Role of electrostatic interactions in amyloid beta-protein (Abeta) oligomer formation: A discrete molecular dynamics study

Pathological folding and oligomer formation of the amyloid beta-protein (Abeta) are widely perceived as central to Alzheimer's disease (AD). Experimental approaches to study Abeta self-assembly are problematic, because most relevant aggregates are quasi-stable and inhomogeneous. We apply a discrete molecular dynamics (DMD) approach combined with a four-bead protein model to study oligomer formation of the amyloid beta-protein (Abeta). We address the differences between the two most common Abeta alloforms, Abeta40 and Abeta42, which oligomerize differently in vitro. We study how the presence of electrostatic interactions (EIs) between pairs of charged amino acids affects Abeta40 and Abeta42 oligomer formation. Our results indicate that EIs promote formation of larger oligomers in both Abeta40 and Abeta42. The Abeta40 size distribution remains unimodal, whereas the Abeta42 distribution is trimodal, as observed experimentally. Abeta42 folded structure is characterized by a turn in the C-terminus that is not present in Abeta40. We show that the same C-terminal region is also responsible for the strongest intermolecular contacts in Abeta42 pentamers and larger oligomers. Our results suggest that this C-terminal region plays a key role in the formation of Abeta42 oligomers and the relative importance of this region increases in the presence of EIs. These results suggest that inhibitors targeting the C-terminal region of Abeta42 oligomers may be able to prevent oligomer formation or structurally modify the assemblies to reduce their toxicity.Comment: Accepted for publication at Biophysical Journa

Spatial prediction of the concentration of selenium (Se) in grain across part of Amhara Region, Ethiopia

Grain and soil were sampled across a large part of Amhara, Ethiopia in a study motivated by prior evidence of selenium (Se) deficiency in the Region's population. The grain samples (teff, Eragrostis tef, and wheat, Triticum aestivum) were analysed for concentration of Se and the soils were analysed for various properties, including Se concentration measured in different extractants. Predictive models for concentration of Se in the respective grains were developed, and the predicted values, along with observed concentrations in the two grains were represented by a multivariate linear mixed model in which selected covariates, derived from remote sensor observations and a digital elevation model, were included as fixed effects. In all modelling steps the selection of predictors was done using false discovery rate control, to avoid over-fitting, and using an α-investment procedure to maximize the statistical power to detect significant relationships by ordering the tests in a sequence based on scientific understanding of the underlying processes likely to control Se concentration in grain. Cross-validation indicated that uncertainties in the empirical best linear unbiased predictions of the Se concentration in both grains were well-characterized by the prediction error variances obtained from the model. The predictions were displayed as maps, and their uncertainty was characterized by computing the probability that the true concentration of Se in grain would be such that a standard serving would not provide the recommended daily allowance of Se. The spatial variation of grain Se was substantial, concentrations in wheat and teff differed but showed the same broad spatial pattern. Such information could be used to target effective interventions to address Se deficiency, and the general procedure used for mapping could be applied to other micronutrients and crops in similar settings

Endothelial Cells Regulate Physiological Cardiomyocyte Growth via VEGFR2-Mediated Paracrine Signaling

Background: Heart failure, which is a major global health problem, is often preceded by pathological cardiac hypertrophy. The expansion of the cardiac vasculature, to maintain adequate supply of oxygen and nutrients, is a key determinant of whether the heart grows in a physiological compensated manner or a pathological decompensated manner. Bidirectional endothelial cell (EC)-cardiomyocyte (CMC) cross talk via cardiokine and angiocrine signaling plays an essential role in the regulation of cardiac growth and homeostasis. Currently, the mechanisms involved in the EC-CMC interaction are not fully understood, and very little is known about the EC-derived signals involved. Understanding how an excess of angiogenesis induces cardiac hypertrophy and how ECs regulate CMC homeostasis could provide novel therapeutic targets for heart failure. Methods: Genetic mouse models were used to delete vascular endothelial growth factor (VEGF) receptors, adeno-associated viral vectors to transduce the myocardium, and pharmacological inhibitors to block VEGF and ErbB signaling in vivo. Cell culture experiments were used for mechanistic studies, and quantitative polymerase chain reaction, microarrays, ELISA, and immunohistochemistry were used to analyze the cardiac phenotypes. Results: Both EC deletion of VEGF receptor (VEGFR)-1 and adeno-associated viral vector-mediated delivery of the VEGFR1-specific ligands VEGF-B or placental growth factor into the myocardium increased the coronary vasculature and induced CMC hypertrophy in adult mice. The resulting cardiac hypertrophy was physiological, as indicated by preserved cardiac function and exercise capacity and lack of pathological gene activation. These changes were mediated by increased VEGF signaling via endothelial VEGFR2, because the effects of VEGF-B and placental growth factor on both angiogenesis and CMC growth were fully inhibited by treatment with antibodies blocking VEGFR2 or by endothelial deletion of VEGFR2. To identify activated pathways downstream of VEGFR2, whole-genome transcriptomics and secretome analyses were performed, and the Notch and ErbB pathways were shown to be involved in transducing signals for EC-CMC cross talk in response to angiogenesis. Pharmacological or genetic blocking of ErbB signaling also inhibited part of the VEGF-B-induced effects in the heart. Conclusions: This study reveals that cross talk between the EC VEGFR2 and CMC ErbB signaling pathways coordinates CMC hypertrophy with angiogenesis, contributing to physiological cardiac growth.</div

