The DNA sequence and comparative analysis of human chromosome 5

Chromosome 5 is one of the largest human chromosomes and contains numerous intrachromosomal duplications, yet it has one of the lowest gene densities. This is partially explained by numerous gene-poor regions that display a remarkable degree of noncoding conservation with non-mammalian vertebrates, suggesting that they are functionally constrained. In total, we compiled 177.7 million base pairs of highly accurate finished sequence containing 923 manually curated protein-coding genes including the protocadherin and interleukin gene families. We also completely sequenced versions of the large chromosome-5-specific internal duplications. These duplications are very recent evolutionary events and probably have a mechanistic role in human physiological variation, as deletions in these regions are the cause of debilitating disorders including spinal muscular atrophy.     

Nanobody-induced perturbation of LFA-1/L-plastin phosphorylation impairs MTOC docking, immune synapse formation and T cell activation

The T cell integrin receptor LFA-1 orchestrates adhesion between T cells and antigen-presenting cells (APCs), resulting in formation of a contact zone known as the immune synapse (IS) which is supported by the cytoskeleton. L-plastin is a leukocyte-specific actin bundling protein that rapidly redistributes to the immune synapse following T cell–APC engagement. We used single domain antibodies (nanobodies, derived from camelid heavy-chain only antibodies) directed against functional and structural modules of L-plastin to investigate its contribution to formation of an immune synapse between Raji cells and human peripheral blood mononuclear cells or Jurkat T cells. Nanobodies that interact either with the EF hands or the actin binding domains of L-plastin both trapped L-plastin in an inactive conformation, causing perturbation of IS formation, MTOC docking towards the plasma membrane, T cell proliferation and IL-2 secretion. Both nanobodies delayed Ser⁵ phosphorylation of L-plastin which is required for enhanced bundling activity. Moreover, one nanobody delayed LFA-1 phosphorylation, reduced the association between LFA-1 and L-plastin and prevented LFA-1 enrichment at the IS. Our findings reveal subtle mechanistic details that are difficult to attain by conventional means and show that L-plastin contributes to immune synapse formation at distinct echelons.     

MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity

Following homozygosity mapping in a single kindred, we identified nonsense and missense mutations in MYO5B, encoding type Vb myosin motor protein, in individuals with microvillus inclusion disease (MVID). MVID is characterized by lack of microvilli on the surface of enterocytes and occurrence of intracellular vacuolar structures containing microvilli. In addition, mislocalization of transferrin receptor in MVID enterocytes suggests that MYO5B deficiency causes defective trafficking of apical and basolateral proteins in MVID.     

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10?12) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10?11) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10??) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10?11) and a tag SNP for NAT2 acetylation status (P = 4 × 10?11), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.     

赤泥-煤矸石基公路路面基层材料的耐久与环境性能

以拜耳法赤泥、煤矸石和粉煤灰等工业固废为基本原料在实验室制备了一种公路路面基层材料,并研究了其力学性能、耐久性能和环境性能.通过开展干湿循环以及冻融循环试验研究了该公路路面基层材料的耐久性能,并利用ICP浸出试验和放射性检测研究其环境性能.结果表明,赤泥-煤矸石基路面基层材料赤泥和煤矸石掺量之和75％、固废总掺量97％时,7d养护后无侧限抗压强度达到6 MPa以上;经过20个干湿循环后,矿渣掺量为5％的路面基层试块强度为5.98 MPa,满足国家标准;经过5个冻融循环后,路面基层材料的7d抗压强度仍然达到6.89 MPa,具有良好的耐久性能.浸出试验结果显示,浸出液中Na+浓度均符合国家饮用水标准,同时浸出液中Zn、Hg、Cu、Pb、Ni等重金属均未检测出;放射性试验结果表明,试验所用纯赤泥的放射性符合相应的国家标准.通过对该路面基层材料进行固碱分析以及能谱分析发现,硅铝体系能有效固结钠离子.此公路路面基层材料具有良好的环境效益和社会效益,拓宽了路面基层材料的选材范围.     

Seed coat thickness in the evolution of angiosperms

The seed habit represents a remarkable evolutionary advance in plant sexual reproduction. Since the Paleozoic, seeds carry a seed coat that protects, nourishes and facilitates the dispersal of the fertilization product(s). The seed coat architecture evolved to adapt to different environments and reproductive strategies in part by modifying its thickness. Here, we review the great natural diversity observed in seed coat thickness among angiosperms and its molecular regulation in Arabidopsis.     

Can we trust Einstein’s accounts of the genesis of special relativity?

There are three kinds of sources available to reconstruct the reflections that led Einstein to special relativity: a few contemporary letters and documents, his impersonal accounts of the genesis of this theory, and recollections of his own path. At first glance, contradictions within and between these sources hamper the reliability of Einstein’s accounts. Yet, a closer analysis reveals much more consistency than foreseen and helps eliminate the dubious, contradictory elements. It then becomes possible to combine the three kinds of sources to produce a minimally speculative and yet fairly coherent account of the genesis of special relativity.