Potential miRNA biomarkers and therapeutic targets for early atherosclerotic lesions

Identification of potential therapeutic targets and biomarkers indicative of burden of early atherosclerosis that occur prior to advancement to life-threatening unstable plaques is the key to eradication of CAD prevalence and incidences. We challenged 16 baboons with a high cholesterol, high fat diet for 2 years and evaluated early-stage atherosclerotic lesions (fatty streaks, FS, and fibrous plaques, FP) in formalin-fixed common iliac arteries (CIA). We used small RNA sequencing to identify expressed miRNAs in CIA and in baseline blood samples of the same animals. We found 412 expressed miRNAs in CIA and 356 in blood samples. Eight miRNAs (miR-7975, -486-5p, -451a, -191-5p, -148a-3p, -17-5p, -378c, and -144-3p) were differentially expressed between paired fatty streak lesion and no-lesion sites of the tissue, and 27 miRNAs (e.g., miR-92a-3p, -5001, -342-3p, miR-28-3p, -21-5p, -221-3p, 146a-5p, and -16-5p) in fibrous plaques. The expression of 14 blood miRNAs significantly correlated with extent of lesions and the number of plaques. We identified coordinately regulated miRNA-gene networks in which miR-17-5p and miR-146a-5p are central hubs and miR-5001 and miR-7975 are potentially novel miRNAs associated with early atherosclerosis. In summary, we have identified miRNAs expressed in lesions and in blood that correlate with lesion burden and are potential therapeutic targets and biomarkers. These findings are a first step in elucidating miRNA regulated molecular mechanisms that underlie early atherosclerosis in a baboon model, enabling translation of our findings to humans

Precessing jets from a moving source and bright X-ray filaments in galaxy clusters

We present hydrodynamical calculations carried out with the 3D yguazu-a code of a precessing jet model, which interacts with a plane parallel wind. This scenario describes an extragalactic jet, in which the jet source is in motion with respect to the surrounding intra-cluster medium. From the numerical results, synthetic emission maps and spectra in X-ray band were obtained. We compare these predictions with observations of the radio jets emanating from the radio-galaxy 4C 26.42 (in the Abell 1795 galaxy cluster). We find that the general morphology of the radio jets can be described by a point-symmetric precessing jet system interacting with a plane parallel wind (i.e., the intra-cluster medium flowing past the galaxy). We also find that our synthetic X-ray emission maps reproduce the observed large scale structures (with sizes of the order of tens of kpc).Comment: Accepted for publication in A&A - 7 Pages, 6 figure

Double-peaked Narrow-Line Signatures of Dual Supermassive Black Holes in Galaxy Merger Simulations

We present a first attempt to model the narrow-line (NL) region of active galactic nuclei (AGN) in hydrodynamic simulations of galaxy mergers, using a novel physical prescription. This model is used to determine the origin of double-peaked NL (dNL) AGN in merging galaxies and their connection to supermassive black hole (SMBH) pairs, motivated by recent observations of such objects. We find that dNL AGN induced by the relative motion of SMBH pairs are a generic but short-lived feature of gaseous major mergers. dNL AGN should often be observed in late-stage mergers, during the kpc-scale phase of SMBH inspiral or soon after the SMBH merger. However, even within the kpc-scale phase, only a minority of dNL AGN are directly induced by SMBH motion; their lifetimes are typically a few Myr. Most double peaks arise from gas kinematics near the SMBH, although prior to the SMBH merger up to 80% of all dNL profiles may be influenced by SMBH motion via altered peak ratios or velocity offsets. The total lifetimes of dNL AGN depend strongly on viewing angle and on properties of the merging galaxies. Also, in a typical merger, at least 10-40% of the double peaks induced by SMBH motion have small projected separations, 0.1-1 kpc, such that dual peaks of stellar surface brightness are not easily resolved. Diffuse tidal features can indicate late-stage galaxy mergers, although they do not distinguish SMBH pairs from merged SMBHs. We show that dNL profiles with peak velocity splittings > 500 km s^-1 or with measurable overall velocity shifts are often associated with SMBH pairs. Our results support the notion that selection of dNL AGN is a promising method for identifying dual SMBH candidates, but demonstrate the critical importance of high-resolution, multi-wavelength follow-up observations, and the use of multiple lines of evidence, for confirming the dual nature of candidate SMBH pairs. (Abridged)Comment: 24 pages, 9 figures. Moderate revisions; accepted to MNRA

RNA Unwinding by NS3 Helicase: A Statistical Approach

The study of double-stranded RNA unwinding by helicases is a problem of basic scientific interest. One such example is provided by studies on the hepatitis C virus (HCV) NS3 helicase using single molecule mechanical experiments. HCV currently infects nearly 3% of the world population and NS3 is a protein essential for viral genome replication. The objective of this study is to model the RNA unwinding mechanism based on previously published data and study its characteristics and their dependence on force, ATP and NS3 protein concentration. In this work, RNA unwinding by NS3 helicase is hypothesized to occur in a series of discrete steps and the steps themselves occurring in accordance with an underlying point process. A point process driven change point model is employed to model the RNA unwinding mechanism. The results are in large agreement with findings in previous studies. A gamma distribution based renewal process was found to model well the point process that drives the unwinding mechanism. The analysis suggests that the periods of constant extension observed during NS3 activity can indeed be classified into pauses and subpauses and that each depend on the ATP concentration. The step size is independent of external factors and seems to have a median value of 11.37 base pairs. The steps themselves are composed of a number of substeps with an average of about 4 substeps per step and an average substep size of about 3.7 base pairs. An interesting finding pertains to the stepping velocity. Our analysis indicates that stepping velocity may be of two kinds- a low and a high velocity