Time-integrated luminosity recorded by the BABAR detector at the PEP-II e+e- collider

This article is the Preprint version of the final published artcile which can be accessed at the link below.We describe a measurement of the time-integrated luminosity of the data collected by the BABAR experiment at the PEP-II asymmetric-energy e+e- collider at the ϒ(4S), ϒ(3S), and ϒ(2S) resonances and in a continuum region below each resonance. We measure the time-integrated luminosity by counting e+e-→e+e- and (for the ϒ(4S) only) e+e-→μ+μ- candidate events, allowing additional photons in the final state. We use data-corrected simulation to determine the cross-sections and reconstruction efficiencies for these processes, as well as the major backgrounds. Due to the large cross-sections of e+e-→e+e- and e+e-→μ+μ-, the statistical uncertainties of the measurement are substantially smaller than the systematic uncertainties. The dominant systematic uncertainties are due to observed differences between data and simulation, as well as uncertainties on the cross-sections. For data collected on the ϒ(3S) and ϒ(2S) resonances, an additional uncertainty arises due to ϒ→e+e-X background. For data collected off the ϒ resonances, we estimate an additional uncertainty due to time dependent efficiency variations, which can affect the short off-resonance runs. The relative uncertainties on the luminosities of the on-resonance (off-resonance) samples are 0.43% (0.43%) for the ϒ(4S), 0.58% (0.72%) for the ϒ(3S), and 0.68% (0.88%) for the ϒ(2S).This work is supported by the US Department of Energy and National Science Foundation, the Natural Sciences and Engineering Research Council (Canada), the Commissariat à l’Energie Atomique and Institut National de Physique Nucléaire et de Physiquedes Particules (France), the Bundesministerium für Bildung und Forschung and Deutsche Forschungsgemeinschaft (Germany), the Istituto Nazionale di Fisica Nucleare (Italy), the Foundation for Fundamental Research on Matter (The Netherlands), the Research Council of Norway, the Ministry of Education and Science of the Russian Federation, Ministerio de Ciencia e Innovación (Spain), and the Science and Technology Facilities Council (United Kingdom). Individuals have received support from the Marie-Curie IEF program (European Union) and the A.P. Sloan Foundation (USA)

Detector Description and Performance for the First Coincidence Observations between LIGO and GEO

For 17 days in August and September 2002, the LIGO and GEO interferometer gravitational wave detectors were operated in coincidence to produce their first data for scientific analysis. Although the detectors were still far from their design sensitivity levels, the data can be used to place better upper limits on the flux of gravitational waves incident on the earth than previous direct measurements. This paper describes the instruments and the data in some detail, as a companion to analysis papers based on the first data.Comment: 41 pages, 9 figures 17 Sept 03: author list amended, minor editorial change

Measurement of the B0-anti-B0-Oscillation Frequency with Inclusive Dilepton Events

The $B^0$-$\bar B^0$ oscillation frequency has been measured with a sample of 23 million \B\bar B pairs collected with the BABAR detector at the PEP-II asymmetric B Factory at SLAC. In this sample, we select events in which both B mesons decay semileptonically and use the charge of the leptons to identify the flavor of each B meson. A simultaneous fit to the decay time difference distributions for opposite- and same-sign dilepton events gives $\Delta m_d = 0.493 \pm 0.012{(stat)}\pm 0.009{(syst)}$ ps$^{-1}$.Comment: 7 pages, 1 figure, submitted to Physical Review Letter

Sociocultural considerations in aging men's health: implications and recommendations for the clinician

http://dx.doi.org/10.1016/j.jomh.2009.07.00

Nanoparticles for Applications in Cellular Imaging

In the following review we discuss several types of nanoparticles (such as TiO2, quantum dots, and gold nanoparticles) and their impact on the ability to image biological components in fixed cells. The review also discusses factors influencing nanoparticle imaging and uptake in live cells in vitro. Due to their unique size-dependent properties nanoparticles offer numerous advantages over traditional dyes and proteins. For example, the photostability, narrow emission peak, and ability to rationally modify both the size and surface chemistry of Quantum Dots allow for simultaneous analyses of multiple targets within the same cell. On the other hand, the surface characteristics of nanometer sized TiO2allow efficient conjugation to nucleic acids which enables their retention in specific subcellular compartments. We discuss cellular uptake mechanisms for the internalization of nanoparticles and studies showing the influence of nanoparticle size and charge and the cell type targeted on nanoparticle uptake. The predominant nanoparticle uptake mechanisms include clathrin-dependent mechanisms, macropinocytosis, and phagocytosis

Cosmological Applications of Gravitational Lensing

The last decade has seen an enormous increase of activity in the field of gravitational lensing, mainly driven by improvements of observational capabilities. I will review the basics of gravitational lens theory, just enough to understand the rest of this contribution, and will then concentrate on several of the main applications in cosmology. Cluster lensing, and weak lensing, will constitute the main part of this review.Comment: 26 pages, including 2 figures (a third figure can be obtained from the author by request) gziped and uuencoded postscript file; to be published in Proceedings of the Laredo Advanced Summer School, Sept. 9