Rapid changes in throughput from single motor cortex neurons to muscle activity

Motor cortex output is capable of considerable reorganization, which involves modulation of excitability within the cortex. Does such reorganization also involve changes beyond the cortex, at the level of throughput from single motor cortex neurons to muscle activity? We examined such throughput during a paradigm that provided incentive for enhancing functional connectivity from motor cortex neurons to muscles. Short-latency throughput from a recorded neuron to muscle activity not present during some behavioral epochs often appeared during others. Such changes in throughput could not always be attributed to a higher neuron firing rate, to more ongoing muscle activity, or to neuronal synchronization, indicating that reorganization of motor cortex output may involve rapid changes in functional connectivity from single motor cortex neurons to alpha-motoneuron pools.     

Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide

Type II topoisomerases (TOP2s) resolve the topological problems of DNA by transiently cleaving both strands of a DNA duplex to form a cleavage complex through which another DNA segment can be transported. Several widely prescribed anticancer drugs increase the population of TOP2 cleavage complex, which leads to TOP2-mediated chromosome DNA breakage and death of cancer cells. We present the crystal structure of a large fragment of human TOP2β complexed to DNA and to the anticancer drug etoposide to reveal structural details of drug-induced stabilization of a cleavage complex. The interplay between the protein, the DNA, and the drug explains the structure-activity relations of etoposide derivatives and the molecular basis of drug-resistant mutations. The analysis of protein-drug interactions provides information applicable for developing an isoform-specific TOP2-targeting strategy.     

Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene

Protein tyrosine phosphatase-1B (PTP-1B) has been implicated in the negative regulation of insulin signaling. Disruption of the mouse homolog of the gene encoding PTP-1B yielded healthy mice that, in the fed state, had blood glucose concentrations that were slightly lower and concentrations of circulating insulin that were one-half those of their PTP-1B+/+ littermates. The enhanced insulin sensitivity of the PTP-1B-/- mice was also evident in glucose and insulin tolerance tests. The PTP-1B-/- mice showed increased phosphorylation of the insulin receptor in liver and muscle tissue after insulin injection in comparison to PTP-1B+/+ mice. On a high-fat diet, the PTP-1B-/- and PTP-1B+/- mice were resistant to weight gain and remained insulin sensitive, whereas the PTP-1B+/+ mice rapidly gained weight and became insulin resistant. These results demonstrate that PTP-1B has a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing it as a potential therapeutic target in the treatment of type 2 diabetes and obesity.     

Erythropoiesis in the rat: differential rates of DNA synthesis and cell proliferation

Direct in vivo estimates of DNA synthesis time in early and late erythroblasts were obtained by using the H(3)- and C(14)-thymidine double-la-beling technique. A double-emulsion autoradiographic procedure was used to resolve the two isotopes. Early erythroblasts were found to proliferate at a rate about five times that of late cells. This results primarily from a shorter mean DNA synthesis time in early cells (2.5 hours) than in late cells (6.5 hours).     

深圳市罗湖区415名社区人群亚健康现况调查

目的 了解深圳市罗湖区社区居民亚健康状态现况及人群分布特点,为亚健康状态的干预提供相关依据.方法 采用多阶段随机抽样,对深圳市罗湖区10个社区健康服务中心415名社区居民采用症状自评量表(SCL-90)进行亚健康测评和身心症状分析.结果 调查对象的SCL-90总分及总均分与全国常模比较差异无统计学意义(P＞0.05),亚健康状态主要表现为躯体症状和精神病性症状;相对于女性,男性易出现偏执症状;相对于高文化人群,低文化人群易出现躯体化、抑郁、焦虑以及敌对、精神病性等障碍;相对年轻人群,老年人群易出现躯体化、强迫、焦虑及抑郁等症状.结论 深圳市罗湖区居民身心健康状况良好,但仍存在一些危害健康的亚健康症状,必须加强社区居民健康教育,对不同健康状态的人群进行相应干预.     

Hypertensive action of 18-hydroxydeoxycorticosterone

18-Hydroxydeoxycorticosterone is an adrenal steroid hormone causing salt and water retention and is secreted in greatly increased amounts in response to the pituitary hormone adrenocorticotropic hormone. Its production is abnormally high in some forms of hypertension in man and rat. Direct proof that 18-hydroxydeoxycorticosterone is capable of causing hypertension is present. Daily subcutaneous injections of 200 micrograms, a low physiological dose, significantly increase the blood pressure of unilaterally nephrectomized saline-treated rats after 2 weeks. This strengthens the hypothesis that 18-hydroxydeoxycorticosterone contributes to the etiology of hypertension, possibly by a mechanism involving stressinduced release of adrenocorticotropic hormone.     

Inactivation of TNF signaling by rationally designed dominant-negative TNF variants

Tumor necrosis factor (TNF) is a key regulator of inflammatory responses and has been implicated in many pathological conditions. We used structure-based design to engineer variant TNF proteins that rapidly form heterotrimers with native TNF to give complexes that neither bind to nor stimulate signaling through TNF receptors. Thus, TNF is inactivated by sequestration. Dominant-negative TNFs represent a possible approach to anti-inflammatory biotherapeutics, and experiments in animal models show that the strategy can attenuate TNF-mediated pathology. Similar rational design could be used to engineer inhibitors of additional TNF superfamily cytokines as well as other multimeric ligands.     

PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells

Protein tyrosine kinases and phosphatases cooperate to regulate normal immune cell function. We examined the role of PEST domain-enriched tyrosine phosphatase (PEP) in regulating T cell antigen-receptor function during thymocyte development and peripheral T cell differentiation. Although normal na?ve T cell functions were retained in pep-deficient mice, effector/memory T cells demonstrated enhanced activation of Lck. In turn, this resulted in increased expansion and function of the effector/memory T cell pool, which was also associated with spontaneous development of germinal centers and elevated serum antibody levels. These results revealed a central role for PEP in negatively regulating specific aspects of T cell development and function.     

A persistent oxygen anomaly reveals the fate of spilled methane in the deep Gulf of Mexico

Methane was the most abundant hydrocarbon released during the 2010 Deepwater Horizon oil spill in the Gulf of Mexico. Beyond relevancy to this anthropogenic event, this methane release simulates a rapid and relatively short-term natural release from hydrates into deep water. Based on methane and oxygen distributions measured at 207 stations throughout the affected region, we find that within ~120 days from the onset of release ~3.0 × 10(10) to 3.9 × 10(10) moles of oxygen were respired, primarily by methanotrophs, and left behind a residual microbial community containing methanotrophic bacteria. We suggest that a vigorous deepwater bacterial bloom respired nearly all the released methane within this time, and that by analogy, large-scale releases of methane from hydrate in the deep ocean are likely to be met by a similarly rapid methanotrophic response.