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.     

Dominant missense mutations in ABCC9 cause Cantú syndrome

Cantú syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the 16 individuals with Cantú syndrome examined. The ABCC9 protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity. All mutations altered amino acids in or close to the transmembrane domains of ABCC9. Using electrophysiological measurements, we show that mutations in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening. Moreover, similarities between the phenotype of individuals with Cantú syndrome and side effects from the K(ATP) channel agonist minoxidil indicate that the mutations in ABCC9 result in channel opening. Given the availability of ABCC9 antagonists, our findings may have direct implications for the treatment of individuals with Cantú syndrome.     

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.     

Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis

Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.     

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.     

Gray Partridge foraging ecology in eastern South Dakota

We examined crop contents of 217 Gray Partridge ( Perdix perdix ) collected during a two-year period in eastern South Dakota. Row crop grains (corn, sunflowers) dominated late fall, winter, and spring diets. Small grains (oats, barley, wheat, rye) were rarely consumed although fields of small grains were widely available. During a severe winter when waste row crop grains were buried by snow, partridge consumed more leafy vegetation. Insects dominated the early summer diet, while foxtail ( Setaria spp.) seeds were a major late summer and early fall food.