BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension (PAH)

YesPulmonary Arterial Hypertension (PAH) is a devastating cardiovascular disorder characterised by the remodelling of pre-capillary pulmonary arteries. The vascular remodelling observed in PAH patients results from excessive proliferation and apoptosis resistance of pulmonary arterial smooth muscle (PASMCs) and endothelial cells (PAECs). We have previously demonstrated that mutations in the type II receptor for bone morphogenetic protein (BMPRII) underlie the majority of the familial and inherited forms of the disease. We have further demonstrated that BMPRII deficiency promotes excessive proliferation and attenuates apoptosis in PASMCs, but the underlying mechanisms remain unclear. The major objective of this study is to investigate how BMPRII deficiency impairs apoptosis in PAH. Using multidisciplinary approaches, we demonstrate that deficiency in the expression of BMPRII impairs apoptosis by modulating the alternative splicing of the apoptotic regulator, Bcl-x (B-cell lymphoma X) transcripts: a finding observed in circulating leukocytes and lungs of PAH subjects, hypoxia-induced PAH rat lungs as well as in PASMCs and PAECs. BMPRII deficiency elicits cell specific effects: promoting the expression of Bcl-xL transcripts in PASMCs whilst inhibiting it in ECs, thus exerting differential apoptotic effects in these cells. The pro-survival effect of BMPRII receptor is mediated through the activin receptor like kinase 1 (ALK1) but not the ALK3 receptor. Finally, we show that BMPRII interacts with the ALK1 receptor and pathogenic mutations in the BMPR2 gene abolish this interaction. Taken together, dysfunctional BMPRII responsiveness impairs apoptosis via the BMPRII-ALK1-Bcl-xL pathway in PAH. We suggest Bcl-xL as a potential biomarker and druggable target.This work was supported by a fellowship (awarded to MTN) from the Department of Health via the NIHR Comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London, Heptagon Life Science Proof of Concept Fund (grant KCL24 to MTN), the Great Britain Sasakawa Foundation (grant B70 to MTN), the Royal Society (grant 43049 to MTN), the Medical Research Council (grant G900865 to RCT, MTN and NWM) and the University of Bradford (grants 003200, 66006/001NAS and DH005 to MTN). NS and MYB were supported by scholarships from the Commonwealth Scholarship Commission, UK and Scientific and Technological Research Council of Turkey (TUBITAK), respectively

Early stage morphology of quench condensed Ag, Pb and Pb/Ag hybrid films

Scanning Tunneling Microscopy (STM) has been used to study the morphology of Ag, Pb and Pb/Ag bilayer films fabricated by quench condensation of the elements onto cold (T=77K), inert and atomically flat Highly Oriented Pyrolytic Graphite (HOPG) substrates. All films are thinner than 10 nm and show a granular structure that is consistent with earlier studies of QC films. The average lateral diameter, $\bar {2r}$, of the Ag grains, however, depends on whether the Ag is deposited directly on HOPG ($\bar {2r}$ = 13 nm) or on a Pb film consisting of a single layer of Pb grains ($\bar {2r}$ = 26.8 nm). In addition, the critical thickness for electrical conduction ($d_{G}$) of Pb/Ag films on inert glass substrates is substantially larger than for pure Ag films. These results are evidence that the structure of the underlying substrate exerts an influence on the size of the grains in QC films. We propose a qualitative explanation for this previously unencountered phenomenon.Comment: 11 pages, 3 figures and one tabl

Fraction-score: a generalized support measure for weighted and maximal co-location pattern mining

Co-location patterns, which capture the phenomenon that objects with certain labels are often located in close geographic proximity, are defined based on a support measure which quantifies the prevalence of a pattern candidate in the form of a label set. Existing support measures share the idea of counting the number of instances of a given label set C as its support, where an instance of C is an object set whose objects collectively carry all labels in C and are located close to one another. However, they suffer from various weaknesses, e.g., fail to capture all possible instances, or overlook the cases when multiple instances overlap. In this paper, we propose a new measure called Fraction-Score which counts instances fractionally if they overlap. Fraction-Score captures all possible instances, and handles the cases where instances overlap appropriately (so that the supports defined are more meaningful and anti-monotonic). We develop efficient algorithms to solve the co-location pattern mining problem defined with Fraction-Score. Furthermore, to obtain representative patterns, we develop an efficient algorithm for mining the maximal co-location patterns, which are those patterns without proper superset patterns. We conduct extensive experiments using real and synthetic datasets, which verified the superiority of our proposals

Exact soliton solution and inelastic two-soliton collision in spin chain driven by a time-dependent magnetic field

We investigate dynamics of exact N-soliton trains in spin chain driven by a time-dependent magnetic field by means of an inverse scattering transformation. The one-soliton solution indicates obviously the spin precession around the magnetic field and periodic shape-variation induced by the time varying field as well. In terms of the general soliton solutions N-soliton interaction and particularly various two-soliton collisions are analyzed. The inelastic collision by which we mean the soliton shape change before and after collision appears generally due to the time varying field. We, moreover, show that complete inelastic collisions can be achieved by adjusting spectrum and field parameters. This may lead a potential technique of shape control of soliton.Comment: 5 pages, 5 figure

Responding to a Community's Concern: A Comparison of Breast Cancer Characteristics and Initial Treatment in Three Selected North Carolina Counties

