Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1.

Neurofibromatosis type I (NF1) is one of the most common single-gene disorders that causes learning deficits in humans. Mice carrying a heterozygous null mutation of the Nfl gene (Nfl(+/-) show important features of the learning deficits associated with NF1 (ref. 2). Although neurofibromin has several known properties and functions, including Ras GTPase-activating protein activity, adenylyl cyclase modulation and microtubule binding, it is unclear which of these are essential for learning in mice and humans. Here we show that the learning deficits of Nf1(+/-) mice can be rescued by genetic and pharmacological manipulations that decrease Ras function. We also show that the Nf1(+/-) mice have increased GABA (gamma-amino butyric acid)-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. Our results indicate that the learning deficits associated with NF1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. Our findings have implications for the development of treatments for learning deficits associated with NF1.     

Lysergic acid diethylamide affects blood flow to specific areas of the conscious rat brain

Zusammenfassung Die i.v. Verabreichung von LSD an Ratten steigert den Blutkreislauf im Hirnstamm sowie im frontalen und parietalen Cortex selektiv. Es wurden durch 6-Nor-LSD, 2-Methyl-LSD und ^{8, 9}-LSD weder wahrnehmbare Verhaltensänderungen noch Änderungen des regionalen Blutkreislaufs verursacht.     

Colony isolation and isozyme variability of the western seep fritillary, Speyeria nokomis apacheana (Nymphalidae), in the western Great Basin

Thirteen Speyeria nokomis apacheana (Edwards) (Nymphalidae) populations from the western Great Basin were assayed for isozyme variability using starch-gel electrophoresis. Eight of the 25 presumptive isozyme loci analyzed were found to be polymorphic. Collections made in 1991and 1992 allowed for between-year comparisons of heterozygosity and the estimation of effective population size for five of the sampled populations. Speyeria nokomis apacheana populations exhibit lower mean heterozygosity levels than other nymphalids. This may be attributed to genetic drift in apparently isolated populations with small effective sizes.     

基于土性相关蒙特卡罗法的争岗滑坡堆积体可靠性分析

针对澜沧江古水水电站争岗滑坡堆积体工程地质务件,在室内剪切试验、工程类比、参数反演基础上综合确定了岩土体力学参数及其统计分布规律.采用基于黏聚力c与内摩擦角φ相关抽样下的蒙特卡罗法对堆积体典型剖面进行了多种工况下的可靠性分析,预测了其未来的变形失稳特征.研究结果表明:当前堆积体B-B'剖面在正常运行工况下的破坏概率为2...     

In vivo genome editing restores haemostasis in a mouse model of haemophilia

Editing of the human genome to correct disease-causing mutations is a promising approach for the treatment of genetic disorders. Genome editing improves on simple gene-replacement strategies by effecting in situ correction of a mutant gene, thus restoring normal gene function under the control of endogenous regulatory elements and reducing risks associated with random insertion into the genome. Gene-specific targeting has historically been limited to mouse embryonic stem cells. The development of zinc finger nucleases (ZFNs) has permitted efficient genome editing in transformed and primary cells that were previously thought to be intractable to such genetic manipulation. In vitro, ZFNs have been shown to promote efficient genome editing via homology-directed repair by inducing a site-specific double-strand break (DSB) at a target locus, but it is unclear whether ZFNs can induce DSBs and stimulate genome editing at a clinically meaningful level in vivo. Here we show that ZFNs are able to induce DSBs efficiently when delivered directly to mouse liver and that, when co-delivered with an appropriately designed gene-targeting vector, they can stimulate gene replacement through both homology-directed and homology-independent targeted gene insertion at the ZFN-specified locus. The level of gene targeting achieved was sufficient to correct the prolonged clotting times in a mouse model of haemophilia B, and remained persistent after induced liver regeneration. Thus, ZFN-driven gene correction can be achieved in vivo, raising the possibility of genome editing as a viable strategy for the treatment of genetic disease.     

