Constant darkness is a circadian metabolic signal in mammals

Environmental light is the 'zeitgeber' (time-giver) of circadian behaviour. Constant darkness is considered a 'free-running' circadian state. Mammals encounter constant darkness during hibernation. Ablation of the master clock synchronizer, the suprachiasmatic nucleus, abolishes torpor, a hibernation-like state, implicating the circadian clock in this phenomenon. Here we report a mechanism by which constant darkness regulates the gene expression of fat catabolic enzymes in mice. Genes for murine procolipase (mClps) and pancreatic lipase-related protein 2 (mPlrp2) are activated in a circadian manner in peripheral organs during 12 h dark:12 h dark (DD) but not light-dark (LD) cycles. This mechanism is deregulated in circadian-deficient mPer1-/-/mPer2m/m mice. We identified circadian-regulated 5'-AMP, which is elevated in the blood of DD mice, as a key mediator of this response. Synthetic 5'-AMP induced torpor and mClps expression in LD animals. Torpor induced by metabolic stress was associated with elevated 5'-AMP levels in DD mice. Levels of glucose and non-esterified fatty acid in the blood are reversed in DD and LD mice. Induction of mClps expression by 5'-AMP in LD mice was reciprocally linked to blood glucose levels. Our findings uncover a circadian metabolic rhythm in mammals.     

The genome sequence of the rice blast fungus Magnaporthe grisea

Magnaporthe grisea is the most destructive pathogen of rice worldwide and the principal model organism for elucidating the molecular basis of fungal disease of plants. Here, we report the draft sequence of the M. grisea genome. Analysis of the gene set provides an insight into the adaptations required by a fungus to cause disease. The genome encodes a large and diverse set of secreted proteins, including those defined by unusual carbohydrate-binding domains. This fungus also possesses an expanded family of G-protein-coupled receptors, several new virulence-associated genes and large suites of enzymes involved in secondary metabolism. Consistent with a role in fungal pathogenesis, the expression of several of these genes is upregulated during the early stages of infection-related development. The M. grisea genome has been subject to invasion and proliferation of active transposable elements, reflecting the clonal nature of this fungus imposed by widespread rice cultivation.     

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.     

Modified binary particle swarm optimization

This paper presents a modified binary particle swarm optimization （BPSO） which adopts concepts of the genotype-phenotype representation and the mutation operator of genetic algorithms. Its main feature is that the BPSO can be treated as a continuous PSO. The proposed BPSO algorithm is tested on various benchmark functions, and its performance is compared with that of the original BPSO. Experimental results show that the modified BPSO outperforms the original BPSO algorithm.     

The medaka draft genome and insights into vertebrate genome evolution

Teleosts comprise more than half of all vertebrate species and have adapted to a variety of marine and freshwater habitats. Their genome evolution and diversification are important subjects for the understanding of vertebrate evolution. Although draft genome sequences of two pufferfishes have been published, analysis of more fish genomes is desirable. Here we report a high-quality draft genome sequence of a small egg-laying freshwater teleost, medaka (Oryzias latipes). Medaka is native to East Asia and an excellent model system for a wide range of biology, including ecotoxicology, carcinogenesis, sex determination and developmental genetics. In the assembled medaka genome (700 megabases), which is less than half of the zebrafish genome, we predicted 20,141 genes, including approximately 2,900 new genes, using 5'-end serial analysis of gene expression tag information. We found single nucleotide polymorphisms (SNPs) at an average rate of 3.42% between the two inbred strains derived from two regional populations; this is the highest SNP rate seen in any vertebrate species. Analyses based on the dense SNP information show a strict genetic separation of 4 million years (Myr) between the two populations, and suggest that differential selective pressures acted on specific gene categories. Four-way comparisons with the human, pufferfish (Tetraodon), zebrafish and medaka genomes revealed that eight major interchromosomal rearrangements took place in a remarkably short period of approximately 50 Myr after the whole-genome duplication event in the teleost ancestor and afterwards, intriguingly, the medaka genome preserved its ancestral karyotype for more than 300 Myr.     

Polarity modified triplex DNA by bromide

Conclusion A py-pu-py triplex DNA containing the polarity modification by replacing the atom H5 of cytosine with Br was examined, mainly for the stability of the formation of the triplex DNA. Our computational results show that the conformation of the strand that contained a replaced H5 by cytosine to Br was destabilized, but the Hoogsteen base pairs were stabilized. Although this approach of modifying the polarity of DNA base has not been tried before, it shows the possibility to improve the stability by the polarity modification.     

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.