Langevin Trajectories between Fixed Concentrations

We consider the trajectories of particles diffusing between two infinite baths of fixed concentrations connected by a channel, e.g. a protein channel of a biological membrane. The steady state influx and efflux of Langevin trajectories at the boundaries of a finite volume containing the channel and parts of the two baths is replicated by termination of outgoing trajectories and injection according to a residual phase space density. We present a simulation scheme that maintains averaged fixed concentrations without creating spurious boundary layers, consistent with the assumed physics

Chiral tunneling and the Klein paradox in graphene

The so-called Klein paradox - unimpeded penetration of relativistic particles through high and wide potential barriers - is one of the most exotic and counterintuitive consequences of quantum electrodynamics (QED). The phenomenon is discussed in many contexts in particle, nuclear and astro- physics but direct tests of the Klein paradox using elementary particles have so far proved impossible. Here we show that the effect can be tested in a conceptually simple condensed-matter experiment by using electrostatic barriers in single- and bi-layer graphene. Due to the chiral nature of their quasiparticles, quantum tunneling in these materials becomes highly anisotropic, qualitatively different from the case of normal, nonrelativistic electrons. Massless Dirac fermions in graphene allow a close realization of Klein's gedanken experiment whereas massive chiral fermions in bilayer graphene offer an interesting complementary system that elucidates the basic physics involved.Comment: 15 pages, 4 figure

Therapeutic DNA vaccine induces broad T cell responses in the gut and sustained protection from viral rebound and AIDS in SIV-infected rhesus macaques.

Immunotherapies that induce durable immune control of chronic HIV infection may eliminate the need for life-long dependence on drugs. We investigated a DNA vaccine formulated with a novel genetic adjuvant that stimulates immune responses in the blood and gut for the ability to improve therapy in rhesus macaques chronically infected with SIV. Using the SIV-macaque model for AIDS, we show that epidermal co-delivery of plasmids expressing SIV Gag, RT, Nef and Env, and the mucosal adjuvant, heat-labile E. coli enterotoxin (LT), during antiretroviral therapy (ART) induced a substantial 2-4-log fold reduction in mean virus burden in both the gut and blood when compared to unvaccinated controls and provided durable protection from viral rebound and disease progression after the drug was discontinued. This effect was associated with significant increases in IFN-γ T cell responses in both the blood and gut and SIV-specific CD8+ T cells with dual TNF-α and cytolytic effector functions in the blood. Importantly, a broader specificity in the T cell response seen in the gut, but not the blood, significantly correlated with a reduction in virus production in mucosal tissues and a lower virus burden in plasma. We conclude that immunizing with vaccines that induce immune responses in mucosal gut tissue could reduce residual viral reservoirs during drug therapy and improve long-term treatment of HIV infection in humans

Impaired perception of facial motion in autism spectrum disorder

Copyright: © 2014 O’Brien et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article has been made available through the Brunel Open Access Publishing Fund.Facial motion is a special type of biological motion that transmits cues for socio-emotional communication and enables the discrimination of properties such as gender and identity. We used animated average faces to examine the ability of adults with autism spectrum disorders (ASD) to perceive facial motion. Participants completed increasingly difficult tasks involving the discrimination of (1) sequences of facial motion, (2) the identity of individuals based on their facial motion and (3) the gender of individuals. Stimuli were presented in both upright and upside-down orientations to test for the difference in inversion effects often found when comparing ASD with controls in face perception. The ASD group’s performance was impaired relative to the control group in all three tasks and unlike the control group, the individuals with ASD failed to show an inversion effect. These results point to a deficit in facial biological motion processing in people with autism, which we suggest is linked to deficits in lower level motion processing we have previously reported

