Inactivation of the apoptosis effector Apaf-1 in malignant melanoma

Metastatic melanoma is a deadly cancer that fails to respond to conventional chemotherapy and is poorly understood at the molecular level. p53 mutations often occur in aggressive and chemoresistant cancers but are rarely observed in melanoma. Here we show that metastatic melanomas often lose Apaf-1, a cell-death effector that acts with cytochrome c and caspase-9 to mediate p53-dependent apoptosis. Loss of Apaf-1 expression is accompanied by allelic loss in metastatic melanomas, but can be recovered in melanoma cell lines by treatment with the methylation inhibitor 5-aza-2'-deoxycytidine (5aza2dC). Apaf-1-negative melanomas are invariably chemoresistant and are unable to execute a typical apoptotic programme in response to p53 activation. Restoring physiological levels of Apaf-1 through gene transfer or 5aza2dC treatment markedly enhances chemosensitivity and rescues the apoptotic defects associated with Apaf-1 loss. We conclude that Apaf-1 is inactivated in metastatic melanomas, which leads to defects in the execution of apoptotic cell death. Apaf-1 loss may contribute to the low frequency of p53 mutations observed in this highly chemoresistant tumour type.     

The p53 tumour suppressor gene

The cell cycle is composed of a series of steps which can be negatively or positively regulated by various factors. Chief among the negative regulators is the p53 protein. Alteration or inactivation of p53 by mutation, or by its interactions with oncogene products of DNA tumour viruses, can lead to cancer. These mutations seem to be the most common genetic change in human cancers.     

Enhancements of energetic particles near the heliospheric termination shock

The spacecraft Voyager 1 is at a distance greater than 85 au from the Sun, in the vicinity of the termination shock that marks the abrupt slowing of the supersonic solar wind and the beginning of the extended and unexplored distant heliosphere. This shock is expected to accelerate 'anomalous cosmic rays', as well as to re-accelerate Galactic cosmic rays and low-energy particles from the inner Solar System. Here we report a significant increase in the numbers of energetic ions and electrons that persisted for seven months beginning in mid-2002. This increase differs from any previously observed in that there was a simultaneous increase in Galactic cosmic ray ions and electrons, anomalous cosmic rays and low-energy ions. The low-intensity level and spectral energy distribution of the anomalous cosmic rays, however, indicates that Voyager 1 still has not reached the termination shock. Rather, the observed increase is an expected precursor event. We argue that the radial anisotropy of the cosmic rays is expected to be small in the foreshock region, as is observed.     

Partial deficiency of erythrocyte spectrin in hereditary spherocytosis

Hereditary spherocytosis (HS) is a common, clinically heterogeneous haemolytic anaemia in which the primary erythrocyte defect is believed to be some abnormality in the spectrin-actin membrane skeleton, leading to loss of surface membrane. Recessively inherited spectrin deficiency with extreme erythrocyte fragility and spherocytosis has been identified in certain mutant mice and two severely anaemic humans. Although suspected, deficiency of spectrin has not been demonstrated in less severe forms of human HS. We not report the quantitation of erythrocytes spectrin by radioimmunoassay. We found that normal erythrocytes contained 240,000 copies of spectrin heterodimer, whereas erythrocytes from 14 patients with a variety of types of HS were all partially deficient in spectrin (range 74,000-200,000 copies), the magnitude of the deficiency correlating with the severity of the disease. Spectrin deficiency of varying degrees is common in HS and probably represents the principal structural defect leading to loss of surface membrane.     

藏药藏茵陈的研究进展及开发利用

本文对近年来藏药特药藏茵陈在资源调查、化学成分、药理活性、临床应用及组织培养等方面的研究进展进行了综述,并提出了开发利用藏茵陈资源的建议.     

山区小康经济-生态文明村落 -小城镇化发展与探索-北川县曲山镇黄家坝村的生态农业思路与实践

山区村镇的生态环境是影响流域全局安全与发展的基本单元.如何设计山区村镇的发展路径是涉及长江这样的大河流域生态重建的重要课题.调整产业结构·生态农业·生态重建·生态环境保护重点工程·生态教育·农业产业化与小城镇化建设的系统思维和因地制宜的规划与实施是关键.北川县黄家坝村正在进行着成功的探索与实践.该村位于长江上游嘉陵江水系湔江下游窄河谷浸蚀区.自然条件和生态环境的退化己使渴望致富的农民体验到自身利益与区域生态环境的密切关系.开始实施按生态微区的自然条件和市场需求发展具有山区地域特色的农、林、药、旅多元经济,多功能庭院经济和农村第三产业,小康经济与环境协调发展,建成生态文明示范村落的初期目标;和发展生态农业,观光农业,围绕县城拓展农业产业化规模,加快小城镇化步伐,积极参与构筑区域生态屏障,不断提高农民物质文化生活水平,确保生态环境基本单元可持续发展的中长期目标.     

HIV preferentially infects HIV-specific CD4+ T cells

HIV infection is associated with the progressive loss of CD4(+) T cells through their destruction or decreased production. A central, yet unresolved issue of HIV disease is the mechanism for this loss, and in particular whether HIV-specific CD4(+) T cells are preferentially affected. Here we show that HIV-specific memory CD4(+) T cells in infected individuals contain more HIV viral DNA than other memory CD4(+) T cells, at all stages of HIV disease. Additionally, following viral rebound during interruption of antiretroviral therapy, the frequency of HIV viral DNA in the HIV-specific pool of memory CD4(+) T cells increases to a greater extent than in memory CD4(+) T cells of other specificities. These findings show that HIV-specific CD4(+) T cells are preferentially infected by HIV in vivo. This provides a potential mechanism to explain the loss of HIV-specific CD4(+) T-cell responses, and consequently the loss of immunological control of HIV replication. Furthermore, the phenomenon of HIV specifically infecting the very cells that respond to it adds a cautionary note to the practice of structured therapy interruption.     

包含分数荷色单态和低质量磁单极的SO(16)GUT模型

本文提出并详细讨论了几个包含分数荷色单态和低质量磁单极的SO(16)GUT模型。前两个模型分别包含±e/3、±e/2的分数荷色单态,第三个模型含有低质量磁单极。文中还计算并讨论了sin~2θ_w的重正化问题。     

Calcium regulation of molluscan myosin ATPase in the absence of actin

In the myosin-linked regulatory mechanism typified by the molluscan scallop adductor muscle, contraction is controlled by Ca2+ binding to sites on the thick filament protein, myosin. The regulatory light chains of myosin heads are involved directly in this mechanism and early studies suggested that, in the absence of Ca2+, these subunits prevent the interaction of a myosin-adenosine nucleotide complex with the actin-containing thin filament. Subsequently, Ashiba et al. reported that the steady-state ATPase of molluscan myosin exhibits a limited degree of Ca2+ activation in the absence of actin. Recently, however, we have shown that steady-state ATPase activity in relaxing conditions is dominated by the unregulated molecules in the myosin preparation. Single-turnover kinetic methods are required to monitor the highly suppressed ATPase activity of the regulated population. Using the latter approach, we report here that scallop myosin ATPase is reduced about 100-fold on removal of Ca2+. The regulatory light chains maintain the relaxed state via conformational changes which suppress the product release steps, irrespective of the presence of actin.