The effects of heat stress on energetic metabolism and insulin homeostasis

Heat stress (HS) is a major environmental hazard for human health and animal agriculture. Changes in metabolism and specifically altered insulin action appear to be critical for the adaptation and ultimately survival to a severe heat load. However, our knowledge of the physiological and metabolic consequences of HS is woefully insufficient. Understanding the biology of HS is critical in order to develop treatment protocols and mitigation strategies against its deleterious effects on both humans and livestock. Interestingly, HS elicits a metabolic profile that somewhat resembles models of endotoxemia/sepsis. Moreover, HS negatively affects intestinal health and the subsequent increase in the permeability to luminal pro-inflammatory molecules might be the link between both models. Therefore, alleviating the effects of HS on the intestinal barrier function may have the potential to prevent or ameliorate its impact on animal health and productivity. Studies conducted for this dissertation utilized sus scrofa as the model, due to the pig\u27s relevance in both animal agriculture and the biomedical field. Study 1 (chapter 2) was conducted to determine the temporal effects of HS on basal and stimulated metabolism. Results indicated that HS decreases both basal and adrenergic-induced adipose tissue mobilization. Heat stress increased basal insulin secretion and decreased circulating thyroid hormones. Early heat exposure decreased glucose disposal in response to a glucose tolerance test, which might suggest increased whole body insulin resistance. However when considering the glucose and insulin responses together, HS pigs required less insulin compared to controls in order to dispose of a similar amount of glucose, which would actually indicate increased insulin sensitivity. Based on the conflicting results obtained in study 1 regarding insulin action, in study 2 (chapter 3) we aimed to define the effects of HS on whole-body insulin action. For this purpose we performed a hyperinsulinemic euglycemic clamp and concluded that, relative to controls, HS pigs required a greater rate of glucose infusion to maintain euglycemia. Further, molecular markers of insulin signaling prior and after insulin stimulation, suggested that the skeletal muscle is partially responsible for the increase in insulin-stimulated glucose uptake observed during HS. Heat stress has deleterious effects on intestinal health that may ultimately mediate its effects on energetic metabolism and productivity. Studies 3 and 4 (chapters 4 and 5) objectives were to establish the feasibility of dietary interventions in order to mitigate HS-induced intestinal barrier dysfunction. Previous research had demonstrated that dietary zinc and whey protein improve intestinal health in a variety of bowel disease models, which led us to hypothesize that their supplementation would alleviate the negative effects of HS on intestinal permeability. Results from these studies indicated that supplemental zinc improves aspects of small intestinal integrity during severe HS. In contrast, the tested dairy products did not mitigate the deleterious consequences HS has on intestinal barrier function. In conclusion, studies 1 and 2 demonstrated that HS markedly alters both lipid and carbohydrate metabolism. Specifically, HS decreases adipose tissue mobilization and increases whole-body insulin sensitivity. In addition, studies 3 and 4 proved that dietary interventions aimed to improve intestinal integrity during HS are plausible. A better understanding of the relative contribution of the intestinal barrier dysfunction to the heat-induced effects on metabolism and ultimately on nutrient partitioning is a prerequisite for designing targeted strategies to mitigate the consequences of HS on human health and animal productivity

NOD1 deficiency promotes an imbalance of thyroid hormones and microbiota homeostasis in mice fed high fat diet

The contribution of the nucleotide-binding oligomerization domain protein NOD1 to obesity has been investigated in mice fed a high fat diet (HFD). Absence of NOD1 accelerates obesity as early as 2 weeks after feeding a HFD. The obesity was due to increases in abdominal and inguinal adipose tissues. Analysis of the resting energy expenditure showed an impaired function in NOD1-deficient animals, compatible with an alteration in thyroid hormone homeostasis. Interestingly, free thyroidal T4 increased in NOD1-deficient mice fed a HFD and the expression levels of UCP1 in brown adipose tissue were significantly lower in NOD1-deficient mice than in the wild type animals eating a HFD, thus contributing to the observed adiposity in NOD1-deficient mice. Feeding a HFD resulted in an alteration of the proinflammatory profile of these animals, with an increase in the infiltration of inflammatory cells in the liver and in the white adipose tissue, and an elevation of the circulating levels of TNF-α. In addition, alterations in the gut microbiota in NOD1-deficient mice correlate with increased vulnerability of their ecosystem to the HFD challenge and affect the immune-metabolic phenotype of obese mice. Together, the data are compatible with a protective function of NOD1 against low-grade inflammation and obesity under nutritional conditions enriched in saturated lipids. Moreover, one of the key players of this early obesity onset is a dysregulation in the metabolism and release of thyroid hormones leading to reduced energy expenditure, which represents a new role for these hormones in the metabolic actions controlled by NOD1.This work was supported by Grants SAF2017-82436R, AGL2017-88801-P and SAF2016-75004R from MINECO/AEI/FEDER/EU, S2017/BMD-3686 from Comunidad de Madrid, CIVP18A3864 from Fundación Ramón Areces and CIBERCV and CIBERHED (funded by the Instituto de Salud Carlos III) and Fondos FEDER.Peer reviewe

A Large Case-Control Study Performed in Spanish Population Suggests That RECQL5 Is the Only RECQ Helicase Involved in Breast Cancer Susceptibility.