Open-label add-on treatment trial of minocycline in fragile X syndrome

<p>Abstract</p> <p>Background</p> <p>Fragile X syndrome (FXS) is a disorder characterized by a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socio-emotional problems. It is hypothesized that the absence of the fragile X mental retardation protein (FMRP) leads to higher levels of matrix metallo-proteinase-9 activity (MMP-9) in the brain. Minocycline inhibits MMP-9 activity, and alleviates behavioural and synapse abnormalities in <it>fmr1 </it>knockout mice, an established model for FXS. This open-label add-on pilot trial was conducted to evaluate safety and efficacy of minocycline in treating behavioural abnormalities that occur in humans with FXS.</p> <p>Methods</p> <p>Twenty individuals with FXS, ages 13-32, were randomly assigned to receive 100 mg or 200 mg of minocycline daily. Behavioural evaluations were made prior to treatment (baseline) and again 8 weeks after daily minocycline treatment. The primary outcome measure was the Aberrant Behaviour Checklist-Community Edition (ABC-C) Irritability Subscale, and the secondary outcome measures were the other ABC-C subscales, clinical global improvement scale (CGI), and the visual analog scale for behaviour (VAS). Side effects were assessed using an adverse events checklist, a complete blood count (CBC), hepatic and renal function tests, and antinuclear antibody screen (ANA), done at baseline and at 8 weeks.</p> <p>Results</p> <p>The ABC-C Irritability Subscale scores showed significant improvement (p < 0.001), as did the VAS (p = 0.003) and the CGI (p < 0.001). The only significant treatment-related side effects were minor diarrhea (n = 3) and seroconversion to a positive ANA (n = 2).</p> <p>Conclusions</p> <p>Results from this study demonstrate that minocycline provides significant functional benefits to FXS patients and that it is well-tolerated. These findings are consistent with the <it>fmr1 </it>knockout mouse model results, suggesting that minocycline modifies underlying neural defects that account for behavioural abnormalities. A placebo-controlled trial of minocycline in FXS is warranted.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Open-Label Trial NCT00858689.</p

Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1,25-dihydroxyvitamin-D, and prostate cancer:a nested case-control study

Vitamin D pathway single nucleotide polymorphisms (SNPs) are potentially useful proxies for investigating whether circulating vitamin D metabolites [total 25-hydroxyvitamin-D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)2D] are causally related to prostate cancer. We investigated associations of sixteen SNPs across seven genes with prostate-specific antigen-detected prostate cancer

Simulation of the many-body dynamical quantum Hall effect in an optical lattice

We propose an experimental scheme to simulate the many-body dynamical quantum Hall effect with ultra-cold bosonic atoms in a one-dimensional optical lattice. We first show that the required model Hamiltonian of a spin-1/2 Heisenberg chain with an effective magnetic field and tunable parameters can be realized in this system. For dynamical response to ramping the external fields, the quantized plateaus emerge in the Berry curvature of the interacting atomic spin chain as a function of the effective spin-exchange interaction. The quantization of this response in the parameter space with the interaction-induced topological transition characterizes the many-body dynamical quantum Hall effect. Furthermore, we demonstrate that this phenomenon can be observed in practical cold-atom experiments with numerical simulations.Comment: 8 pages, 3 figures; accepted in Quantum Information Processin

Direct and indirect measurement of somatic cell count as indicator of intramammary infection in dairy goats

<p>Abstract</p> <p>Background</p> <p>Mastitis is the most important and costly disease in dairy goat production. Subclinical mastitis is common in goats and is mainly caused by contagious bacteria. Several methods to diagnose subclinical mastitis are available. In this study indirect measurement of somatic cell count (SCC) by California Mastitis Test (CMT) and direct measurement of SCC using a portable deLaval cell counter (DCC) are evaluated. Swedish goat farmers would primarily benefit from diagnostic methods that can be used at the farm. The purpose of the study was to evaluate SCC measured by CMT and DCC as possible markers for intramammary infection (IMI) in goats without clinical symptoms of mastitis. Moreover to see how well indirect measurement of SCC (CMT) corresponded to direct measurement of SCC (DCC).</p> <p>Method</p> <p>Udder half milk samples were collected once from dairy goats (n = 111), in five different farms in Northern and Central Sweden. Only clinically healthy animals were included in the study. All goats were in mid to late lactation at sampling. Milk samples were analyzed for SCC by CMT and DCC at the farm, and for bacterial growth at the laboratory.</p> <p>Results</p> <p>Intramammary infection, defined as growth of udder pathogens, was found in 39 (18%) of the milk samples. No growth was found in 180 (81%) samples while 3 (1%) samples were contaminated. The most frequently isolated bacterial species was coagulase negative staphylococci (CNS) (72% of all isolates), followed by <it>Staphylococcus aureus </it>(23% of all isolates). Somatic cell count measured by DCC was strongly (p = 0.000) associated with bacterial growth. There was also a very strong association between CMT and bacterial growth. CMT 1 was associated with freedom of IMI while CMT ≥2 was associated with IMI. Indirect measurement of SCC by CMT was well correlated with SCC measured by DCC.</p> <p>Conclusions</p> <p>According to the results, SCC measured with CMT or DCC can predict udder infection in goats, and CMT can be used as a predictor of the SCC.</p

