A 1-acetamido derivative of 6-epi-valienamine: an inhibitor of a diverse group of β-N-acetylglucosaminidases

The synthesis of an analogue of 6-epi-valienamine bearing an acetamido group and its characterisation as an inhibitor of β-N-acetylglucosaminidases are described. The compound is a good inhibitor of both human O-GlcNAcase and human β-hexosaminidase, as well as two bacterial β-N-acetylglucosaminidases. A 3-D structure of the complex of Bacteroides thetaiotaomicron BtGH84 with the inhibitor shows the unsaturated ring is surprisingly distorted away from its favoured solution phase conformation and reveals potential for improved inhibitor potency

Use of the parabiotic model in studies of cutaneous wound healing to define the participation of circulating cells

Previous experimental studies to assess the contribution of blood-borne circulating (BBC) cells to cutaneous wound healing have relied on discontinuous pulsing of labeled BBC elements or bone marrow transplant protocols. Such approaches do not allow the examination of stable BBC cells that have matured in a physiologically normal host. We have used a parabiotic murine model for cutaneous wound healing to evaluate the relative contribution of stable populations of peripheral blood cells expressing the green fluorescent protein (GFP) transgene in otherwise normal animals. Circulating cells (mature and immature) expressing the GFP transgene were easily detected and quantified in wounds of GFP− parabiotic twins during all evaluated stages of the healing response. Using multiple antibody probes, the relative contribution of various subsets of BBC cells could be comparatively assessed. In early wounds, some cells expressing mesenchymal epitopes were documented to be of hematopoietic origin, indicating the utility of this model in assessing cell plasticity in the context of tissue regeneration and repair. Application of this approach enables further investigation into the contribution of peripheral blood in normal and abnormal healing responses.National Institutes of Health (U.S.) (NIH 5 T32 HL007627- 22 Physician-Scientist Training Grant)National Institutes of Health (U.S.) (NIH/NIDDK (5 P30 DK36836-20))Brigham and Women’s Hospital (Program in Dermatopathology core grant (SDRC))National Institutes of Health. (U.S.). Department of Health and Human Services (Brigham and Women’s Hospital’s Program in Dermatopathology core grant (SPORE)

Osteopontin Mediates Obesity-Induced Adipose Tissue Macrophage Infiltration and Insulin Resistance in Mice

Obesity is associated with a state of chronic, low-grade inflammation characterized by abnormal cytokine production and macrophage infiltration into adipose tissue, which may contribute to the development of insulin resistance. During immune responses, tissue infiltration by macrophages is dependent on the expression of osteopontin, an extracellular matrix protein and proinflammatory cytokine that promotes monocyte chemotaxis and cell motility. In the present study, we used a murine model of diet-induced obesity to examine the role of osteopontin in the accumulation of adipose tissue macrophages and the development of insulin resistance during obesity. Mice exposed to a high-fat diet exhibited increased plasma osteopontin levels, with elevated expression in macrophages recruited into adipose tissue. Obese mice lacking osteopontin displayed improved insulin sensitivity in the absence of an effect on diet-induced obesity, body composition, or energy expenditure. These mice further demonstrated decreased macrophage infiltration into adipose tissue, which may reflect both impaired macrophage motility and attenuated monocyte recruitment by stromal vascular cells. Finally, obese osteopontin-deficient mice exhibited decreased markers of inflammation, both in adipose tissue and systemically. Taken together, these results suggest that osteopontin may play a key role in linking obesity to the development of insulin resistance by promoting inflammation and the accumulation of macrophages in adipose tissue

Statistical characterisation of full-disk EUV/XUV solar irradiance and correlation with solar activity

We investigate the distribution of fluctuations in solar irradiance when integrated over the full disk, obtained using extreme ultraviolet/soft X-ray observations from the SOHO CELIAS/SEM instrument. This time series sums over both the contributions of single distinguishable flares, and of many other processes. By detrending we select events with timescales of less than a few hours such as waves, slow flows, and CMEs. The statistics generated by this range of phenomena can be characterised by power-law-tailed distributions. We show that (i) during the high-activity period 2000 Jan-June the tail exponent a(T)=1.5 +/- 0.1; (ii) during the low-activity period 1996 Jan-June a(T)=3.0 +/- 0.2; and (iii) in general a(T) decreases with increasing activity.Comment: 4 pages, 5 figures; v.2 R-squared goodness of fits adde

Deep learning based pipeline for fingerprinting using brain functional MRI connectivity data