Around 50% of the familial breast cancer (BC) cases are estimated to be caused by germline variants in known low-, moderate-, and high-risk susceptibility genes, while the other half is of unknown genetic origin. In the present study, we wanted to evaluate the role of the RECQ helicases, some of which have been studied in the past as candidates, with unclear results about their role in the disease. Using next-generation sequencing (NGS) technology, we analyzed the whole coding sequence of BLM, RECQL1, RECQL4, RECQL5, and WRN in almost 2000 index cases from BC Spanish families that had previously tested negative for the known BC susceptibility genes (BRCAX) and compared the results with the controls extracted from gnomAD. Our results suggest that BLM, RECQL1, RECQL4, and WRN do not play a major role in BC susceptibility. However, in the combined analysis, joining the present results with those previously reported in a series of 1334 BC Spanish patients and controls, we found a statistically significant association between Loss of Function (LoF) variants in RECQL5 and BC risk, with an OR of 2.56 (p = 0.009; 95% CI, 1.18-4.98). Our findings support our previous work and places the RECQL5 gene as a new moderate-risk BC gene.A.O. is partially funded by FIS PI19/00640 supported by FEDER funds and the Spanish Network on Rare Diseases (CIBERER). M.d.l.H. is partially funded by FIS PI20/00110 supported by FEDER funds.S

Next Generation Flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma

[EN]Flow cytometry has become a highly valuable method to monitor minimal residual disease (MRD) and evaluate the depth of complete response (CR) in bone marrow (BM) of multiple myeloma (MM) after therapy. However, current flow-MRD has lower sensitivity than molecular methods and lacks standardization. Here we report on a novel next generation flow (NGF) approach for highly sensitive and standardized MRD detection in MM. An optimized 2-tube 8-color antibody panel was constructed in five cycles of design-evaluation-redesign. In addition, a bulk-lysis procedure was established for acquisition of ⩾107 cells/sample, and novel software tools were constructed for automatic plasma cell gating. Multicenter evaluation of 110 follow-up BM from MM patients in very good partial response (VGPR) or CR showed a higher sensitivity for NGF-MRD vs conventional 8-color flow-MRD -MRD-positive rate of 47 vs 34% (P=0.003)-. Thus, 25% of patients classified as MRD-negative by conventional 8-color flow were MRD-positive by NGF, translating into a significantly longer progression-free survival for MRD-negative vs MRD-positive CR patients by NGF (75% progression-free survival not reached vs 7 months; P=0.02). This study establishes EuroFlow-based NGF as a highly sensitive, fully standardized approach for MRD detection in MM which overcomes the major limitations of conventional flow-MRD methods and is ready for implementation in routine diagnostics.This work has been supported by the International Myeloma Foundation-Black Swan Research Initiative, the Red Temática de Investigación Cooperativa en Cáncer (RTICC); grant SA079U14 from the Consejería de Educación, Junta de Castilla y León, Valladolid, Spain and; grant DTS15/00119 from Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain

Marco activo de recursos de innovación docente: Madrid

Una guía de espacios e instituciones para actividades educativas complementarias en enseñanza secundaria y Formación Profesional

Healthcare workers hospitalized due to COVID-19 have no higher risk of death than general population. Data from the Spanish SEMI-COVID-19 Registry

Aim To determine whether healthcare workers (HCW) hospitalized in Spain due to COVID-19 have a worse prognosis than non-healthcare workers (NHCW). Methods Observational cohort study based on the SEMI-COVID-19 Registry, a nationwide registry that collects sociodemographic, clinical, laboratory, and treatment data on patients hospitalised with COVID-19 in Spain. Patients aged 20-65 years were selected. A multivariate logistic regression model was performed to identify factors associated with mortality. Results As of 22 May 2020, 4393 patients were included, of whom 419 (9.5%) were HCW. Median (interquartile range) age of HCW was 52 (15) years and 62.4% were women. Prevalence of comorbidities and severe radiological findings upon admission were less frequent in HCW. There were no difference in need of respiratory support and admission to intensive care unit, but occurrence of sepsis and in-hospital mortality was lower in HCW (1.7% vs. 3.9%; p = 0.024 and 0.7% vs. 4.8%; p<0.001 respectively). Age, male sex and comorbidity, were independently associated with higher in-hospital mortality and healthcare working with lower mortality (OR 0.211, 95%CI 0.067-0.667, p = 0.008). 30-days survival was higher in HCW (0.968 vs. 0.851 p<0.001). Conclusions Hospitalized COVID-19 HCW had fewer comorbidities and a better prognosis than NHCW. Our results suggest that professional exposure to COVID-19 in HCW does not carry more clinical severity nor mortality

Profundización en metodologías y espacios docentes innovadores

Fac. de FilologíaFALSEsubmitte

Assessment for English language education on the programs at the Agricultural Engineering School of Madrid

The convergence process among European academic degrees pursues the exchange of graduate students and the adaptation of university programs to social demand. Within the framework of the European Higher Education, European universities will need to be more competitive not only by increasing or maintaining the student enrolment, but also in their academic performance. Thus, the reinforcing of English language education within the University Programs might play an important role to reach these objectives. In this sense, a complete survey was accomplished at the Agricultural Egineering School of Madrid (ETSIA ) addressing issues such as: identification the needs for bilingual instruction at ETSIA, identification resources needed and interest and background in English language of students and professors (San José et al., 2013). The conclusions and recommendations to promote the bilingual instruction in the ETSIA, taking into account the approaches followed by other Spanish universities, are presented in this work