HIV preferentially infects HIV-specific CD4+ T cells

HIV infection is associated with the progressive loss of CD4(+) T cells through their destruction or decreased production. A central, yet unresolved issue of HIV disease is the mechanism for this loss, and in particular whether HIV-specific CD4(+) T cells are preferentially affected. Here we show that HIV-specific memory CD4(+) T cells in infected individuals contain more HIV viral DNA than other memory CD4(+) T cells, at all stages of HIV disease. Additionally, following viral rebound during interruption of antiretroviral therapy, the frequency of HIV viral DNA in the HIV-specific pool of memory CD4(+) T cells increases to a greater extent than in memory CD4(+) T cells of other specificities. These findings show that HIV-specific CD4(+) T cells are preferentially infected by HIV in vivo. This provides a potential mechanism to explain the loss of HIV-specific CD4(+) T-cell responses, and consequently the loss of immunological control of HIV replication. Furthermore, the phenomenon of HIV specifically infecting the very cells that respond to it adds a cautionary note to the practice of structured therapy interruption.     

Sirtuin activators mimic caloric restriction and delay ageing in metazoans

Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.     

RNAi-mediated gene silencing in non-human primates

The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg(-1). A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.     

Dynamic Analysis of Cable Roofs Under Transient Wind:A Comparison Between Time Domain and Frequency Domain Approaches

At present, high-speed computing capabilities and advanced nonlinear dynamic finite element procedures enable detailed dynamic analysis of cable structures. Although deterministic approaches require considerable analysis time and effort in relation to modeling, running, and data processing, they seem to be the only alternative to obtain high accuracy. Detailed dynamic analysis of cable roof networks is sophisticated and requires advanced modeling expertise. This paper presents a comparison between detailed nonlinear dynamic analysis and a simplified frequency domain approach to estimate the maximum probable response of weakly nonlinear cable roofs. The approach can be considered as alternative to detailed time-domain analysis in the preliminary design phase, or can be used to validate results obtained from more elaborated numerical models. The proposed method is illustrated with two examples of cable net roofs that were also analysed in the time domain.     

An endoribonuclease-prepared siRNA screen in human cells identifies genes essential for cell division

RNA interference (RNAi) is an evolutionarily conserved defence mechanism whereby genes are specifically silenced through degradation of messenger RNAs; this process is mediated by homologous double-stranded (ds)RNA molecules. In invertebrates, long dsRNAs have been used for genome-wide screens and have provided insights into gene functions. Because long dsRNA triggers a nonspecific interferon response in many vertebrates, short interfering (si)RNA or short hairpin (sh)RNAs must be used for these organisms to ensure specific gene silencing. Here we report the generation of a genome-scale library of endoribonuclease-prepared short interfering (esi)RNAs from a sequence-verified complementary DNA collection representing 15,497 human genes. We used 5,305 esiRNAs from this library to screen for genes required for cell division in HeLa cells. Using a primary high-throughput cell viability screen followed by a secondary high content videomicroscopy assay, we identified 37 genes required for cell division. These include several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown. Thus, our study uncovers new aspects of cell division and establishes esiRNA as a versatile approach for genomic RNAi screens in mammalian cells.     

Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β

Extracellular plaques of amyloid-β and intraneuronal neurofibrillary tangles made from tau are the histopathological signatures of Alzheimer's disease. Plaques comprise amyloid-β fibrils that assemble from monomeric and oligomeric intermediates, and are prognostic indicators of Alzheimer's disease. Despite the importance of plaques to Alzheimer's disease, oligomers are considered to be the principal toxic forms of amyloid-β. Interestingly, many adverse responses to amyloid-β, such as cytotoxicity, microtubule loss, impaired memory and learning, and neuritic degeneration, are greatly amplified by tau expression. Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-β are strongly associated with Alzheimer's disease, are more toxic than amyloid-β, residues 1-42 (Aβ(1-42)) and Aβ(1-40), and have been proposed as initiators of Alzheimer's disease pathogenesis. Here we report a mechanism by which pE-Aβ may trigger Alzheimer's disease. Aβ(3(pE)-42) co-oligomerizes with excess Aβ(1-42) to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from Aβ(1-42) alone. Tau is required for cytotoxicity, and LNOs comprising 5% Aβ(3(pE)-42) plus 95% Aβ(1-42) (5% pE-Aβ) seed new cytotoxic LNOs through multiple serial dilutions into Aβ(1-42) monomers in the absence of additional Aβ(3(pE)-42). LNOs isolated from human Alzheimer's disease brain contained Aβ(3(pE)-42), and enhanced Aβ(3(pE)-42) formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. We conclude that Aβ(3(pE)-42) confers tau-dependent neuronal death and causes template-induced misfolding of Aβ(1-42) into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that Aβ(3(pE)-42) acts similarly at a primary step in Alzheimer's disease pathogenesis.     

