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.     

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.     

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.     

有限单元法 并行稀疏静力学和本征值求解

有限单元法（FEM）及其软件是求解大型工程应用的最有效工具之一。在这类应用问题中，有效的方程和本征值求解器扮演着至关重要的角色。稀疏矩阵及其求解技术已经足够成熟并在商用软件中实现。然而，截至目前，关于稀疏系数方程求解、Lanczos域分解或FEM并行计算的详细介绍的书籍尚不多见。     

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.     

Novel Criteria for Exponential Stability of Linear Non-Autonomous Functional Differential Equations

General linear non-autonomous functional differential equations are considered. Explicit criteria for exponential stability are given. Furthermore, the authors present an explicit robust stability bound for systems subject to time-varying perturbations. Two examples are given to illustrate the obtained results.