julilili42/papers huggingface dataset:
L-Typ-Kalzium-Kanäle im Hörsystem
2014-09-01

Abstract The voltage-activated L-type calcium channels Ca v 1.2 and Ca v 1.3 mediate Ca 2+ influx into neurons at the soma or at dendrites, whereas they are not observed at the presynapse. Surprisingly, in the inner ear, Ca v 1.3 is indispensable for signal transmission from the cochlear inner hair cells to the postsynaptic auditory nerve fibers. Due to Ca v 1.3 channel clustering at ribbons, i.e. specific presynaptic structures of the hair cells, they promote Ca 2+ influx which triggers calcium-dependent fusion of synaptic vesicles with the plasma membrane. Consequently, mutations in Cacna1d, the gene that encodes Ca v 1.3, cause deafness. Additionally, Ca v 1.3 plays an important part in the central auditory system. Lack of the channel results in severe changes in auditory pathway cytoarchitecture and in abnormal electrophysiological performance of auditory neurons. Furthermore, developmental refinement of tonotopic inhibitory projections in sound localization circuits is disrupted. These aberrations are associated with abnormal sound processing in the auditory pathway. Cacna1d therefore represents a prototypal deafness associated gene, in which mutations result in both peripheral and central auditory deficiencies. This, in turn, has implications for auditory rehabilitation using cochlear implants which address only peripheral dysfunctions. Exploratory research into the closely related Ca v 1.2 isoform points to an important role of this channel in acoustic trauma. Ca v 1.2 is mainly expressed in the auditory nerve, but apparently not essential for normal auditory function. Rather, loss of function of the channel does influence the effects of traumatic noise exposure. Loss of this channel induced by noise trauma results in reduced auditory threshold increase. This phenomenon points to the fact that Ca v 1.2-mediated Ca 2+ influx is involved in noise trauma induced damage. Deeper insight into this function might result in new therapeutic approaches.
Abstract 057: High Salt (NaCl) Reduces The Activation And Function Of Alternatively Activated (M2) Macrophages Via Epigenetic Modifications
2014-09-01

High intake of dietary salt (sodium chloride; NaCl) is attributed to the development of hypertension and cardiovascular disease, and has been proposed to be a cause for the rapid increase in autoimmune diseases in western civilisations. We have recently shown that NaCl has a pro-inflammatory effect and boosts the activation of Th17 cells in vitro, with mice fed a high salt diet having an accelerated and more severe experimental autoimmune encephalomyelitis. In this study, we examine how the activation of alternatively activated (M2) macrophages is affected by NaCl. In stark contrast to our study with Th17 cells, we find that high salt dose-dependently decreased M2 activation in IL-4+IL-13 stimulated BM-derived mouse macrophages. Genes important for M2 activation, including Mrc1, Arg1, Ym1, Fizz1 and PD-L2, all had a blunted expression in the presence of NaCl; an effect which was not observed in tonicity controls (mannitol or urea), implying a specific action of NaCl. Transcription factors important for modulating M2 function (Irf4 and Klf4) were similarly affected. In contrast to our previous findings in Th17 cells, the effect of salt on M2 activation was not mediated via Sgk-1. To explore the mechanism for the effect of NaCl on M2 activation we performed gene expression analysis simultaneously with genome wide epigenetic modification analysis (ChIP-seq for H3K4me3 and H4ac). The results of this revealed that NaCl modulated epigenetic marks at genes important for M2 activation, and additionally identified new genes which were affected. Finally, we asked if these salt-mediated changes in M2 gene profiles, translated into effects on their function. Using an in vitro assay, we found that NaCl-treated M2 macrophages have a reduced ability to suppress the activation of effector T cells. Our study reveals a novel effect of NaCl on M2 activation and function, and gives support to the notion that the modulation of immune cell function by high dietary salt is relevant to hypertension and autoimmune diseases.
L-type calcium channels in the auditory system
2014-09-01

