α-syn fibrils (PFFs) into primary hippocampal neurons induced α-syn aggregation and accumulation. Likewise, intrastriatal inoculation of PFFs into mice and non-human primates generates Lewy bodies and Lewy neurites associated with PD-like neurodegeneration. Herein, we investigate the putative effects of synthetic human PFFs on cultured rat ventral midbrain dopamine (DA) neurons. A time- and dose-dependent accumulation of α-syn was observed following PFFs exposure that also underwent phosphorylation at serine 129. PFFs treatment decreased the expression levels of synaptic proteins, caused alterations in axonal transport-related proteins, and increased H2AX Ser139 phosphorylation. Mitochondrial impairment (including modulation of mitochondrial dynamics-associated protein content), enhanced oxidative stress, and an inflammatory response were also detected in our experimental paradigm. In attempt to unravel a potential molecular mechanism of PFFs neurotoxicity, the expression of inducible nitric oxide synthase was blocked; a significant decline in protein nitration levels and protection against PFFs-induced DA neuron death were observed. Combined exposure to PFFs and rotenone resulted in an additive toxicity. Strikingly, many of the harmful effects found were more prominent in DA rather than non-DA neurons, suggestive of higher susceptibility to degenerate. These findings provide new insights into the role of α-syn in the pathogenesis of PD and could represent a novel and valuable model to study DA-related neurodegeneration.     

Numerical study of unsteady cavitation on 2D NACA0015 hydrofoil using free/open source software

The free/open source software as OpenFOAM, Salome meshing and python language under Debian Linux system are evaluated to model unsteady cavitating turbulent flow around a NACA0015 hydrofoil. Based on the cavitation model proposed by Kunz and large eddy simu- lation （LES） method, we denote the benefits of free software and open source tools as an alternative to proprietary software of computational fluid mechanics, and provided a modified cavitation model to improve numerical accuracy. The simulation results of typical break-off cycle for cavitation shedding are compared to available experimental data, and validated using image processing to find percentage of similarities. The sheet cavity frequency of 7.752 Hz was obtained based on cavitation evolution and pressure fluctuations. The study gives relevant information for CFD software development in the future.     

Reconstructing Native American population history

The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved. One contentious issue is whether the settlement occurred by means of a single migration or multiple streams of migration from Siberia. The pattern of dispersals within the Americas is also poorly understood. To address these questions at a higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. Here we show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call 'First American'. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan speakers on both sides of the Panama isthmus, who have ancestry from both North and South America.     

The circumsporozoite protein is an immunodominant protective antigen in irradiated sporozoites

Malaria infection starts when mosquitoes inject sporozoites into the skin. The parasites enter the blood stream and make their way to the liver where they develop into the exo-erythrocytic forms (EEFs). Immunization with irradiated sporozoites (IrSp) leads to robust protection against malaria infection in rodents, monkeys and humans by eliciting antibodies to circumsporozoite protein (CS) that inhibit sporozoite infectivity, and T cells that destroy the EEFs. To study the role of non-CS antigens in protection, we produced CS transgenic mice that were tolerant to CS T-cell epitopes. Here we show that in the absence of T-cell-dependent immune responses to CS, protection induced by immunization with two doses of IrSp was greatly reduced. Thus, although hundreds of other Plasmodium genes are expressed in sporozoites and EEFs, CS is a dominant protective antigen. Nevertheless, sterile immunity could be obtained by immunization of CS transgenics with three doses of IrSp.     

尿激酶体外抑制人体免疫缺损病毒的侵染能力

人体免疫缺损病毒的包膜蛋白gp120的V3环区包含一段在人类蛋白质中很少出现的高度保守序列，但这段序列与纤溶酶原被纤溶酶原激活剂酶切位点附近序列有同源性．由于V3环区在人体免疫缺损病毒侵染细胞过程中的重要性，评估了尿激酶对人体免疫缺损病毒侵染能力的影响．通过检测逆转录酶活力，P24抗原的表达和合胞体形成情况发现尿激酶可以抑制人体免疫缺损病毒对多种淋巴瘤和白血病细胞系，如MT4、CCM、H9和外周血单核细胞的侵染能力，并且这种抑制与尿激酶浓度呈剂量依赖关系．那些能够被尿激酶抑制的人体免疫缺损病毒株其V3环区序列必须与纤溶酶原激活区亭列同源，实验事常用病毒株包括BRU和RF以及某些野生病毒株．研究结果显示尿激酶在体外实验中可以抑制人体免疫缺损病毒的侵染能力．     

Locating Highly Connected Nodes in P2P Networks with Heterogeneous Structures

Peer-to-peer (P2P) networks aggregate enormous storage and processing resources while minimizing entry and scaling costs. Gnutella-like P2P networks are complex heterogeneous networks, in which the underlying overlay topology has a power-law node degree distribution. While scale-free networks have great robustness against random failures, they are vulnerable to deliberate attacks where highly connected nodes are eliminated. Since high degree nodes play an important role in maintaining the connectivity, this paper presents an algorithm based on random walks to locate high degree nodes in P2P networks. Simulations demonstrate that the algorithm performs well in various scenarios and that heterogeneous P2P networks are very sensitive to deliberate attacks.     

Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia

Chuvash polycythemia is an autosomal recessive disorder that is endemic to the mid-Volga River region. We previously mapped the locus associated with Chuvash polycythemia to chromosome 3p25. The gene associated with von Hippel-Lindau syndrome, VHL, maps to this region, and homozygosity with respect to a C-->T missense mutation in VHL, causing an arginine-to-tryptophan change at amino-acid residue 200 (Arg200Trp), was identified in all individuals affected with Chuvash polycythemia. The protein VHL modulates the ubiquitination and subsequent destruction of hypoxia-inducible factor 1, subunit alpha (HIF1alpha). Our data indicate that the Arg200Trp substitution impairs the interaction of VHL with HIF1alpha, reducing the rate of degradation of HIF1alpha and resulting in increased expression of downstream target genes including EPO (encoding erythropoietin), SLC2A1 (also known as GLUT1, encoding solute carrier family 2 (facilitated glucose transporter), member 1), TF (encoding transferrin), TFRC (encoding transferrin receptor (p90, CD71)) and VEGF (encoding vascular endothelial growth factor).     

Electrical discharge from a thundercloud top to the lower ionosphere

For over a century, numerous undocumented reports have appeared about unusual large-scale luminous phenomena above thunderclouds and, more than 80 years ago, it was suggested that an electrical discharge could bridge the gap between a thundercloud and the upper atmosphere. Since then, two classes of vertically extensive optical flashes above thunderclouds have been identified-sprites and blue jets. Sprites initiate near the base of the ionosphere, develop very rapidly downwards at speeds which can exceed 107 m s-1 (ref. 15), and assume many different geometrical forms. In contrast, blue jets develop upwards from cloud tops at speeds of the order of 105 m s-1 and are characterized by a blue conical shape. But no experimental data related to sprites or blue jets have been reported which conclusively indicate that they establish a direct path of electrical contact between a thundercloud and the lower ionosphere. Here we report a video recording of a blue jet propagating upwards from a thundercloud to an altitude of about 70 km, taken at the Arecibo Observatory, Puerto Rico. Above an altitude of 42 km-normally the upper limit for blue jets and the lower terminal altitude for sprites-the flash exhibited some features normally observed in sprites. As we observed this phenomenon above a relatively small thunderstorm cell, we speculate that it may be common and therefore represent an unaccounted for component of the global electric circuit.