The role of the disulfide bond in the interaction of islet amyloid polypeptide with membranes

Human islet amyloid polypeptide (hIAPP) forms amyloid fibrils in pancreatic islets of patients with type 2 diabetes mellitus. It has been suggested that the N-terminal part, which contains a conserved intramolecular disulfide bond between residues 2 and 7, interacts with membranes, ultimately leading to membrane damage and β-cell death. Here, we used variants of the hIAPP1–19 fragment and model membranes of phosphatidylcholine and phosphatidylserine (7:3, molar ratio) to examine the role of this disulfide in membrane interactions. We found that the disulfide bond has a minor effect on membrane insertion properties and peptide conformational behavior, as studied by monolayer techniques, 2H NMR, ThT-fluorescence, membrane leakage, and CD spectroscopy. The results suggest that the disulfide bond does not play a significant role in hIAPP–membrane interactions. Hence, the fact that this bond is conserved is most likely related exclusively to the biological activity of IAPP as a hormone

Measurement of the 2νββ decay half-life of 150Nd and a search for 0νββ decay processes with the full exposure from the NEMO-3 detector

We present results from a search for neutrinoless double-β (0νββ) decay using 36.6 g of the isotope 150Nd with data corresponding to a live time of 5.25 y recorded with the NEMO-3 detector. We construct a complete background model for this isotope, including a measurement of the two-neutrino double-β decay half-life of T2ν 1=2 ¼ ½9.34 0.22ðstatÞ þ0.62 −0.60 ðsystÞ × 1018 y for the ground state transition, which represents the most precise result to date for this isotope. We perform a multivariate analysis to search for 0νββ decays in order to improve the sensitivity and, in the case of observation, disentangle the possible underlying decay mechanisms. As no evidence for 0νββ decay is observed, we derive lower limits on half-lives for several mechanisms involving physics beyond the standard model. The observed lower limit, assuming light Majorana neutrino exchange mediates the decay, is T0ν 1=2 > 2.0 × 1022 y at the 90% C.L., corresponding to an upper limit on the effective neutrino mass of hmνi < 1.6–5.3 eV

RNA Interference Mediated Inhibition of Dengue Virus Multiplication and Entry in HepG2 Cells

Background: Dengue virus-host cell interaction initiates when the virus binds to the attachment receptors followed by endocytic internalization of the virus particle. Successful entry into the cell is necessary for infection initiation. Currently, there is no protective vaccine or antiviral treatment for dengue infection. Targeting the viral entry pathway has become an attractive therapeutic strategy to block infection. This study aimed to investigate the effect of silencing the GRP78 and clathrin-mediated endocytosis on dengue virus entry and multiplication into HepG2 cells. Methodology/Principal Findings: HepG2 cells were transfected using specific siRNAs to silence the cellular surface receptor (GRP78) and clathrin-mediated endocytosis pathway. Gene expression analysis showed a marked down-regulation of the targeted genes (87.2%, 90.3%, and 87.8 % for GRP78, CLTC, and DNM2 respectively) in transfected HepG2 cells when measured by RT-qPCR. Intracellular and extracellular viral RNA loads were quantified by RT-qPCR to investigate the effect of silencing the attachment receptor and clathrin-mediated endocytosis on dengue virus entry. Silenced cells showed a significant reduction of intracellular (92.4%) and extracellular viral RNA load (71.4%) compared to non-silenced cells. Flow cytometry analysis showed a marked reduction of infected cells (89.7%) in silenced HepG2 cells compared to non-silenced cells. Furthermore, the ability to generate infectious virions using the plaque assay was reduced 1.07 log in silenced HepG2 cells

Climate-driven range extension of Amphistegina (protista, foraminiferida) : models of current and predicted future ranges

© The Author(s), 2013. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS ONE 8 (2013): e54443, doi:10.1371/journal.pone.0054443.Species-range expansions are a predicted and realized consequence of global climate change. Climate warming and the poleward widening of the tropical belt have induced range shifts in a variety of marine and terrestrial species. Range expansions may have broad implications on native biota and ecosystem functioning as shifting species may perturb recipient communities. Larger symbiont-bearing foraminifera constitute ubiquitous and prominent components of shallow water ecosystems, and range shifts of these important protists are likely to trigger changes in ecosystem functioning. We have used historical and newly acquired occurrence records to compute current range shifts of Amphistegina spp., a larger symbiont-bearing foraminifera, along the eastern coastline of Africa and compare them to analogous range shifts currently observed in the Mediterranean Sea. The study provides new evidence that amphisteginid foraminifera are rapidly progressing southwestward, closely approaching Port Edward (South Africa) at 31°S. To project future species distributions, we applied a species distribution model (SDM) based on ecological niche constraints of current distribution ranges. Our model indicates that further warming is likely to cause a continued range extension, and predicts dispersal along nearly the entire southeastern coast of Africa. The average rates of amphisteginid range shift were computed between 8 and 2.7 km year−1, and are projected to lead to a total southward range expansion of 267 km, or 2.4° latitude, in the year 2100. Our results corroborate findings from the fossil record that some larger symbiont-bearing foraminifera cope well with rising water temperatures and are beneficiaries of global climate change.This work was supported by grants from the German Science Foundation (DFG; www.dfg.de) to ML and SL (LA 884/10-1, LA 884/5-1)

Genome-wide association study identifies multiple risk loci for renal cell carcinoma

Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10−10), 3p22.1 (rs67311347, P=2.5 × 10−8), 3q26.2 (rs10936602, P=8.8 × 10−9), 8p21.3 (rs2241261, P=5.8 × 10−9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10−8), 11q22.3 (rs74911261, P=2.1 × 10−10) and 14q24.2 (rs4903064, P=2.2 × 10−24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility

The mistery of Gustave Flaubert's death: could sudden unexpected death in epilepsy be part of the context? O mistério da morte de Gustave Flaubert: pode a morte súbita em epilepsia fazer parte o contexto?

Epilepsy is the most common serious neurological condition and sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Information concerning risk factors for SUDEP is conflicting, but high seizure frequency is a potential risk factor. Additionally, potential pathomechanisms for SUDEP are unknown, but it is very probable that cardiac arrhythmias during and between seizures or transmission of epileptic activity to the heart via the autonomic nervous system potentially play a role. More than two decades ago, temporal lobe epilepsy was suggested as having been the ''nervous disease'' of Gustave Flaubert, one of the most important French novelists. In these lines, as the circumstances of his death were the subject of fabulous and mysterious speculations, we postulated in this paper that Falubert' death could be due SUDEP phenomenon.<br>A epilepsia é a condição neurológica crônica grave mais comum e a morte súbita em epilepsia (SUDEP) é a mais importante causa de morte diretamente relacionada à epilepsia. Informações sobre fatores de risco para SUDEP são conflitantes, porém, a alta freqüência de crises epilépticas é um fator de risco em potencial. Além disso, os mecanismos causais para SUDEP ainda não estão conhecidos, mas é muito provável que arritmias cardíacas durante e entre as crises epilépticas ou a transmissão da atividade epiléptica para o coração via sistema nervoso autônomo desempenhem um importante papel. Mais de duas décadas atrás, foi proposto que a "doença nervosa" de Gustave Flaubert, um dos mais importantes novelistas franceses, era epilepsia do lobo temporal. Nesse sentido, como a morte de Gustave Flaubert ainda seja motivo de misteriosa especulação, nosso artigo propõe que a mesma poderia estar relacionada ao fenômeno de SUDEP