SU5416 sensitizes ovarian cancer cells to cisplatin through inhibition of nucleotide excision repair

SU5416 is reported to be a selective inhibitor of vascular endothelial growth factor, and it has metwith limited success in the clinic. In the present study, we investigated whether SU5416 could augment cisplatin-induced cytotoxicity in human ovarian cancer cells. When used as a single agent, 2-h exposures to SU5416 were not harmful to the cells up to doses of 100 microM. For 48-h exposures, the SU5416 IC20 and IC50 were 17 and 34 microM, respectively. When used with cisplatin, the effect of SU5416 was sequence dependent. SU5416 given first was subadditive, whereas cisplatin given first was supraadditive. Cisplatin was given as a 1-h exposure. Augmented cisplatin cytotoxicity was seen with 2-h exposures to SU5416 at doses of 17-34 microM. This was associated with a decrease in cisplatin-DNA adduct repair, as measured by atomic absorbance spectrometry. Treatment of the ovarian carcinoma cells with SU5416 was also associated with a reduced expression of ERCC-1 protein and c-jun mRNA, as well as a decrease in c-Jun and JNK activities. We conclude that SU5416 can be used to augment cisplatin-induced cell killing at doses that are non-toxic. This effect may occur through direct or indirect reduction of the activity of AP-1 and DNA repair.     

cdx4 mutants fail to specify blood progenitors and can be rescued by multiple hox genes

Organogenesis is dependent on the formation of distinct cell types within the embryo. Important to this process are the hox genes, which are believed to confer positional identities to cells along the anteroposterior axis. Here, we have identified the caudal-related gene cdx4 as the locus mutated in kugelig (kgg), a zebrafish mutant with an early defect in haematopoiesis that is associated with abnormal anteroposterior patterning and aberrant hox gene expression. The blood deficiency in kgg embryos can be rescued by overexpressing hoxb7a or hoxa9a but not hoxb8a, indicating that the haematopoietic defect results from perturbations in specific hox genes. Furthermore, the haematopoietic defect in kgg mutants is not rescued by scl overexpression, suggesting that cdx4 and hox genes act to make the posterior mesoderm competent for blood development. Overexpression of cdx4 during zebrafish development or in mouse embryonic stem cells induces blood formation and alters hox gene expression. Taken together, these findings demonstrate that cdx4 regulates hox genes and is necessary for the specification of haematopoietic cell fate during vertebrate embryogenesis.     

T-type calcium channel regulation by specific G-protein betagamma subunits

Low-voltage-activated (LVA) T-type calcium channels have a wide tissue distribution and have well-documented roles in the control of action potential burst generation and hormone secretion. In neurons of the central nervous system and secretory cells of the adrenal and pituitary, LVA channels are inhibited by activation of G-protein-coupled receptors that generate membrane-delimited signals, yet these signals have not been identified. Here we show that the inhibition of alpha1H (Ca(v)3.2), but not alpha(1G) (Ca(v)3.1) LVA Ca2+ channels is mediated selectively by beta2gamma2 subunits that bind to the intracellular loop connecting channel transmembrane domains II and III. This region of the alpha1H channel is crucial for inhibition, because its replacement abrogates inhibition and its transfer to non-modulated alpha1G channels confers beta2gamma2-dependent inhibition. betagamma reduces channel activity independent of voltage, a mechanism distinct from the established betagamma-dependent inhibition of non-L-type high-voltage-activated channels of the Ca(v)2 family. These studies identify the alpha1H channel as a new effector for G-protein betagamma subunits, and highlight the selective signalling roles available for particular betagamma combinations.     

Comparative analyses of multi-species sequences from targeted genomic regions

The systematic comparison of genomic sequences from different organisms represents a central focus of contemporary genome analysis. Comparative analyses of vertebrate sequences can identify coding and conserved non-coding regions, including regulatory elements, and provide insight into the forces that have rendered modern-day genomes. As a complement to whole-genome sequencing efforts, we are sequencing and comparing targeted genomic regions in multiple, evolutionarily diverse vertebrates. Here we report the generation and analysis of over 12 megabases (Mb) of sequence from 12 species, all derived from the genomic region orthologous to a segment of about 1.8 Mb on human chromosome 7 containing ten genes, including the gene mutated in cystic fibrosis. These sequences show conservation reflecting both functional constraints and the neutral mutational events that shaped this genomic region. In particular, we identify substantial numbers of conserved non-coding segments beyond those previously identified experimentally, most of which are not detectable by pair-wise sequence comparisons alone. Analysis of transposable element insertions highlights the variation in genome dynamics among these species and confirms the placement of rodents as a sister group to the primates.     

Neuronal populations and single cells representing learned auditory objects

The neural representations associated with learned auditory behaviours, such as recognizing individuals based on their vocalizations, are not well described. Higher vertebrates learn to recognize complex conspecific vocalizations that comprise sequences of easily identified, naturally occurring auditory objects, which should facilitate the analysis of higher auditory pathways. Here we describe the first example of neurons selective for learned conspecific vocalizations in adult animals--in starlings that have been trained operantly to recognize conspecific songs. The neuronal population is found in a non-primary forebrain auditory region, exhibits increased responses to the set of learned songs compared with novel songs, and shows differential responses to categories of learned songs based on recognition training contingencies. Within the population, many cells respond highly selectively to a subset of specific motifs (acoustic objects) present only in the learned songs. Such neuronal selectivity may contribute to song-recognition behaviour, which in starlings is sensitive to motif identity. In this system, both top-down and bottom-up processes may modify the tuning properties of neurons during recognition learning, giving rise to plastic representations of behaviourally meaningful auditory objects.     

轴的疲劳强度计算

本文分析了受非零平均应力的复合应力作用的轴的疲劳强度设计.提出了与强度理论相结合的通用计算公式.这些公式是按线性疲劳界限导出的.还提出了平均应力为负值时轴的疲劳强度设计公式.     

考虑定价、生产能力和原料采购的VMI系统Pareto最优及其实现

首先讨论在考虑定价、生产能力和原料采购的VMI系统非合作博弈的基础上实现VMI系统Pareto最优的一般条件,其次给出了在Stackelberg博弈下的可行Pareto最优集问题,然后提出了实现生产商和定货商Pareto最优的Nash讨价还价模型,最后给出了算例加以说明合作给企业带来了较大的利润增加.     

RNA·RNA干扰

回顾了RNA的主要研究历程，生物功能的多样性和应用前景；介绍了RNA干扰的发现历程。作用机制和应用前景。     

新疆蝗虫学研究概况

综述了新疆蝗虫的物种调查情况,迄今为止共计有 １５７ 种。从区域、区系、生态地理 ３个方面综述了新疆蝗虫的分布情况,分析了如此分布的成因,讨论了新疆蝗虫的生物学特性并提出了新疆蝗虫学研究发展方向及有待解决的问题