Accurate whole human genome sequencing using reversible terminator chemistry

DNA sequence information underpins genetic research, enabling discoveries of important biological or medical benefit. Sequencing projects have traditionally used long (400-800 base pair) reads, but the existence of reference sequences for the human and many other genomes makes it possible to develop new, fast approaches to re-sequencing, whereby shorter reads are compared to a reference to identify intraspecies genetic variation. Here we report an approach that generates several billion bases of accurate nucleotide sequence per experiment at low cost. Single molecules of DNA are attached to a flat surface, amplified in situ and used as templates for synthetic sequencing with fluorescent reversible terminator deoxyribonucleotides. Images of the surface are analysed to generate high-quality sequence. We demonstrate application of this approach to human genome sequencing on flow-sorted X chromosomes and then scale the approach to determine the genome sequence of a male Yoruba from Ibadan, Nigeria. We build an accurate consensus sequence from >30x average depth of paired 35-base reads. We characterize four million single-nucleotide polymorphisms and four hundred thousand structural variants, many of which were previously unknown. Our approach is effective for accurate, rapid and economical whole-genome re-sequencing and many other biomedical applications.     

Semi-annual oscillations in Saturn's low-latitude stratospheric temperatures

Observations of oscillations of temperature and wind in planetary atmospheres provide a means of generalizing models for atmospheric dynamics in a diverse set of planets in the Solar System and elsewhere. An equatorial oscillation similar to one in the Earth's atmosphere has been discovered in Jupiter. Here we report the existence of similar oscillations in Saturn's atmosphere, from an analysis of over two decades of spatially resolved observations of its 7.8-microm methane and 12.2-microm ethane stratospheric emissions, where we compare zonal-mean stratospheric brightness temperatures at planetographic latitudes of 3.6 degrees and 15.5 degrees in both the northern and the southern hemispheres. These results support the interpretation of vertical and meridional variability of temperatures in Saturn's stratosphere as a manifestation of a wave phenomenon similar to that on the Earth and in Jupiter. The period of this oscillation is 14.8 +/- 1.2 terrestrial years, roughly half of Saturn's year, suggesting the influence of seasonal forcing, as is the case with the Earth's semi-annual oscillation.     

A DEA-TOPSIS method for multiple criteria decision analysis in emergency management

A hybrid approach of DEA (data envelopment analysis) and TOPSIS (technique for order performance (preference) by similarity to ideal solution) is proposed for multiple criteria decision analysis in emergency management. Two DEA-based optimization models are constructed to facilitate identifying parameter information regarding criterion weights and quantifying qualitative criteria in TOPSIS. An emergency management case study utilizing data from the Emergency Management Australia (EMA) Disasters Database is provided to demonstrate the feasibility of the proposed analysis procedure.     

中国竹类真菌资源和多样性(英文)

本文作者对中国竹类真菌的研究历史、多样性、生活史、地理分布、寄主选择性、组织选择性和竹类真菌的演替作了文献综述。至今中国大陆已经报道了 189种包括 75属竹类真菌 ;此外在香港还报道了 79种包括 58属的竹类真菌。这些竹类真菌大多数是子囊菌 ,其次为担子菌和半知菌。柄锈科 (Pucciniaceae)种类多样性最丰富 ,有 2 0种 ;次之为黑痣菌科 (Phyllachoraceae)有 15种 ,炭角菌科 (Xylariaceae)有 9种 ,煤炱科 (Capnodiaceae)有 8种。     

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.     

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.     

Value-entanglement and the integrity of scientific research

Throughout much of the 20th century, philosophers of science maintained a position known as the value-free ideal, which holds that non-epistemic (e.g., moral, social, political, or economic) values should not influence the evaluation and acceptance of scientific results. In the last few decades, many philosophers of science have rejected this position by arguing that non-epistemic values can and should play an important role in scientific judgment and decision-making in a variety of contexts, including the evaluation and acceptance of scientific results. Rejecting the value-free ideal creates some new and vexing problems, however. One of these is that relinquishing this philosophical doctrine may undermine the integrity of scientific research if practicing scientists decide to allow non-epistemic values to impact their judgment and decision-making. A number of prominent philosophers of science have sought to show how one can reject the value-free ideal without compromising the integrity of scientific research. In this paper, we examine and critique their views and offer our own proposal for protecting and promoting scientific integrity. We argue that the literature on research ethics and its focus on adherence to norms, rules, policies, and procedures that together promote the aims of science can provide a promising foundation for building an account of scientific integrity. These norms, rules, policies, and procedures provide a level of specificity that is lacking in most philosophical discussions of science and values, and they suggest an important set of tasks for those working in science and values—namely, assessing, justifying, and prioritizing them. Thus, we argue that bringing together the literature on research ethics with the literature on science and values will enrich both areas and generate a more sophisticated and detailed account of scientific integrity.     

Inference to the best explanation and Norton's material theory of induction

I argue that we should consider Norton's material theory of induction as consisting of two largely independent claims. First, there is the claim that material facts license inductions - a claim which I interpret as a type of contextualism about induction. Second, there is the claim that there are no universal rules of induction. While a good case can be made for the first claim, I believe that Norton's arguments for the second claim are lacking. In particular, I spell out Norton's argument against the claim that all induction may be reduced to inference to the best explanation, and argue that it is not persuasive. Rejecting this part of Norton's theory does not however require us to abandon the first claim that material facts license inductions. In this way, I distinguish the parts of the material theory of induction we should happily accept from the parts about which we should be more skeptical.     

Forecasting using high‐frequency data: a comparison of asymmetric financial duration models

The first purpose of this paper is to assess the short‐run forecasting capabilities of two competing financial duration models. The forecast performance of the Autoregressive Conditional Multinomial–Autoregressive Conditional Duration (ACM‐ACD) model is better than the Asymmetric Autoregressive Conditional Duration (AACD) model. However, the ACM‐ACD model is more complex in terms of the computational setting and is more sensitive to starting values. The second purpose is to examine the effects of market microstructure on the forecasting performance of the two models. The results indicate that the forecast performance of the models generally decreases as the liquidity of the stock increases, with the exception of the most liquid stocks. Furthermore, a simple filter of the raw data improves the performance of both models. Finally, the results suggest that both models capture the characteristics of the micro data very well with a minimum sample length of 20 days. Copyright © 2008 John Wiley & Sons, Ltd.