Structures of APC/C(Cdh1) with substrates identify Cdh1 and Apc10 as the D-box co-receptor

The ubiquitylation of cell-cycle regulatory proteins by the large multimeric anaphase-promoting complex (APC/C) controls sister chromatid segregation and the exit from mitosis. Selection of APC/C targets is achieved through recognition of destruction motifs, predominantly the destruction (D)-box and KEN (Lys-Glu-Asn)-box. Although this process is known to involve a co-activator protein (either Cdc20 or Cdh1) together with core APC/C subunits, the structural basis for substrate recognition and ubiquitylation is not understood. Here we investigate budding yeast APC/C using single-particle electron microscopy and determine a cryo-electron microscopy map of APC/C in complex with the Cdh1 co-activator protein (APC/C(Cdh1)) bound to a D-box peptide at ～10 ? resolution. We find that a combined catalytic and substrate-recognition module is located within the central cavity of the APC/C assembled from Cdh1, Apc10--a core APC/C subunit previously implicated in substrate recognition--and the cullin domain of Apc2. Cdh1 and Apc10, identified from difference maps, create a co-receptor for the D-box following repositioning of Cdh1 towards Apc10. Using NMR spectroscopy we demonstrate specific D-box-Apc10 interactions, consistent with a role for Apc10 in directly contributing towards D-box recognition by the APC/C(Cdh1) complex. Our results rationalize the contribution of both co-activator and core APC/C subunits to D-box recognition and provide a structural framework for understanding mechanisms of substrate recognition and catalysis by the APC/C.     

作物品种区域试验的评价体系及评价方法

从作物品种区域试验的实际需要出发,提出了区域试验的试验评价和品种评价的体系,并对具体评价方法和指标作了概述和比较,指出了其中尚待解决的难点,同时论述了区域试验中应注意的问题.表1,参29.     

Decentralized Bezout Identity and a Parametrization of Decentralized Controllers for Singular Systems

1　 IntroductionConsider a singular decentralized control system of the formEx(t) =Ax(t) ∑Ni=1Biui(t)yi =Cix(t) ,i∈ N ={ 1 ,2 ,… ,N}(1 )where x(t)∈ Rn is the state vector,ui(t)∈ Rmi and yi(t)∈ Rpi are respectively the localcontrol input and measure outputvectors of the ith control channel.The matrix E may besingular,i.e.,rank(E) 相似文献   

等离子熔积成形混相瞬态场的Level-Set方法模拟

提出了一种二维等离子熔积成形瞬态模型,该模型描述了液／气界面的自由表面发展,并模拟了熔池内流体流动和传热．采用Level—Set方法处理液／气界面边界条件,考虑了熔体流动的主要驱动力——表面张力梯度、表面曲率、浮力以及工件表面的对流散热等因素．用固液相统一模型来描述固／液界面处的熔融和凝固过程,并开发了相应的软件．对高温合金K163在不同扫描速度下的熔积层表面形貌、温度场以及熔池内流场进行了模拟分析．     

基于神经网络的图像描述方法研究

自动识别和描述图像的内容是人工智能中一个重要的研究方向,它涉及计算机视觉和自然语言处理技术。针对这一难题,提出了一种由深层神经网络模型生成自然语言句子来描述图像内容的方法。该方法提出的模型由卷积神经网络(Convolution Neural Network,CNN)和循环神经网络(Recurrent Neural Network,RNN)组成,其中,CNN用来提取输入图像的特征生成固定长度的特征向量,该特征向量初始化RNN来生成句子。在MSCOCO图像描述数据集上的实验结果表明了该模型所生成句子的语法准确性和语义准确性,且优于先前的基线模型。     

Identification of low-frequency variants associated with gout and serum uric acid levels

We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 × 10(-16), at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 × 10(-21)). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 × 10(-16)). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits.     

The pathogenesis of cardiac fibrosis

Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. This review discusses the cellular effectors and molecular pathways implicated in the pathogenesis of cardiac fibrosis. Although activated myofibroblasts are the main effector cells in the fibrotic heart, monocytes/macrophages, lymphocytes, mast cells, vascular cells and cardiomyocytes may also contribute to the fibrotic response by secreting key fibrogenic mediators. Inflammatory cytokines and chemokines, reactive oxygen species, mast cell-derived proteases, endothelin-1, the renin/angiotensin/aldosterone system, matricellular proteins, and growth factors (such as TGF-β and PDGF) are some of the best-studied mediators implicated in cardiac fibrosis. Both experimental and clinical evidence suggests that cardiac fibrotic alterations may be reversible. Understanding the mechanisms responsible for initiation, progression, and resolution of cardiac fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease.     

Male-pattern baldness susceptibility locus at 20p11

We conducted a genome-wide association study for androgenic alopecia in 1,125 men and identified a newly associated locus at chromosome 20p11.22, confirmed in three independent cohorts (n = 1,650; OR = 1.60, P = 1.1 x 10(-14) for rs1160312). The one man in seven who harbors risk alleles at both 20p11.22 and AR (encoding the androgen receptor) has a sevenfold-increased odds of androgenic alopecia (OR = 7.12, P = 3.7 x 10(-15)).