RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome

韩家淮教授课题组的这项研究揭示了活性氧簇（ROS）通过直接特异地氧化受体相互作用丝氨酸/苏氨酸激酶1（RIP1）上的三个关键的半胱氨酸，进而特异地增强RIP1在S161上的自磷酸化，从而促进坏死小体的形成和程序性细胞坏死的发生。证实了RIP1的激酶活性在程序性细胞坏死中的主要功能是自磷酸化S161，且S161就是人们长期寻找的RIP1上与坏死相关的功能性磷酸化位点。坏死小体的形成是程序性细胞坏死发生的必要复合物，而S161的磷酸化是RIP1有效募集RIP3形成有功能的坏死小体所必需的。由于ROS的产生依赖于坏死小体里的RIP3的功能，因此ROS介导了程序性坏死通路里的正反馈调控。研究阐明了ROS促进程序性细胞坏死的分子机制，回答了领域内长期存在的两个科学问题，对全面解析程序性坏死机制并协助疾病治疗具有重要意义。 张荧荧和苏晟为该论文的共同第一作者。该项研究得到了973计划和国家自然科学基金委员会重点和重大研究计划项目的经费支持。【Abstract】Necroptosis is a type of programmed cell death with great significance in many pathological processes. Tumour necrosis factor-a(TNF), a proinflammatory cytokine, is a prototypic trigger of necroptosis. It is known that mitochondrial reactive oxygen species (ROS) promote necroptosis, and that kinase activity of receptor interacting protein 1 (RIP1) is required for TNF-induced necroptosis. However, how ROS function and what RIP1 phosphorylates to promote necroptosis are largely unknown. Here we show that three crucial cysteines in RIP1 are required for sensing ROS, and ROS subsequently activates RIP1 autophosphorylation on serine residue 161 (S161). The major function of RIP1 kinase activity in TNF-induced necroptosis is to autophosphorylate S161. This specific phosphorylation then enables RIP1 to recruit RIP3 and form a functional necrosome, a central controller of necroptosis. Since ROS induction is known to require necrosomal RIP3, ROS therefore function in a positive feedback circuit that ensures effective induction of necroptosis.This work was supported by the National Natural Science Foundation of China (91029304, 31420103910, 31330047 and 81630042), the National Basic Research Program of China (973 Program; 2015CB553800, 2013CB944903, 2014CB541804), the 111 Project (B12001), the National Science Foundation of China for Fostering Talents in Basic Research (J1310027)

Ppm1b negatively regulates necroptosis through dephosphorylating ​Rip3

该研究论文发现蛋白磷酸酶Ppm1b 通过去磷酸化RIP3负调控程序性细胞坏死（necroptosis），阐明了RIP3磷酸化状态的精确调控对于细胞和机体在生理和病理状态下的存活至关重要。The auto-phosphorylation of murine ​receptor-interacting protein 3 (​Rip3) on Thr 231 and Ser 232 in the necrosome is required to trigger necroptosis. However, how ​Rip3 phosphorylation is regulated is still largely unknown. Here we identified ​protein phosphatase 1B (​Ppm1b) as a ​Rip3 phosphatase and found that ​Ppm1b restricts necroptosis in two settings: spontaneous necroptosis caused by ​Rip3 auto-phosphorylation in resting cells, and ​tumour necrosis factor-α (​TNF)-induced necroptosis in cultured cells. We revealed that ​Ppm1b selectively suppresses necroptosis through the dephosphorylation of ​Rip3, which then prevents the recruitment of ​mixed lineage kinase domain-like protein (​Mlkl) to the necrosome. We further showed that ​Ppm1b deficiency (​Ppm1bd/d) in mice enhanced ​TNF-induced death in a ​Rip3-dependent manner, and the role of ​Ppm1b in inhibiting necroptosis was evidenced by elevated ​Rip3 phosphorylation and tissue damage in the caecum of ​TNF-treated ​Ppm1bd/d mice. These data indicate that ​Ppm1b negatively regulates necroptosis through dephosphorylating ​Rip3 in vitro and in vivo

Temporal population variability in local forest communities has mixed effects on tree species richness across a latitudinal gradient

