四位中国数学大师的创新精神及其启示

对华罗庚、丘成桐、吴文俊、谷超豪四位中国数学大师的创新精神进行了全面的分析与阐释,在此基础上得到几点重要启示.     

Femtosecond X-ray protein nanocrystallography

X-ray crystallography provides the vast majority of macromolecular structures, but the success of the method relies on growing crystals of sufficient size. In conventional measurements, the necessary increase in X-ray dose to record data from crystals that are too small leads to extensive damage before a diffraction signal can be recorded. It is particularly challenging to obtain large, well-diffracting crystals of membrane proteins, for which fewer than 300 unique structures have been determined despite their importance in all living cells. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes. More than 3,000,000 diffraction patterns were collected in this study, and a three-dimensional data set was assembled from individual photosystem I nanocrystals (～200?nm to 2?μm in size). We mitigate the problem of radiation damage in crystallography by using pulses briefer than the timescale of most damage processes. This offers a new approach to structure determination of macromolecules that do not yield crystals of sufficient size for studies using conventional radiation sources or are particularly sensitive to radiation damage.     

Initial genome sequencing and analysis of multiple myeloma

Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.     

对发展远程教育的几点建议

基于计算机网络的现代远程教育是随着现代信息技术的发展而产生的一种新型教育方式,发展远程教育是现代教育的需要.论及了我国目前远程教育存在的问题及对发展远程教育的思考.     

Ocular dominance shift in kitten visual cortex caused by imbalance in retinal electrical activity

Monocular lid suture during the sensitive period early in the life of a kitten disrupts normal development of inputs from the two eyes to the visual cortex, causing a decrease in the fraction of cortical cells responding to the deprived eye. Such an ocular dominance shift has been assumed to depend on patterned visual experience, because no change in cortical physiology is produced by inequalities between the two eyes in retinal illumination or temporally modulated diffuse light stimulation. A higher-level process, involving gating signals from areas outside striate cortex, has been proposed to ensure that sustained changes in synaptic efficacy occur only in response to behaviourally significant visual inputs. To test whether such a process is necessary for ocular dominance plasticity, we treated 4-week-old kittens with visual deprivation and monocular tetrodotoxin (TTX) injections to create an imbalance in the electrical activities of the two retinas in the absence of patterned vision. After 1 week of treatment we determined the ocular dominance distribution of single units in primary visual cortex. In all kittens studied, a significant ocular dominance shift was found. In addition to this physiological change, there was an anatomical change in the lateral geniculate nucleus, where cells were larger in laminae receiving input from the more active eye. Our results indicate that patterned vision is not necessary for visual cortical plasticity, and that an imbalance in spontaneous retinal activity alone can produce a significant ocular dominance shift.     

我国工业化与城市化关系的互动与协调

城市化是人类社会发展的必然趋势，是人类社会明进步的基本标志，世界各国实现城市化的历史与现实表明：工业化是城市化的直接原因和物质载体，而城市化又是工业化的必然结果。两相互联系，相互促进。我国要实现城市化的历史重任，必须正确处理工业化与城市化的关系，促进工业化与城市化的协调发展。     

基于分位数回归模型的资产价格泡沫对市场风险的影响

资产"泡沫"是指资产的市场价格对其基础价值的偏离.泡沫的存在会改变投资者预期,助推资产价格上涨,使投资者低估风险,危及市场稳定运行.在度量沪深股票市场中的泡沫程度的基础上,应用分位数回归模型研究了泡沫对市场风险的影响.得出以下结论:泡沫与市场风险存在相关关系,泡沫越大市场风险越大,且泡沫对长期风险的影响比短期风险更大.市场风险受到短期泡沫和长期泡沫的共同影响.泡沫在短期内助推资产价格上涨,使短期内市场风险下降;而长期来看,泡沫破裂可能性增大,市场风险增加.     

Substrate-targeting gamma-secretase modulators

Selective lowering of Abeta42 levels (the 42-residue isoform of the amyloid-beta peptide) with small-molecule gamma-secretase modulators (GSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer's disease. To identify the target of these agents we developed biotinylated photoactivatable GSMs. GSM photoprobes did not label the core proteins of the gamma-secretase complex, but instead labelled the beta-amyloid precursor protein (APP), APP carboxy-terminal fragments and amyloid-beta peptide in human neuroglioma H4 cells. Substrate labelling was competed by other GSMs, and labelling of an APP gamma-secretase substrate was more efficient than a Notch substrate. GSM interaction was localized to residues 28-36 of amyloid-beta, a region critical for aggregation. We also demonstrate that compounds known to interact with this region of amyloid-beta act as GSMs, and some GSMs alter the production of cell-derived amyloid-beta oligomers. Furthermore, mutation of the GSM binding site in the APP alters the sensitivity of the substrate to GSMs. These findings indicate that substrate targeting by GSMs mechanistically links two therapeutic actions: alteration in Abeta42 production and inhibition of amyloid-beta aggregation, which may synergistically reduce amyloid-beta deposition in Alzheimer's disease. These data also demonstrate the existence and feasibility of 'substrate targeting' by small-molecule effectors of proteolytic enzymes, which if generally applicable may significantly broaden the current notion of 'druggable' targets.     

The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor

Mammalian Toll-like receptors (TLRs) 3, 7, 8 and 9 initiate immune responses to infection by recognizing microbial nucleic acids; however, these responses come at the cost of potential autoimmunity owing to inappropriate recognition of self nucleic acids. The localization of TLR9 and TLR7 to intracellular compartments seems to have a role in facilitating responses to viral nucleic acids while maintaining tolerance to self nucleic acids, yet the cell biology regulating the transport and localization of these receptors remains poorly understood. Here we define the route by which TLR9 and TLR7 exit the endoplasmic reticulum and travel to endolysosomes in mouse macrophages and dendritic cells. The ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. Notably, although both the full-length and cleaved forms of TLR9 are capable of binding ligand, only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. Furthermore, conditions that prevent receptor proteolysis, including forced TLR9 surface localization, render the receptor non-functional. We propose that ectodomain cleavage represents a strategy to restrict receptor activation to endolysosomal compartments and prevent TLRs from responding to self nucleic acids.     

The genome of the choanoflagellate Monosiga brevicollis and the origin of metazoans

Choanoflagellates are the closest known relatives of metazoans. To discover potential molecular mechanisms underlying the evolution of metazoan multicellularity, we sequenced and analysed the genome of the unicellular choanoflagellate Monosiga brevicollis. The genome contains approximately 9,200 intron-rich genes, including a number that encode cell adhesion and signalling protein domains that are otherwise restricted to metazoans. Here we show that the physical linkages among protein domains often differ between M. brevicollis and metazoans, suggesting that abundant domain shuffling followed the separation of the choanoflagellate and metazoan lineages. The completion of the M. brevicollis genome allows us to reconstruct with increasing resolution the genomic changes that accompanied the origin of metazoans.