Metabolic reprogramming involving glycolysis in the hibernating brown bear skeletal muscle

Background: In mammals, the hibernating state is characterized by biochemical adjustments, which include metabolic rate depression and a shift in the primary fuel oxidized from carbohydrates to lipids. A number of studies of hibernating species report an upregulation of the levels and/or activity of lipid oxidizing enzymes in muscles during torpor, with a concomitant downregulation for glycolytic enzymes. However, other studies provide contrasting data about the regulation of fuel utilization in skeletal muscles during hibernation. Bears hibernate with only moderate hypothermia but with a drop in metabolic rate down to ~ 25% of basal metabolism. To gain insights into how fuel metabolism is regulated in hibernating bear skeletal muscles, we examined the vastus lateralis proteome and other changes elicited in brown bears during hibernation. Results: We show that bear muscle metabolic reorganization is in line with a suppression of ATP turnover. Regulation of muscle enzyme expression and activity, as well as of circulating metabolite profiles, highlighted a preference for lipid substrates during hibernation, although the data suggested that muscular lipid oxidation levels decreased due to metabolic rate depression. Our data also supported maintenance of muscle glycolysis that could be fuelled from liver gluconeogenesis and mobilization of muscle glycogen stores. During hibernation, our data also suggest that carbohydrate metabolism in bear muscle, as well as protein sparing, could be controlled, in part, by actions of n-3 polyunsaturated fatty acids like docosahexaenoic acid. Conclusions: Our work shows that molecular mechanisms in hibernating bear skeletal muscle, which appear consistent with a hypometabolic state, likely contribute to energy and protein savings. Maintenance of glycolysis could help to sustain muscle functionality for situations such as an unexpected exit from hibernation that would require a rapid increase in ATP production for muscle contraction. The molecular data we report here for skeletal muscles of bears hibernating at near normal body temperature represent a signature of muscle preservation despite atrophying conditions

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Evidence of meltwater retention within the Greenland ice sheet

Greenland ice sheet mass losses have increased in recent decades with more than half of these attributed to surface meltwater runoff. However, the magnitudes of englacial storage, firn retention, internal refreezing and other hydrologic processes that delay or reduce true water export to the global ocean remain less understood, partly due to a scarcity of in situ measurements. Here, ice sheet surface meltwater runoff and proglacial river discharge between 2008 and 2010 near Kangerlussuaq, southwestern Greenland were used to establish sub- and englacial meltwater storage for a small ice sheet watershed (36–64 km2). This watershed lacks significant potential meltwater storage in firn, surface lakes on the ice sheet and in the proglacial area, and receives limited proglacial precipitation. Thus, ice sheet surface runoff not accounted for by river discharge can reasonably be attributed to retention in sub- and englacial storage. Evidence for meltwater storage within the ice sheet includes (1) characteristic dampened daily river discharge amplitudes relative to ice sheet runoff; (2) three cold-season river discharge anomalies at times with limited ice sheet surface melt, demonstrating that meltwater may be retained up to 1–6 months; (3) annual ice sheet watershed runoff is not balanced by river discharge, and while near water budget closure is possible as much as 54% of melting season ice sheet runoff may not escape to downstream rivers; (4) even the large meltwater retention estimate (54%) is equivalent to less than 1% of the ice sheet volume, which suggests that storage in en- and subglacial cavities and till is plausible. While this study is the first to provide evidence for meltwater retention and delayed release within the Greenland ice sheet, more information is needed to establish how widespread this is along the Greenland ice sheet perimeter

Greenland

Coastal Surface Air Temperatures Record-setting high air temperatures were registered at all of the west Greenland long-term meteorological stations (Table 5.2). At Nuuk (Fig. 5.19), winter 2009/10 and spring and summer in 2010 were the warmest since 1873, when measurements began. At Prins Christian Sund, as at Nuuk, 2010 annual anomalies were three standard deviations above the 1971–2000 baseline. Warm anomalies were greatest at Aasiaat, where winter temperatures were 7°C above the 1971–2000 baseline, which is three standard deviations above the mean. Temperature anomalies extended west into Arctic Canada (see also section 5e5), but not into east and northeast Greenland

Diagnosis and management of acute lower gastrointestinal bleeding: European Society of Gastrointestinal Endoscopy (ESGE) Guideline

Main Recommendations 1 ESGE recommends that the initial assessment of patients presenting with acute lower gastrointestinal bleeding should include: a history of co-morbidities and medications that promote bleeding; hemodynamic parameters; physical examination (including digital rectal examination); and laboratory markers. A risk score can be used to aid, but should not replace, clinician judgment. Strong recommendation, low quality evidence. 2 ESGE recommends that, in patients presenting with a self-limited bleed and no adverse clinical features, an Oakland score of ≤?8 points can be used to guide the clinician decision to discharge the patient for outpatient investigation. Strong recommendation, moderate quality evidence. 3 ESGE recommends, in hemodynamically stable patients with acute lower gastrointestinal bleeding and no history of cardiovascular disease, a restrictive red blood cell transfusion strategy, with a hemoglobin threshold of ≤?7?g/dL prompting red blood cell transfusion. A post-transfusion target hemoglobin concentration of 7-9?g/dL is desirable. Strong recommendation, low quality evidence. 4 ESGE recommends, in hemodynamically stable patients with acute lower gastrointestinal bleeding and a history of acute or chronic cardiovascular disease, a more liberal red blood cell transfusion strategy, with a hemoglobin threshold of ≤?8?g/dL prompting red blood cell transfusion. A post-transfusion target hemoglobin concentration of ≥?10?g/dL is desirable. Strong recommendation, low quality evidence. 5 ESGE recommends that, in patients with major acute lower gastrointestinal bleeding, colonoscopy should be performed sometime during their hospital stay because there is no high quality evidence that early colonoscopy influences patient outcomes. Strong recommendation, low quality of evidence. 6 ESGE recommends that patients with hemodynamic instability and suspected ongoing bleeding undergo computed tomography angiography before endoscopic or radiologic treatment to locate the site of bleeding. Strong recommendation, low quality evidence. 7 ESGE recommends withholding vitamin K antagonists in patients with major lower gastrointestinal bleeding and correcting their coagulopathy according to the severity of bleeding and their thrombotic risk. In patients with hemodynamic instability, we recommend administering intravenous vitamin K and four-factor prothrombin complex concentrate (PCC), or fresh frozen plasma if PCC is not available. Strong recommendation, low quality evidence. 8 ESGE recommends temporarily withholding direct oral anticoagulants at presentation in patients with major lower gastrointestinal bleeding. Strong recommendation, low quality evidence. 9 ESGE does not recommend withholding aspirin in patients taking low dose aspirin for secondary cardiovascular prevention. If withheld, low dose aspirin should be resumed, preferably within 5 days or even earlier if hemostasis is achieved or there is no further evidence of bleeding. Strong recommendation, moderate quality evidence. 10 ESGE does not recommend routinely discontinuing dual antiplatelet therapy (low dose aspirin and a P2Y12 receptor antagonist) before cardiology consultation. Continuation of the aspirin is recommended, whereas the P2Y12 receptor antagonist can be continued or temporarily interrupted according to the severity of bleeding and the ischemic risk. If interrupted, the P2Y12 receptor antagonist should be restarted within 5 days, if still indicated. Strong recommendation, low quality evidence.SCOPUS: ar.jDecretOANoAutActifinfo:eu-repo/semantics/publishe