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Progressive multiple sclerosis (MS) is characterized by unrelenting neurodegeneration, which causes cumulative disability and is refractory to current treatments. Drug development to prevent disease progression is an urgent clinical need yet is constrained by an incomplete understanding of its complex pathogenesis. Using spatial transcriptomics and proteomics on fresh-frozen human MS brain tissue, we identified multicellular mechanisms of progressive MS pathogenesis and traced their origin in relation to spatially distributed stages of neurodegeneration. By resolving ligand-receptor interactions in local microenvironments, we discovered defunct trophic and anti-inflammatory intercellular communications within areas of early neuronal decline. Proteins associated with neuronal damage in patient samples showed mechanistic concordance with published in vivo knockdown and central nervous system (CNS) disease models, supporting their causal role and value as potential therapeutic targets in progressive MS. Our findings provide a new framework for drug development strategies, rooted in an understanding of the complex cellular and signaling dynamics in human diseased tissue that facilitate this debilitating disease.

The tumor microenvironment (TME) plays a pivotal role in cancer progression, and, in ovarian cancer (OvCa), the primary TME is the omentum. Here, we show that the diabetes drug metformin alters mesothelial cells in the omental microenvironment. Metformin interrupts bidirectional signaling between tumor and mesothelial cells by blocking OvCa cell TGF-β signaling and mesothelial cell production of CCL2 and IL-8. Inhibition of tumor-stromal crosstalk by metformin is caused by the reduced expression of the tricarboxylic acid (TCA) enzyme succinyl CoA ligase (SUCLG2). Through repressing this TCA enzyme and its metabolite, succinate, metformin activated prolyl hydroxylases (PHDs), resulting in the degradation of hypoxia-inducible factor 1α (HIF1α) in mesothelial cells. Disruption of HIF1α-driven IL-8 signaling in mesothelial cells by metformin results in reduced OvCa invasion in an organotypic 3D model. These findings indicate that tumor-promoting signaling between mesothelial and OvCa cells in the TME can be targeted using metformin.

The Helicobacter pylori protein CagA (cytotoxin-associated gene A) is associated with an increased risk for gastric cancer formation. After attachment to epithelial cells, the bacteria inject CagA via a type IV secretion apparatus into host cells, where it exerts its biological activity. Host cell responses to intracellular CagA have been linked exclusively to signaling motifs in the C terminus of the CagA protein. Little is known about the functional role of the remaining CagA protein. Using transgenic expression of CagA mutants in epithelial cells, we were able to identify a novel CagA inhibitory domain at the N terminus consisting of the first 200 amino acids. This domain localizes to cell-cell contacts and increases the rate and strength of cell-cell adhesion in epithelial cells. Thus, it compensates for the loss of cell-cell adhesion induced by the C terminus of the CagA protein. Consistent with its stabilizing role on cell-cell adhesion, the CagA N terminus domain reduces the CagA-induced β-catenin transcriptional activity in the nucleus. Furthermore, it inhibits apical surface constriction and cell elongations, host cell phenotypes induced by the C terminus in polarized epithelia. Therefore, our study suggests that CagA contains an intrinsic inhibitory domain that reduces host cell responses to CagA, which have been associated with the formation of cancer.

As humans become more and more sedentary, physical capacities also become lost along with aerobic fitness, muscular strength, coordination, and action-reaction time. This situation can lead to not only absence from work (back pain is the most common reason in European Union (EU), but especially, workplace accidents. In this article we want to combine our experience with exercise physiology and physical capacities with our medical work in a critical environment. We tested over ten years, the fitness profile of 1200 Italian Alpine Soldiers, and gave them a scientific training program. We obtained a trained and homogeneous team (homogeneous, in terms of aerobic and anaerobic fitness). Here, we detail changes to aerobic and anaerobic fitness that occurred as a result of soldiers' participation in a training program. We consider this method necessary for safe work in a critical environment. © 2020 PAGEPress Publications. All rights reserved.

Global Proprioceptive Resonance (GPR) is a recently developed approach conceived to solicit the various cutaneous mechanoreceptors, through application of mechanical multifocal vibration at low amplitude and at definite body sites, limiting the stimulation of the profound structures. This interventional study evaluated the effects of GPR on cardiorespiratory function during the post-exertional recovery period. A group of volunteers involved in Triathlon (a multisport discipline consisting of sequential swim, cycle, and run disciplines higly demanding in terms of metabolic engagment), underwent two maximal incremental exercise tests until exhaustion followed alternatively to (a) a 13 minutes section of GPR or (b) a standard low intensity exercise acute trend of the same duration. These effects of these two approaches were compared in terms of recovery of: heart rate (HR), respiratory rate (RR), peripheral oxygen saturation (SpO2) and venous lactate concentration (Lac). The physiological parameters (HR, RR, SpO2 and Lac) recorded in the pre-exertion session showed similar values between the 40 volunteers while several differences were recorded in the post-exertion phase. After 6 min of GPR recovery it was recorded a drop in RR below baseline (19.4±4.15 min-1 vs. 12.2± 0.4 min-1; p

Recently, extracellular RNases of the RNase A superfamily, with the characteristic CKxxNTF sequence signature, have been identified in fish. This has led to the recognition that these RNases are present in the whole vertebrate subphylum. In fact, they comprise the only enzyme family unique to vertebrates. Four RNases from zebrafish (Danio rerio) have been previously reported and have a very low RNase activity; some of these are endowed, like human angiogenin, with powerful angiogenic and bactericidal activities. In the present paper, we report the three-dimensional structure, the thermodynamic behaviour and the biological properties of a novel zebrafish RNase, ZF-RNase-5. The investigation of its structural and functional properties, extended to all other subfamily members, provides an inclusive description of the whole zebrafish RNase subfamily.