Abstract The voltage-activated L-type calcium channels Cav1.2 and Cav1.3 mediate Ca 2+ influx into neurons at the soma or at dendrites, whereas they are not observed at the presynapse. Surprisingly, in the inner ear, Cav1.3 is indispensable for signal transmission from the presynaptic cochlear inner hair cells to the postsynaptic auditory nerve fibers. Due to Cav1.3 channel clustering at ribbons, i.e., specific presynaptic structures of the hair cells, they promote Ca 2+ influx, which triggers calcium-dependent fusion of synaptic vesicles with the plasma membrane. Mutations in Cacna1d, a gene that encodes Cav1.3, result in deafness because release of the neurotransmitter glutamate at the synapses is abolished. Moreover, studies of the auditory pathway have revealed that Cav1.3 plays an important part in the central auditory system as well. Absence of the channel results in severe changes in auditory pathway cytoarchitecture and in abnormal electrophysiological performance of auditory neurons. Furthermore, developmental refinement of tonotopic inhibitory projections in sound localization circuits is disrupted. These aberrations are associated with abnormal sound processing in the auditory pathway. This goes to show that the Cav1.3 channel is essential for inner ear functioning as well as auditory pathway development and performance. Cacna1d therefore represents a prototypal deafness-associated gene, in which mutations result in both peripheral and central auditory deficiencies. This, in turn, has implications for auditory rehabilitation using cochlear implants that address only peripheral dysfunctions. Exploratory research into the closely related Cav1.2 isoform points to an important role of this channel in acoustic trauma. Cav1.2 is mainly expressed in the auditory nerve, but apparently not essential for normal auditory function. Loss of function of the channel, however, does influence the effects of traumatic noise exposure. Loss of this channel induced by noise trauma results in reduced auditory threshold increase-as compared with the control group. This phenomenon points to the fact that Cav1.2-mediated Ca 2+ influx is involved in noise trauma-induced damage. Deeper insight into this function might result in new therapeutic approaches.
IMPROVEMENT OF OVERALL SURVIVAL WITH PRIMARY BREAST CANCER WITH MICROMESTASES TO THE BONE MARROW BY ADJUVANT CLODRONATE THERAPY
2014-09-01

Supplementation of oral clodronate to postoperative adjuvant treatment for breast cancer (BC) considerably improves overall and relapse-free survival rates. The paper gives the results of a long-term follow-up of patients during a prospective randomized controlled study.Subjects and methods. The study included patients with primary BC receiving clodronate in a dose of 1600 mg/day in combination with the conventional adjuvant therapy for BC.Results. An analysis of 290 of 302 patients indicated a significant increase in overall survival in the clodronate group at a median fol- low-up of 103±12 months; during 8.5 years after primary surgical treatment, 20.4% and 40.7% of patients died in the clodronate and control groups, respectively (p = 0.04). The clodronate group did not show a considerable reduction in the rate of metastatic lesions in the bone and visceral organs or an increase in the relapse-free period following 36- and 55-month follow-ups.Conclusions. The findings of better late overall survival rates confirm the results of earlier studies of oral clodronate in combination with the conventional adjuvant therapy for BC.
Event-related alpha suppression in response to facial motion
2014-09-01

While biological motion refers to both face and body movements, little is known about the visual perception of facial motion.We therefore examined alpha wave suppression as a reduction in power is thought to reflect visual activity, in addition to attentional reorienting and memory processes.Nineteen neurologically healthy adults were tested on their ability to discriminate between successive facial motion captures.These animations exhibited both rigid and non-rigid facial motion, as well as speech expressions.The structural and surface appearance of these facial animations did not differ, thus participants decisions were based solely on differences in facial movements.Upright, orientation-inverted and luminanceinverted facial stimuli were compared.At occipital and parieto-occipital regions, upright facial motion evoked a transient increase in alpha which was then followed by a significant reduction.This finding is discussed in terms of neural efficiency, gating mechanisms and neural synchronization.Moreover, there was no difference in the amount of alpha suppression evoked by each facial stimulus at occipital regions, suggesting early visual processing remains unaffected by manipulation paradigms.However, upright facial motion evoked greater suppression at parieto-occipital sites, and did so in the shortest latency.Increased activity within this region may reflect higher attentional reorienting to natural facial motion but also involvement of areas associated with the visual control of body effectors.
Daylight Vision Repair by Cell Transplantation
2014-09-02

