Developing anti-neoplastic biotherapeutics against eIF4F

Biotherapeutics have revolutionized modern medicine by providing medicines that would not have been possible with small molecules. With respect to cancer therapies, this represents the current sector of the pharmaceutical industry having the largest therapeutic impact, as exemplified by the development of recombinant antibodies and cell-based therapies. In cancer, one of the most common regulatory alterations is the perturbation of translational control. Among these, changes in eukaryotic initiation factor 4F (eIF4F) are associated with tumor initiation, progression, and drug resistance in a number of settings. This, coupled with the fact that systemic suppression of eIF4F appears well tolerated, indicates that therapeutic agents targeting eIF4F hold much therapeutic potential. Here, we discuss opportunities offered by biologicals for this purpose.     

Pocket gophers ( Thomomys talpoides ) in successional stages of spruce-fir forest in Idaho

This study examined (1) the relative abundance of the pocket gopher ( Thomomys talpoides ) in four successive stages (1–10, 11–39, 40–79, and 80+ years following disturbance) of spruce-fir forest; (2) the relationship between number of gopher sign (mounds and earth plugs) with gopher density; and (3) a method of sampling pocket gopher populations using a 500 by 4 m strip transect. The number of gopher mounds was significantly correlated with the number of earth plugs. Data were pooled and a categorical log linear analysis used to test for significant differences in pocket gopher sign between the four successive stages. The 1–10 and the 80+ -year-old sites had significantly more gopher sign than the 11–39 and the 40–79 year-old sites. No significant differences were found between the 11–39 and the 40–79-year-old sites, or between the 1–10 and the 80+ -year-old sites. The difference in population densities may be due to understory vegetation differences between the successional stages. There was a significant correlation between amount of gopher sign and gophers caught in each of the study sites. This indicates that counts of pocket gopher sign may be used to estimate pocket gopher density. The strip transect is recommended as the most appropriate method when sampling heterogeneous habitats or when there is cause to suspect gopher populations may be aggregated within the area rather than spaced randomly or regularly.     

Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia

The Abl kinase inhibitor imatinib mesylate is the preferred treatment for Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) in chronic phase but is much less effective in CML blast crisis or Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). Here, we show that Bcr-Abl activated the Src kinases Lyn, Hck and Fgr in B-lymphoid cells. BCR-ABL1 retrovirus-transduced marrow from mice lacking all three Src kinases efficiently induced CML but not B-ALL in recipients. The kinase inhibitor CGP76030 impaired the proliferation of B-lymphoid cells expressing Bcr-Abl in vitro and prolonged survival of mice with B-ALL but not CML. The combination of CGP76030 and imatinib was superior to imatinib alone in this regard. The biochemical target of CGP76030 in leukemia cells was Src kinases, not Bcr-Abl. These results implicate Src family kinases as therapeutic targets in Ph(+) B-ALL and suggest that simultaneous inhibition of Src and Bcr-Abl kinases may benefit individuals with Ph(+) acute leukemia.     

An endoribonuclease-prepared siRNA screen in human cells identifies genes essential for cell division

RNA interference (RNAi) is an evolutionarily conserved defence mechanism whereby genes are specifically silenced through degradation of messenger RNAs; this process is mediated by homologous double-stranded (ds)RNA molecules. In invertebrates, long dsRNAs have been used for genome-wide screens and have provided insights into gene functions. Because long dsRNA triggers a nonspecific interferon response in many vertebrates, short interfering (si)RNA or short hairpin (sh)RNAs must be used for these organisms to ensure specific gene silencing. Here we report the generation of a genome-scale library of endoribonuclease-prepared short interfering (esi)RNAs from a sequence-verified complementary DNA collection representing 15,497 human genes. We used 5,305 esiRNAs from this library to screen for genes required for cell division in HeLa cells. Using a primary high-throughput cell viability screen followed by a secondary high content videomicroscopy assay, we identified 37 genes required for cell division. These include several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown. Thus, our study uncovers new aspects of cell division and establishes esiRNA as a versatile approach for genomic RNAi screens in mammalian cells.     

Identification of genes involved in Drosophila melanogaster geotaxis,a complex behavioral trait

Identifying the genes involved in polygenic traits has been difficult. In the 1950s and 1960s, laboratory selection experiments for extreme geotaxic behavior in fruit flies established for the first time that a complex behavioral trait has a genetic basis. But the specific genes responsible for the behavior have never been identified using this classical model. To identify the individual genes involved in geotaxic response, we used cDNA microarrays to identify candidate genes and assessed fly lines mutant in these genes for behavioral confirmation. We have thus determined the identities of several genes that contribute to the complex, polygenic behavior of geotaxis.     

《苏州河》:在好莱坞与法国新浪潮之间

作为一部经典的中国独立电影,<苏州河>不仅描绘了魅力上海的底层生活世界,而且生动地表明中国新生代导演如何在全球类型电影创作的互文文本中确定自身的独特位置.作者从类型分析、叙事结构和视觉风格等方面,细致地探讨了怂<苏州河>与好莱坞以及法国新浪潮电影之间吊诡的互文关系.     

Distribution and status of the yellow-faced pocket gopher in Kansas

Previous research suggests that the yellow-faced pocket gopher ( Cratogeomys castanops ) occupies a restricted range in western Kansas that is surrounded by the range of the plains pocket gopher ( Geomys bursarius ), which is regarded as a superior competitor. To determine whether the plains pocket gopher has encroached on the range of the yellow-faced pocket gopher in the past 35 years and to better understand the geographic relationships of these species, we trapped pocket gophers in western Kansas and collected soil texture and land cover data. We used ArcView 3.2 to map the distributions of these species in the study area, as well as the kinds of soil and land cover found in their potential home ranges. Although the distributions of the 2 species overlap, they are strictly parapatric. The apparent cause of this parapatric relationship is differential tolerance of soil textures. The distribution of the yellow-faced pocket gopher in Kansas is limited to just 7 counties divided into 2 populations, both surrounded by the distribution of the plains pocket gopher. We found no evidence that the range of the plains pocket gopher has expanded at the expense of the yellow-faced pocket gopher in the past 35 years. Thus, although the yellow-faced pocket gopher remains a “species of greatest conservation need” in Kansas because of agricultural threats, it evidently is not imperiled at this time.