"基因电脑克隆"软件SiClone的并行优化研究与实现

生物信息学中,发现、鉴别新基因是承上启下的一步,它既承接了过往如“基因组测序”的工作,又是未来“后基因时代”研究的基石．“基因电脑克隆”是利用计算手段发现、鉴别新基因的方法,SiClone软件实现了“基因电脑克隆”功能．本文对SiClone软件操作的数据库提出并行处理方案,并详述了基于MPI(message passing interface)平台实现的并行优化版本PSiClone．根据已得到的EST数据库,展示了软件并行版PSiClone的运行性能,试验数据库EST序列条数仅仅是NCBI(The National Center for Biotechnology Information)dbEST庞大数据库的很小部分,这也暗示我们软件的并行工作对于大数据库的比较和运算将更有应用前景．     

Oxidative changes of lipids monitored by MALDI MS

Oxidation processes of lipids are of paramount interest from many viewpoints. For instance, oxidation processes are highly important under in vivo conditions because molecules with regulatory functions are generated by oxidation of lipids or free fatty acids. Additionally, many inflammatory diseases are accompanied by lipid oxidation and, therefore, oxidation products are also useful disease (bio)markers. Thus, there is also considerable interest in methods of (oxidized) lipid analysis.Nowadays, soft ionization mass spectrometric (MS) methods are regularly used to study oxidative lipid modifications due to their high sensitivities and the extreme mass resolution. Although electrospray ionization (ESI) MS is so far most popular, applications of matrix-assisted laser desorption and ionization (MALDI) MS are increasing. This review aims to summarize the so far available data on MALDI analyses of oxidized lipids. In addition to model systems, special attention will be paid to the monitoring of oxidized lipids under in vivo conditions, particularly the oxidation of (human) lipoproteins. It is not the aim of this review to praise MALDI as the “best” method but to provide a critical survey of the advantages and drawbacks of this method.     

How well can post-traumatic stress disorder be predicted from pre-trauma risk factors? An exploratory study in the WHO World Mental Health Surveys

Post‐traumatic stress disorder (PTSD) should be one of the most preventable mental disorders, since many people exposed to traumatic experiences (TEs) could be targeted in first response settings in the immediate aftermath of exposure for preventive intervention. However, these interventions are costly and the proportion of TE‐exposed people who develop PTSD is small. To be cost‐effective, risk prediction rules are needed to target high‐risk people in the immediate aftermath of a TE. Although a number of studies have been carried out to examine prospective predictors of PTSD among people recently exposed to TEs, most were either small or focused on a narrow sample, making it unclear how well PTSD can be predicted in the total population of people exposed to TEs. The current report investigates this issue in a large sample based on the World Health Organization (WHO)'s World Mental Health Surveys. Retrospective reports were obtained on the predictors of PTSD associated with 47,466 TE exposures in representative community surveys carried out in 24 countries. Machine learning methods (random forests, penalized regression, super learner) were used to develop a model predicting PTSD from information about TE type, socio‐demographics, and prior histories of cumulative TE exposure and DSM‐IV disorders. DSM‐IV PTSD prevalence was 4.0% across the 47,466 TE exposures. 95.6% of these PTSD cases were associated with the 10.0% of exposures (i.e., 4,747) classified by machine learning algorithm as having highest predicted PTSD risk. The 47,466 exposures were divided into 20 ventiles (20 groups of equal size) ranked by predicted PTSD risk. PTSD occurred after 56.3% of the TEs in the highest‐risk ventile, 20.0% of the TEs in the second highest ventile, and 0.0‐1.3% of the TEs in the 18 remaining ventiles. These patterns of differential risk were quite stable across demographic‐geographic sub‐samples. These results demonstrate that a sensitive risk algorithm can be created using data collected in the immediate aftermath of TE exposure to target people at highest risk of PTSD. However, validation of the algorithm is needed in prospective samples, and additional work is warranted to refine the algorithm both in terms of determining a minimum required predictor set and developing a practical administration and scoring protocol that can be used in routine clinical practice.     

A SnapShot of Ubiquitin Chain Elongation: LYSINE 48-TETRA-UBIQUITIN SLOWS DOWN UBIQUITINATION*

We have explored the mechanisms of polyubiquitin chain assembly with reconstituted ubiquitination of IκBα and β-catenin by the Skp1-cullin 1-βTrCP F-box protein (SCF^βTrCP) E3 ubiquitin (Ub) ligase complex. Competition experiments revealed that SCF^βTrCP formed a complex with IκBα and that the Nedd8 modified E3-substrate platform engaged in dynamic interactions with the Cdc34 E2 Ub conjugating enzyme for chain elongation. Using “elongation intermediates” containing β-catenin linked with Ub chains of defined length, it was observed that a Lys-48-Ub chain of a length greater than four, but not its Lys-63 linkage counterparts, slowed the rate of additional Ub conjugation. Thus, the Ub chain length and linkage impact kinetic rates of chain elongation. Given that Lys-48-tetra-Ub is packed into compact conformations due to extensive intrachain interactions between Ub subunits, this topology may limit the accessibility of SCF^βTrCP/Cdc34 to the distal Ub Lys-48 and result in slowed elongation.     