In this work we describe an appropriate pipeline for using deep-learning as a form of improving the brain functional connectivity-based fingerprinting process which is based in functional Magnetic Resonance Imaging (fMRI) data-processing results. This pipeline approach is mostly intended for neuroscientists, biomedical engineers, and physicists that are looking for an easy form of using fMRI-based Deep-Learning in identifying people, drastic brain alterations in those same people, and/or pathologic consequences to people’s brains. Computer scientists and engineers can also gain by noticing the data-processing improvements obtained by using the here-proposed pipeline. With our best approach, we obtained an average accuracy of 0.3132 ± 0.0129 and an average validation cost of 3.1422 ± 0.0668, which clearly outperformed the published Pearson correlation approach performance with a 50 Nodes parcellation which had an accuracy of 0.237.Thanks to Eduarda Sousa for support. NFL was supported by a fellowship of the project MEDPERSYST - POCI-01-0145-FEDER-016428, funded by Portugal’s FCT. This work was also supported by NORTE-01-0145-FEDER-000013, and NORTE 2020 under the Portugal 2020 Partnership Agreement through the FEDER, plus it was funded by the European Commission (FP7) “SwitchBox - Maintaining health in old age through homeostasis” (Contract HEALTH-F2-2010-259772), and co-financed by the Portuguese North Regional Operational Program (ON.2 – O Novo Norte), under the QREN through FEDER, and by the “Fundação Calouste Gulbenkian” (Portugal) (Contract grant number: P-139977; project “TEMPO - Better mental health during ageing based on temporal prediction of individual brain ageing trajectories”). We gratefully acknowledge the support of the NVIDIA Corporation with their donation of a Quadro P6000 board used in this research. This work was also supported by COMPETE: POCI-01-0145-FEDER-007043 and FCT within the Project Scope: UID/CEC/00319/2013.info:eu-repo/semantics/publishedVersio

Tema Con Variazioni: Quantum Channel Capacity

Channel capacity describes the size of the nearly ideal channels, which can be obtained from many uses of a given channel, using an optimal error correcting code. In this paper we collect and compare minor and major variations in the mathematically precise statements of this idea which have been put forward in the literature. We show that all the variations considered lead to equivalent capacity definitions. In particular, it makes no difference whether one requires mean or maximal errors to go to zero, and it makes no difference whether errors are required to vanish for any sequence of block sizes compatible with the rate, or only for one infinite sequence.Comment: 32 pages, uses iopart.cl

Extracellular Hsp72 concentration relates to a minimum endogenous criteria during acute exercise-heat exposure

Extracellular heat-shock protein 72 (eHsp72) concentration increases during exercise-heat stress when conditions elicit physiological strain. Differences in severity of environmental and exercise stimuli have elicited varied response to stress. The present study aimed to quantify the extent of increased eHsp72 with increased exogenous heat stress, and determine related endogenous markers of strain in an exercise-heat model. Ten males cycled for 90 min at 50% O2peak in three conditions (TEMP, 20°C/63% RH; HOT, 30.2°C/51%RH; VHOT, 40.0°C/37%RH). Plasma was analysed for eHsp72 pre, immediately post and 24-h post each trial utilising a commercially available ELISA. Increased eHsp72 concentration was observed post VHOT trial (+172.4%) (P<0.05), but not TEMP (-1.9%) or HOT (+25.7%) conditions. eHsp72 returned to baseline values within 24hrs in all conditions. Changes were observed in rectal temperature (Trec), rate of Trec increase, area under the curve for Trec of 38.5°C and 39.0°C, duration Trec ≥ 38.5°C and ≥ 39.0°C, and change in muscle temperature, between VHOT, and TEMP and HOT, but not between TEMP and HOT. Each condition also elicited significantly increasing physiological strain, described by sweat rate, heart rate, physiological strain index, rating of perceived exertion and thermal sensation. Stepwise multiple regression reported rate of Trec increase and change in Trec to be predictors of increased eHsp72 concentration. Data suggests eHsp72 concentration increases once systemic temperature and sympathetic activity exceeds a minimum endogenous criteria elicited during VHOT conditions and is likely to be modulated by large, rapid changes in core temperature

Temporal blastemal cell gene expression analysis in the kidney reveals new Wnt and related signaling pathway genes to be essential for Wilms' tumor onset

Wilms' tumors (WTs) originate from metanephric blastema cells that are unable to complete differentiation, resulting in triphasic tumors composed of epithelial, stromal and blastemal cells, with the latter harboring molecular characteristics similar to those of the earliest kidney development stages. Precise regulation of Wnt and related signaling pathways has been shown to be crucial for correct kidney differentiation. In this study, the gene expression profile of Wnt and related pathways was assessed in laser-microdissected blastemal cells in WTs and differentiated kidneys, in human and in four temporal kidney differentiation stages (i.e. E15.5, E17.5, P1.5 and P7.5) in mice, using an orthologous cDNA microarray platform. A signaling pathway-based gene signature was shared between cells of WT and of earliest kidney differentiation stages, revealing genes involved in the interruption of blastemal cell differentiation in WT. Reverse transcription-quantitative PCR showed high robustness of the microarray data demonstrating 75 and 56% agreement in the initial and independent sample sets, respectively. The protein expression of CRABP2, IGF2, GRK7, TESK1, HDGF, WNT5B, FZD2 and TIMP3 was characterized in WTs and in a panel of human fetal kidneys displaying remarkable aspects of differentiation, which was recapitulated in the tumor. Taken together, this study reveals new genes candidate for triggering WT onset and for therapeutic treatment targets