Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing

Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.     

More extreme swings of the South Pacific convergence zone due to greenhouse warming

The South Pacific convergence zone (SPCZ) is the Southern Hemisphere's most expansive and persistent rain band, extending from the equatorial western Pacific Ocean southeastward towards French Polynesia. Owing to its strong rainfall gradient, a small displacement in the position of the SPCZ causes drastic changes to hydroclimatic conditions and the frequency of extreme weather events--such as droughts, floods and tropical cyclones--experienced by vulnerable island countries in the region. The SPCZ position varies from its climatological mean location with the El Ni?o/Southern Oscillation (ENSO), moving a few degrees northward during moderate El Ni?o events and southward during La Ni?a events. During strong El Ni?o events, however, the SPCZ undergoes an extreme swing--by up to ten degrees of latitude toward the Equator--and collapses to a more zonally oriented structure with commensurately severe weather impacts. Understanding changes in the characteristics of the SPCZ in a changing climate is therefore of broad scientific and socioeconomic interest. Here we present climate modelling evidence for a near doubling in the occurrences of zonal SPCZ events between the periods 1891-1990 and 1991-2090 in response to greenhouse warming, even in the absence of a consensus on how ENSO will change. We estimate the increase in zonal SPCZ events from an aggregation of the climate models in the Coupled Model Intercomparison Project phases 3 and 5 (CMIP3 and CMIP5) multi-model database that are able to simulate such events. The change is caused by a projected enhanced equatorial warming in the Pacific and may lead to more frequent occurrences of extreme events across the Pacific island nations most affected by zonal SPCZ events.     

High-throughput decoding of antitrypanosomal drug efficacy and resistance

The concept of disease-specific chemotherapy was developed a century ago. Dyes and arsenical compounds that displayed selectivity against trypanosomes were central to this work, and the drugs that emerged remain in use for treating human African trypanosomiasis (HAT). The importance of understanding the mechanisms underlying selective drug action and resistance for the development of improved HAT therapies has been recognized, but these mechanisms have remained largely unknown. Here we use all five current HAT drugs for genome-scale RNA interference target sequencing (RIT-seq) screens in Trypanosoma brucei, revealing the transporters, organelles, enzymes and metabolic pathways that function to facilitate antitrypanosomal drug action. RIT-seq profiling identifies both known drug importers and the only known pro-drug activator, and links more than fifty additional genes to drug action. A bloodstream stage-specific invariant surface glycoprotein (ISG75) family mediates suramin uptake, and the AP1 adaptin complex, lysosomal proteases and major lysosomal transmembrane protein, as well as spermidine and N-acetylglucosamine biosynthesis, all contribute to suramin action. Further screens link ubiquinone availability to nitro-drug action, plasma membrane P-type H(+)-ATPases to pentamidine action, and trypanothione and several putative kinases to melarsoprol action. We also demonstrate a major role for aquaglyceroporins in pentamidine and melarsoprol cross-resistance. These advances in our understanding of mechanisms of antitrypanosomal drug efficacy and resistance will aid the rational design of new therapies and help to combat drug resistance, and provide unprecedented molecular insight into the mode of action of antitrypanosomal drugs.     

Potentiation of neuroblastoma metastasis by loss of caspase-8

Neuroblastoma, the most common paediatric solid tumour, arises from defective neural crest cells. Genetic alterations occur frequently in the most aggressive neuroblastomas. In particular, deletion or suppression of the proapoptotic enzyme caspase-8 is common in malignant, disseminated disease, although the effect of this loss on disease progression is unclear. Here we show that suppression of caspase-8 expression occurs during the establishment of neuroblastoma metastases in vivo, and that reconstitution of caspase-8 expression in deficient neuroblastoma cells suppressed their metastases. Caspase-8 status was not a predictor of primary tumour growth; rather, caspase-8 selectively potentiated apoptosis in neuroblastoma cells invading the collagenous stroma at the tumour margin. Apoptosis was initiated by unligated integrins by means of a process known as integrin-mediated death. Loss of caspase-8 or integrin rendered these cells refractory to integrin-mediated death, allowed cellular survival in the stromal microenvironment, and promoted metastases. These findings define caspase-8 as a metastasis suppressor gene that, together with integrins, regulates the survival and invasive capacity of neuroblastoma cells.     

The emergence of geometric order in proliferating metazoan epithelia

The predominantly hexagonal cell pattern of simple epithelia was noted in the earliest microscopic analyses of animal tissues, a topology commonly thought to reflect cell sorting into optimally packed honeycomb arrays. Here we use a discrete Markov model validated by time-lapse microscopy and clonal analysis to demonstrate that the distribution of polygonal cell types in epithelia is not a result of cell packing, but rather a direct mathematical consequence of cell proliferation. On the basis of in vivo analysis of mitotic cell junction dynamics in Drosophila imaginal discs, we mathematically predict the convergence of epithelial topology to a fixed equilibrium distribution of cellular polygons. This distribution is empirically confirmed in tissue samples from vertebrate, arthropod and cnidarian organisms, suggesting that a similar proliferation-dependent cell pattern underlies pattern formation and morphogenesis throughout the metazoa.     

Electrostatic orientation during electron transfer between flavodoxin and cytochrome c

Various studies have shown that reaction rates between reversibly binding electron transfer proteins depend strongly on solution ionic strength. These observations suggest that intermolecular electrostatic interactions are important in facilitating the formation of a productive reaction complex. A recently examined system involves the reduction of vertebrate cytochrome c by bacterial flavodoxin. Although this is a nonphysiological reaction, it proceeds with rates typical for natural partners and is similarly inhibited at high ionic strengths. Here we describe computational studies which examine the role of electrostatics in the formation of a putative reaction complex between flavodoxin and cytochrome c. The results suggest that electrostatic interactions preorient the molecules before they make physical contact, facilitating the formation of an optimal reaction complex.     

Models and perspectives on stage: remarks on Giere’s Scientific perspectivism

Ron Giere’s recent book Scientific perspectivism sets out an account of science that attempts to forge a via media between two popular extremes: absolutist, objectivist realism on the one hand, and social constructivism or skeptical anti-realism on the other. The key for Giere is to treat both scientific observation and scientific theories as perspectives, which are limited, partial, contingent, context-, agent- and purpose-dependent, and pluralism-friendly, while nonetheless world-oriented and modestly realist. Giere’s perspectivism bears significant similarity to earlier ideas of Paul Feyerabend and John Dewey. Comparing these to Giere’s work not only uncovers a consilience of ideas, but also can help to fill out Giere’s account in places where it is not fully developed, as well as helping us understand the work of these earlier authors and their continuing relevance to contemporary concerns in philosophy of science.     

基于视点变化的徒手作图输入变形

提出了一种直观,高效地用于概念设计作用图的等手输入,进行几何变形的方法,采用此方法可以徒手输入两笔曲线（参考曲线和目标曲线）,并据此二曲线来移动多边形模型的顶点,从而达到变形三维模型的目的,解决了大曲率变形时产生的自相关问题,另外,还可用来定义变形影响区域。     

采用网格再划分技术的网格推延造型

提出了一种对自由多边形物体直观高效的三维网格推延造型方法,采用这种造型方法,用户可以在已有的三维物体上勾勒两笔二维轮廓,从而推延了新的空间网格曲面,阐述了两种网格再划分技术,网格优化和网格细分,在此基础上,详细介绍了网格推延造型的方法,该方法能广泛地应用于多边形物体的自由造型。