Among the local processes that determine species diversity in ecological communities, fluctuation‐dependent mechanisms that are mediated by temporal variability in the abundances of species populations have received significant attention. Higher temporal variability in the abundances of species populations can increase the strength of temporal niche partitioning but can also increase the risk of species extinctions, such that the net effect on species coexistence is not clear. We quantified this temporal population variability for tree species in 21 large forest plots and found much greater variability for higher latitude plots with fewer tree species. A fitted mechanistic model showed that among the forest plots, the net effect of temporal population variability on tree species coexistence was usually negative, but sometimes positive or negligible. Therefore, our results suggest that temporal variability in the abundances of species populations has no clear negative or positive contribution to the latitudinal gradient in tree species richness

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Global importance of large-diameter trees

Aim: To examine the contribution of large‐diameter trees to biomass, stand structure, and species richness across forest biomes. Location: Global. Time period: Early 21st century. Major taxa studied: Woody plants. Methods: We examined the contribution of large trees to forest density, richness and biomass using a global network of 48 large (from 2 to 60 ha) forest plots representing 5,601,473 stems across 9,298 species and 210 plant families. This contribution was assessed using three metrics: the largest 1% of trees ≥ 1 cm diameter at breast height (DBH), all trees ≥ 60 cm DBH, and those rank‐ordered largest trees that cumulatively comprise 50% of forest biomass. Results: Averaged across these 48 forest plots, the largest 1% of trees ≥ 1 cm DBH comprised 50% of aboveground live biomass, with hectare‐scale standard deviation of 26%. Trees ≥ 60 cm DBH comprised 41% of aboveground live tree biomass. The size of the largest trees correlated with total forest biomass (r2 = .62, p < .001). Large‐diameter trees in high biomass forests represented far fewer species relative to overall forest richness (r2 = .45, p < .001). Forests with more diverse large‐diameter tree communities were comprised of smaller trees (r2 = .33, p < .001). Lower large‐diameter richness was associated with large‐diameter trees being individuals of more common species (r2 = .17, p = .002). The concentration of biomass in the largest 1% of trees declined with increasing absolute latitude (r2 = .46, p < .001), as did forest density (r2 = .31, p < .001). Forest structural complexity increased with increasing absolute latitude (r2 = .26, p < .001). Main conclusions: Because large‐diameter trees constitute roughly half of the mature forest biomass worldwide, their dynamics and sensitivities to environmental change represent potentially large controls on global forest carbon cycling. We recommend managing forests for conservation of existing large‐diameter trees or those that can soon reach large diameters as a simple way to conserve and potentially enhance ecosystem services

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Scale-dependent relationships between tree species richness and ecosystem function in forests

The relationship between species richness and ecosystem function, as measured by productivity or biomass, is of long-standing theoretical and practical interest in ecology. This is especially true for forests, which represent a majority of global biomass, productivity and biodiversity. Here, we conduct an analysis of relationships between tree species richness, biomass and productivity in 25 forest plots of area 8–50 ha from across the world. The data were collected using standardized protocols, obviating the need to correct for methodological differences that plague many studies on this topic. We found that at very small spatial grains (0.04 ha) species richness was generally positively related to productivity and biomass within plots, with a doubling of species richness corresponding to an average 48% increase in productivity and 53% increase in biomass. At larger spatial grains (0.25 ha, 1 ha), results were mixed, with negative relationships becoming more common. The results were qualitatively similar but much weaker when we controlled for stem density: at the 0.04 ha spatial grain, a doubling of species richness corresponded to a 5% increase in productivity and 7% increase in biomass. Productivity and biomass were themselves almost always positively related at all spatial grains. Synthesis. This is the first cross-site study of the effect of tree species richness on forest biomass and productivity that systematically varies spatial grain within a controlled methodology. The scale-dependent results are consistent with theoretical models in which sampling effects and niche complementarity dominate at small scales, while environmental gradients drive patterns at large scales. Our study shows that the relationship of tree species richness with biomass and productivity changes qualitatively when moving from scales typical of forest surveys (0.04 ha) to slightly larger scales (0.25 and 1 ha). This needs to be recognized in forest conservation policy and management