PAX4 preserves endoplasmic reticulum integrity preventing beta cell degeneration in a mouse model of type 1 diabetes mellitus

[Aims/hypothesis]: A strategy to enhance pancreatic islet functional beta cell mass (BCM) while restraining inflammation, through the manipulation of molecular and cellular targets, would provide a means to counteract the deteriorating glycaemic control associated with diabetes mellitus. The aims of the current study were to investigate the therapeutic potential of such a target, the islet-enriched and diabetes-linked transcription factor paired box 4 (PAX4), to restrain experimental autoimmune diabetes (EAD) in the RIP-B7.1 mouse model background and to characterise putative cellular mechanisms associated with preserved BCM. [Methods]: Two groups of RIP-B7.1 mice were genetically engineered to: (1) conditionally express either PAX4 (BPTL) or its diabetes-linked mutant variant R129W (mutBPTL) using doxycycline (DOX); and (2) constitutively express luciferase in beta cells through the use of RIP. Mice were treated or not with DOX, and EAD was induced by immunisation with a murine preproinsulin II cDNA expression plasmid. The development of hyperglycaemia was monitored for up to 4 weeks following immunisation and alterations in the BCM were assessed weekly by non-invasive in vivo bioluminescence intensity (BLI). In parallel, BCM, islet cell proliferation and apoptosis were evaluated by immunocytochemistry. Alterations in PAX4- and PAX4R129W-mediated islet gene expression were investigated by microarray profiling. PAX4 preservation of endoplasmic reticulum (ER) homeostasis was assessed using thapsigargin, electron microscopy and intracellular calcium measurements. [Results]: PAX4 overexpression blunted EAD, whereas the diabetes-linked mutant variant PAX4R129W did not convey protection. PAX4-expressing islets exhibited reduced insulitis and decreased beta cell apoptosis, correlating with diminished DNA damage and increased islet cell proliferation. Microarray profiling revealed that PAX4 but not PAX4R129W targeted expression of genes implicated in cell cycle and ER homeostasis. Consistent with the latter, islets overexpressing PAX4 were protected against thapsigargin-mediated ER-stress-related apoptosis. Luminal swelling associated with ER stress induced by thapsigargin was rescued in PAX4-overexpressing beta cells, correlating with preserved cytosolic calcium oscillations in response to glucose. In contrast, RNA interference mediated repression of PAX4-sensitised MIN6 cells to thapsigargin cell death. [Conclusions/interpretation]: The coordinated regulation of distinct cellular pathways particularly related to ER homeostasis by PAX4 not achieved by the mutant variant PAX4R129W alleviates beta cell degeneration and protects against diabetes mellitus. The raw data for the RNA microarray described herein are accessible in the Gene Expression Omnibus database under accession number GSE62846

Artificial Intelligence and Machine Learning Approaches to Energy Demand-Side Response: A Systematic Review

Recent years have seen an increasing interest in Demand Response (DR) as a means to provide flexibility, and hence improve the reliability of energy systems in a cost-effective way. Yet, the high complexity of the tasks associated with DR, combined with their use of large-scale data and the frequent need for near real-time de-cisions, means that Artificial Intelligence (AI) and Machine Learning (ML) — a branch of AI — have recently emerged as key technologies for enabling demand-side response. AI methods can be used to tackle various challenges, ranging from selecting the optimal set of consumers to respond, learning their attributes and pref-erences, dynamic pricing, scheduling and control of devices, learning how to incentivise participants in the DR schemes and how to reward them in a fair and economically efficient way. This work provides an overview of AI methods utilised for DR applications, based on a systematic review of over 160 papers, 40 companies and commercial initiatives, and 21 large-scale projects. The papers are classified with regards to both the AI/ML algorithm(s) used and the application area in energy DR. Next, commercial initiatives are presented (including both start-ups and established companies) and large-scale innovation projects, where AI methods have been used for energy DR. The paper concludes with a discussion of advantages and potential limitations of reviewed AI techniques for different DR tasks, and outlines directions for future research in this fast-growing area

Estradiol Regulates Energy Balance by Ameliorating Hypothalamic Ceramide-Induced ER Stress

Compelling evidence has shown that, besides its putative effect on the regulation of the gonadal axis, estradiol (E2) exerts a dichotomic effect on the hypothalamus to regulate food intake and energy expenditure. The anorectic effect of E2 is mainly mediated by its action on the arcuate nucleus (ARC), whereas its effects on brown adipose tissue (BAT) thermogenesis occur in the ventromedial nucleus (VMH). Here, we demonstrate that central E2 decreases hypothalamic ceramide levels and endoplasmic reticulum (ER) stress. Pharmacological or genetic blockade of ceramide synthesis and amelioration of ER stress selectively occurring in the VMH recapitulate the effect of E2, leading to increased BAT thermogenesis, weight loss, and metabolic improvement. These findings demonstrate that E2 regulation of ceramide-induced hypothalamic lipotoxicity and ER stress is an important determinant of energy balance, suggesting that dysregulation of this mechanism may underlie some changes in energy homeostasis seen in femalesThe research leading to these results has received funding from Xunta de Galicia (R.N.: 2015-CP080 and 2016-PG057; M.L.: 2015-CP079), MINECO co-funded by the FEDER Program of EU (R.N.: BFU2015-70664R; D.P.: SAF2016-77526-R; C.D.: BFU2017-87721; M.L.: SAF2015-71026-R and BFU2015-70454-REDT/Adipoplast). The CiMUS is supported by the Xunta de Galicia (2016-2019, ED431G/05). L.L.-P. is a recipient of a fellowship from Xunta de Galicia (ED481A-2016/094); E.R.-P. is a recipient of a fellowship from MINECO (BES-2015-072743); A.E.-S. is a recipient of a fellowship from MINECO (FPI/BES-2016-077439); C.R. is a recipient of a fellowship from MINECO (FPU16/04582). CIBER Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIIIS

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

On the multiscale characterization of effective hydraulic conductivity in random heterogeneous media: a historical survey and some new perspectives

International audienceIn large scale heterogeneous aquifer simulations, determining the appropriate coarsening scale λ to define an effective hydraulic conductivity Keff is a challenging task, that involves a trade-off between accuracy and cost. Efficiently adjusting the scale λ is then key, in particular for uncertainty quantification. In this paper, we obtain improved analytical results for the variance of Keff, valid at any scale, in the context of energy dissipation formulation. Using this formulation, we then derive an efficient Keff numerical estimator, and compare it with those of the potential-flow average and permeameter formulations in 2D, for lognormal and binary media, over a wide range of λ and of heterogeneity. We analyze the probability density function (pdf), mean, and variance, of these estimators, comparing them with the analytical results. In the lognormal case, the pdf’s are rather similar for the three estimators, and remain lognormal at all scales. In the binary case, slow convergence to an asymptotic regime is observed close to the percolation threshold

Técnica laparoscópica reversa en el manejo quirúrgico de la endometriosis profunda del tabique rectovaginal: experiencia preliminar

Antecedentes: El tratamiento quirúrgico de la endometriosis profunda es un procedimiento complejo, asociado a un alto riesgo de complicaciones. Recientemente, el uso de la técnica laparoscópica reversa aparece como una variante técnica interesante con el fin de disminuir las complicaciones. Objetivo: Describir nuestra experiencia preliminar y demostrar la factibilidad de la técnica laparoscópica reversa en el tratamiento de la endometriosis profunda del tabique rectovaginal. Método: Reporte de 5 casos a partir de base de datos prospectiva. Resultados: La edad promedio de las pacientes fue 34,2 años (rango: 32-37 años). Todas las pacientes presentaban dismenorrea y dispareunia profunda de larga evolución y en 3 de ellas existía el antecedente de cirugías previas por endometriosis. El tiempo quirúrgico promedio fue 313 minutos (rango: 180-450 minutos). Todas las cirugías se completaron por laparoscopía y no se registraron complicaciones. La anatomía patológica confirmó endometriosis en todos los casos. El seguimiento promedio fue de 4 meses (rango: 2-8 meses). Conclusión: La técnica laparoscópica reversa es una alternativa factible en el manejo quirúrgico de la endometriosis profunda, sin embargo es una técnica compleja y debe ser realizada por equipos experimentados en cirugía laparoscópica

Pancreatic alpha-cell mass in the early-onset and advanced stage of a mouse model of experimental autoimmune diabetes

Most studies in type 1 diabetes (T1D) have focused on the loss of the pancreatic beta-cell population. However, despite the involvement of the alpha-cell in the aetiology and complications of T1D, little is known about the regulation of the pancreatic alpha-cell mass in this disease. The need for a better understanding of this process is further emphasized by recent findings suggesting that alpha-cells may constitute a potential reservoir for beta-cell regeneration. In this study, we characterized the pancreatic alpha-cell mass and its regulatory processes in the transgenic RIP-B7.1 mice model of experimental autoimmune diabetes (EAD). Diabetic mice presented insulitis, hyperglycaemia, hypoinsulinemia and hyperglucagonemia along with lower pancreatic insulin content. While alpha-cell mass and pancreatic glucagon content were preserved at the early-onset of EAD, both parameters were reduced in the advanced phase. At both stages, alpha-cell size, proliferation and ductal neogenesis were up-regulated, whereas apoptosis was almost negligible. Interestingly, we found an increase in the proportion of glucagon-containing cells positive for insulin or the beta-cell transcription factor PDX1. Our findings suggest that pancreatic alpha-cell renewal mechanisms are boosted during the natural course of EAD, possibly as an attempt to maintain the alpha-cell population and/or to increase beta-cell regeneration via alpha-cell transdifferentiation.This research was supported by grants from the Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación and Fondo Europeo de Desarrollo Regional (BFU2013-42789; BFU2017-86579-R; BFU2016-77125-R; BFU2017-83588-P), Generalitat Valenciana (PROMETEOII/2015/016) and the Juvenile Diabetes Research Foundation (17-2013-372 to B.R.G.). L.M. holds a Juan de la Cierva fellowship from the Ministerio de Ciencia, Innovación y Universidades (IJCI-2015-24482). CIBERDEM is an initiative of the Instituto de Salud Carlos III

