Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists

Synchronizing rhythms of behaviour and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors REV-ERB-α and REV-ERB-β have an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism. Here we describe the identification of potent synthetic REV-ERB agonists with in vivo activity. Administration of synthetic REV-ERB ligands alters circadian behaviour and the circadian pattern of core clock gene expression in the hypothalami of mice. The circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle and adipose tissue was also altered, resulting in increased energy expenditure. Treatment of diet-induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dyslipidaemia and hyperglycaemia. These results indicate that synthetic REV-ERB ligands that pharmacologically target the circadian rhythm may be beneficial in the treatment of sleep disorders as well as metabolic diseases.     

A physical map of the chicken genome

Strategies for assembling large, complex genomes have evolved to include a combination of whole-genome shotgun sequencing and hierarchal map-assisted sequencing. Whole-genome maps of all types can aid genome assemblies, generally starting with low-resolution cytogenetic maps and ending with the highest resolution of sequence. Fingerprint clone maps are based upon complete restriction enzyme digests of clones representative of the target genome, and ultimately comprise a near-contiguous path of clones across the genome. Such clone-based maps are used to validate sequence assembly order, supply long-range linking information for assembled sequences, anchor sequences to the genetic map and provide templates for closing gaps. Fingerprint maps are also a critical resource for subsequent functional genomic studies, because they provide a redundant and ordered sampling of the genome with clones. In an accompanying paper we describe the draft genome sequence of the chicken, Gallus gallus, the first species sequenced that is both a model organism and a global food source. Here we present a clone-based physical map of the chicken genome at 20-fold coverage, containing 260 contigs of overlapping clones. This map represents approximately 91% of the chicken genome and enables identification of chicken clones aligned to positions in other sequenced genomes.     

The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer

Most susceptibility to colorectal cancer (CRC) is not accounted for by known risk factors. Because MLH1, MSH2 and MSH6 mutations underlie high-penetrance CRC susceptibility in hereditary nonpolyposis colon cancer (HNPCC), we hypothesized that attenuated alleles might also underlie susceptibility to sporadic CRC. We looked for gene variants associated with HNPCC in Israeli probands with familial CRC unstratified with respect to the microsatellite instability (MSI) phenotype. Association studies identified a new MLH1 variant (415G-->C, resulting in the amino acid substitution D132H) in approximately 1.3% of Israeli individuals with CRC self-described as Jewish, Christian and Muslim. MLH1 415C confers clinically significant susceptibility to CRC. In contrast to classic HNPCC, CRCs associated with MLH1 415C usually do not have the MSI defect, which is important for clinical mutation screening. Structural and functional analyses showed that the normal ATPase function of MLH1 is attenuated, but not eliminated, by the MLH1 415G-->C mutation. The new MLH1 variant confers a high risk of CRC and identifies a previously unrecognized mechanism in microsatellite-stable tumors. These studies suggest that variants of mismatch repair proteins with attenuated function may account for a higher proportion of susceptibility to sporadic microsatellite-stable CRC than previously assumed.     

A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk

The identification of common variants that contribute to the genesis of human inherited disorders remains a significant challenge. Hirschsprung disease (HSCR) is a multifactorial, non-mendelian disorder in which rare high-penetrance coding sequence mutations in the receptor tyrosine kinase RET contribute to risk in combination with mutations at other genes. We have used family-based association studies to identify a disease interval, and integrated this with comparative and functional genomic analysis to prioritize conserved and functional elements within which mutations can be sought. We now show that a common non-coding RET variant within a conserved enhancer-like sequence in intron 1 is significantly associated with HSCR susceptibility and makes a 20-fold greater contribution to risk than rare alleles do. This mutation reduces in vitro enhancer activity markedly, has low penetrance, has different genetic effects in males and females, and explains several features of the complex inheritance pattern of HSCR. Thus, common low-penetrance variants, identified by association studies, can underlie both common and rare diseases.     

Assessment of superoxide-mediated release of vascular-inhibitory factor(s) from endothelial cells by using a two-bath system

Summary Release of a vascular-inhibitory factor from endothelial cells (EC), different from endothelium-derived relaxant factor (EDRF), was identified through use of a two-bath system. This two-bath system precluded the effects of oxygen-free radicals that appear when electrical field stimulation (EFS) is directly imposed on detector muscle.     

