Female sex hormones are necessary for the metabolic effects mediated by loss of Interleukin 18 signaling

Objective: Interleukin (IL)-18 plays a crucial role in maintaining metabolic homeostasis and levels of this cytokine are influenced by gender, age, and sex hormones. The role of gender on IL-18 signaling, however, is unclear. We hypothesized that the presence of female sex hormone could preserve the metabolic phenotype of the IL-18R−/− animals. Methods: We studied female mice with a global deletion of the α isoform of the IL-18 receptor (IL-18R−/−) and littermates control. Three studies were done: 1) animals fed a high fat diet (HFD) for 16 weeks; 2) animals fed chow diet for 72 weeks and 3) animals (3 weeks-old) randomized to either bilateral ovariectomy (OVX) or control surgery (SHAM) and followed for 16 weeks. Results: Female IL-18R−/− mice gained less weight and maintained glucose homeostasis on a chow diet compared with HFD, but no differences between genotypes were observed. The maintenance of body weight and glucose homeostasis in IL-18R−/− mice was lost with aging. By 72 weeks of age, IL-18R−/− mice became heavier compared with WT mice due to an increase in both visceral and subcutaneous adiposity and displayed glucose intolerance. OVX did not affect body weight in IL-18R−/− mice but exacerbated glucose intolerance and impaired liver insulin signaling when compared with SHAM mice. Conclusions: Female mice harboring a global deletion of the IL-18R, only present the same phenotype as reported in male IL-18R−/− mice if they are aged or have undergone OVX, in which circulating estrogen is likely to be blunted. The role of estrogen signaling in the protection against altered metabolic homeostasis in IL-18R−/− mice appears to be mediated by liver insulin signaling. We therefore suggest that the metabolic effects mediated by loss of IL-18 signaling are only present in a female sex hormone free environment. Keywords: IL-18, Obesity, Insulin resistance, Gende

MicroRNA-194 modulates glucose metabolism and its skeletal muscle expression is reduced in diabetes

BACKGROUND: The regulation of microRNAs (miRNAs) at different stages of the progression of type 2 diabetes mellitus (T2DM) and their role in glucose homeostasis was investigated. METHODS: Microarrays were used to assess miRNA expression in skeletal muscle biopsies taken from healthy individuals and patients with pre-diabetes or T2DM, and insulin resistant offspring of rat dams fed a high fat diet during pregnancy. RESULTS: Twenty-three miRNAs were differentially expressed in patients with T2DM, and 7 in the insulin resistant rat offspring compared to their controls. Among these, only one miRNA was similarly regulated: miR-194 expression was significantly reduced by 25 to 50% in both the rat model and in human with pre-diabetes and established diabetes. Knockdown of miR-194 in L6 skeletal muscle cells induced an increase in basal and insulin-stimulated glucose uptake and glycogen synthesis. This occurred in conjunction with an increased glycolysis, indicated by elevated lactate production. Moreover, oxidative capacity was also increased as we found an enhanced glucose oxidation in presence of the mitochondrial uncoupler FCCP. When miR-194 was down-regulated in vitro, western blot analysis showed an increased phosphorylation of AKT and GSK3β in response to insulin, and an increase in expression of proteins controlling mitochondrial oxidative phosphorylation. CONCLUSIONS: Type 2 diabetes mellitus is associated with regulation of several miRNAs in skeletal muscle. Interestingly, miR-194 was a unique miRNA that appeared regulated across different stages of the disease progression, from the early stages of insulin resistance to the development of T2DM. We have shown miR-194 is involved in multiple aspects of skeletal muscle glucose metabolism from uptake, through to glycolysis, glycogenesis and glucose oxidation, potentially via mechanisms involving AKT, GSK3 and oxidative phosphorylation. MiR-194 could be down-regulated in patients with early features of diabetes as an adaptive response to facilitate tissue glucose uptake and metabolism in the face of insulin resistance

The MeerKAT international GHz tiered extragalactic exploration (MIGHTEE) survey

The MIGHTEE large survey project will survey four of the most well-studied extragalactic deep fields, totalling 20 square degrees to µJy sensitivity at Giga-Hertz frequencies, as well as an ultra-deep image of a single ∼1 deg2 MeerKAT pointing. The observations will provide radio continuum, spectral line and polarisation information. As such, MIGHTEE, along with the excellent multi-wavelength data already available in these deep fields, will allow a range of science to be achieved. Specifically, MIGHTEE is designed to significantly enhance our understanding of, (i) the evolution of AGN and star-formation activity over cosmic time, as a function of stellar mass and environment, free of dust obscuration; (ii) the evolution of neutral hydrogen in the Universe and how this neutral gas eventually turns into stars after moving through the molecular phase, and how efficiently this can fuel AGN activity; (iii) the properties of cosmic magnetic fields and how they evolve in clusters, filaments and galaxies. MIGHTEE will reach similar depth to the planned SKA all-sky survey, and thus will provide a pilot to the cosmology experiments that will be carried out by the SKA over a much larger survey volume

The Panchromatic Afterglow of GW170817: The full uniform dataset, modeling, comparison with previous results and implications