HCV IRES manipulates the ribosome to promote the switch from translation initiation to elongation.

The internal ribosome entry site (IRES) of the hepatitis C virus (HCV) drives noncanonical initiation of protein synthesis necessary for viral replication. Functional studies of the HCV IRES have focused on 80S ribosome formation but have not explored its role after the 80S ribosome is poised at the start codon. Here, we report that mutations of an IRES domain that docks in the 40S subunit's decoding groove cause only a local perturbation in IRES structure and result in conformational changes in the IRES-rabbit 40S subunit complex. Functionally, the mutations decrease IRES activity by inhibiting the first ribosomal translocation event, and modeling results suggest that this effect occurs through an interaction with a single ribosomal protein. The ability of the HCV IRES to manipulate the ribosome provides insight into how the ribosome's structure and function can be altered by bound RNAs, including those derived from cellular invaders

A comparison of approximation techniques for variance-based sensitivity analysis of biochemical reaction systems

<p>Abstract</p> <p>Background</p> <p>Sensitivity analysis is an indispensable tool for the analysis of complex systems. In a recent paper, we have introduced a thermodynamically consistent variance-based sensitivity analysis approach for studying the robustness and fragility properties of biochemical reaction systems under uncertainty in the standard chemical potentials of the activated complexes of the reactions and the standard chemical potentials of the molecular species. In that approach, key sensitivity indices were estimated by Monte Carlo sampling, which is computationally very demanding and impractical for large biochemical reaction systems. Computationally efficient algorithms are needed to make variance-based sensitivity analysis applicable to realistic cellular networks, modeled by biochemical reaction systems that consist of a large number of reactions and molecular species.</p> <p>Results</p> <p>We present four techniques, derivative approximation (DA), polynomial approximation (PA), Gauss-Hermite integration (GHI), and orthonormal Hermite approximation (OHA), for <it>analytically </it>approximating the variance-based sensitivity indices associated with a biochemical reaction system. By using a well-known model of the mitogen-activated protein kinase signaling cascade as a case study, we numerically compare the approximation quality of these techniques against traditional Monte Carlo sampling. Our results indicate that, although DA is computationally the most attractive technique, special care should be exercised when using it for sensitivity analysis, since it may only be accurate at low levels of uncertainty. On the other hand, PA, GHI, and OHA are computationally more demanding than DA but can work well at high levels of uncertainty. GHI results in a slightly better accuracy than PA, but it is more difficult to implement. OHA produces the most accurate approximation results and can be implemented in a straightforward manner. It turns out that the computational cost of the four approximation techniques considered in this paper is orders of magnitude smaller than traditional Monte Carlo estimation. Software, coded in MATLAB^®, which implements all sensitivity analysis techniques discussed in this paper, is available free of charge.</p> <p>Conclusions</p> <p>Estimating variance-based sensitivity indices of a large biochemical reaction system is a computationally challenging task that can only be addressed via approximations. Among the methods presented in this paper, a technique based on orthonormal Hermite polynomials seems to be an acceptable candidate for the job, producing very good approximation results for a wide range of uncertainty levels in a fraction of the time required by traditional Monte Carlo sampling.</p