Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis

Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.     

Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach

We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases.     

Drosophila Piwi functions in Hsp90-mediated suppression of phenotypic variation

Canalization, also known as developmental robustness, describes an organism's ability to produce the same phenotype despite genotypic variations and environmental influences. In Drosophila, Hsp90, the trithorax-group proteins and transposon silencing have been previously implicated in canalization. Despite this, the molecular mechanism underlying canalization remains elusive. Here using a Drosophila eye-outgrowth assay sensitized by the dominant Kr(irregular facets-1)(Kr(If-1)) allele, we show that the Piwi-interacting RNA (piRNA) pathway, but not the short interfering RNA or micro RNA pathway, is involved in canalization. Furthermore, we isolated a protein complex composed of Hsp90, Piwi and Hop, the Hsp70/Hsp90 organizing protein homolog, and we demonstrated the function of this complex in canalization. Our data indicate that Hsp90 and Hop regulate the piRNA pathway through Piwi to mediate canalization. Moreover, they point to epigenetic silencing of the expression of existing genetic variants and the suppression of transposon-induced new genetic variation as two major mechanisms underlying piRNA pathway-mediated canalization.     

Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome

3MC syndrome has been proposed as a unifying term encompassing the overlapping Carnevale, Mingarelli, Malpuech and Michels syndromes. These rare autosomal recessive disorders exhibit a spectrum of developmental features, including characteristic facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability and genital, limb and vesicorenal anomalies. Here we studied 11 families with 3MC syndrome and identified two mutated genes, COLEC11 and MASP1, both of which encode proteins in the lectin complement pathway (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3, respectively). CL-K1 is highly expressed in embryonic murine craniofacial cartilage, heart, bronchi, kidney and vertebral bodies. Zebrafish morphants for either gene develop pigmentary defects and severe craniofacial abnormalities. Finally, we show that CL-K1 serves as a guidance cue for neural crest cell migration. Together, these findings demonstrate a role for complement pathway factors in fundamental developmental processes and in the etiology of 3MC syndrome.     

青藏高原及周边地区近期冰川状态失常与灾变风险

青藏高原及周边地区是除南、北极地区之外全球最重要的冰川资源富集地.近百年来,青藏高原及周边地区冰川整体处于缓慢退缩状态,但20世纪90年代以来,这种状态发生了根本变化.以东帕米尔-喀喇昆仑-西昆仑地区冰川相对稳定甚至部分冰川前进为特征的"喀喇昆仑异常"是青藏高原及周边地区冰川状态失常的一种表现形式;而青藏高原东南地区冰川加速退缩则是这一地区冰川失常的另一种表现形式.高海拔地区的异常升温是青藏高原及周边地区冰川状态失常的重要驱动力.另外,这种冰川状态失常还与气候变暖背景下的西风和季风大气环流过程有关.随着全球变暖的加剧,冰川状态失常直接导致冰崩、冰湖溃决等灾变风险的增加.应对青藏高原及周边地区冰川状态失常的不利影响,需要进一步加强冰川变化监测与研究,加大冰川灾害防范力度.     

中国煤中金属元素成矿区带

从煤中提取锗、镓等金属已经取得实质性进展,煤逐渐成为多种战略性金属矿产的主要来源,但对煤中金属元素矿产资源尚缺乏系统的矿床学理论支撑.本文在以往煤中金属元素矿产资源研究成果的基础上,结合野外实地调查,总结了煤中锗、镓、锂、稀土资源矿化特征,并以丰富的煤中金属高异常点、区域构造背景及演化、地层沉积环境特征、煤层煤质特征等为依据,将全国煤中锗、镓等金属元素矿产资源划分为7个成矿区带,进而讨论了各成矿区带地质特征,为煤中金属元素矿产资源研究提供地质理论依据.     

基于机会约束的手术计划随机模型与算法

本文研究多服务台手术计划调度问题,考虑手术时间的不确定性,提出手术室加班时间的机会约束,以一定的概率保证病人的手术时间不超过手术室的开放时间,建立随机优化机会约束手术计划调度模型,确定手术室的开放和分配决策.基于手术时间离散的概率情景,引入0-1变量转化机会约束,得到了0-1整数线性规划的等价模型.为了提高模型的求解效率,提出两类有效不等式,并设计最长路径算法分离第二类有效不等式,利用分支切割方法进行模型求解.算例分析,基于北京某医院的实际数据,验证算法的有效性,确定最优的手术计划调度方案,有效地优化配置手术室资源.     

D2D通信中基于帕累托占优的非合作博弈功率控制算法

D2D (device to device)通信系统中传统能效函数仅能捕获瞬时数据流量,而无法获取特定时间段内数据流量的能效。为此,本文将吞吐量和终端使用时间之积作为效用函数,以终端使用时间内的吞吐量最大化为目标,并将其建模为非合作功率控制博弈(non conperative power control game,NPG)问题并得到其纳什均衡解。然而,理论分析表明该纳什均衡解非帕累托有效,故而引入功率线性代价函数来改进效用函数。最后,为了得到帕累托占优解,应用超模博弈理论研究该纳什均衡解的特性,并设计出一个低复杂度的双层迭代最优价格均衡求解算法。理论分析和仿真结果表明所提算法不仅提升系统效用值和终端使用时间,还可以保持系统公平性。     

全面二孩政策下对实施教育、医疗、就业配套措施的研究

全面二孩政策的实施与生殖健康、妇幼保健和入托入学等一系列行业与部门息息相关.通过调查居民二孩生育意愿,从教育、医疗和就业3个方面研究在全面二孩政策下人们产生的新需求,使用RPART分析和方差分析等方法深入分析调查数据,研究如何布局好二孩政策的配套措施,消除居民的生育顾虑,促进二孩政策的推行,解决我国面临的人口老龄化问题,优化人口结构.