UBE2QL1 is Disrupted by a Constitutional Translocation Associated with Renal Tumor Predisposition and is a Novel Candidate Renal Tumor Suppressor Gene

Investigation of rare familial forms of renal cell carcinoma (RCC) has led to the identification of genes such as VHL and MET that are also implicated in the pathogenesis of sporadic RCC. In order to identify a novel candidate renal tumor suppressor gene, we characterized the breakpoints of a constitutional balanced translocation, t(5;19)(p15.3;q12), associated with familial RCC and found that a previously uncharacterized gene UBE2QL1 was disrupted by the chromosome 5 breakpoint. UBE2QL1 mRNA expression was downregulated in 78.6% of sporadic RCC and, although no intragenic mutations were detected, gene deletions and promoter region hypermethylation were detected in 17.3% and 20.3%, respectively, of sporadic RCC. Reexpression of UBE2QL1 in a deficient RCC cell line suppressed anchorage-independent growth. UBE2QL1 shows homology to the E2 class of ubiquitin conjugating enzymes and we found that (1) UBE2QL1 possesses an active-site cysteine (C88) that is monoubiquitinated in vivo, and (2) UBE2QL1 interacts with FBXW7 (an F box protein providing substrate recognition to the SCF E3 ubiquitin ligase) and facilitates the degradation of the known FBXW7 targets, CCNE1 and mTOR. These findings suggest UBE2QL1 as a novel candidate renal tumor suppressor gen

Seasonal phosphorus and carbon dynamics in a temperate shelf sea (Celtic Sea): uptake, partitioning, release, turnover and stoichiometry.

The seasonal cycle of resource availability in shelf seas has a strong selective pressure on phytoplankton diversity and the biogeochemical cycling of key elements, such as carbon (C) and phosphorus (P). Shifts in carbon consumption relative to P availability, via changes in cellular stoichiometry for example, can lead to an apparent ‘excess’ of carbon production. We made measurements of inorganic P (Pi) uptake, in parallel to C-fixation, by plankton communities in the Celtic Sea (NW European Shelf) in spring (April 2015), summer (July 2015) and autumn (November 2014). Short-term (< 8 h) Pi-uptake coupled with dissolved organic phosphorus (DOP) release, in parallel to net (24 h) primary production (NPP), were all measured across an irradiance gradient designed to typify vertically and seasonally varying light conditions. Rates of Pi-uptake were highest during spring and lowest in the low light conditions of autumn, although biomass-normalised Pi-uptake was highest in the summer. The release of DOP was highest in November and declined to low levels in July, indicative of efficient utilization and recycling of the low levels of Pi available. Examination of daily turnover times of the different particulate pools, including estimates of phytoplankton and bacterial carbon, indicated a differing seasonal influence of autotrophs and heterotrophs in P-dynamics, with summer conditions associated with a strong bacterial influence and the early spring period with fast growing phytoplankton. These seasonal changes in autotrophic and heterotrophic influence, coupled with changes in resource availability (Pi, light) resulted in seasonal changes in the stoichiometry of NPP to daily Pi-uptake (C:P ratio); from relatively C-rich uptake in November and late April, to P-rich uptake in early April and July. Overall, these results highlight the seasonally varying influence of both autotrophic and heterotrophic components of shelf sea ecosystems on the relative uptake of C and P

Dissolution Dominates Silica Cycling in a Shelf Sea Autumn Bloom

Autumn phytoplankton blooms represent key periods of production in temperate and high‐latitude seas. Biogenic silica (bSiO2) production, dissolution, and standing stocks were determined in the Celtic Sea (United Kingdom) during November 2014. Dissolution rates were in excess of bSiO2 production, indicating a net loss of bSiO2. Estimated diatom bSiO2 contributed ≤10% to total bSiO2, with detritalbSiO2 supportingrapidSicycling.Basedontheaveragebiomass‐specificdissolutionrate(0.2day−1), 3weekswouldbeneededtodissolve99%ofthebSiO2 present.NegativenetbSiO2 productionwasassociated with low‐light conditions (<4 E·m−2·day−1). Our observations imply that dissolution dominates Si cycling during autumn, with low‐light conditions also likely to influence Si cycling during winter and early spring

Warming impairs trophic transfer efficiency in a long-term field experiment

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this recordIn natural ecosystems, the efficiency of energy transfer from resources to consumers determines the biomass structure of food webs. As a general rule, about 10% of the energy produced in one trophic level makes it up to the next1–3. Recent theory suggests this energy transfer could be further constrained if rising temperatures increase metabolic growth costs4, although experimental confirmation in whole ecosystems is lacking. We quantified nitrogen transfer efficiency (a proxy for overall energy transfer) in freshwater plankton in artificial ponds exposed to 7 years of experimental warming. We provide the first direct experimental evidence that, relative to ambient conditions, 4 °C of warming can decrease trophic transfer efficiency by up to 56%. In addition, both phytoplankton and zooplankton biomass were lower in the warmed ponds, indicating major shifts in energy uptake, transformation and transfer5,6. These new findings reconcile observed warming-driven changes in individual-level growth costs and carbon-use efficiency across diverse taxa4,7–10 with increases in the ratio of total respiration to gross primary production at the ecosystem level11–13. Our results imply that an increasing proportion of the carbon fixed by photosynthesis will be lost to the atmosphere as the planet warms, impairing energy flux through food chains, with negative implications for larger consumers and the functioning of entire ecosystems.AXA Research FundNatural Environment Research Council (NERC)European Research Council (ERC

