A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL)

The importance of individual microRNAs (miRNAs) has been established in specific cancers. However, a comprehensive analysis of the contribution of miRNAs to the pathogenesis of any specific cancer is lacking. Here we show that in T-cell acute lymphoblastic leukemia (T-ALL), a small set of miRNAs is responsible for the cooperative suppression of several tumor suppressor genes. Cross-comparison of miRNA expression profiles in human T-ALL with the results of an unbiased miRNA library screen allowed us to identify five miRNAs (miR-19b, miR-20a, miR-26a, miR-92 and miR-223) that are capable of promoting T-ALL development in a mouse model and which account for the majority of miRNA expression in human T-ALL. Moreover, these miRNAs produce overlapping and cooperative effects on tumor suppressor genes implicated in the pathogenesis of T-ALL, including IKAROS (also known as IKZF1), PTEN, BIM, PHF6, NF1 and FBXW7. Thus, a comprehensive and unbiased analysis of miRNA action in T-ALL reveals a striking pattern of miRNA-tumor suppressor gene interactions in this cancer.     

Systems engineering research

In this paper, we propose selected research topics that are believed central to progress and growth in the application of systems engineering （SE）. As a professional activity, and as an intellectual activity, systems engineering has strong links to such associated disciplines as decision analysis, operation research, project management, quality management, and systems design. When focussing on systems engineering research, we should distinguish between subjects that are of systems engineering essence and others that more closely correspond to those that are more relevant for related disciplines.     

A single gene network accurately predicts phenotypic effects of gene perturbation in Caenorhabditis elegans

The fundamental aim of genetics is to understand how an organism's phenotype is determined by its genotype, and implicit in this is predicting how changes in DNA sequence alter phenotypes. A single network covering all the genes of an organism might guide such predictions down to the level of individual cells and tissues. To validate this approach, we computationally generated a network covering most C. elegans genes and tested its predictive capacity. Connectivity within this network predicts essentiality, identifying this relationship as an evolutionarily conserved biological principle. Critically, the network makes tissue-specific predictions-we accurately identify genes for most systematically assayed loss-of-function phenotypes, which span diverse cellular and developmental processes. Using the network, we identify 16 genes whose inactivation suppresses defects in the retinoblastoma tumor suppressor pathway, and we successfully predict that the dystrophin complex modulates EGF signaling. We conclude that an analogous network for human genes might be similarly predictive and thus facilitate identification of disease genes and rational therapeutic targets.     

A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia

We report the first identified mutation in the gene encoding human cytochrome c (CYCS). Glycine 41, invariant throughout eukaryotes, is substituted by serine in a family with autosomal dominant thrombocytopenia caused by dysregulated platelet formation. The mutation yields a cytochrome c variant with enhanced apoptotic activity in vitro. Notably, the family has no other phenotypic indication of abnormal apoptosis, implying that cytochrome c activity is not a critical regulator of most physiological apoptosis.     

English engineer John Smeaton's experimental method(s): Optimisation,hypothesis testing and exploratory experimentation

In this paper I provide a detailed account of eighteenth-century engineer John Smeaton's experimental methods, with the aim of bringing our understanding of his work into line with recent research in the history and philosophy of science. Starting from his use of the technique of parameter variation, I identify three distinct methodological aims in the research he carried out on waterwheels, windmills and hydraulic mortars. These aims are: optimisation, hypothesis testing and maxim generation. The main claim of this paper is that Smeaton did more than merely improve engineering methods by systematising earlier artisanal approaches, which is the classic view of Smeaton's method developed by historians of technology in the 1990s. I argue instead that his approach bridged the divide between science and technology, by integrating both hypothesis testing and exploratory experimentation. This is borne out, in particular, by the way that Smeaton emphasised the exploratory side of the work he published in the Philosophical Transactions, in contrast to his account of the construction of the Eddystone lighthouse, which was aimed at a broader, non-specialist public. I contribute to recent research on exploratory experimentation by showing – in line with other work on this topic – that exploratory experimentation is not incompatible with hypothesis testing. This new perspective on Smeaton's method will hopefully lead to further research and new insights into the relation between science and technology at the start of the Industrial Revolution.     

Stonefly (Plecoptera) records from the basin ranges of Nevada and Utah

Distributional records are given for 40 stonefly species on 15 isolated mountain ranges in Nevada and Utah.     

ESTIMATING THE NONCENTRALITY PARAMETER OF A t-DISTRIBUTION

Inadmissibility of a traditional class of noncentrality parameter esti-mators under quadratic loss is established.The result is heuristically motivatedby the form of generalized Bayes estimators and is proved via unbiased estimatorsof the risk function and a solution to an integro-differential inequality.