Two ten-billion-solar-mass black holes at the centres of giant elliptical galaxies

Observational work conducted over the past few decades indicates that all massive galaxies have supermassive black holes at their centres. Although the luminosities and brightness fluctuations of quasars in the early Universe suggest that some were powered by black holes with masses greater than 10 billion solar masses, the remnants of these objects have not been found in the nearby Universe. The giant elliptical galaxy Messier 87 hosts the hitherto most massive known black hole, which has a mass of 6.3 billion solar masses. Here we report that NGC 3842, the brightest galaxy in a cluster at a distance from Earth of 98 megaparsecs, has a central black hole with a mass of 9.7 billion solar masses, and that a black hole of comparable or greater mass is present in NGC 4889, the brightest galaxy in the Coma cluster (at a distance of 103 megaparsecs). These two black holes are significantly more massive than predicted by linearly extrapolating the widely used correlations between black-hole mass and the stellar velocity dispersion or bulge luminosity of the host galaxy. Although these correlations remain useful for predicting black-hole masses in less massive elliptical galaxies, our measurements suggest that different evolutionary processes influence the growth of the largest galaxies and their black holes.     

A role for VEGF as a negative regulator of pericyte function and vessel maturation

Angiogenesis does not only depend on endothelial cell invasion and proliferation: it also requires pericyte coverage of vascular sprouts for vessel stabilization. These processes are coordinated by vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) through their cognate receptors on endothelial cells and vascular smooth muscle cells (VSMCs), respectively. PDGF induces neovascularization by priming VSMCs/pericytes to release pro-angiogenic mediators. Although VEGF directly stimulates endothelial cell proliferation and migration, its role in pericyte biology is less clear. Here we define a role for VEGF as an inhibitor of neovascularization on the basis of its capacity to disrupt VSMC function. Specifically, under conditions of PDGF-mediated angiogenesis, VEGF ablates pericyte coverage of nascent vascular sprouts, leading to vessel destabilization. At the molecular level, VEGF-mediated activation of VEGF-R2 suppresses PDGF-Rbeta signalling in VSMCs through the assembly of a previously undescribed receptor complex consisting of PDGF-Rbeta and VEGF-R2. Inhibition of VEGF-R2 not only prevents assembly of this receptor complex but also restores angiogenesis in tissues exposed to both VEGF and PDGF. Finally, genetic deletion of tumour cell VEGF disrupts PDGF-Rbeta/VEGF-R2 complex formation and increases tumour vessel maturation. These findings underscore the importance of VSMCs/pericytes in neovascularization and reveal a dichotomous role for VEGF and VEGF-R2 signalling as both a promoter of endothelial cell function and a negative regulator of VSMCs and vessel maturation.     

Involvement of chemokine receptors in breast cancer metastasis

Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1alpha and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.     

On the complexity of self.

Self peptides bound to self major histocompatibility complex (MHC) molecules have been implicated both in positive and in negative selection of T cells during intrathymic development. We report here that the novel MHC-restricted monoclonal antibody Y-Ae detects the MHC class II bound form of a major self peptide. Y-Ae binds approximately 12% of the relevant MHC class II molecules on self antigen presenting cells. The peptide detected by Y-Ae is one of several major peptides eluted from the MHC molecule. These data suggest that self peptides presented by self MHC class II molecules at densities sufficient to signal a CD4 T cell are of very limited complexity. Furthermore, as Y-Ae stains antigen presenting cells that mediate negative selection but not thymic cortical epithelial cells that drive positive selection, differential expression of self peptide:self MHC class II complexes may be a key feature of intrathymic selection.     

核能谱与两类转动惯量的精确表达式

用最小二乘拟合法,将稀土区的能谱实验数据,拟合不同的能谱公式,从而证明E=a〔(1+bI(I+1))~(1/2)-1〕是符合得较好的,本文还推导了与上述能谱相应的两类转动惯量,并以此与实验计算值进行比较,结果仍很满意.