Sex-Specific Effects of Blood Pressure Lowering Pharmacotherapy for the Prevention of Cardiovascular Disease: An Individual Participant-Level Data Meta-Analysis.

BACKGROUND: Whether the relative effects of blood pressure (BP)-lowering treatment on cardiovascular outcomes differ by sex, particularly when BP is not substantially elevated, has been uncertain. METHODS: We conducted an individual participant-level data meta-analysis of randomized controlled trials of pharmacological BP lowering. We pooled the data and categorized participants by sex, systolic BP categories in 10-mm Hg increments from <120 to ≥170 mm Hg, and age categories spanning from <55 to ≥85 years. We used fixed-effect one-stage individual participant-level data meta-analyses and applied Cox proportional hazard models, stratified by trial, to analyze the data. RESULTS: We included data from 51 randomized controlled trials involving 358 636 (42% women) participants. Over 4.2 years of median follow-up, a 5-mm Hg reduction in systolic BP decreased the risk of major cardiovascular events both in women and men (hazard ratio [95% CI], 0.92 [0.89-0.95] for women and 0.90 [0.88-0.93] for men; P for interaction, 1). There was no evidence for heterogeneity of relative treatment effects by sex for the major cardiovascular disease, its components, or across the different baseline BP categories (all P for interaction, ≥0.57). The effects in women and men were consistent across age categories and the types of antihypertensive medications (all P for interaction, ≥0.14). CONCLUSIONS: The effects of BP reduction were similar in women and men across all BP and age categories at randomization and with no evidence to suggest that drug classes had differing effects by sex. This study does not substantiate sex-based differences in BP-lowering treatment

Drought rewires the cores of food webs

Droughts are intensifying across the globe, with potentially devastating implications for freshwater ecosystems. We used new network science approaches to investigate drought impacts on stream food webs and explored potential consequences for web robustness to future perturbations. The substructure of the webs was characterized by a core of richly connected species surrounded by poorly connected peripheral species. Although drought caused the partial collapse of the food webs, the loss of the most extinction-prone peripheral species triggered a substantial rewiring of interactions within the networks’ cores. These shifts in species interactions in the core conserved the underlying core/periphery substructure and stability of the drought-impacted webs. When we subsequently perturbed the webs by simulating species loss in silico, the rewired drought webs were as robust as the larger, undisturbed webs. Our research unearths previously unknown compensatory dynamics arising from within the core that could underpin food web stability in the face of environmental perturbations

Legal determinants of external finance revisited : the inverse relationship between investor protection and societal well-being

This paper investigates relationships between corporate governance traditions and quality of life as measured by a number of widely reported indicators. It provides an empirical analysis of indicators of societal health in developed economies using a classification based on legal traditions. Arguably the most widely cited work in the corporate governance literature has been the collection of papers by La Porta et al. which has shown, inter alia, statistically significant relationships between legal traditions and various proxies for investor protection. We show statistically significant relationships between legal traditions and various proxies for societal health. Our comparative evidence suggests that the interests of investors may not be congruent with the interests of wider society, and that the criteria for judging the effectiveness of approaches to corporate governance should not be restricted to financial metrics

Blood pressure-lowering treatment for prevention of major cardiovascular diseases in people with and without type 2 diabetes: an individual participant-level data meta-analysis