Walks4work: Rationale and study design to investigate walking at lunchtime in the workplace setting

Background: Following recruitment of a private sector company, an 8week lunchtime walking intervention was implemented to examine the effect of the intervention on modifiable cardiovascular disease risk factors, and further to see if walking environment had any further effect on the cardiovascular disease risk factors. Methods. For phase 1 of the study participants were divided into three groups, two lunchtime walking intervention groups to walk around either an urban or natural environment twice a week during their lunch break over an 8week period. The third group was a waiting-list control who would be invited to join the walking groups after phase 1. In phase 2 all participants were encouraged to walk during their lunch break on self-selecting routes. Health checks were completed at baseline, end of phase 1 and end of phase 2 in order to measure the impact of the intervention on cardiovascular disease risk. The primary outcome variables of heart rate and heart rate variability were measured to assess autonomic function associated with cardiovascular disease. Secondary outcome variables (Body mass index, blood pressure, fitness, autonomic response to a stressor) related to cardiovascular disease were also measured. The efficacy of the intervention in increasing physical activity was objectively monitored throughout the 8-weeks using an accelerometer device. Discussion. The results of this study will help in developing interventions with low researcher input with high participant output that may be implemented in the workplace. If effective, this study will highlight the contribution that natural environments can make in the reduction of modifiable cardiovascular disease risk factors within the workplace. © 2012 Brown et al.; licensee BioMed Central Ltd

Influenza nucleoprotein delivered with aluminium salts protects mice from an influenza virus that expresses an altered nucleoprotein sequence

Influenza virus poses a difficult challenge for protective immunity. This virus is adept at altering its surface proteins, the proteins that are the targets of neutralizing antibody. Consequently, each year a new vaccine must be developed to combat the current recirculating strains. A universal influenza vaccine that primes specific memory cells that recognise conserved parts of the virus could prove to be effective against both annual influenza variants and newly emergent potentially pandemic strains. Such a vaccine will have to contain a safe and effective adjuvant that can be used in individuals of all ages. We examine protection from viral challenge in mice vaccinated with the nucleoprotein from the PR8 strain of influenza A, a protein that is highly conserved across viral subtypes. Vaccination with nucleoprotein delivered with a universally used and safe adjuvant, composed of insoluble aluminium salts, provides protection against viruses that either express the same or an altered version of nucleoprotein. This protection correlated with the presence of nucleoprotein specific CD8 T cells in the lungs of infected animals at early time points after infection. In contrast, immunization with NP delivered with alum and the detoxified LPS adjuvant, monophosphoryl lipid A, provided some protection to the homologous viral strain but no protection against infection by influenza expressing a variant nucleoprotein. Together, these data point towards a vaccine solution for all influenza A subtypes

Reducing Bit-Vector Polynomials to SAT using Gröbner Bases

We address the satisfiability of systems of polynomial equations over bit-vectors. Instead of conventional bit-blasting, we exploit word-level inference to translate these systems into non-linear pseudo-boolean constraints. We derive the pseudo-booleans by simulating bit assignments through the addition of (linear) polynomials and applying a strong form of propagation by computing Gröbner bases. By handling bit assignments symbolically, the number of Gröbner basis calculations, along with the number of assignments, is reduced. The final Gröbner basis yields expressions for the bit-vectors in terms of the symbolic bits, together with non-linear pseudo-boolean constraints on the symbolic variables, modulo a power of two. The pseudo-booleans can be solved by translation into classical linear pseudo-boolean constraints (without a modulo) or by encoding them as propositional formulae, for which a novel translation process is described

Paradoxes and Mechanisms for Choice under Risk

Experiments on choice under risk typically involve multiple decisions by individual subjects. The choice of mechanism for selecting decision(s) for payoff is an essential design feature unless subjects isolate each one of the multiple decisions. We report treatments with different payoff mechanisms but the same decision tasks. The data show large differences across mechanisms in subjects’ revealed risk preferences, a clear violation of isolation. We illustrate the importance of these mechanism effects by identifying their implications for classical tests of theories of decision under risk. We discuss theoretical properties of commonly used mechanisms, and new mechanisms introduced herein, in order to clarify which mechanisms are theoretically incentive compatible for which theories. We identify behavioral properties of some mechanisms that can introduce bias in elicited risk preferences – from cross-task contamination – even when the mechanism used is theoretically incentive compatible. We explain that selection of a payoff mechanism is an important component of experimental design in many topic areas including social preferences, public goods, bargaining, and choice under uncertainty and ambiguity as well as experiments on decisions under risk

Bowel associated dermatosis – arthritis syndrome: a case report

We report a rare case of Bowel Associated Dermatosis – Arthritis Syndrome in a young patient with complex Crohn's disease who presented with fever, arthritis, rash and worsening of diarrhea with abdominal pain, who promptly responded to a short course of steroids