Abstract Human daylight vision depends on cone photoreceptors and their degeneration results in visual impairment and blindness as observed in several eye diseases including age-related macular degeneration, cone-rod dystrophies, or late stage retinitis pigmentosa, with no cure available. Preclinical cell replacement approaches in mouse retina have been focusing on rod dystrophies, due to the availability of sufficient donor material from the rod-dominated mouse retina, leaving the development of treatment options for cone degenerations not well studied. Thus, an abundant and traceable source for donor cone-like photoreceptors was generated by crossing neural retina leucine zipper-deficient (Nrl−/−) mice with an ubiquitous green fluorescent protein (GFP) reporter line resulting in double transgenic tg(Nrl−/−; aGFP) mice. In Nrl−/− retinas, all rods are converted into cone-like photoreceptors that express CD73 allowing their enrichment by CD73-based magnetic activated cell sorting prior transplantation into the subretinal space of adult wild-type, cone-only (Nrl−/−), or cone photoreceptor function loss 1 (Cpfl1) mice. Donor cells correctly integrated into host retinas, acquired mature photoreceptor morphology, expressed cone-specific markers, and survived for up to 6 months, with significantly increased integration rates in the cone-only Nrl−/− retina. Individual retinal ganglion cell recordings demonstrated the restoration of photopic responses in cone degeneration mice following transplantation suggesting, for the first time, the feasibility of daylight vision repair by cell replacement in the adult mammalian retina. Stem Cells 2015;33:79–90
Competing Salt Effects on Phase Behavior of Protein Solutions: Tailoring of Protein Interaction by the Binding of Multivalent Ions and Charge Screening
2014-09-02

The phase behavior of protein solutions is affected by additives such as crowder molecules or salts. In particular, upon addition of multivalent counterions, a reentrant condensation can occur; i.e., protein solutions are stable for low and high multivalent ion concentrations but aggregating at intermediate salt concentrations. The addition of monovalent ions shifts the phase boundaries to higher multivalent ion concentrations. This effect is found to be reflected in the protein interactions, as accessed via small-angle X-ray scattering. Two simulation schemes (a Monte Carlo sampling of the counterion binding configurations using the detailed protein structure and an analytical coarse-grained binding model) reproduce the shifts of the experimental phase boundaries. The results support a consistent picture of the protein interactions responsible for the phase behavior. The repulsive Coulomb interaction is varied by the binding of multivalent counterions and additionally screened by any increase of the ionic strength. The attractive interaction is induced by the binding of multivalent ions, most likely due to ion bridging between protein molecules. The overall picture of these competing interactions provides interesting insight into possible mechanisms for tailoring interactions in solutions via salt effects.
ballaxy: web services for structural bioinformatics
2014-09-02

Abstract Motivation: Web-based workflow systems have gained considerable momentum in sequence-oriented bioinformatics. In structural bioinformatics, however, such systems are still relatively rare; while commercial stand-alone workflow applications are common in the pharmaceutical industry, academic researchers often still rely on command-line scripting to glue individual tools together. Results: In this work, we address the problem of building a web-based system for workflows in structural bioinformatics. For the underlying molecular modelling engine, we opted for the BALL framework because of its extensive and well-tested functionality in the field of structural bioinformatics. The large number of molecular data structures and algorithms implemented in BALL allows for elegant and sophisticated development of new approaches in the field. We hence connected the versatile BALL library and its visualization and editing front end BALLView with the Galaxy workflow framework. The result, which we call ballaxy, enables the user to simply and intuitively create sophisticated pipelines for applications in structure-based computational biology, integrated into a standard tool for molecular modelling. Availability and implementation: ballaxy consists of three parts: some minor modifications to the Galaxy system, a collection of tools and an integration into the BALL framework and the BALLView application for molecular modelling. Modifications to Galaxy will be submitted to the Galaxy project, and the BALL and BALLView integrations will be integrated in the next major BALL release. After acceptance of the modifications into the Galaxy project, we will publish all ballaxy tools via the Galaxy toolshed. In the meantime, all three components are available from http://www.ball-project.org/ballaxy . Also, docker images for ballaxy are available at https://registry.hub.docker.com/u/anhi/ballaxy/dockerfile/ . ballaxy is licensed under the terms of the GPL. Supplementary information : Supplementary data are available at Bioinformatics online. Contact: anna.hildebrandt@bioinf.uni-sb.de or andreas.hildebrandt@uni-mainz.de
Impact of response evaluation for resectable esophageal adenocarcinoma – A retrospective cohort study
2014-09-02