BACKGROUND: Controversy exists as to whether the threshold for blood pressure-lowering treatment should differ between people with and without type 2 diabetes. We aimed to investigate the effects of blood pressure-lowering treatment on the risk of major cardiovascular events by type 2 diabetes status, as well as by baseline levels of systolic blood pressure. METHODS: We conducted a one-stage individual participant-level data meta-analysis of major randomised controlled trials using the Blood Pressure Lowering Treatment Trialists' Collaboration dataset. Trials with information on type 2 diabetes status at baseline were eligible if they compared blood pressure-lowering medications versus placebo or other classes of blood pressure-lowering medications, or an intensive versus a standard blood pressure-lowering strategy, and reported at least 1000 persons-years of follow-up in each group. Trials exclusively on participants with heart failure or with short-term therapies and acute myocardial infarction or other acute settings were excluded. We expressed treatment effect per 5 mm Hg reduction in systolic blood pressure on the risk of developing a major cardiovascular event as the primary outcome, defined as the first occurrence of fatal or non-fatal stroke or cerebrovascular disease, fatal or non-fatal ischaemic heart disease, or heart failure causing death or requiring hospitalisation. Cox proportional hazard models, stratified by trial, were used to estimate hazard ratios (HRs) separately by type 2 diabetes status at baseline, with further stratification by baseline categories of systolic blood pressure (in 10 mm Hg increments from <120 mm Hg to ≥170 mm Hg). To estimate absolute risk reductions, we used a Poisson regression model over the follow-up duration. The effect of each of the five major blood pressure-lowering drug classes, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β blockers, calcium channel blockers, and thiazide diuretics, was estimated using a network meta-analysis framework. This study is registered with PROSPERO, CRD42018099283. FINDINGS: We included data from 51 randomised clinical trials published between 1981 and 2014 involving 358 533 participants (58% men), among whom 103 325 (29%) had known type 2 diabetes at baseline. The baseline mean systolic/diastolic blood pressure of those with and without type 2 diabetes was 149/84 mm Hg (SD 19/11) and 153/88 mm Hg (SD 21/12), respectively. Over 4·2 years median follow-up (IQR 3·0-5·0), a 5 mm Hg reduction in systolic blood pressure decreased the risk of major cardiovascular events in both groups, but with a weaker relative treatment effect in participants with type 2 diabetes (HR 0·94 [95% CI 0·91-0·98]) compared with those without type 2 diabetes (0·89 [0·87-0·92]; pinteraction=0·0013). However, absolute risk reductions did not differ substantially between people with and without type 2 diabetes because of the higher absolute cardiovascular risk among participants with type 2 diabetes. We found no reliable evidence for heterogeneity of treatment effects by baseline systolic blood pressure in either group. In keeping with the primary findings, analysis using stratified network meta-analysis showed no evidence that relative treatment effects differed substantially between participants with type 2 diabetes and those without for any of the drug classes investigated. INTERPRETATION: Although the relative beneficial effects of blood pressure reduction on major cardiovascular events were weaker in participants with type 2 diabetes than in those without, absolute effects were similar. The difference in relative risk reduction was not related to the baseline blood pressure or allocation to different drug classes. Therefore, the adoption of differential blood pressure thresholds, intensities of blood pressure lowering, or drug classes used in people with and without type 2 diabetes is not warranted. FUNDING: British Heart Foundation, UK National Institute for Health Research, and Oxford Martin School

Antarctic ice sheet discharge driven by atmosphere-ocean feedbacks at the Last Glacial Termination.

Reconstructing the dynamic response of the Antarctic ice sheets to warming during the Last Glacial Termination (LGT; 18,000-11,650 yrs ago) allows us to disentangle ice-climate feedbacks that are key to improving future projections. Whilst the sequence of events during this period is reasonably well-known, relatively poor chronological control has precluded precise alignment of ice, atmospheric and marine records, making it difficult to assess relationships between Antarctic ice-sheet (AIS) dynamics, climate change and sea level. Here we present results from a highly-resolved 'horizontal ice core' from the Weddell Sea Embayment, which records millennial-scale AIS dynamics across this extensive region. Counterintuitively, we find AIS mass-loss across the full duration of the Antarctic Cold Reversal (ACR; 14,600-12,700 yrs ago), with stabilisation during the subsequent millennia of atmospheric warming. Earth-system and ice-sheet modelling suggests these contrasting trends were likely Antarctic-wide, sustained by feedbacks amplified by the delivery of Circumpolar Deep Water onto the continental shelf. Given the anti-phase relationship between inter-hemispheric climate trends across the LGT our findings demonstrate that Southern Ocean-AIS feedbacks were controlled by global atmospheric teleconnections. With increasing stratification of the Southern Ocean and intensification of mid-latitude westerly winds today, such teleconnections could amplify AIS mass loss and accelerate global sea-level rise

Ellipsoidal analysis of coordination polyhedra

The idea of the coordination polyhedron is essential to understanding chemical structure. Simple polyhedra in crystalline compounds are often deformed due to structural complexity or electronic instabilities so distortion analysis methods are useful. Here we demonstrate that analysis of the minimum bounding ellipsoid of a coordination polyhedron provides a general method for studying distortion, yielding parameters that are sensitive to various orders in metal oxide examples. Ellipsoidal analysis leads to discovery of a general switching of polyhedral distortions at symmetry-disallowed transitions in perovskites that may evidence underlying coordination bistability, and reveals a weak off-centre ‘d(5) effect' for Fe(3+) ions that could be exploited in multiferroics. Separating electronic distortions from intrinsic deformations within the low temperature superstructure of magnetite provides new insights into the charge and trimeron orders. Ellipsoidal analysis can be useful for exploring local structure in many materials such as coordination complexes and frameworks, organometallics and organic molecules