Sequence variants in the PTCH1 gene associate with spine bone mineral density and osteoporotic fractures

Bone mineral density (BMD) is a measure of osteoporosis and is useful in evaluating the risk of fracture. In a genome-wide association study of BMD among 20,100 Icelanders, with follow-up in 10,091 subjects of European and East-Asian descent, we found a new BMD locus that harbours the PTCH1 gene, represented by rs28377268 (freq. 11.4–22.6%) that associates with reduced spine BMD (P=1.0 × 10−11, β=−0.09). We also identified a new spine BMD signal in RSPO3, rs577721086 (freq. 6.8%), that associates with increased spine BMD (P=6.6 × 10−10, β=0.14). Importantly, both variants associate with osteoporotic fractures and affect expression of the PTCH1 and RSPO3 genes that is in line with their influence on BMD and known biological function of these genes. Additional new BMD signals were also found at the AXIN1 and SOST loci and a new lead SNP at the EN1 locus

Genome landscapes and bacteriophage codon usage

Across all kingdoms of biological life, protein-coding genes exhibit unequal usage of synonmous codons. Although alternative theories abound, translational selection has been accepted as an important mechanism that shapes the patterns of codon usage in prokaryotes and simple eukaryotes. Here we analyze patterns of codon usage across 74 diverse bacteriophages that infect E. coli, P. aeruginosa and L. lactis as their primary host. We introduce the concept of a `genome landscape,' which helps reveal non-trivial, long-range patterns in codon usage across a genome. We develop a series of randomization tests that allow us to interrogate the significance of one aspect of codon usage, such a GC content, while controlling for another aspect, such as adaptation to host-preferred codons. We find that 33 phage genomes exhibit highly non-random patterns in their GC3-content, use of host-preferred codons, or both. We show that the head and tail proteins of these phages exhibit significant bias towards host-preferred codons, relative to the non-structural phage proteins. Our results support the hypothesis of translational selection on viral genes for host-preferred codons, over a broad range of bacteriophages.Comment: 9 Color Figures, 5 Tables, 53 Reference

Low frequency 1/f noise in doped manganite grain-boundary junctions

We have performed a systematic analysis of the low frequency 1/f-noise in single grain boundary junctions in the colossal magnetoresistance material La_{2/3}Ca_{1/3}MnO_{3-delta}. The grain boundary junctions were formed in epitaxial La_{2/3}Ca_{1/3}MnO_{3-delta} films deposited on SrTiO_3 bicrystal substrates and show a large tunneling magnetoresistance of up to 300% at 4.2 K as well as ideal, rectangular shaped resistance versus applied magnetic field curves. Below the Curie temperature T_C the measured 1/f noise is dominated by the grain boundary. The dependence of the noise on bias current, temperature and applied magnetic field gives clear evidence that the large amount of low frequency noise is caused by localized sites with fluctuating magnetic moments in a heavily disordered grain boundary region. At 4.2 K additional temporally unstable Lorentzian components show up in the noise spectra that are most likely caused by fluctuating clusters of interacting magnetic moments. Noise due to fluctuating domains in the junction electrodes is found to play no significant role.Comment: 9 pages, 7 figure

Conditional statistics of electron transport in interacting nanoscale conductors

Interactions between nanoscale semiconductor structures form the basis for charge detectors in the solid state. Recent experimental advances have demonstrated the on-chip detection of single electron transport through a quantum dot (QD). The discreteness of charge in units of e leads to intrinsic fluctuations in the electrical current, known as shot noise. To measure these single-electron fluctuations a nearby coherent conductor, called a quantum point contact (QPC), interacts with the QD and acts as a detector. An important property of the QPC charge detector is noninvasiveness: the system physically affects the detector, not visa-versa. Here we predict that even for ideal noninvasive detectors such as the QPC, when a particular detector result is observed, the system suffers an informational backaction, radically altering the statistics of transport through the QD as compared to the unconditional shot noise. We develop a theoretical model to make predictions about the joint current probability distributions and conditional transport statistics. The experimental findings reported here demonstrate the reality of informational backaction in nanoscale systems as well as a variety of new effects, such as conditional noise enhancement, which are in essentially perfect agreement with our model calculations. This type of switching telegraph process occurs abundantly in nature, indicating that these results are applicable to a wide variety of systems.Comment: 16 pages, 3 figures, to appear in Nature Physic

Mycobacterium tuberculosis ClpP Proteases Are Co-transcribed but Exhibit Different Substrate Specificities

PMCID: PMC3613350This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

High genetic diversity at the extreme range edge: nucleotide variation at nuclear loci in Scots pine (Pinus sylvestris L.) in Scotland

