Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.     

Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation

We found mutations in the gene PQBP1 in 5 of 29 families with nonsyndromic (MRX) and syndromic (MRXS) forms of X-linked mental retardation (XLMR). Clinical features in affected males include mental retardation, microcephaly, short stature, spastic paraplegia and midline defects. PQBP1 has previously been implicated in the pathogenesis of polyglutamine expansion diseases. Our findings link this gene to XLMR and shed more light on the pathogenesis of this common disorder.     

Generation and annotation of the DNA sequences of human chromosomes 2 and 4

Human chromosome 2 is unique to the human lineage in being the product of a head-to-head fusion of two intermediate-sized ancestral chromosomes. Chromosome 4 has received attention primarily related to the search for the Huntington's disease gene, but also for genes associated with Wolf-Hirschhorn syndrome, polycystic kidney disease and a form of muscular dystrophy. Here we present approximately 237 million base pairs of sequence for chromosome 2, and 186 million base pairs for chromosome 4, representing more than 99.6% of their euchromatic sequences. Our initial analyses have identified 1,346 protein-coding genes and 1,239 pseudogenes on chromosome 2, and 796 protein-coding genes and 778 pseudogenes on chromosome 4. Extensive analyses confirm the underlying construction of the sequence, and expand our understanding of the structure and evolution of mammalian chromosomes, including gene deserts, segmental duplications and highly variant regions.     

Habitat characteristics of leatherside chub ( Gila copei ) at two spatial scales

Populations of leatherside chub ( Gila copei ), a little-known species native to the eastern Great Basin, have declined and their distribution has become fragmented. To determine habitat requirements and possible factors responsible for population decline, we quantified macrohabitats and microhabitats occupied by leatherside chub. Macrohabitat was surveyed at 59 sites in the Sevier River drainage of south central Utah, and microhabitats occupied by leatherside chub were measured at 3 locations spanning the species latitudinal range. Characteristics of points in the stream where leatherside chub occurred were compared to points where they did not occur. Abundance of brown trout ( Salmo trutta ) and elevation were weakly negatively correlated with leatherside chub distribution on a macrohabitat scale. Microhabitats occupied by leatherside chub were characterized by low water velocities (2.5-45 cm sec -1 ), intermediate water depths (25-65 cm), and low percent composition of sand-silt or gravel substrates. This study suggests that the presence of introduced brown trout may have led to the decline of leatherside chub.     

A physical map of the mouse genome

A physical map of a genome is an essential guide for navigation, allowing the location of any gene or other landmark in the chromosomal DNA. We have constructed a physical map of the mouse genome that contains 296 contigs of overlapping bacterial clones and 16,992 unique markers. The mouse contigs were aligned to the human genome sequence on the basis of 51,486 homology matches, thus enabling use of the conserved synteny (correspondence between chromosome blocks) of the two genomes to accelerate construction of the mouse map. The map provides a framework for assembly of whole-genome shotgun sequence data, and a tile path of clones for generation of the reference sequence. Definition of the human-mouse alignment at this level of resolution enables identification of a mouse clone that corresponds to almost any position in the human genome. The human sequence may be used to facilitate construction of other mammalian genome maps using the same strategy.     

Plant composition and erosion potential of a grazed wetland in the salmon river subbasin, Idaho

Wetlands are dynamic habitats with many unique, important functions including filtering sediments and providing diverse habitats for fish and wildlife. Wetlands in the western United States are particularly important because they offer habitat for a number of protected runs of endangered fish species. Historically, livestock grazing has altered wetland and riparian area form and function by facilitating exotic species invasions, altering spatial heterogeneity of vegetation, and increasing erosion. In this study we examined vegetation structure and erosion potential in a wetland meadow exposed to unregulated grazing along Deer Creek in the Salmon River subbasin, Idaho. We characterized the vegetation composition and structure within the study area and attempted to assess potential erosion conditions using the Revised Universal Soil Loss Equation (RUSLE), an empirical approach developed by the U.S. Department of Agriculture—Agricultural Research Service (USDA-ARS). We found no significant spatial variability in species richness and noted a moderate number of exotic species in the total plant composition. Plant cover was higher near slightly entrenched banks, indicating that uncontrolled livestock were primarily occupying gently sloped streambanks and the interior of the meadow. Based on current vegetation composition and RUSLE results, uncontrolled grazing may be negatively impacting the study area. If uncontrolled grazing were excluded or carefully managed in the wetland meadows of the upper portion of the Deer Creek watershed, a reduction in excess sediments to Deer Creek may occur.     

Grasping the spirit in nature: Anschauung in Ørsted's epistemology of science and beauty

The intersection between art, poetry, philosophy and science was the leitmotif which guided the lives and careers of romantic natural philosophers including that of the Danish natural philosopher, H. C. Ørsted. A simple model of Ørsted’s career would be one in which it was framed by two periods of philosophical speculation: the youth’s curious and idealistic interest in new attractive thoughts and the experienced man’s mature reflections at the end of his life. We suggest that a closer look at the epistemological aspects of his works on the theory of beauty reveals a connection between this late work and his early philosophical work including experimental philosophy, but also with the work in teaching and textbook writing, that lies in between. The latter includes Ørsted’s view on the application of mathematics in natural philosophy as well as his failed attempt at a genetic presentation of elementary geometry.     

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.     

Sequencing of a rice centromere uncovers active genes

Centromeres are the last frontiers of complex eukaryotic genomes, consisting of highly repetitive sequences that resist mapping, cloning and sequencing. The centromere of rice Chromosome 8 (Cen8) has an unusually low abundance of highly repetitive satellite DNA, which allowed us to determine its sequence. A region of approximately 750 kb in Cen8 binds rice CENH3, the centromere-specific H3 histone. CENH3 binding is contained within a larger region that has abundant dimethylation of histone H3 at Lys9 (H3-Lys9), consistent with Cen8 being embedded in heterochromatin. Fourteen predicted and at least four active genes are interspersed in Cen8, along with CENH3 binding sites. The retrotransposons located in and outside of the CENH3 binding domain have similar ages and structural dynamics. These results suggest that Cen8 may represent an intermediate stage in the evolution of centromeres from genic regions, as in human neocentromeres, to fully mature centromeres that accumulate megabases of homogeneous satellite arrays.     

Regulation of p53 activity through lysine methylation

p53 is a tumour suppressor that regulates the cellular response to genotoxic stresses. p53 is a short-lived protein and its activity is regulated mostly by stabilization via different post-translational modifications. Here we report a novel mechanism of p53 regulation through lysine methylation by Set9 methyltransferase. Set9 specifically methylates p53 at one residue within the carboxyl-terminus regulatory region. Methylated p53 is restricted to the nucleus and the modification positively affects its stability. Set9 regulates the expression of p53 target genes in a manner dependent on the p53-methylation site. The crystal structure of a ternary complex of Set9 with a p53 peptide and the cofactor product S-adenosyl-l-homocysteine (AdoHcy) provides the molecular basis for recognition of p53 by this lysine methyltransferase.