The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome

We determined the complete genome sequence of Clostridium difficile strain 630, a virulent and multidrug-resistant strain. Our analysis indicates that a large proportion (11%) of the genome consists of mobile genetic elements, mainly in the form of conjugative transposons. These mobile elements are putatively responsible for the acquisition by C. difficile of an extensive array of genes involved in antimicrobial resistance, virulence, host interaction and the production of surface structures. The metabolic capabilities encoded in the genome show multiple adaptations for survival and growth within the gut environment. The extreme genome variability was confirmed by whole-genome microarray analysis; it may reflect the organism's niche in the gut and should provide information on the evolution of virulence in this organism.     

Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome

Genomic disorders are characterized by the presence of flanking segmental duplications that predispose these regions to recurrent rearrangement. Based on the duplication architecture of the genome, we investigated 130 regions that we hypothesized as candidates for previously undescribed genomic disorders. We tested 290 individuals with mental retardation by BAC array comparative genomic hybridization and identified 16 pathogenic rearrangements, including de novo microdeletions of 17q21.31 found in four individuals. Using oligonucleotide arrays, we refined the breakpoints of this microdeletion, defining a 478-kb critical region containing six genes that were deleted in all four individuals. We mapped the breakpoints of this deletion and of four other pathogenic rearrangements in 1q21.1, 15q13, 15q24 and 17q12 to flanking segmental duplications, suggesting that these are also sites of recurrent rearrangement. In common with the 17q21.31 deletion, these breakpoint regions are sites of copy number polymorphism in controls, indicating that these may be inherently unstable genomic regions.     

Principal components analysis corrects for stratification in genome-wide association studies

Population stratification--allele frequency differences between cases and controls due to systematic ancestry differences-can cause spurious associations in disease studies. We describe a method that enables explicit detection and correction of population stratification on a genome-wide scale. Our method uses principal components analysis to explicitly model ancestry differences between cases and controls. The resulting correction is specific to a candidate marker's variation in frequency across ancestral populations, minimizing spurious associations while maximizing power to detect true associations. Our simple, efficient approach can easily be applied to disease studies with hundreds of thousands of markers.     

Naturalization and habitat relationships of bitter nightshade ( Solanum dulcamara ) in central Utah

Ten plant communities containing bitter nightshade ( Solanum dulcamara ) were studied and the ecology and naturalizing relationships of bitter nightshade in central Utah area were investigated. Biotic and abiotic factors from each area were statistically analyzed. The data indicated that bitter nightshade was negatively correlated (P       

Does time-symmetry imply retrocausality? How the quantum world says “Maybe”?

It has often been suggested that retrocausality offers a solution to some of the puzzles of quantum mechanics: e.g., that it allows a Lorentz-invariant explanation of Bell correlations, and other manifestations of quantum nonlocality, without action-at-a-distance. Some writers have argued that time-symmetry counts in favour of such a view, in the sense that retrocausality would be a natural consequence of a truly time-symmetric theory of the quantum world. Critics object that there is complete time-symmetry in classical physics, and yet no apparent retrocausality. Why should the quantum world be any different?This note throws some new light on these matters. I call attention to a respect in which quantum mechanics is different, under some assumptions about quantum ontology. Under these assumptions, the combination of time-symmetry without retrocausality is unavailable in quantum mechanics, for reasons intimately connected with the differences between classical and quantum physics (especially the role of discreteness in the latter). Not all interpretations of quantum mechanics share these assumptions, however, and in those that do not, time-symmetry does not entail retrocausality.     

Effects of Douglas-fir foliage age class on western spruce budworm oviposition choice and larval performance

The western spruce budworm ( Choristoneura occidentalis Freeman) prefers to feed on flushing buds and current-year needles of Douglas-fir ( Pseudotsuga menziesii [Mirb.] Franco). Budworm larvae will not typically consume older age classes of needles unless all current-year foliage is depleted. We tested the following null hypotheses: (1) budworm larvae can feed on foliage with a wide range of qualities (i.e., current 1-, 2-, or 3-year-old needles) without measurable effects on fitness; and (2) budworm adults do not show any oviposition preference linked to the age of the foliage they fed on as larvae. We used both laboratory and field experiments. There was strong evidence to support rejection of hypothesis 1. Budworm larvae had greater survival from the 4th instar to pupal stage when they fed on current-year foliage (43%-52% survival) versus older age classes of foliage (0-25% survival). Pupae from current-year foliage were also heavier than pupae from ≥ 1-year-old foliage. There was weak evidence to support rejecting hypothesis 2; budworm adults that fed had fed on current-year or 3-year-old foliage as larvae preferred to oviposit on current-year foliage. Similar conclusions were drawn from the laboratory and field experiments.     

Systematic identification of genomic markers of drug sensitivity in cancer cells

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.     

Accurate whole-genome sequencing and haplotyping from 10 to 20 human cells

Recent advances in whole-genome sequencing have brought the vision of personal genomics and genomic medicine closer to reality. However, current methods lack clinical accuracy and the ability to describe the context (haplotypes) in which genome variants co-occur in a cost-effective manner. Here we describe a low-cost DNA sequencing and haplotyping process, long fragment read (LFR) technology, which is similar to sequencing long single DNA molecules without cloning or separation of metaphase chromosomes. In this study, ten LFR libraries were made using only ～100?picograms of human DNA per sample. Up to 97% of the heterozygous single nucleotide variants were assembled into long haplotype contigs. Removal of false positive single nucleotide variants not phased by multiple LFR haplotypes resulted in a final genome error rate of 1 in 10?megabases. Cost-effective and accurate genome sequencing and haplotyping from 10-20 human cells, as demonstrated here, will enable comprehensive genetic studies and diverse clinical applications.     

Resveratrol improves health and survival of mice on a high-calorie diet

Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.     

The occurrence of reducible compounds in an invertebrate structure protein ofBuccinum undatum (L.)

Summary Reducible compounds, probably similar to lysine-derived cross-links found in collagen and elastin, have been detected in an invertebrate scleroprotein, the egg case ofBuccinum undatum (L.)During this studyN. R. Price was in receipt of an S.R.C. research assistantship.