ISG15 protects human Tregs from interferon alpha-induced contraction in a cell-intrinsic fashion

Objectives: Type I interferons (IFNs) inhibit regulatory T-cell (Treg) expansion and activation, making them beneficial in antiviral responses, but detrimental in autoimmune diseases. Herein, we investigate the role of ISG15 in human Tregs in the context of refractoriness to type I IFN stimulation. Methods: ISG15 expression and Treg dynamics were analysed in vitro and ex vivo from patients with chronic hepatitis C, with lupus and ISG15 deficiency. Results: ISG15 is expressed at high levels in human Tregs, renders them refractory to the IFN-STAT1 signal, and protects them from IFN-driven contraction. In vitro, Tregs from healthy controls upregulate ISG15 upon activation to higher levels than conventional CD4 T cells, and ISG15-silenced Tregs are more susceptible to IFNα-induced contraction. In human ISG15 deficiency, patient Tregs display an elevated IFN signature relative to Tregs from healthy control. In vivo, in patients with chronic hepatitis C, 2 days after starting pegIFN/ribavirin therapy, a stronger ISG15 inducibility correlates with a milder Treg depletion. Ex vivo, in systemic lupus erythematosus patients, higher levels of ISG15 are associated to reduced STAT1 phosphorylation in response to IFNα, and also to increased frequencies of Tregs, characterising active disease. Conclusion: Our results reveal a Treg-intrinsic role of ISG15 in dictating their refractoriness to the IFN signal, thus preserving the Treg population under inflammatory conditions

Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer

Tregs can contribute to tumor progression by suppressing antitumor immunity. Exceptionally, in human colorectal cancer (CRC), Tregs are thought to exert beneficial roles in controlling pro-tumor chronic inflammation. The goal of our study was to characterize CRC-infiltrating Tregs at multiple levels, by phenotypical, molecular and functional evaluation of Tregs from the tumor site, compared to non-tumoral mucosa and peripheral blood of CRC patients. The frequency of Tregs was higher in mucosa than in blood, and further significantly increased in tumor. Ex vivo, those Tregs suppressed the proliferation of tumor-infiltrating CD8(+) and CD4(+) T cells. A differential compartmentalization was detected between Helioshigh and Helios(low) Treg subsets (thymus-derived versus peripherally induced): while Helios(low) Tregs were enriched in both sites, only Helios(high) Tregs accumulated significantly and specifically in tumors, displayed a highly demethylated TSDR region and contained high proportions of cells expressing CD39 and OX40, markers of activation and suppression. Besides the suppression of T cells, Tregs may contribute to CRC progression also through releasing IL-17, or differentiating into Tfr cells that potentially antagonize a protective Tfh response, events that were both detected in tumor-associated Tregs. Overall, our data indicate that Treg accumulation may contribute through multiple mechanisms to CRC establishment and progression

The global impact of non-communicable diseases on macro-economic productivity: a systematic review