Nucleotide polymorphism at 12 nuclear loci was studied in Scots pine populations across an environmental gradient in Scotland, to evaluate the impacts of demographic history and selection on genetic diversity. At eight loci, diversity patterns were compared between Scottish and continental European populations. At these loci, a similar level of diversity (θsil=~0.01) was found in Scottish vs mainland European populations, contrary to expectations for recent colonization, however, less rapid decay of linkage disequilibrium was observed in the former (ρ=0.0086±0.0009, ρ=0.0245±0.0022, respectively). Scottish populations also showed a deficit of rare nucleotide variants (multi-locus Tajima's D=0.316 vs D=−0.379) and differed significantly from mainland populations in allelic frequency and/or haplotype structure at several loci. Within Scotland, western populations showed slightly reduced nucleotide diversity (πtot=0.0068) compared with those from the south and east (0.0079 and 0.0083, respectively) and about three times higher recombination to diversity ratio (ρ/θ=0.71 vs 0.15 and 0.18, respectively). By comparison with results from coalescent simulations, the observed allelic frequency spectrum in the western populations was compatible with a relatively recent bottleneck (0.00175 × 4Ne generations) that reduced the population to about 2% of the present size. However, heterogeneity in the allelic frequency distribution among geographical regions in Scotland suggests that subsequent admixture of populations with different demographic histories may also have played a role

Control of substrate gating and translocation into ClpP by channel residues and ClpX binding

ClpP is a self-compartmentalized protease, which has very limited degradation activity unless it associates with ClpX to form ClpXP or with ClpA to form ClpAP. Here, we show that ClpX binding stimulates ClpP cleavage of peptides larger than a few amino acids and enhances ClpP active-site modification. Stimulation requires ATP binding but not hydrolysis by ClpX. The magnitude of this enhancement correlates with increasing molecular weight of the molecule entering ClpP. Amino-acid substitutions in the channel loop or helix A of ClpP enhance entry of larger substrates into the free enzyme, eliminate ClpX binding in some cases, and are not further stimulated by ClpX binding in other instances. These results support a model in which the channel residues of free ClpP exclude efficient entry of all but the smallest peptides into the degradation chamber, with ClpX binding serving to relieve these inhibitory interactions. Specific ClpP channel variants also prevent ClpXP translocation of certain amino-acid sequences, suggesting that the wild-type channel plays an important role in facilitating broad translocation specificity. In combination with previous studies, our results indicate that collaboration between ClpP and its partner ATPases opens a gate that functions to exclude larger substrates from isolated ClpP.National Institutes of Health (U.S.) (Grant number AI-15706

Neuregulin 1 and susceptibility to schizophrenia

To access full text version of this article. Please click on the hyperlink "View/Open" at the bottom of this pageThe cause of schizophrenia is unknown, but it has a significant genetic component. Pharmacologic studies, studies of gene expression in man, and studies of mouse mutants suggest involvement of glutamate and dopamine neurotransmitter systems. However, so far, strong association has not been found between schizophrenia and variants of the genes encoding components of these systems. Here, we report the results of a genomewide scan of schizophrenia families in Iceland; these results support previous work, done in five populations, showing that schizophrenia maps to chromosome 8p. Extensive fine-mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia. NRG1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors. Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, NRG1 hypomorphs have fewer functional NMDA receptors than wild-type mice. We also demonstrate that the behavioral phenotypes of the NRG1 hypomorphs are partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia

Loss of heterozygosity at chromosome 11 in breast cancer: association of prognostic factors with genetic alterations.

We examined DNA from 116 female and four male breast cancer patients for loss of heterozygosity (LOH). DNA was analysed by polymerase chain reaction using ten microsatellite markers on chromosome 11. Three distinct regions of LOH were identified: 11p15.5, 11q13 and 11q22-qter with a LOH frequency of 19, 23 and 37-43% respectively. The marker D11S969 showing the highest frequency of LOH (43%) is located at the 11q24.1-q25 region. No previous molecular genetic studies have shown frequent LOH at the region telomeric to q23 on chromosome 11. Southern analysis revealed that LOH at 11q13 was due to amplification, whereas LOH at 11q22qter was due to deletion. LOH at 11p15.5 was associated with paucity of hormone receptor proteins, high S-phase and positive node status. An association was found between LOH at 11q13 and positive node status. LOH at the 11q22-qter region correlated with a high S-phase fraction. A significant association was found between LOH at 11p15 and chromosome regions 17q21 (the BRCA1 region) and 3p

Synergistic Sensing: Application of SiNWs-PANI:MOx_x Heterostructures for Human Respiratory Monitoring

In this study we investigate novel hybrid structure of silicon nanowires (SiNWs) coated with PANI:metaloxide(MO$_x$) nanoparticles i.e., WO$_3$ and TiO$_2$. The SiNWs were fabricated using MACE, whereas PANI:MO$_x$ were deposited using chemical oxidative polymerization method on SiNWs. To this date little attempts has been done to utilize such hybrid structures for respiratory sensing. The structures were characterized using RAMAN spectroscopy, X-ray diffraction, Electron disperssive spectroscopy, and Scanning electron microscopy. The electrical characterization to obtain respiratory sensing reveals excellent response compared to those obtained for SiNWs:MO$_x$ and SiNWs:PANI. Such enhancement in sensitivity is attributed to formation p-n heterojunction along side with wider conduction channel provided of PANI, increased porosity in SiNWs/PANI:WO$_3$ hybrid structures, providing active sites, increased oxygen vacancies and large surface area compared to that of pure MO$_x$ nanoparticles. Further, an improved drift in base line and sensor stability was established for the structure with PANI:WO$_3$ as compared to the PANI:TiO$_2$.Comment: 12 figures, 16 pages, 44 reference