Clonal selection drives genetic divergence of metastatic medulloblastoma

Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.     

Emergence as Non-Aggregativity and the Biases of Reductionisms

Most philosophical accounts of emergence are incompatible with reduction. Most scientists regard a system property as emergent relative to properties of its parts if it depends upon their mode of organization-a view consistent with reduction. Emergence is a failure of aggregativity, in which ``the whole is nothing more than the sum of its parts'. Aggregativity requires four conditions, giving powerful tools for analyzing modes of organization. Differently met for different decompositions of the system, and in different degrees, the structural conditions can provide evaluation criteria for choosing decompositions, ``natural kinds', and detecting functional localization fallacies, approximations, and various biases of vulgar reductionisms. This analysis of emergence and use of these conditions as heuristics is consistent with a broader reductionistic methodology.     

模拟结果为什么比实际更暖:简化气候模型结果（英文）

设计了一个非专业人士能够使用、最简化的气候敏感模型,用来研究人类活动所导致的全球变暖的幅度问题.在1990年的第一次IPCC评估报告中,IPCC对其报告中预测的未来全球变暖幅度很有信心,但是随后的观测结果显示全球的变暖幅度只有预测的一半.而自2001年起,全球变暖出现停滞,但是仅仅考虑到二氧化碳浓度的增加,很少有模型能够模拟出这一变化.在已出版的IPCC第五次评估报告的草稿中,IPCC大幅度削减了近期变暖的幅度,并以专家评估代替了模型预测.但是报告中关于未来气候长期变化的预测仍被保留.如果把IPCC模型的总反馈从1.9 W m–2 K–1调整到1.5 W m–2 K–1,气候敏感模型中模拟的温度将从3.2 K降至2.2 K.同时由于反馈很可能是净负反馈,更合适的估计应该是1.0 K.1.0 K是一个能够实现的增幅,21世纪的实际变暖将会小于1 K.即使燃烧所有可开采的化石燃料也不会使全球变暖的幅度超过2.2 K,这一增加幅度也将趋于平稳.本文认为解决IPCC第四、五次报告中评估方法的差异非常关键.一旦这些差异得到解决,人类活动导致的全球变暖在22世纪以及几个世纪以后的平稳态将有可能不会超过IPCC当前模型预测的1/3~1/2.     

Mutations of the BRAF gene in human cancer

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.     

Living systems analysis and neoclassical economics: Towards a new economics paradigm

This paper points out the flaws in the neoclassical economics paradigm which invalidate it as an economic policy tool and place it in the realm of illusion. An evolutionary paradigm would be more appropriate. The paper outlines how the primary regulatory processes in living systems analysis (LSA) can be applied to both the design of configurations of resources in the secondary regulatory processes and the creation of new resources so as to optimize the output of the economic system as a whole. It is the degree of government intervention which is important, and how it is integrated, not whether there will or will not be intervention.     

Human health effects of exposure to cadmium

Summary The health effects of human exposure to cadmium are discussed with emphases on intake, absorption, body burden, and excretion; osteomalacia in Japan; hypertension; and proteinuria, emphysema, osteomalacia, and cancer in workers. Elevated blood pressure has not been observed as a result of excessive exposures to cadmium in Japan or the workplace. Renal tubular dysfunction and consequent proteinuria is generally accepted as the main effect following long-term, low-level exposure to cadmium. Studies of workers show that proteinuria may develop after the first year of exposure or many years after the last exposure. Proteinuria and deterioration of renal function may continue even after cessation of exposure. The immediate health significance of low-level proteinuria is still under debate. However, there is evidence that long-term renal tubular dysfunction may lead to abnormalities of calcium metabolism and osteomalacia. The few autopsy and crosssectional studies of workers do not permit conclusions to be drawn regarding the relationship between cadmium exposure and emphysema. Retrospective and historical-prospective studies are needed to settle this important question. No conclusive evidence has been published regarding cadmium-induced cancer in humans. However, there is sufficient evidence to regard cadmium as a suspect renal and prostate carcinogen. Because of equivocal results and the absence of dose-response relationships, the studies reviewed should be used with caution in making regulatory decisions and low-dose risk assessments.     

A computer-based system for collection and analysis of circadian rest-activity data

Summary A computer-based system for collection and analysis of circadian rest-activity data was developed. The system has the advantage of a minimal amount of interface hardware and uses standard laboratory computer equipment permitting easy collection and automatic visualization and analysis of the data. The flexibility of the programs allows manipulation of the presentation format as needed and further refinements of the data analyses are possible.