生物序列分析

这次演讲将回顾近 1 0多年来应用某些随机模型于生物序列分析的研究工作 .这些模型本身有很长的历史 ,可追溯到 3 0多年以前 ,尽管从那时起 ,这些模型已经产生了很多新的变种 .在生物序列分析中模型的作用是归总那些涉及到在生物信息学中已知的模体 (motif)或域 (domain)的信息 ,并且提供一种工具在另一序列片段中寻找模体或域的实例 (instance) .我们将逐步介绍模体模型 ,从非常简单的 ,非随机情况开始 ,进而是更复杂的情况 ,直至近来的关于模体的剖面隐马氏模型 .第二个例子是来自利用一个或两个物种的序列数据进行基因发现 ,其中广义隐马氏模型或广义成对 (pair)隐马氏模型已被证实非常有效     

The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease.

We identified three distinct mutations and six mutant alleles in GDAP1 in three families with axonal Charcot-Marie-Tooth (CMT) neuropathy and vocal cord paresis, which were previously linked to the CMT4A locus on chromosome 8q21.1. These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes.     

Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1.

Neurofibromatosis type I (NF1) is one of the most common single-gene disorders that causes learning deficits in humans. Mice carrying a heterozygous null mutation of the Nfl gene (Nfl(+/-) show important features of the learning deficits associated with NF1 (ref. 2). Although neurofibromin has several known properties and functions, including Ras GTPase-activating protein activity, adenylyl cyclase modulation and microtubule binding, it is unclear which of these are essential for learning in mice and humans. Here we show that the learning deficits of Nf1(+/-) mice can be rescued by genetic and pharmacological manipulations that decrease Ras function. We also show that the Nf1(+/-) mice have increased GABA (gamma-amino butyric acid)-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. Our results indicate that the learning deficits associated with NF1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. Our findings have implications for the development of treatments for learning deficits associated with NF1.     

The failing heart.

Cardiomyopathies are disorders affecting heart muscle that usually result in inadequate pumping of the heart. They are the most common cause of heart failure and each year kill more than 10,000 people in the United States. In recent years, there have been breakthroughs in understanding the molecular mechanisms involved in this group of conditions, with knowledge of the genetic basis for cardiomyopathies perhaps seeing the largest advance, enabling clinicians to devise improved diagnostic strategies and preparing the stage for new therapies.     

A calcium sensor in the sodium channel modulates cardiac excitability.

Sodium channels are principal molecular determinants responsible for myocardial conduction and maintenance of the cardiac rhythm. Calcium ions (Ca2+) have a fundamental role in the coupling of cardiac myocyte excitation and contraction, yet mechanisms whereby intracellular Ca2+ may directly modulate Na channel function have yet to be identified. Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. Mutations targeted to the IQ domain disrupted CaM binding and eliminated Ca2+/CaM-dependent slow inactivation, whereas the gating effects of Ca2+/CaM were restored by intracellular application of a peptide modelled after the IQ domain. A naturally occurring mutation (A1924T) in the IQ domain altered hH1 function in a manner characteristic of the Brugada arrhythmia syndrome, but at the same time inhibited slow inactivation induced by Ca2+/CaM, yielding a clinically benign (arrhythmia free) phenotype.     

复线电气化区段施工感应电对人体的危害及防护对策

感应电会对人体造成伤害。从电磁感应和静电感应原理入手，分析了产生感应电的过程，并就如何防止感应电的危害提出了防护对策，有一定实用价值。     

链条炉存在的问题及解决方法

从炉排横向配风不均、风室压火、煤层厚度阻力及锅炉燃烧等方面分析了链条锅炉存在的问题，并针对存在的问题提出了相应的解决办法。     

Microbial degradation of bitumen

Summary A blown bitumen Mexphalte R 90/40 with a high content of saturated hydrocarbons was degraded by several microorganisms to the same extent. In batch cultures ofSaccharomycopsis lipolytica, maximal biodegradation was estimated to be about 9% w/w, 3.2·10^–3 g/cm² and 3.1·10^–3 cm of degraded bitumen. The Mexphalte R 90/40 degradation rate was closely coupled to biofilm formation. The microbial activity concerned predominantly the oxidation of saturated hydrocarbons. A direct distillation bitumen 80/100 with a low content of saturated hydrocarbons and a high content of aromatic hydrocarbons and resins was more resistant to biodegradation.     

Function of DnaJ and DnaK as chaperones in origin-specific DNA binding by RepA

Heat-shock proteins are normal constituents of cells whose synthesis is increased on exposure to various forms of stress. They are interesting because of their ubiquity and high conservation during evolution. Two families of heat-shock proteins, hsp60s and hsp70s, have been implicated in accelerating protein folding and oligomerization and also in maintaining proteins in an unfolded state, thus facilitating membrane transport. The Escherichia coli hsp70 analogue, DnaK, and two other heat-shock proteins, DnaJ and GrpE, are required for cell viability at high temperatures and are involved in DNA replication of phage lambda and plasmids P1 and F. These three proteins are involved in replication in vitro of P1 DNA along with many host replication proteins and the P1 RepA initiator protein. RepA exists in a stable protein complex with DnaJ containing a dimer each of RepA and DnaJ. We report here that DnaK and DnaJ mediate an alteration in the P1 initiator protein, rendering it much more active for oriP1 DNA binding.     

Abnormal pattern detected in fragile-X patients by pulsed-field gel electrophoresis.

The fragile-X syndrome is the most frequent inherited form of mental retardation, with an incidence of 1 in 1,500 males. It is characterized by the presence of a fragile site at Xq27.3 induced in vitro by folate deprivation or by inhibitors of deoxynucleotide synthesis. Its mode of inheritance is unusual for an X-linked trait, with incomplete penetrance in both males and females. Some phenotypically normal males transmit the mutation to all their daughters who rarely express any symptoms, but penetrance is high in sons and daughters of these carrier women. Genetic and physical mapping of the Xq27-q28 region has confirmed that the disease locus is located at or very near the fragile site. Hypotheses proposed to account for the abnormalities in the inheritance of the disease include sequence rearrangements by meiotic recombination or a mutation that affects reactivation of an inactive X chromosome during differentiation of female germ cells. To detect such rearrangements, or methylation changes that may reflect a locally inactive X chromosome, we used pulsed-field gel analysis of DNA from fragile-X patients with probes close to the fragile-X locus. The probe Do33 (DXS465) detected abnormal patterns in fragile-X patients, but not in normal controls or in non-expressing male transmitters.