Recombination: Multiply infected spleen cells in HIV patients

The genome of the human immunodeficiency virus is highly prone to recombination, although it is not obvious whether recombinants arise infrequently or whether they are constantly being spawned but escape identification because of the massive and rapid turnover of virus particles. Here we use fluorescence in situ hybridization to estimate the number of proviruses harboured by individual splenocytes from two HIV patients, and determine the extent of recombination by sequencing amplified DNA from these cells. We find an average of three or four proviruses per cell and evidence for huge numbers of recombinants and extensive genetic variation. Although this creates problems for phylogenetic analyses, which ignore recombination effects, the intracellular variation may help to broaden immune recognition.     

CO2浓度变化对欧洲区域气候影响的数值研究

给出了大气中二氧化碳浓度加倍引起的德国南部及邻近阿尔卑斯山区5年1月和 7月气温和降水率变化的模拟结果.模式采用在大气环流模式(ECHAM3)中嵌套的中尺度气候和化学模式(MCCM).模拟结果显示:区域平均气温(地面上2 m处温度)的5年平均1月增加0.8℃,7月增加4.7℃;区域降水率的5年逐月平均则显示1月无变化,7月减少40 %.讨论了气温、降水率以及降水频率等变化的空间分布,也给出了控制试验(1×CO2) 和敏感试验(2×CO2)中气温和降水率的年际变化模拟结果.     

CO_2浓度变化对欧洲区域气候影响的数值研究

给出了大气中二氧化碳浓度加倍引起的德国南部及邻近阿尔卑斯山区5年1月和 7月气温和降水率变化的模拟结果.模式采用在大气环流模式(ECHAM3)中嵌套的中尺度气候 和化学模式(MCCM).模拟结果显示:区域平均气温(地面上２ ｍ处温度)的5年平均1月增 加0.8℃,7月增加4.7℃;区域降水率的5年逐月平均则显示1月无变化,7月减少40 ％.讨论了气温、降水率以及降水频率等变化的空间分布,也给出了控制试验(1×CO2) 和敏感试验(2×CO2)中气温和降水率的年际变化模拟结果.     

Prevention of graft-versus-host-disease with preserved graft-versus-leukemia-effect by ex vivo and in vivo modulation of CD4+ T-cells

This is the first report showing that an epitope-specific ex vivo modulation of an allogeneic hematopoietic stem cell graft by the anti-human CD4 antibody MAX.16H5 IgG₁ simultaneously facilitates the anti-tumor capacity of the graft (Graft-versus-leukemia effect, GvL) and the long-term suppression of the deleterious side effect Graft-versus-host-disease (GvHD). To distinguish and consolidate GvL from GvHD, the anti-human CD4 antibody MAX16.H5 IgG₁ was tested in murine GvHD and tumor models. The survival rate was significantly increased in recipients receiving a MAX.16H5 IgG₁ short-term (2 h) pre-incubated graft even when tumor cells were co-transplanted or when recipient mice were treated by MAX.16H5 IgG₁ before transplantation. After engraftment, regulatory T-cells are generated only supporting the GvL effect. It was also possible to transfer the immune tolerance from GvHD-free recipient chimeras into third party recipient mice without the need of reapplication of MAX.16H5 IgG₁ anti-human CD4 antibodies. These findings are also benefical for patients with leukemia when no matched related or unrelated donor is available and provides a safer allogeneic HSCT, which is more effective against leukemia. It also facilitates allogeneic (stem) cell transplantations for other indications (e.g., autoimmune-disorders).     