After preoperative chemotherapy, outcomes of esophageal carcinoma are best predicted utilizing pathological tumor stage and histologic tumor regression. Clinical response assessments were not useful for guidance of treatment.
Change of Measure
2014-09-02

In finance, derivative instruments such as options, swaps or futures can be used for both hedging and speculation purposes. The theory of mathematical finance is one of the most successful applications of probability theory, Black-Scholes model is concerned with an economy consisting of two assets such as a risky asset and a risk-free asset. Trading strategy and self-financing trading strategy form the basis of creating a martingale framework to price a contingent claim. Girsanov's theorem is especially important in the theory of financial mathematics as it tells how to convert from the physical measure to the risk-neutral measure. In contrast, the converse of Girsanov's theorem says that every equivalent measure is given by a change in drift. Thus, by changing the measure it is equivalent to changing the drift and hence in the Black-Scholes model there is only one equivalent risk-neutral measure.
General Probability Theory
2014-09-02

Probability theory is a branch of mathematics that deals with mathematical models of trials whose outcomes depend on chance. This chapter reviews some basic concepts of the probability theory that are needed to begin solving stochastic calculus problems. The set of all possible outcomes of an experiment is called the sample space. Any subset of the sample space is known as an event. The collection of events can be defined as a subcollection. The chapter focuses on an approach to probability which is a branch of measure theory. The reason for taking a measure-theoretic path is that it leads to a unified treatment of both discrete and continuous random variables, as well as a general definition of conditional expectation. The conditional expectation is extremely important in probability theory and also for its wide application in mathematical finance such as pricing options and other derivative products.
Stochastic Differential Equations
2014-09-02

A stochastic differential equation (SDE) is a differential equation in which one or more of the terms has a random component. SDEs are frequently used to model diverse phenomena such as stock prices, interest rates or volatilities to name but a few. They have continuous paths with both random and non-random components and to drive the random component of the model they usually incorporate a Wiener process. Random fluctuations are employed in conjunction with the Wiener process, such as the Poisson process when modelling discontinuous jumps. This chapter focuses on the SDEs having only the Wiener process. The theory of SDEs is a framework for expressing the dynamical models that include both the random and non-random components. The chapter also focuses on Feynman-Kac theorem that describes an important link between stochastic differential equations and partial differential equations.
Lenalidomide and Dexamethasone in Transplant-Ineligible Patients with Myeloma
2014-09-03

The combination melphalan-prednisone-thalidomide (MPT) is considered a standard therapy for patients with myeloma who are ineligible for stem-cell transplantation. However, emerging data on the use of lenalidomide and low-dose dexamethasone warrant a prospective comparison of the two approaches.
A Cautious Note on Auxiliary Variables That Can Increase Bias in Missing Data Problems
2014-09-03

The treatment of missing data in the social sciences has changed tremendously during the last decade. Modern missing data techniques such as multiple imputation and full-information maximum likelihood are used much more frequently. These methods assume that data are missing at random. One very common approach to increase the likelihood that missing at random is achieved consists of including many covariates as so-called auxiliary variables. These variables are either included based on data considerations or in an inclusive fashion; that is, taking all available auxiliary variables. In this article, we point out that there are some instances in which auxiliary variables exhibit the surprising property of increasing bias in missing data problems. In a series of focused simulation studies, we highlight some situations in which this type of biasing behavior can occur. We briefly discuss possible ways how one can avoid selecting bias-inducing covariates as auxiliary variables.
Theory and Analysis of Total, Direct, and Indirect Causal Effects
2014-09-03

