Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy

Host genetics has an important role in leprosy, and variants in the shared promoter region of PARK2 and PACRG were the first major susceptibility factors identified by positional cloning. Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan, located close to the HLA complex. In both a Vietnamese familial sample and an Indian case-control sample, the low-producing lymphotoxin-alpha (LTA)+80 A allele was significantly associated with an increase in leprosy risk (P = 0.007 and P = 0.01, respectively). Analysis of an additional case-control sample from Brazil and an additional familial sample from Vietnam showed that the LTA+80 effect was much stronger in young individuals. In the combined sample of 298 Vietnamese familial trios, the odds ratio of leprosy for LTA+80 AA/AC versus CC subjects was 2.11 (P = 0.000024), which increased to 5.63 (P = 0.0000004) in the subsample of 121 trios of affected individuals diagnosed before 16 years of age. In addition to identifying LTA as a major gene associated with early-onset leprosy, our study highlights the critical role of case- and population-specific factors in the dissection of susceptibility variants in complex diseases.     

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.     

Domains specifying thrombin-receptor interaction.

Platelet activation by the coagulation protease thrombin is central to arterial thrombosis, a major cause of morbidity and mortality. We recently isolated a complementary DNA encoding the platelet thrombin receptor. The extracellular amino-terminal extension of this seven transmembrane domain receptor contains the putative thrombin cleavage site LDPR/S which is critical for receptor activation. By replacing this cleavage site with the cleavage site for enterokinase, we have created a functional enterokinase receptor. This result demonstrates that all information necessary for receptor activation is provided by receptor proteolysis. Nanomolar enterokinase concentrations are required to activate this new receptor, in contrast to the picomolar thrombin concentrations that activate wild-type thrombin receptor. We identified a receptor domain critical for thrombin's remarkable potency at its receptor. This domain resembles the carboxyl tail of the leech anticoagulant hirudin and functions by binding to thrombin's anion-binding exosite. Our studies thus define a model for thrombin-receptor interaction. The utility of this model was demonstrated by the design of novel thrombin inhibitors based on receptor peptides.     

Don't mess with the matrix.

Extracellular matrix (ECM) remodeling is critical to morphogenesis and homeostasis. The identification of inactivating mutations in a gene encoding one of its modifying enzymes, matrix metalloproteinase 2 (MMP-2), in people with a hereditary disorder in which the bones disintegrate, represents the first genetic evidence that the proteolysis of the ECM mediates human growth and development. It also underscores the need for an intricate balance between breakdown and deposition of the ECM.     

卷积码的有限响应输入序列及其码距特性

研究了卷积码的有限响应输入序列的特性和卷积码的误比特率的实用特性，提出了汉明距的一种解析求解法．利用这些特性和解析求解法，能够完全取代编码器设计中现有的计算机模拟方法，在搜索好码和计算误比特率方面具有明显的优越性，并可应用于Ｔｕｒｂｏ码中交织器的设计     

Stratigraphy and paleontology of the marine Jurrassic strata in Vietnam

Marine Jurassic strata in Vietnam have yielded characteristic ammonites and occur in: (1) west Quang Binh Province located in the eastern margin of the Nam Theun Basin (the main part of which is located in Middle Laos); (2) the Nong Son Basin situated in the north of the Kon Tum Geoblock; (3) the Da Lat Basin, the largest Jurassic basin in Vietnam, extending from the southern margin of the Kon Tum Geoblock to southeast of Ho Chi Minh City. In the first two, Lower Jurassic marine beds occupy the lower part of the section and grade up into Middle Jurassic red beds. In central Da Lat Basin the section consists completely of marine strata containing many ammonite levels dated from Early Sinemurian to Bajocian, whereas the marginal basin section is like the first two areas. Based particularly on biostratigraphical evidence, a marine transgression is considered to have entered the Indochina Block as early as the Late Hettangian. During the early transgression the fauna was distinctly endemic, showing the separate character of the basins, but since the Late Sinemurian, communication between the Da Lat and other basins was established; the marine regime in Da Lat Basin ended around the Late Bathonian.     

A loss-of-function RNA interference screen for molecular targets in cancer

The pursuit of novel therapeutic agents in cancer relies on the identification and validation of molecular targets. Hallmarks of cancer include self-sufficiency in growth signals and evasion from apoptosis; genes that regulate these processes may be optimal for therapeutic attack. Here we describe a loss-of-function screen for genes required for the proliferation and survival of cancer cells using an RNA interference library. We used a doxycycline-inducible retroviral vector for the expression of small hairpin RNAs (shRNAs) to construct a library targeting 2,500 human genes. We used retroviral pools from this library to infect cell lines representing two distinct molecular subgroups of diffuse large B-cell lymphoma (DLBCL), termed activated B-cell-like DLBCL and germinal centre B-cell-like DLBCL. Each vector was engineered to contain a unique 60-base-pair 'bar code', allowing the abundance of an individual shRNA vector within a population of transduced cells to be measured using microarrays of the bar-code sequences. We observed that a subset of shRNA vectors was depleted from the transduced cells after three weeks in culture only if shRNA expression was induced. In activated B-cell-like DLBCL cells, but not germinal centre B-cell-like DLBCL cells, shRNAs targeting the NF-kappaB pathway were depleted, in keeping with the essential role of this pathway in the survival of activated B-cell-like DLBCL. This screen uncovered CARD11 as a key upstream signalling component responsible for the constitutive IkappaB kinase activity in activated B-cell-like DLBCL. The methodology that we describe can be used to establish a functional taxonomy of cancer and help reveal new classes of therapeutic targets distinct from known oncogenes.     

基于谐波线性化的滞环电流抗扰动控制方法

滞环控制的PWM变换器是强非线性环节,有扰动时加大了控制难度。分析了滞环电流控制原理、谐波线性化方法及系统稳定性,得出滞环电流控制传递函数模型、时滞和环宽与其他参数的函数关系、环宽的计算公式。根据滞环电流控制的特点,提出了将谐波线性化方法和ITAE优化控制、背驰定律结合实现对滞环电流抗扰动控制的方法。MATLAB仿真结果表明,谐波线性化处理后的控制器能够快速跟踪信号,同时具有较强的抗扰动能力,有很强工程适用性。     

自适应语音压缩感知方法

针对固定正交基下语音信号稀疏化程度低、适应性差的问题,提出了一种自适应的语音稀疏化方法,并将其应用到语音压缩感知理论中.该方法首先采用线性预测系数的加权线性组合对语音信号进行线性预测,并以线性预测残差基作为信号基.然后,按照稀疏约束条件训练出稀疏表示的过完备字典,并交替应用1-范数稀疏约束的追踪和奇异值分解算法,达到字典与稀疏系数同步更新.该方法从信号特征入手,学习并提取特征或纹理信息,能较好地实现语音信号的稀疏化,提高语音压缩感知的重构性能.实验结果显示,与其他正交基方法相比,该方法的语音稀疏化程度高.语音质量的主客观评价结果显示,该方法具有良好的重构性能.