BACKGROUND A 2007 national report identified North Carolina's Edgecombe County as having among the highest breast cancer incidence and mortality rates nationally, motivating the initiation of a task force and other local efforts to address the problem. The goal of this study is to examine county breast cancer characteristics before and after the report, including whether geographic variation may mask racial disparities in this majority African American community. METHOD With guidance from community partners, breast cancer cases from 2000 to 2012 in Edgecombe, Nash, and Orange Counties (N = 2,641) were obtained from the North Carolina Central Cancer Registry. Bivariate and trend analyses of tumor and treatment characteristics were examined by county and race. RESULTS Women in Edgecombe and Nash Counties were diagnosed with more advanced stage, higher grade tumors. African Americans in Edgecombe and Nash Counties were diagnosed with advanced disease more often than African Americans in Orange County. Average time-to-treatment was well within guideline recommendations. Incidence and mortality rates appear to have declined, with variation in measures of racial differences over time. LIMITATIONS Changes in coding standards across the observation period required reliance on coarse measures that may partially mute useful findings. CONCLUSIONS Racial disparities remain a concern in North Carolina; however, they appear to be less profound than in the 2007 national report. The portentous statistics in the report represent an all-time high, after which some, but not all, measures reflect positive change amidst ongoing local efforts to improve breast cancer knowledge and care

On the spherical-axial transition in supernova remnants

A new law of motion for supernova remnant (SNR) which introduces the quantity of swept matter in the thin layer approximation is introduced. This new law of motion is tested on 10 years observations of SN1993J. The introduction of an exponential gradient in the surrounding medium allows to model an aspherical expansion. A weakly asymmetric SNR, SN1006, and a strongly asymmetric SNR, SN1987a, are modeled. In the case of SN1987a the three observed rings are simulated.Comment: 19 figures and 14 pages Accepted for publication in Astrophysics & Space Science in the year 201

Magnetothemopower study of quasi two-dimensional organic conductor α\alpha-(BEDT-TTF)2_2KHg(SCN)4_4

We have used a low-frequency magneto-thermopower (MTEP) method to probe the high magnetic field ground state behavior of $\alpha$-(BEDT-TTF)$_2$KHg(SCN)$_4$ along all three principal crystallographic axes at low temperatures. The thermopower tensor coefficients ($S_{xx}, S_{yx}$ and $S_{zz}$) have been measured to 30 T, beyond the anomalous low temperature, field-induced transition at 22.5 T. We find a significant anisotropy in the MTEP signal, and also observe large quantum oscillations associated with the de Haas - van Alphen effect. The anisotropy indicates that the ground state properties are clearly driven by mechanisms that occur along specific directions for the in-plane electronic structure. Both transverse and longitudinal magnetothermopower show asymptotic behavior in field, which can be explained in terms of magnetic breakdown of compensated closed orbits.Comment: 9 pages, 10 figure

Simulating (electro)hydrodynamic effects in colloidal dispersions: smoothed profile method

Previously, we have proposed a direct simulation scheme for colloidal dispersions in a Newtonian solvent [Phys.Rev.E 71,036707 (2005)]. An improved formulation called the ``Smoothed Profile (SP) method'' is presented here in which simultaneous time-marching is used for the host fluid and colloids. The SP method is a direct numerical simulation of particulate flows and provides a coupling scheme between the continuum fluid dynamics and rigid-body dynamics through utilization of a smoothed profile for the colloidal particles. Moreover, the improved formulation includes an extension to incorporate multi-component fluids, allowing systems such as charged colloids in electrolyte solutions to be studied. The dynamics of the colloidal dispersions are solved with the same computational cost as required for solving non-particulate flows. Numerical results which assess the hydrodynamic interactions of colloidal dispersions are presented to validate the SP method. The SP method is not restricted to particular constitutive models of the host fluids and can hence be applied to colloidal dispersions in complex fluids

Magnetothermal Conductivity of Highly Oriented Pyrolytic Graphite in the Quantum Limit

We report on the magnetic field (0T$\le B \le 9$T) dependence of the longitudinal thermal conductivity $\kappa(T,B)$ of highly oriented pyrolytic graphite in the temperature range 5 K $\le T\le$ 20 K for fields parallel to the $c-$axis. We show that $\kappa(T,B)$ shows large oscillations in the high-field region (B > 2 T) where clear signs of the Quantum-Hall effect are observed in the Hall resistance. With the measured longitudinal electrical resistivity we show that the Wiedemann-Franz law is violated in the high-field regime.Comment: 4 Figures, to be published in Physical Review B (2003

The evolution of microstructure and electrical performance in doped Mn-Co and Cu-Mn oxide layers with the extended oxidation time

Mn-Co and Cu-Mn based alloy coatings are deposited on 430 SS by high energy micro-arc alloying process, and then alloy coatings are oxidized at 750 ℃ in air to form the spinel oxides. Some composite oxides, such as Co3O4, Mn2O3 and (Mn,Co)3O4, are formed at the initial stage of oxidation. The single-phase spinel (pure MnCo2O4) without impurity phases is only found on the surface of Co-33Mn-17Cu oxide layer with the extended oxidation time, its area-specific resistance values at 500 ℃ to 800 ℃ are low and close to that of Mn-35Cu oxide layer which mainly composed of Cu1.2Mn1.8O4 spinel