TNF-induced necroptosis and PARP-1-mediated necrosis represent distinct routes to programmed necrotic cell death

Programmed necrosis is important in many (patho)physiological settings. For specific therapeutic intervention, however, a better knowledge is required whether necrosis occurs through one single “core program” or through several independent pathways. Previously, the poly(ADP-ribose) polymerase (PARP) pathway has been suggested as a crucial element of tumor necrosis factor (TNF)-mediated necroptosis. Here, we show that TNF-induced necroptosis and the PARP pathway represent distinct and independent routes to programmed necrosis. First, DNA-alkylating agents such as 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) or methyl methanesulfonate rapidly activate the PARP pathway, whereas this is a late and secondary event in TNF-induced necroptosis. Second, inhibition of the PARP pathway does not protect against TNF-induced necroptosis, e.g., the PARP-1 inhibitor 3-AB prevented MNNG- but not TNF-induced adenosine-5′-triposphate depletion, translocation of apoptosis-inducing factor, and necrosis. Likewise, olaparib, a more potent and selective PARP-1 inhibitor failed to block TNF-induced necroptosis, identical to knockdown/knockout of PARP-1, pharmacologic and genetic interference with c-Jun N-terminal kinases and calpain/cathepsin proteases as further components of the PARP pathway. Third, interruption of TNF-induced necroptosis by interference with ceramide generation, RIP1 or RIP3 function or by the radical scavenger butylated hydroxyanisole did not prevent programmed necrosis through the PARP pathway. In summary, our results suggest that the currently established role of the PARP pathway in TNF-induced necroptosis needs to be revised, with consequences for the design of future therapeutic strategies.     

Regioselective reactions for programmable resveratrol oligomer synthesis

Although much attention has been devoted to resveratrol, a unique polyphenol produced by plants and credited as potentially being responsible for the 'French paradox'--the observation that French people have a relatively low incidence of coronary heart disease, even though their diet is high in saturated fats--the oligomers of resveratrol have been largely ignored despite their high biological activity. Challenges in achieving their isolation in sufficient quantity from natural sources, coupled with an inability to prepare them easily synthetically, are seen as the main obstacles. Here we report a programmable, controlled and potentially scalable synthesis of the resveratrol family via a three-stage design. The synthetic approach requires strategy- and reagent-guided chemical functionalizations to differentiate two distinct cores possessing multiple sites with the same or similar reactivity, ultimately leading to five higher-order natural products. This work demonstrates that challenging, positionally selective functionalizations of complex materials are possible where biosynthetic studies have indicated otherwise, it provides materials and tools with which to unlock the full biochemical potential of this family of natural products, and it affords an intellectual framework within which other oligomeric families could potentially be accessed.     

Molecular chaperones in protein folding and proteostasis

Most proteins must fold into defined three-dimensional structures to gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance.     

Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences

We report a high-quality draft of the genome sequence of the grey, short-tailed opossum (Monodelphis domestica). As the first metatherian ('marsupial') species to be sequenced, the opossum provides a unique perspective on the organization and evolution of mammalian genomes. Distinctive features of the opossum chromosomes provide support for recent theories about genome evolution and function, including a strong influence of biased gene conversion on nucleotide sequence composition, and a relationship between chromosomal characteristics and X chromosome inactivation. Comparison of opossum and eutherian genomes also reveals a sharp difference in evolutionary innovation between protein-coding and non-coding functional elements. True innovation in protein-coding genes seems to be relatively rare, with lineage-specific differences being largely due to diversification and rapid turnover in gene families involved in environmental interactions. In contrast, about 20% of eutherian conserved non-coding elements (CNEs) are recent inventions that postdate the divergence of Eutheria and Metatheria. A substantial proportion of these eutherian-specific CNEs arose from sequence inserted by transposable elements, pointing to transposons as a major creative force in the evolution of mammalian gene regulation.     

构建基于SEURAT的化学/生物信息系统(英文)

在现代药物研发中,科学家们每天都会面对海量的数据。因此,能系统化的组织并迅速处理这些数据成为研发新药的关键。对于药物研发所需的生物化学数据的存储、检索等技术已经在过去几十年中逐步发展起来,但对中小型的药物研发企业来说,要将这些技术组合起来,建立真正系统化的解决方案,仍旧耗资巨大。依据日常所需,基于Schrodinger公司的SEURAT软件,建立了一个公司内部的化学/生物信息系统,管理了公司内部药物研发所产生的海量数据,满足了广大科研人员的日常需求。