南岭亚高山泥炭地现代有壳变形虫环境指示意义的初步研究——以湖南省大坪泥炭地为例

南岭亚高山泥炭湿地在维持华南亚热地区生态系统和区域水平衡中起关键作用,但在这一区域的古环境定量重建工作还未有系统展开.有壳变形虫是古环境定量重建的有效代用指标.本文以南岭西部的湖南大坪泥炭为例,选取23个样品点,初步开展了该地区现代有壳变形虫的种类组成变化鉴定工作,通过多元统计分析发现,水位埋深(water-table depth, WTD)是影响本地区有壳变形虫种类组成变化的最主要环境因子,这一结果与国外其他地区的研究结果相一致.据此,利用国际上广泛使用的生物-环境因子转换函数模型,初步构建了本研究区域现代泥炭湿地有壳变形虫-水位埋深转换函数关系.研究结果表明,所有转换函数预测的水位埋深与实测水位埋深都呈一定的相关性,但受制于本次采样面积小、鉴定样本量较少和水位环境梯度较窄的条件下,转换函数的预测性能还比较差.此次工作可为将来系统开展华南亚热带地区高山泥炭湿地的古水文定量重建工作奠定宝贵的基础数据.     

Demographic and environmental relations of two rare Astragalus species endemic to Washington County, Utah: Astragalus holmgreniorum and A. ampullarioides

Two endemic locoweeds of Washington County, Utah, Astragalus holmgreniorum and A. ampullarioides , were recently listed as federally endangered plant species (Federal Register 2001). They both occur in few, small populations surrounded by increasing human activity in the St. George, Utah, area. Demographic and habitat studies have been ongoing since 1992 and results of those studies are presented here. Astragalus holmgreniorum (Holmgren locoweed) is presently limited to 1 larger population and 2 smaller, isolated populations on the eastern and western edges of its range. It is a short-lived perennial that grows primarily on the Virgin limestone member of the Moenkopi Formation. Density of A. holmgreniorum over the 10-year study averaged about 2 plants per m 2 . The number of living plants of this species perhaps never exceeds 10,000. In drought years A. holmgreniorum populations are as much as 95% smaller than in years with adequate water, and few plants produce flowers that successfully contribute to the seed bank. Astragalus ampullarioides (Shivwits locoweed) occurs in 4 populations where plant density fluctuated between 0.5 and 4.8 per m 2 during our study period (average = 2.6). This locoweed is restricted to clay soils of the Chinle Formation. Direct threats to both Astragalus species include widespread urbanization, road construction, population fragmentation, and off-highway vehicle use. Indirect threats include competition from aggressive, introduced annual species such as Bromus rubens, B. tectorum, Malcolmia africana , and Erodium cicutarium . Our data show that 3 of 4 species most closely associated with these Astragalus species are introduced. Studies of seed banks and reproduction biology, as well as continued monitoring of these Astragalus species, are critically needed. Studies of the consequences of competition from alien and native species on seedling establishment of these locoweeds are especially needed.     

开发非注射给药新方法

虽然注射能很好地将药物送到作用部位,但是,没有人喜欢注射治疗,因为注射会刺破皮肤,使人感觉不舒服。每天多次的注射会造成注射部位局部损伤,令人难以接受。尽管一些口服药物疗效好,但不易被降解。不过,大多数口服药物容易被消化酶降解或者难以通过肠上皮。对于一些较大的易被破坏的药物分子,是否可以采用其他的全身给药方法？如何改进口服药物？ 英国加的夫大学威尔士药物学院的凯拉韦（Ｉ．Ｋｅｌｌａｗａｙ）预测：在未来 １０年里,通过肺部进行全身给药将成为一种十分重要的途径。胰岛素、生长激素、基因治疗药物都可以利用这…