Cellular mechanisms responsible for cell-to-cell spreading of prions

Prions are infectious agents that cause fatal neurodegenerative diseases. Current evidence indicates that they are essentially composed of an abnormally folded protein (PrP^Sc). These abnormal aggregated PrP^Sc species multiply in infected cells by recruiting and converting the host PrP^C protein into new PrP^Sc. How prions move from cell to cell and progressively spread across the infected tissue is of crucial importance and may provide experimental opportunity to delay the progression of the disease. In infected cells, different mechanisms have been identified, including release of infectious extracellular vesicles and intercellular transfer of PrP^Sc-containing organelles through tunneling nanotubes. These findings should allow manipulation of the intracellular trafficking events targeting PrP^Sc in these particular subcellular compartments to experimentally address the relative contribution of these mechanisms to in vivo prion pathogenesis. In addition, such information may prompt further experimental strategies to decipher the causal roles of protein misfolding and aggregation in other human neurodegenerative 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.     

PTC124 targets genetic disorders caused by nonsense mutations

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.     

Schrödinger and Dirac equations for the hydrogen atom, and Laguerre polynomials

It is usually claimed that the Laguerre polynomials were popularized by Schrödinger when creating wave mechanics; however, we show that he did not immediately identify them in studying the hydrogen atom. In the case of relativistic Dirac equations for an electron in a Coulomb field, Dirac gave only approximations, Gordon and Darwin gave exact solutions, and Pidduck first explicitly and elegantly introduced the Laguerre polynomials, an approach neglected by most modern treatises and articles. That Laguerre polynomials were not very popular before their use in quantum mechanics, probably because they had been little used in classical mathematical physics, is confirmed by the fact that, as we show, they had been rediscovered independently several times during the nineteenth century, in published or unpublished studies of Abel, Murphy, Chebyshev, and Laguerre.     

一种快速分层递阶DSmT近似推理融合方法(C)

针对超幂集空间中部分不确定焦元或者混合焦元具有信度赋值的情形,将混合焦元转化为统一形式;根据纯不确定焦元平分原则进行平分信度赋值,并将新的或固有的冲突焦元的信度赋值分配到相应的单子焦元上;利用二叉树分组技术对单子焦元进行刚性分组,实现细粒度超向粗粒度超幂集空间的映射;运用DSmT组合规则和比例冲突分配规则对粗化超幂集空...     

How Sweet It Is: Sugar,Science, and the State

Americans import large amounts of sugar, levy a stiff tariff on it, and base this tariff on the saccharine content of each sample, and thus the assessment of sugar quality for tax purposes was enormously important. It was also among the most difficult challenges of a scientific or technical nature facing the federal government in the nineteenth century, and the issues it raised would often recur as science-based quality control became an essential feature of industry.     

矩形分流墩墩体壁压特性及其空化研究

通过系统的模型试验研究了中，低佛氏数下急流越过矩形分流墩，墩后通大气的情况下，墩体壁压及其空化可能性，得到了墩顶挑射流态下，墩上游和墩体壁压分布规律；分析了墩体阻力系数与相对墩高，收缩比及控制断面佛氏数的分布规律。试验结果证明，当墩后充分供气时，墩体产生空蚀的可能性极小。     

Physical performance and Darwinian fitness in lizards

Strong evidence for a genetic basis of variation in physical performance has accumulated. Considering one of the basic tenets of evolutionary physiology--that physical performance and darwinian fitness are tightly linked--one may expect phenotypes with exceptional physiological capacities to be promoted by natural selection. Why then does physical performance remain considerably variable in human and other animal populations? Our analysis of locomotor performance in the common lizard (Lacerta vivipara) demonstrates that initial endurance (running time to exhaustion measured at birth) is indeed highly heritable, but natural selection in favour of this trait can be unexpectedly weak. A manipulation of dietary conditions unravels a proximate mechanism explaining this pattern. Fully fed individuals experience a marked reversal of performance within only one month after birth: juveniles with low endurance catch up, whereas individuals with high endurance lose their advantage. In contrast, dietary restriction allows highly endurant neonates to retain their locomotor superiority as they age. Thus, the expression of a genetic predisposition to high physical performance strongly depends on the environment experienced early in life.