We present the full panchromatic afterglow light curve data of GW170817, including new radio data as well as archival optical and X-ray data, between 0.5 and 940 days post-merger. By compiling all archival data, and reprocessing a subset of it, we have ensured that the panchromatic dataset is uniform and therefore immune to the differences in data processing or flux determination methods used by different groups. Simple power-law fits to the uniform afterglow light curve indicate a t^(0.86±0.04) rise, a t^(−1.90±0.12) decline, and a peak occurring at 155±4 days. The afterglow is optically thin throughout its evolution, consistent with a single spectral index (−0.569±0.002) across all epochs. This gives a precise and updated estimate of the electron power-law index, p=2.138±0.004. By studying the diffuse X-ray emission from the host galaxy, we place a conservative upper limit on the hot ionized ISM density, <0.01 cm⁻³, consistent with previous afterglow studies. Using the late-time afterglow data we rule out any long-lived neutron star remnant having magnetic field strength between 10^(10.4) G and 10¹⁶ G. Our fits to the afterglow data using an analytical model that includes VLBI proper motion from Mooley et al (2018), and a structured jet model that ignores the proper motion, indicates that the proper motion measurement needs to be considered while seeking an accurate estimate of the viewing angle

Health care professionals’ views of the factors influencing the decision to refer patients to a stroke rehabilitation trial

Background: Effective recruitment is an essential element of successful research but notoriously difficult to achieve. This article examines health care professionals' views on the factors influencing decision-making regarding referral to a stroke rehabilitation trial. Methods: Semi-structured interviews and a card-sorting task were undertaken with stroke service staff in acute and community hospital trusts. Data analysis used a thematic framework approach. Results: Twenty-seven qualified health care professionals from 12 (6 acute and 6 community) hospital trusts and one charity participated. Four main factors emerged: patient-related, professional views, the organisation and research logistics, which all contributed to staff's decision about whether to refer patients to a trial. Clinicians identified patient-related factors as the most frequent influence and considered themselves the patients' advocate. They used their knowledge of the patient to anticipate the patients' reaction to possible participation and tended to only refer those whom they perceived would respond positively. Participants also identified experience of research, a sense of ownership of the project and a positive view of the intervention being evaluated as factors influencing referral. The need to prioritise clinical matters, meet managerial demands and cope with constant change were organisational factors impacting negatively on referral. Staff often simply forgot about recruitment in the face of other higher priorities. Quick, simple, flexible research processes that were closely aligned with existing ways of working were felt to facilitate recruitment. Conclusions: Patient- and professional-related factors were the most frequent influence on clinicians' recruitment decisions, which often had a 'gate-keeping' effect. Managerial and clinical responsibility to juggle multiple (often higher) priorities was also an important factor. To facilitate recruitment, researchers need to develop strategies to approach potential participants as directly as possible to enable them to make their own decisions about participation; ensure that research processes are as quick and simple as possible; align with existing clinical pathways and systems; and give regular reminders and ongoing support to promote recruitment

Human Resource and Funding Constraints for Essential Surgery in District Hospitals in Africa: A Retrospective Cross-Sectional Survey

In the second of two papers investigating surgical provision in eight district hospitals in Saharan African countries, Margaret Kruk and colleagues describe the range of providers of surgical care and anesthesia and estimate the related costs

A Unique Human-Fox Burial from a Pre-Natufian Cemetery in the Levant (Jordan)

New human burials from northern Jordan provide important insights into the appearance of cemeteries and the nature of human-animal relationships within mortuary contexts during the Epipalaeolithic period (c. 23,000–11,600 cal BP) in the Levant, reinforcing a socio-ideological relationship that goes beyond predator-prey. Previous work suggests that archaeological features indicative of social complexity occur suddenly during the latest Epipalaeolithic phase, the Natufian (c. 14,500–11,600 cal BP). These features include sedentism, cemeteries, architecture, food production, including animal domestication, and burials with elaborate mortuary treatments. Our findings from the pre-Natufian (Middle Epipalaeolithic) cemetery of ‘Uyun al-Hammam demonstrate that joint human-animal mortuary practices appear earlier in the Epipalaeolithic. We describe the earliest human-fox burial in the Near East, where the remains of dogs have been found associated with human burials at a number of Natufian sites. This is the first time that a fox has been documented in association with human interments pre-dating the Natufian and with a particular suite of grave goods. Analysis of the human and animal bones and their associated artefacts provides critical data on the nature and timing of these newly-developing relationships between people and animals prior to the appearance of domesticated dogs in the Natufian

Real-world evidence from the first online healthcare analytics platform—Livingstone. Validation of its descriptive epidemiology module

Incidence and prevalence are key epidemiological determinants characterizing the quantum of a disease. We compared incidence and prevalence estimates derived automatically from the first ever online, essentially real-time, healthcare analytics platform—Livingstone—against findings from comparable peer-reviewed studies in order to validate the descriptive epidemiology module. The source of routine NHS data for Livingstone was the Clinical Practice Research Datalink (CPRD). After applying a general search strategy looking for any disease or condition, 76 relevant studies were first retrieved, of which 10 met pre-specified inclusion and exclusion criteria. Findings reported in these studies were compared with estimates produced automatically by Livingstone. The published reports described elements of the epidemiology of 14 diseases or conditions. Lin’s concordance correlation coefficient (CCC) was used to evaluate the concordance between findings from Livingstone and those detailed in the published studies. The concordance of incidence values in the final year reported by each study versus Livingstone was 0.96 (95% CI: 0.89–0.98), whilst for all annual incidence values the concordance was 0.93 (0.91–0.94). For prevalence, concordance for the final annual prevalence reported in each study versus Livingstone was 1.00 (0.99–1.00) and for all reported annual prevalence values, the concordance was 0.93 (0.90–0.95). The concordance between Livingstone and the latest published findings was near perfect for prevalence and substantial for incidence. For the first time, it is now possible to automatically generate reliable descriptive epidemiology from routine health records, and in near-real time. Livingstone provides the first mechanism to rapidly generate standardised, descriptive epidemiology for all clinical events from real world data