Hormonal induction of steroid sulphatase in the mouse

Summary By comparing steroid sulphatase levels per se, and also ratios to -galactosidase, in 6 sets of mice — normal females, entire and castrated males both with and without exogenous testosterone administration — we obtained support for the contention that induction of this enzyme is in part controlled by male hormones.     

Examination of naturally occurring polyacetylenes and α-terthienyl for their ability to induce cytogenetic damage

Summary -Terthienyl and 5 polyacetylenes were examined for chromosome damaging activity using Syrian hamster cells. None of these naturally occurring compounds induced sister chromatid exchanges and neither -terthienyl nor phenylheptatriyne induced chromosome aberrations.The authors wish to thank the National Science and Engineering Research Council for financial support of this research.     

Chu Shih-chieh's Suan-hsüeh ch'i-meng (introduction to mathematical studies)

Conclusion The multi-faceted content of the SHCM and its collection of rules and tables made it an important mathematical work not only in China, but also in Korea and Japan. This book clearly demonstrated Chu's predominant interest in the field of algebra and his contribution to the solution of numerical equations of higher degree, which was a prelude to his famous treatise the Ssu-yüan yü-chien.     

用子波变换分析方法实时监测视觉诱发电位的潜伏期

诱发电位的实时监测在临床中有重要意义。本文提出利用多分辨率子波分析技术来实时监测视觉诱发电位的潜伏期。为克服随机噪声的影响，我们引入相邻响应的相关系数来修正所检测得的潜伏期的偏移，并应用前一次响应的波峰位置来决定当前的搜寻范围。实验表明，本方法能实时监测视觉诱发电位的潜伏期。     

Selective Smoothed Finite Element Method

The paper examines three selective schemes for the smoothed finite element method (SFEM) which was formulated by incorporating a cell-wise strain smoothing operation into the standard compatible finite element method (FEM). These selective SFEM schemes were formulated based on three selective integration FEM schemes with similar properties found between the number of smoothing cells in the SFEM and the number of Gaussian integration points in the FEM. Both scheme 1 and scheme 2 are free of nearly incompressible locking, but scheme 2 is more general and gives better results than scheme 1. In addition, scheme 2 can be applied to anisotropic and nonlinear situations, while scheme 1 can only be applied to isotropic and linear situations. Scheme 3 is free of shear locking. This scheme can be applied to plate and shell problems. Results of the numerical study show that the selective SFEM schemes give more accurate results than the FEM schemes.     

A loss-of-function RNA interference screen for molecular targets in cancer

The pursuit of novel therapeutic agents in cancer relies on the identification and validation of molecular targets. Hallmarks of cancer include self-sufficiency in growth signals and evasion from apoptosis; genes that regulate these processes may be optimal for therapeutic attack. Here we describe a loss-of-function screen for genes required for the proliferation and survival of cancer cells using an RNA interference library. We used a doxycycline-inducible retroviral vector for the expression of small hairpin RNAs (shRNAs) to construct a library targeting 2,500 human genes. We used retroviral pools from this library to infect cell lines representing two distinct molecular subgroups of diffuse large B-cell lymphoma (DLBCL), termed activated B-cell-like DLBCL and germinal centre B-cell-like DLBCL. Each vector was engineered to contain a unique 60-base-pair 'bar code', allowing the abundance of an individual shRNA vector within a population of transduced cells to be measured using microarrays of the bar-code sequences. We observed that a subset of shRNA vectors was depleted from the transduced cells after three weeks in culture only if shRNA expression was induced. In activated B-cell-like DLBCL cells, but not germinal centre B-cell-like DLBCL cells, shRNAs targeting the NF-kappaB pathway were depleted, in keeping with the essential role of this pathway in the survival of activated B-cell-like DLBCL. This screen uncovered CARD11 as a key upstream signalling component responsible for the constitutive IkappaB kinase activity in activated B-cell-like DLBCL. The methodology that we describe can be used to establish a functional taxonomy of cancer and help reveal new classes of therapeutic targets distinct from known oncogenes.     

RNAi-mediated gene silencing in non-human primates

The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg(-1). A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.     

Upper intestinal lipids regulate energy and glucose homeostasis

Upon the entry of nutrients into the small intestine, nutrient sensing mechanisms are activated to allow the body to adapt appropriately to the incoming nutrients. To date, mounting evidence points to the existence of an upper intestinal lipid-induced gut–brain neuronal axis to regulate energy homeostasis. Moreover, a recent discovery has also revealed an upper intestinal lipid-induced gut–brain–liver neuronal axis involved in the regulation of glucose homeostasis. In this mini-review, we will focus on the mechanisms underlying the activation of these respective neuronal axes by upper intestinal lipids.     

Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7

Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics.