Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of α-dystroglycan

Walker-Warburg syndrome (WWS) is an autosomal recessive multisystem disorder characterized by complex eye and brain abnormalities with congenital muscular dystrophy (CMD) and aberrant a-dystroglycan glycosylation. Here we report mutations in the ISPD gene (encoding isoprenoid synthase domain containing) as the second most common cause of WWS. Bacterial IspD is a nucleotidyl transferase belonging to a large glycosyltransferase family, but the role of the orthologous protein in chordates is obscure to date, as this phylum does not have the corresponding non-mevalonate isoprenoid biosynthesis pathway. Knockdown of ispd in zebrafish recapitulates the human WWS phenotype with hydrocephalus, reduced eye size, muscle degeneration and hypoglycosylated a-dystroglycan. These results implicate ISPD in a-dystroglycan glycosylation in maintaining sarcolemma integrity in vertebrates.     

miRNA regulation of Sdf1 chemokine signaling provides genetic robustness to germ cell migration

microRNAs (miRNAs) function as genetic rheostats to control gene output. Based on their role as modulators, it has been postulated that miRNAs canalize development and provide genetic robustness. Here, we uncover a previously unidentified regulatory layer of chemokine signaling by miRNAs that confers genetic robustness on primordial germ cell (PGC) migration. In zebrafish, PGCs are guided to the gonad by the ligand Sdf1a, which is regulated by the sequestration receptor Cxcr7b. We find that miR-430 regulates sdf1a and cxcr7 mRNAs. Using target protectors, we demonstrate that miR-430-mediated regulation of endogenous sdf1a (also known as cxcl12a) and cxcr7b (i) facilitates dynamic expression of sdf1a by clearing its mRNA from previous expression domains, (ii) modulates the levels of the decoy receptor Cxcr7b to avoid excessive depletion of Sdf1a and (iii) buffers against variation in gene dosage of chemokine signaling components to ensure accurate PGC migration. Our results indicate that losing miRNA-mediated regulation can expose otherwise buffered genetic lesions leading to developmental defects.     

Melatonin and mitochondrial function during ischemia/reperfusion injury

Ischemia/reperfusion (IR) injury occurs in many organs and tissues, and contributes to morbidity and mortality worldwide. Melatonin, an endogenously produced indolamine, provides a strong defense against IR injury. Mitochondrion, an organelle for ATP production and a decider for cell fate, has been validated to be a crucial target for melatonin to exert its protection against IR injury. In this review, we first clarify the mechanisms underlying mitochondrial dysfunction during IR and melatonin’s protection of mitochondria under this condition. Thereafter, special focus is placed on the protective actions of melatonin against IR injury in brain, heart, liver, and others. Finally, we explore several potential future directions of research in this area. Collectively, the information compiled here will serve as a comprehensive reference for the actions of melatonin in IR injury identified to date and will hopefully aid in the design of future research and increase the potential of melatonin as a therapeutic agent.     

基于离散时间风险模型下的亏损破产概率的研究

新定义离散时间风险模型下的亏损破产概率为初始盈余u,亏损额度不大于y的破产概率。利用离散时间风险模型下的终时破产概率的计算规律,得到初始盈余水平在不同条件下的亏损破产概率的具体表达形式,并且数值模拟了一定条件下不同参数取值对亏损破产概率的影响情况,数据表明当亏损边界固定时,随着初始盈余水平的增加,亏损破产概率水平逐渐减小;当初始盈余水平固定时,随着亏损边界的增加,亏损破产概率水平逐渐增多。     

TiC对原位自生钛基复合材料高温变形的影响

通过等温热压模拟试验研究了原位自生5% TiC(体积分数,下同)颗粒增强Ti-1100复合材料在1000~1150℃的热变形行为.在不同的温度区间内计算了原位自生5%TiC/Ti-1100复合材料的塑性变形激活能.结果发现,TiC颗粒对钛基材料的热变形行为有明显影响.复合材料的塑性变形激活能在不同的温度区间内变化.在1000℃,复合材料的表观塑性变形激活能为536 kJ/mol,显著高于纯钛合金的激活能;在1150℃,计算出的复合材料表观塑性变形激活能为245.2 kJ/mol,略大于纯钛合金的激活能.变形激活能的显著差别显示复合材料的变形机制发生了变化.在此温度区间内,TiC/Ti复合材料的变形机制受到TiC颗粒以及基体中α/β相比例的影响.     

Na+ binding to meizothrombin desF1

Meizothrombin is the physiologically active intermediate generated by a single cleavage of prothrombin at R320 to separate the A and B chains. Recent evidence has suggested that meizothrombin, like thrombin, is a Na(+)-activated enzyme. In this study we present the first X-ray crystal structure of human meizothrombin desF1 solved in the presence of the active site inhibitor PPACK at 2.1 A resolution. The structure reveals a Na(+) binding site whose architecture is practically identical to that of human thrombin. Stopped-flow measurements of Na(+) binding to meizothrombin desF1 document a slow phase of fluorescence change with a k(obs) decreasing hyperbolically with increasing [Na(+)], consistent with the existence of three conformations in equilibrium, E*, E and E:Na(+), as for human thrombin. Evidence that meizothrombin exists in multiple conformations provides valuable new information for studies of the mechanism of prothrombin activation.     

X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations

Cornelia de Lange syndrome is a multisystem developmental disorder characterized by facial dysmorphisms, upper limb abnormalities, growth delay and cognitive retardation. Mutations in the NIPBL gene, a component of the cohesin complex, account for approximately half of the affected individuals. We report here that mutations in SMC1L1 (also known as SMC1), which encodes a different subunit of the cohesin complex, are responsible for CdLS in three male members of an affected family and in one sporadic case.     

非线性方程求解的新算法

采用黄金分割思想,构造了一种非线性代数方程求解的新算法.该算法在迭代过程中不用计算导数,且至少二阶收敛.实验表明,该算法比弦割法和抛物线法的收敛速度更快.     

摄影与生活

在我们居住的城市中，每天都可以看到大量的影像，几乎很少有任何别的东西可以这么满目皆是了。在我们国家的历史上，也没有任何一种社会形态中，曾经出现过这么集中、这么密集的视觉影像信息。摄影已成为人们工作、生活的一个重要角色。