Crystal structure of the intensely sweet protein monellin

Two unusual proteins, discovered in African berries, possess the interesting property of having a very high specificity for the sweet receptors. These proteins, monellin and thaumatin, are approximately 100,000 times sweeter than sugar on a molar basis and several thousand times sweeter on a weight basis. Neither contains carbohydrates or modified amino acids. Several interesting observations have been made about the two proteins: native conformations are important for the sweet taste, although both proteins are intensely sweet, there are no statistically significant sequence similarities between them; and despite the absence of sequence similarity, antibodies against thaumatin compete for monellin (as well as many other sweet compounds, but not for chemically modified non-sweet monellin) and vice versa. To understand the structural basis of these observations we determined the crystal structure of thaumatin, and report here the structure of monellin at 3 A resolution. Monellin consists of two peptide chains, the A chain of 44 residues and the B chain of 50 residues. We find no similarity between the backbone structure of monellin and that of thaumatin.     

一种新型计算机硬盘保护卡

介绍一种适用于公共机房维护的硬盘保护卡,给出了保护卡中ROM获取BI0S系统控制的方法和启动ROM的构造,并介绍了保护卡对硬盘I／O重新定位和COMS数据保护及保护卡的硬件设计,该卡可防止人为因素和计算机病毒对计算机软件系统的破坏．     

Activation of the TRPC1 cation channel by metabotropic glutamate receptor mGluR1

Group I metabotropic glutamate receptors (consisting of mGluR1 and mGluR5) are G-protein-coupled neurotransmitter receptors that are found in the perisynaptic region of the postsynaptic membrane. These receptors are not activated by single synaptic volleys but rather require bursts of activity. They are implicated in many forms of neural plasticity including hippocampal long-term potentiation and depression, cerebellar long-term depression, associative learning, and cocaine addiction. When activated, group I mGluRs engage two G-protein-dependent signalling mechanisms: stimulation of phospholipase C and activation of an unidentified, mixed-cation excitatory postsynaptic conductance (EPSC), displaying slow activation, in the plasma membrane. Here we report that the mGluR1-evoked slow EPSC is mediated by the TRPC1 cation channel. TRPC1 is expressed in perisynaptic regions of the cerebellar parallel fibre-Purkinje cell synapse and is physically associated with mGluR1. Manipulations that interfere with TRPC1 block the mGluR1-evoked slow EPSC in Purkinje cells; however, fast transmission mediated by AMPA-type glutamate receptors remains unaffected. Furthermore, co-expression of mGluR1 and TRPC1 in a heterologous system reconstituted a mGluR1-evoked conductance that closely resembles the slow EPSC in Purkinje cells.     

Phase diagram of a two-component Fermi gas with resonant interactions

The pairing of fermions lies at the heart of superconductivity and superfluidity. The stability of these pairs determines the robustness of the superfluid state, and the quest for superconductors with high critical temperature equates to a search for systems with strong pairing mechanisms. Ultracold atomic Fermi gases present a highly controllable model system for studying strongly interacting fermions. Tunable interactions (through Feshbach collisional resonances) and the control of population or mass imbalance among the spin components provide unique opportunities to investigate the stability of pairing-and possibly to search for exotic forms of superfluidity. A major controversy has surrounded the stability of superfluidity against an imbalance between the two spin components when the fermions interact resonantly (that is, at unitarity). Here we present the phase diagram of a spin-polarized Fermi gas of (6)Li atoms at unitarity, experimentally mapping out the superfluid phases versus temperature and density imbalance. Using tomographic techniques, we reveal spatial discontinuities in the spin polarization; this is the signature of a first-order superfluid-to-normal phase transition, and disappears at a tricritical point where the nature of the phase transition changes from first-order to second-order. At zero temperature, there is a quantum phase transition from a fully paired superfluid to a partially polarized normal gas. These observations and the implementation of an in situ ideal gas thermometer provide quantitative tests of theoretical calculations on the stability of resonant superfluidity.     

Phytochrome signalling is mediated through nucleoside diphosphate kinase 2.

Because plants are sessile, they have developed intricate strategies to adapt to changing environmental variables, including light. Their growth and development, from germination to flowering, is critically influenced by light, particularly at red (660 nm) and far-red (730 nm) wavelengths. Higher plants perceive red and far-red light by means of specific light sensors called phytochromes(A-E). However, very little is known about how light signals are transduced to elicit responses in plants. Here we report that nucleoside diphosphate kinase 2 (NDPK2) is an upstream component in the phytochrome signalling pathway in the plant Arabidopsis thaliana. In animal and human cells, NDPK acts as a tumour suppressor. We show that recombinant NDPK2 in Arabidopsis preferentially binds to the red-light-activated form of phytochrome in vitro and that this interaction increases the activity of recombinant NDPK2. Furthermore, a mutant lacking NDPK2 showed a partial defect in responses to both red and farred light, including cotyledon opening and greening. These results indicate that NDPK2 is a positive signalling component of the phytochrome-mediated light-signal-transduction pathway in Arabidopsis.