Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.     

Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes

Epidemics of drug-resistant bacteria emerge worldwide, even as resistant strains frequently have reduced fitness compared to their drug-susceptible counterparts. Data from model systems suggest that the fitness cost of antimicrobial resistance can be reduced by compensatory mutations; however, there is limited evidence that compensatory evolution has any significant role in the success of drug-resistant bacteria in human populations. Here we describe a set of compensatory mutations in the RNA polymerase genes of rifampicin-resistant M. tuberculosis, the etiologic agent of human tuberculosis (TB). M. tuberculosis strains harboring these compensatory mutations showed a high competitive fitness in vitro. Moreover, these mutations were associated with high fitness in vivo, as determined by examining their relative clinical frequency across patient populations. Of note, in countries with the world's highest incidence of multidrug-resistant (MDR) TB, more than 30% of MDR clinical isolates had this form of mutation. Our findings support a role for compensatory evolution in the global epidemics of MDR TB.     

Forecasting commodity prices: GARCH,jumps, and mean reversion

In examining stochastic models for commodity prices, central questions often revolve around time‐varying trend, stochastic convenience yield and volatility, and mean reversion. This paper seeks to assess and compare alternative approaches to modelling these effects, with focus on forecast performance. Three specifications are considered: (i) random‐walk models with GARCH and normal or Student‐t innovations; (ii) Poisson‐based jump‐diffusion models with GARCH and normal or Student‐t innovations; and (iii) mean‐reverting models that allow for uncertainty in equilibrium price. Our empirical application makes use of aluminium spot and futures price series at daily and weekly frequencies. Results show: (i) models with stochastic convenience yield outperform all other competing models, and for all forecast horizons; (ii) the use of futures prices does not always yield lower forecast error values compared to the use of spot prices; and (iii) within the class of (G)ARCH random‐walk models, no model uniformly dominates the other. Copyright © 2008 John Wiley & Sons, Ltd.     

Imaging of Titan from the Cassini spacecraft

Titan, the largest moon of Saturn, is the only satellite in the Solar System with a substantial atmosphere. The atmosphere is poorly understood and obscures the surface, leading to intense speculation about Titan's nature. Here we present observations of Titan from the imaging science experiment onboard the Cassini spacecraft that address some of these issues. The images reveal intricate surface albedo features that suggest aeolian, tectonic and fluvial processes; they also show a few circular features that could be impact structures. These observations imply that substantial surface modification has occurred over Titan's history. We have not directly detected liquids on the surface to date. Convective clouds are found to be common near the south pole, and the motion of mid-latitude clouds consistently indicates eastward winds, from which we infer that the troposphere is rotating faster than the surface. A detached haze at an altitude of 500 km is 150-200 km higher than that observed by Voyager, and more tenuous haze layers are also resolved.     

基于着陆器地基测量的火星定向参数确定

火星定向参数的精确测定对约束火星内部结构以及极区干冰变化的建模具有重要意义.基于未来的火星着陆任务,仿真分析了利用双程多普勒与距离测量方法直接跟踪着陆器,解算火星定向参数所能达到的精度.结果表明,通过双程多普勒和双程测距直接跟踪火星着陆器超过200个工作日,将显著提高火星岁差、章动以及日长变化参数的精度,约800个工作日后,岁差参数精度可较目前提高5–10倍,章动参数精度可达到10–30 mas,日长变化与钱德勒摆动参数精度可收敛至5–10 mas,这一精度水平可以满足研究火星内部结构与大气物质交换的需要.通过分析不同纬度着陆器的解算结果,发现高纬度的着陆器有必要进行距离测量,以保持岁差和章动参数的解算精度.此外,研究还发现,当火星星历误差小于75 m时,双程多普勒数据解算火星定向参数的精度不受影响,而对于双程测距数据来说,只有当火星历表精度优于0.15 m时,定向参数的解算结果才具有可信性.     

Forensic Science: Current State and Perspective by a Group of Early Career Researchers

Forensic science and its influence on policing and the criminal justice system have increased since the beginning of the twentieth century. While the philosophies of the forensic science pioneers remain the pillar of modern practice, rapid advances in technology and the underpinning sciences have seen an explosion in the number of disciplines and tools. Consequently, the way in which we exploit and interpret the remnant of criminal activity are adapting to this changing environment. In order to best exploit the trace, an interdisciplinary approach to both research and investigation is required. In this paper, nine postdoctoral research fellows from a multidisciplinary team discuss their vision for the future of forensic science at the crime scene, in the laboratory and beyond. This paper does not pretend to be exhaustive of all fields of forensic science, but describes a portion of the postdoctoral fellows’ interests and skills.     

Gold nanoparticles induce nuclear damage in breast cancer cells,which is further amplified by hyperthermia

Gold nanoparticles have emerged as promising tools for cancer research and therapy, where they can promote thermal killing. The molecular mechanisms underlying these events are not fully understood. The geometry and size of gold nanoparticles can determine the severity of cellular damage. Therefore, small and big gold nanospheres as well as gold nanoflowers were evaluated side-by-side. To obtain quantitative data at the subcellular and molecular level, we assessed how gold nanoparticles, either alone or in combination with mild hyperthermia, altered the physiology of cultured human breast cancer cells. Our analyses focused on the nucleus, because this organelle is essential for cell survival. We showed that all the examined gold nanoparticles associated with nuclei. However, their biological effects were quantitatively different. Thus, depending on the shape and size, gold nanoparticles changed multiple nuclear parameters. They redistributed stress-sensitive regulators of nuclear biology, altered the nuclear morphology, reorganized nuclear laminae and envelopes, and inhibited nucleolar functions. In particular, gold nanoparticles reduced the de novo biosynthesis of RNA in nucleoli, the subnuclear compartments that produce ribosomes. While small gold nanospheres and nanoflowers, but not big gold nanospheres, damaged the nucleus at normal growth temperature, several of these defects were further exacerbated by mild hyperthermia. Taken together, the toxicity of gold nanoparticles correlated with changes in nuclear organization and function. These results emphasize that the cell nucleus is a prominent target for gold nanoparticles of different morphologies. Moreover, we demonstrated that RNA synthesis in nucleoli provides quantitative information on nuclear damage and cancer cell survival.     

Common nonsynonymous variants in PCSK1 confer risk of obesity

Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.