Diabetes impairs wound healing by Dnmt1-dependent dysregulation of hematopoietic stem cells differentiation towards macrophages

People with type 2 diabetes mellitus (T2DM) have a 25-fold higher risk of limb loss than non-diabetics due in large part to impaired wound healing. Here, we show that the impaired wound healing phenotype found in T2D mice is recapitulated in lethally irradiated wild type recipients, whose hematopoiesis is reconstituted with hematopoietic stem cells (HSCs) from T2D mice, indicating an HSC-autonomous mechanism. This impaired wound healing phenotype of T2D mice is due to a Nox-2-dependent increase in HSC oxidant stress that decreases microRNA let-7d-3p, which, in turn, directly upregulates Dnmt1, leading to the hypermethylation of Notch1, PU.1, and Klf4. This HSC-autonomous mechanism reduces the number of wound macrophages and skews their polarization towards M1 macrophages. These findings reveal a novel inflammatory mechanism by which a metabolic disorder induces an epigenetic mechanism in HSCs, which predetermines the gene expression of terminally differentiated inflammatory cells that controls their number and function

First simultaneous optical/near-infrared imaging of an X-ray selected, high-redshift cluster of galaxies with GROND: the galaxy population of XMMU J0338.7+0030 at z=1.1

The XMM-Newton Distant Cluster Project is a serendipitous survey for clusters of galaxies at redshifts z>=0.8 based on deep archival XMM-Newton observations. ... Low-significance candidate high-z clusters are followed up with the seven-channel imager GROND (Gamma-Ray Burst Optical and Near-Infrared Detector) that is mounted at a 2m-class telescope. ... The test case is XMMU J0338.7+0030, suggested to be at z~1.45+/-0.15 from the analysis of the z-H vs H colour-magnitude diagram obtained from the follow-up imaging. Later VLT-FORS2 spectroscopy enabled us to identify four members, which set this cluster at z=1.097+/-0.002. To reach a better knowledge of its galaxy population, we observed XMMU J0338.7+0030 with GROND for about 6 hr. The publicly available photo-z code le Phare was used. The Ks-band number counts of the non-stellar sources out of the 832 detected down to z'~26 AB-mag in the 3.9x4.3 square arcmin region of XMMU J0338.7+0030 imaged at all GROND bands clearly exceed those computed in deep fields/survey areas at ~20.5 - 22.5 AB-mag. The photo-z's of the three imaged spectroscopic members yield z=1.12+/-0.09. The spatial distribution and the properties of the GROND sources with a photo-z in the range 1.01 - 1.23 confirm the correspondence of the X-ray source with a galaxy over-density at a significance of at least 4.3 sigma. Candidate members that are spectro-photometrically classified as elliptical galaxies define a red locus in the i'-z' vs z' colour-magnitude diagram that is consistent with the red sequence of the cluster RDCS J0910+5422 at z=1.106. XMMU J0338.7+0030 hosts also a population of bluer late-type spirals and irregulars. The starbursts among the photometric members populate both loci, consistently with previous results. The analysis of the available data set indicates that XMMU J0338.7+0030 is a low-mass cluster (M_200 ~ 1E14 M_sun) at z=1.1. (Abridged)Comment: accepted for publication in Astronomy & Astrophysics Main Journal, 27 pages, 24 figures, 1 tabl

Conformational Preferences of the Full Chicken Prion Protein in Solution and Its Differences with Respect to Mammals

We investigate the conformations of the full chicken prion protein (ChPrP1-267) in solution at neutral pH with molecular dynamics simulations. We focus on the persistence of its secondary structure motifs using a recently proposed protein chirality indicator [A. Pietropaolo et al. , Proteins 2008, 70, 667–677]. From this, we find a high rigidity of helix 2 (ChPrP178-195) and of the hexarepeat domain, which is turn rich, and a plasticity of the short b-sheet, consistent with the available NMR structural details. We also determine the extent of solvation for each residue, revealing local minima for such structured regions. These features hint at a possible origin of the high resistance to proteolysis of the avian prion proteins and of its capability in preventing the aggregation in comparison to mammals