Revisión de la clasificación de especies en categorías de amenaza en Chile Review of the species classification in categories of threat in Chile

A partir de 1985 comienzan los esfuerzos del Estado de Chile, con el apoyo de especialistas, para generar listas de especies de plantas (1985) y animales (1987) con altos a moderados riesgos de extinción en el corto plazo producto de actividades antrópicas (i.e., especies amenazadas). Las siete categorías de amenazas utilizadas para la fauna coinciden con las empleadas por la Unión Internacional para la Conservación de la Naturaleza (UICN) en 1982; para la flora hubo coincidencia en solo cinco de las categorías utilizadas. En el año 1994, la Ley 19300 de Bases del Medio Ambiente estableció seis categorías de estados de conservación. El Reglamento para la Clasificación de Especies Silvestres, promulgado el 2005, definió estas seis categorías haciendo una combinación entre lo propuesto por la UICN en 2001 y 1982. La generación de este sistema híbrido que no era comparable con el utilizado ampliamente en el mundo, restringió severamente la posibilidad de clasificar a las especies con amenaza inferior al nivel de Vulnerable. Complicaciones adicionales se generaron con la inclusión de categorías de conservación en la Ley 19473 de Caza (1996), la Ley 20283 sobre Recuperación del Bosque Nativo y Fomento Forestal (2008), y sus respectivos reglamentos. La Ley 20417 (publicada el 26 de enero 2010) modificó la ley 19300 e incorporó las categorías recomendadas por la UICN. Ahora el Estado requiere adecuar varios cuerpos legales para avanzar en el conocimiento del estado de conservación de la flora y la fauna nacional, y consecuentemente, asegurar la implementación de medidas efectivas de protección de la biodiversidad.<br>Since 1985, the Chilean government with the participation and support of different specialists in plant and animal conservation, started the publication of checklists (i.e. red books) of plant (1985) and animal species (1987) with high to modérate risk of extinction due to human activities (i.e. threatened species). The seven categories of threats used in these publications matched those used by the International Unión for the Conservation of Nature (IUCN) in 1982; nonetheless, for the flora there was matching only in five of the categories used. In 1994, the Law 19300 on the General Bases of the Environment established six categories of conservation status. The regulations for the classification of the wild species in Conservation categories, enacted in 2005, defined these six categories, which resulted from a combination of those proposed by the IUCN in 2001 and 1982. The generation of this hybrid system, which is not fully comparable with that of the IUCN (2001) and widely used in the rest of the world, has severely restricted the possibility of classifying species with a threat level lower than "Vulnerable". Further complications were generated due to the definition of conservation categories that appeared in the Laws 19473 (1996) regulating the hunting activity and 20283 (2008) supporting the native forest recovery and forestry development. The Law 20417 (enacted in January 26, 2010) modified the Law 19300 and incorporated the categories recommended by IUCN. Currently, the State requires adapting several legal bodies to advance in the knowledge of the conservation status of the nation's flora and fauna, and consequently, ensure the implementation of effective efforts to protect our biodiversity

GATA6 controls Insulin biosynthesis and secretion in Adult ß cell

GATA4 and GATA6 play essential, but redundant, roles in pancreas formation in mice, and GATA6 mutations cause pancreatic agenesis in humans. GATA6 mutations have also recently been linked to adult-onset diabetes, with subclinical or no exocrine insufficiency, suggesting an important role for GATA6 in human β-cell physiology. To investigate the role of GATA6 in the adult endocrine pancreas, we generated mice in which Gata6 is specifically inactivated in the pancreas. These mice develop glucose intolerance. Islets deficient in GATA6 activity display decreased insulin content and impaired insulin secretion. Gata6-deficient β-cells exhibit ultrastructural abnormalities, including increased immature insulin granules, swollen mitochondria, and disorganized endoplasmic reticulum. We also demonstrate that Pdx1 expression in adult β-cells depends on GATA sites in transgenic reporter mice and that loss of GATA6 greatly affects β-cell–specific gene expression. These findings demonstrate the essential role of GATA6 in β-cell functionL.V. was supported by a contract from Spanish Ministry of Economy and Competitiveness (RYC-2013-14533). E.R.-S. was supported by a “Juan de la Cierva” postdoctoral fellowship from Spanish Ministry of Economy and Competitiveness (IJCI-2014-19251). This work was supported by grants from ISCIII cofunded by Fondos FEDER (PI14/01015, RD/0019/0028, and RD16/0011/0034 to B.S. and PI14/ 0804 to A.R.) and “Ramón y Cajal” program from the Spanish Ministry of Economy and Competitiveness (PI14/0804, RYC-2013-14533 to A.R.). P.M. was supported by a Juan de la Cierva fellowship from Spanish Ministry of Science and Innovation and by a Stand-Alone Grant from the Austrian Science Fund (FWF P27361-B23). Work by I.Q. was supported by the Spanish Ministry of Economy and Competitiveness (BFU2016-77125-R). Work by D.A.C. was supported by the Nicolás Monardes program of Andalusian Ministry of Health (C-0015-2014) and the Andalusian Ministry of Science and Innovation (CTS-7478).Peer reviewe