Mediation analysis, or more generally models with direct and indirect effects, are commonly used in the behavioral sciences. As we show in our illustrative example, traditional methods of mediation analysis that omit confounding variables can lead to systematically biased direct and indirect effects, even in the context of a randomized experiment. Therefore, several definitions of causal effects in mediation models have been presented in the literature (Baron & Kenny, 1986 ; Imai, Keele, & Tingley, 2010 ; Pearl, 2012 ). We illustrate the stochastic theory of causal effects as an alternative foundation of causal mediation analysis based on probability theory. In this theory we define total, direct, and indirect effects and show how they can be identified in the context of our illustrative example. A particular strength of the stochastic theory of causal effects are the causality conditions that imply causal unbiasedness of effect estimates. The causality conditions have empirically testable implications and can be used for covariate selection. In the discussion, we highlight some similarities and differences of the stochastic theory of causal effects with other theories of causal effects.
A Novel Multivalent OspA Vaccine against Lyme Borreliosis Is Safe and Immunogenic in an Adult Population Previously Infected with Borrelia burgdorferi Sensu Lato
2014-09-03

ABSTRACT Lyme borreliosis (LB) patients who recover, as well as previously infected asymptomatic individuals, remain vulnerable to reinfection with Borrelia burgdorferi sensu lato . There is limited information available about the use of OspA vaccines in this population. In this study, a randomized double-blind phase I/II trial was performed to investigate the safety and immunogenicity of a novel multivalent OspA vaccine in healthy adults who were either seronegative or seropositive for previous B. burgdorferi sensu lato infection. The participants received three monthly priming immunizations with either 30 μg or 60 μg alum-adjuvanted OspA antigen and a booster vaccination either 6 months or 9 to 12 months after the first immunization. The antibody responses to the six OspA serotypes included in the vaccine were evaluated. Adverse events were predominantly mild and transient and were similar in the seronegative and seropositive populations. Substantial enzyme-linked immunosorbent assay (ELISA) and surface-binding antibody responses against all six OspA antigens were induced after the primary immunization schedule in both populations, and they were substantially increased with both booster schedules. The antibody responses induced by the two doses were similar in the seronegative population, but there was a significant dose response in the seropositive population. These data indicate that the novel multivalent OspA vaccine is well tolerated and immunogenic in individuals previously infected with B. burgdorferi sensu lato . (This study is registered at ClinicalTrials.gov under registration no. NCT01504347.)
Random Mutagenesis of the Multidrug Transporter AcrB from Escherichia coli for Identification of Putative Target Residues of Efflux Pump Inhibitors
2014-09-03

ABSTRACT Efflux is an important mechanism of bacterial multidrug resistance (MDR), and the inhibition of MDR pumps by efflux pump inhibitors (EPIs) could be a promising strategy to overcome MDR. 1-(1-Naphthylmethyl)-piperazine (NMP) and phenylalanine-arginine-β-naphthylamide (PAβN) are model EPIs with activity in various Gram-negative bacteria expressing AcrB, the major efflux pump of Escherichia coli , or similar homologous pumps of the resistance-nodulation-cell division class. The aim of the present study was to generate E. coli AcrB mutants resistant to the inhibitory action of the two model EPIs and to identify putative EPI target residues in order to better understand mechanisms of pump inhibition. Using an in vitro random mutagenesis approach focusing on the periplasmic domain of AcrB, we identified the double mutation G141D N282Y, which substantially compromised the synergistic activity of NMP with linezolid, was associated with similar intracellular linezolid concentrations in the presence and absence of NMP, and did not impair the intrinsic MICs of various pump substrates and dye accumulation. We propose that these mutations near the outer face of the distal substrate binding pocket reduce NMP trapping. Other residues found to be relevant for efflux inhibition by NMP were G288 and A279, but mutations at these sites also changed the susceptibility to several pump substrates. Unlike with NMP, we were unable to generate AcrB periplasmic domain mutants with resistance or partial resistance to the EPI activity of PAβN, which is consistent with the modes of action of PAβN differing from those of NMP.