Renal bioaccumulation of trace elements in urban and rural Sri Lankan populations: A preliminary study based on post mortem tissue analysis

IntroductionEnvironmental pollution, especially by toxic trace elements, is a global health concern. Heavy metals such as Cadmium (Cd), Arsenic (As) and Lead (Pb) are associated with numerous disorders and are considered by some as an aetiological factor for the Chronic Kidney Disease (CKDu¹) epidemic in Sri Lanka. This study explores patterns of bioaccumulation of six trace elements in kidneys obtained during forensic autopsies from urban and rural regions in Sri Lanka.MethodsKidney samples obtained from one urban district (n = 13) and three rural districts (n = 18) were lyophilized, microwave digested and profiled by ICP-MS techniques.Results and DiscussionThe mean age of the sampled population was 47.9 ± 11.3 yrs. Median (IQR) for Cd, As, Pb, Cr, Zn and Se were, 14.67(8.04–22.47) μg/g, 0.44(0.29–0.56) μg/g, 0.11(0.07–0.30) μg/g, 0.15(0.1096–0.3274), 25.55(17.24–39.35) μg/g and 0.52(0.37−0.84) μg/g, respectively. Cd, Zn and Se levels were significantly higher (p < 0.05) among the urban samples compared to that of the rural group. Zn and Se levels were higher among younger age groups. As, Pb and Cr did not show any significant differences between the two cohorts nor any correlations with age.ConclusionThis population-specific baseline study provides an insight into the differences in exposure to toxic trace elements and essential elements between urban and rural populations. Residents in CKDu affected rural districts did not appear to be at risk of toxic heavy metal exposure, however their renal bioaccumulation of nephroprotective essential elements was lower than urban residents.     

Bayesian Estimation of Hunting Success Rate and Harvest for Spatially Correlated Post‐stratified Data

We consider the estimation of success rate and harvest under post survey stratification at the sub‐domain (county) level. Often in this situation, the population size for the sub‐domain is unknown and the random mechanism that dictates the sample size for sub‐domains is ignored. Finding good estimators of success rate and harvest is very important for wildlife abundance. A Bayesian hierarchical model is developed to estimate both success rate and harvest simultaneously. The model includes a random sub‐domain sample size correlated with the number of successes in the sub‐domain, fixed week effects, random geographic effects, and spatial correlations between neighboring sub‐domains. The computation is done by Gibbs sampling and adaptive rejection sampling techniques. The method developed is illustrated using data from the Missouri Turkey Hunting Survey. The estimation of success rate is improved by treating the the sub‐domain sample size as a random variable instead of a fixed constant. The Bayesian model yields a reasonable harvest estimation. The spatial pattern of the estimated harvest matches the pattern of the check station data.     

Can modulators of apolipoproteinB biogenesis serve as an alternate target for cholesterol-lowering drugs?

Understanding the molecular defects underlying cardiovascular disease is necessary for the development of therapeutics. The most common method to lower circulating lipids, which reduces the incidence of cardiovascular disease, is statins, but other drugs are now entering the clinic, some of which have been approved. Nevertheless, patients cannot tolerate some of these therapeutics, the drugs are costly, and/or the treatments are approved for only rare forms of disease. Efforts to find alternative treatments have focused on other factors, such as apolipoproteinB (apoB), which transports cholesterol in the blood stream. The levels of apoB are regulated by endoplasmic reticulum (ER) associated degradation as well as by a post ER degradation pathway in model systems, and we suggest that these events provide novel therapeutic targets. We discuss first how cardiovascular disease arises and how cholesterol is regulated, and then summarize the mechanisms of action of existing treatments for cardiovascular disease. We then review the apoB biosynthetic pathway, focusing on steps that might be amenable to therapeutic interventions.     

对重症医学科进修生的临床教学体会

重症医学在我国发展较为滞后,多数重症医学科医生来自于其他专业,缺乏重症医学专业知识及临床实践经验。建立完善、科学、有效的重症医学科进修生管理和培养模式对于进一步提高危重症救治专业人才的水平至关重要。我科室通过总结多年的进修生教学经验,以"病例分析学习(case based learning,CBL)+多学科协作(multiple department team,MDT)"教学模式为主导,以病例幻灯竞赛为契机激发进修医生学习的主观能动性;以专业英语为特色;重视临床科研教学;制定规范化培训制度,实行导师负责制,开展定期考核。显著提高了重症医学科进修生的医疗及科研水平。     

Carcinogenic purine N-oxide ester modifies covalently all common bases in polynucleotides

The carcinogen 1-methyl-3-hydroxyxanthine after esterification binds covalently to polynucleotides, RNA and DNA. All four ribopolynucleotides and poly(dT) are targets. Depending on reaction conditions, covalent binding is greatest to poly(A) followed by poly(U), poly(dT), poly(G), poly(C), RNA and DNA. Maximal covalent modification of DNA is one moiety per 360 nucleotides. All modified polynucleotides, RNA and DNA, except poly guanylic acid have been enzymatically digested and the major adducts characterized as nucleosides.