© 2015, The Author(s). Non-communicable diseases (NCDs) have large economic impact at multiple levels. To systematically review the literature investigating the economic impact of NCDs [including coronary heart disease (CHD), stroke, type 2 diabetes mellitus (DM), cancer (lung, colon, cervical and breast), chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)] on macro-economic productivity. Systematic search, up to November 6th 2014, of medical databases (Medline, Embase and Google Scholar) without language restrictions. To identify additional publications, we searched the reference lists of retrieved studies and contacted authors in the field. Randomized controlled trials, cohort, case–control, cross-sectional, ecological studies and modelling studies carried out in adults (>18 years old) were included. Two independent reviewers performed all abstract and full text selection. Disagreements were resolved through consensus or consulting a third reviewer. Two independent reviewers extracted data using a predesigned data collection form. Main outcome measure was the impact of the selected NCDs on productivity, measured in DALYs, productivity costs, and labor market participation, including unemployment, return to work and sick leave. From 4542 references, 126 studies met the inclusion criteria, many of which focused on the impact of more than one NCD on productivity. Breast cancer was the most common (n = 45), followed by stroke (n = 31), COPD (n = 24), colon cancer (n = 24), DM (n = 22), lung cancer (n = 16), CVD (n = 15), cervical cancer (n = 7) and CKD (n = 2). Four studies were from the WHO African Region, 52 from the European Region, 53 from the Region of the Americas and 16 from the Western Pacific Region, one from the Eastern Mediterranean Region and none from South East Asia. We found large regional differences in DALYs attributable to NCDs but especially for cervical and lung cancer. Productivity losses in the USA ranged from 88 million US dollars (USD) for COPD to 20.9 billion USD for colon cancer. CHD costs the Australian economy 13.2 billion USD per year. People with DM, COPD and survivors of breast and especially lung cancer are at a higher risk of reduced labor market participation. Overall NCDs generate a large impact on macro-economic productivity in most WHO regions irrespective of continent and income. The absolute global impact in terms of dollars and DALYs remains an elusive challenge due to the wide heterogeneity in the included studies as well as limited information from low- and middle-income countries.WHO; Nestle´ Nutrition (Nestec Ltd.); Metagenics Inc.; and AX

Path planning for underwater information gathering based on genetic algorithms and data stochastic models

Recent technological developments have paved the way to the employment of Autonomous Underwater Vehicles (AUVs) for monitoring and exploration activities of marine environments. Traditionally, in information gathering scenarios for monitoring purposes, AUVs follow predefined paths that are not efficient in terms of information content and energy consumption. Informative Path Planning (IPP) represents a valid alternative, defining the path that maximises the gathered information. This work proposes a Genetic Path Planner (GPP), which consists in an IPP strategy based on a Genetic Algorithm, with the aim of generating a path that simultaneously maximises the information gathered and the coverage of the inspected area. The proposed approach has been tested offline for monitoring and inspection applications of Posidonia Oceanica (PO) in three different geographical areas. The a priori knowledge about the presence of PO, in probabilistic terms, has been modelled utilising a Gaussian Process (GP), trained on real marine data. The GP estimate has then been exploited to retrieve an information content of each position in the areas of interest. A comparison with other two IPP approaches has been carried out to assess the performance of the proposed algorithm

Dermal adipose tissue secretes HGF to promote human hair growth and pigmentation

YesHair follicles (HFs) are immersed within dermal white adipose tissue (dWAT), yet human adipocyte-HF communication remains unexplored. Therefore, we investigated how perifollicular adipocytes affect the physiology of organ-cultured human anagen scalp HFs. Quantitative (immuno-)histomorphometry, microCT and transmission electron microscopy showed that the number and size of perifollicular adipocytes declined during anagen-catagen transition, whilst fluorescence lifetime imaging revealed increased lipid oxidation in adipocytes surrounding the bulge/sub-bulge region. Ex vivo, dWAT significantly stimulated hair matrix keratinocyte proliferation and HF pigmentation. Both dWAT pericytes and PREF1/DLK1+ adipocyte progenitors secreted hepatocyte growth factor (HGF) during human HF-dWAT co-culture, for which the c-Met receptor is expressed in the hair matrix and dermal papilla. These effects were abrogated by an HGF-neutralising antibody, and reproduced using recombinant HGF. Laser capture microdissection-based microarray analysis of the hair matrix showed that dWAT-derived HGF up-regulated KRT27, KRT73, KRT75, KRT84, KRT86 and TCHH. Mechanistically, HGF stimulated Wnt/β-catenin activity in the HM by inhibiting SFRP1 in the dermal papilla, up-regulating matrix AXIN2, LEF1, WNT6 and WNT10B expression. Our study demonstrates that dWAT regulates human hair growth and pigmentation via HGF secretion, and thus identifies important, molecular and cellular targets for therapeutic intervention in disorders of human hair growth and pigmentation

L'interruzione volontaria di gravidanza in Italia 1984 e primo semestre 1985

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