Angiotensin mediates renal fibrosis in the nephropathy of glycogen storage disease type Ia

Patients with glycogen storage disease type Ia (GSD-Ia) develop renal disease of unknown etiology despite intensive dietary therapies. This renal disease shares many clinical and pathological similarities to diabetic nephropathy. We studied the expression of angiotensinogen, angiotensin type 1 receptor, transforming growth factor-β1, and connective tissue growth factor in mice with GSD-Ia and found them to be elevated compared to controls. While increased renal expression of angiotensinogen was evident in 2-week-old mice with GSD-Ia, the renal expression of transforming growth factor-β and connective tissue growth factor did not increase for another week; consistent with upregulation of these factors by angiotensin II. The expression of fibronectin and collagens I, III, and IV was also elevated in the kidneys of mice with GSD-Ia, compared to controls. Renal fibrosis was characterized by a marked increase in the synthesis and deposition of extracellular matrix proteins in the renal cortex and histological abnormalities including tubular basement membrane thickening, tubular atrophy, tubular dilation, and multifocal interstitial fibrosis. Our results suggest that activation of the angiotensin system has an important role in the pathophysiology of renal disease in patients with GSD-Ia

Constant Curvature Coefficients and Exact Solutions in Fractional Gravity and Geometric Mechanics

We study fractional configurations in gravity theories and Lagrange mechanics. The approach is based on Caputo fractional derivative which gives zero for actions on constants. We elaborate fractional geometric models of physical interactions and we formulate a method of nonholonomic deformations to other types of fractional derivatives. The main result of this paper consists in a proof that for corresponding classes of nonholonomic distributions a large class of physical theories are modelled as nonholonomic manifolds with constant matrix curvature. This allows us to encode the fractional dynamics of interactions and constraints into the geometry of curve flows and solitonic hierarchies.Comment: latex2e, 11pt, 27 pages, the variant accepted to CEJP; added and up-dated reference

Screening-based discovery of <em>Aspergillus fumigatus </em>plant-type chitinase inhibitors

AbstractA limited therapeutic arsenal against increasing clinical disease due to Aspergillus spp. necessitates urgent characterisation of new antifungal targets. Here we describe the discovery of novel, low micromolar chemical inhibitors of Aspergillus fumigatus family 18 plant-type chitinase A1 (AfChiA1) by high-throughput screening (HTS). Analysis of the binding mode by X-ray crystallography confirmed competitive inhibition and kinetic studies revealed two compounds with selectivity towards fungal plant-type chitinases. These inhibitors provide new chemical tools to probe the effects of chitinase inhibition on A. fumigatus growth and virulence, presenting attractive starting points for the development of further potent drug-like molecules

Subsurface Supergranular Vertical Flows as Measured Using Large Distance Separations in Time-Distance Helioseismology

As large--distance rays (say, 10\,-\,$24 ^\circ$) approach the solar surface approximately vertically, travel times measured from surface pairs for these large separations are mostly sensitive to vertical flows, at least for shallow flows within a few Mm of the solar surface. All previous analyses of supergranulation have used smaller separations and have been hampered by the difficulty of separating the horizontal and vertical flow components. We find that the large separation travel times associated with supergranulation cannot be studied using the standard phase-speed filters of time-distance helioseismology. These filters, whose use is based upon a refractive model of the perturbations, reduce the resultant travel time signal by at least an order of magnitude at some distances. More effective filters are derived. Modeling suggests that the center--annulus travel time difference $[\delta t_{\rm{oi}}]$ in the separation range $\Delta=10$\,-\,$24 ^\circ$ is insensitive to the horizontally diverging flow from the centers of the supergranules and should lead to a constant signal from the vertical flow. Our measurement of this quantity, 5.1 \pm 0.1\secs, is constant over the distance range. This magnitude of signal cannot be caused by the level of upflow at cell centers seen at the photosphere of 10\ms extended in depth. It requires the vertical flow to increase with depth. A simple Gaussian model of the increase with depth implies a peak upward flow of 240\ms at a depth of 2.3\Mm and a peak horizontal flow of 700\ms at a depth of 1.6\Mm.Comment: Solar Physics; 15 pages, 6 figure

Surface-focused Seismic Holography of Sunspots: I. Observations

We present a comprehensive set of observations of the interaction of p-mode oscillations with sunspots using surface-focused seismic holography. Maps of travel-time shifts, relative to quiet-Sun travel times, are shown for incoming and outgoing p modes as well as their mean and difference. We compare results using phase-speed filters with results obtained with filters that isolate single p-mode ridges, and further divide the data into multiple temporal frequency bandpasses. The f mode is removed from the data. The variations of the resulting travel-time shifts with magnetic-field strength and with the filter parameters are explored. We find that spatial averages of these shifts within sunspot umbrae, penumbrae, and surrounding plage often show strong frequency variations at fixed phase speed. In addition, we find that positive values of the mean and difference travel-time shifts appear exclusively in waves observed with phase-speed filters that are dominated by power in the low-frequency wing of the p1 ridge. We assess the ratio of incoming to outgoing p-mode power using the ridge filters and compare surface-focused holography measurements with the results of earlier published p-mode scattering measurements using Fourier-Hankel decomposition.Comment: Solar Physics, accepte

Rho GTPase function in flies: insights from a developmental and organismal perspective.

Morphogenesis is a key event in the development of a multicellular organism and is reliant on coordinated transcriptional and signal transduction events. To establish the segmented body plan that underlies much of metazoan development, individual cells and groups of cells must respond to exogenous signals with complex movements and shape changes. One class of proteins that plays a pivotal role in the interpretation of extracellular cues into cellular behavior is the Rho family of small GTPases. These molecular switches are essential components of a growing number of signaling pathways, many of which regulate actin cytoskeletal remodeling. Much of our understanding of Rho biology has come from work done in cell culture. More recently, the fruit fly Drosophila melanogaster has emerged as an excellent genetic system for the study of these proteins in a developmental and organismal context. Studies in flies have greatly enhanced our understanding of pathways involving Rho GTPases and their roles in development

Finite-time destruction of entanglement and non-locality by environmental influences

Entanglement and non-locality are non-classical global characteristics of quantum states important to the foundations of quantum mechanics. Recent investigations have shown that environmental noise, even when it is entirely local in influence, can destroy both of these properties in finite time despite giving rise to full quantum state decoherence only in the infinite time limit. These investigations, which have been carried out in a range of theoretical and experimental situations, are reviewed here.Comment: 27 pages, 6 figures, review article to appear in Foundations of Physic

Perspectives in Global Helioseismology, and the Road Ahead

We review the impact of global helioseismology on key questions concerning the internal structure and dynamics of the Sun, and consider the exciting challenges the field faces as it enters a fourth decade of science exploitation. We do so with an eye on the past, looking at the perspectives global helioseismology offered in its earlier phases, in particular the mid-to-late 1970s and the 1980s. We look at how modern, higher-quality, longer datasets coupled with new developments in analysis, have altered, refined, and changed some of those perspectives, and opened others that were not previously available for study. We finish by discussing outstanding challenges and questions for the field.Comment: Invited review; to appear in Solar Physics (24 pages, 6 figures