Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms.

Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ~1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing

Association of MC1R Variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study

<p><b>Background</b> Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited.</p> <p><b>Methods</b> We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided.</p> <p><b>Results</b> Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10−6 ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; Ptrend = 1.86 × 10−8). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10−6 ≤ P ≤ .02).</p> <p><b>Conclusion</b> Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.</p&gt

Measurement of the Electric Form Factor of the Neutron at Q^2 = 0.3-0.8 (GeV/c)^2

The electric form factor of the neutron, G_En, has been measured at the Mainz Microtron by recoil polarimetry in the quasielastic D(e_pol,e'n_pol)p reaction. Three data points have been extracted at squared four-momentum transfers Q^2 = 0.3, 0.6 and 0.8 (GeV/c)^2. Corrections for nuclear binding effects have been applied.Comment: 9 pages, 7 figures, 2 tables. Accepted for publication in EPJ

Detection of Exocometary CO within the 440 Myr Old Fomalhaut Belt: A Similar CO+CO 2 Ice Abundance in Exocomets and Solar System Comets

Recent Atacama Large Millimeter/submillimeter Array observations present mounting evidence for the presence of exocometary gas released within Kuiper Belt analogs around nearby main-sequence stars. This represents a unique opportunity to study their ice reservoir at the younger ages when volatile delivery to planets is most likely to occur. We here present the detection of CO J = 2-1 emission colocated with dust emission from the cometary belt in the 440 Myr old Fomalhaut system. Through spectrospatial filtering, we achieve a 5.4σ detection and determine that the ring's sky-projected rotation axis matches that of the star. The CO mass derived ((0.65\mbox{--}42)\times {10}^{-7}\,{M}_{\oplus }) is the lowest of any circumstellar disk detected to date and must be of exocometary origin. Using a steady-state model, we estimate the CO+CO2 mass fraction of exocomets around Fomalhaut to be between 4.6% and 76%, consistent with solar system comets and the two other belts known to host exocometary gas. This is the first indication of a similarity in cometary compositions across planetary systems that may be linked to their formation scenario and is consistent with direct interstellar medium inheritance. In addition, we find tentative evidence that $(49\pm 27)$% of the detected flux originates from a region near the eccentric belt's pericenter. If confirmed, the latter may be explained through a recent impact event or CO pericenter glow due to exocometary release within a steady-state collisional cascade. In the latter scenario, we show how the azimuthal dependence of the CO release rate leads to asymmetries in gas observations of eccentric exocometary belts

Debris Disks: Probing Planet Formation

Debris disks are the dust disks found around ~20% of nearby main sequence stars in far-IR surveys. They can be considered as descendants of protoplanetary disks or components of planetary systems, providing valuable information on circumstellar disk evolution and the outcome of planet formation. The debris disk population can be explained by the steady collisional erosion of planetesimal belts; population models constrain where (10-100au) and in what quantity (>1Mearth) planetesimals (>10km in size) typically form in protoplanetary disks. Gas is now seen long into the debris disk phase. Some of this is secondary implying planetesimals have a Solar System comet-like composition, but some systems may retain primordial gas. Ongoing planet formation processes are invoked for some debris disks, such as the continued growth of dwarf planets in an unstirred disk, or the growth of terrestrial planets through giant impacts. Planets imprint structure on debris disks in many ways; images of gaps, clumps, warps, eccentricities and other disk asymmetries, are readily explained by planets at >>5au. Hot dust in the region planets are commonly found (<5au) is seen for a growing number of stars. This dust usually originates in an outer belt (e.g., from exocomets), although an asteroid belt or recent collision is sometimes inferred.Comment: Invited review, accepted for publication in the 'Handbook of Exoplanets', eds. H.J. Deeg and J.A. Belmonte, Springer (2018

Route planning with transportation network maps: an eye-tracking study.

Planning routes using transportation network maps is a common task that has received little attention in the literature. Here, we present a novel eye-tracking paradigm to investigate psychological processes and mechanisms involved in such a route planning. In the experiment, participants were first presented with an origin and destination pair before we presented them with fictitious public transportation maps. Their task was to find the connecting route that required the minimum number of transfers. Based on participants' gaze behaviour, each trial was split into two phases: (1) the search for origin and destination phase, i.e., the initial phase of the trial until participants gazed at both origin and destination at least once and (2) the route planning and selection phase. Comparisons of other eye-tracking measures between these phases and the time to complete them, which depended on the complexity of the planning task, suggest that these two phases are indeed distinct and supported by different cognitive processes. For example, participants spent more time attending the centre of the map during the initial search phase, before directing their attention to connecting stations, where transitions between lines were possible. Our results provide novel insights into the psychological processes involved in route planning from maps. The findings are discussed in relation to the current theories of route planning

Endothelin-1 Predicts Hemodynamically Assessed Pulmonary Arterial Hypertension in HIV Infection.

BackgroundHIV infection is an independent risk factor for PAH, but the underlying pathogenesis remains unclear. ET-1 is a robust vasoconstrictor and key mediator of pulmonary vascular homeostasis. Higher levels of ET-1 predict disease severity and mortality in other forms of PAH, and endothelin receptor antagonists are central to treatment, including in HIV-associated PAH. The direct relationship between ET-1 and PAH in HIV-infected individuals is not well described.MethodsWe measured ET-1 and estimated pulmonary artery systolic pressure (PASP) with transthoracic echocardiography (TTE) in 106 HIV-infected individuals. Participants with a PASP ≥ 30 mmHg (n = 65) underwent right heart catheterization (RHC) to definitively diagnose PAH. We conducted multivariable analysis to identify factors associated with PAH.ResultsAmong 106 HIV-infected participants, 80% were male, the median age was 52 years and 77% were on antiretroviral therapy. ET-1 was significantly associated with higher values of PASP [14% per 0.1 pg/mL increase in ET-1, p = 0.05] and PASP ≥ 30 mmHg [PR (prevalence ratio) = 1.24, p = 0.012] on TTE after multivariable adjustment for PAH risk factors. Similarly, among the 65 individuals who underwent RHC, ET-1 was significantly associated with higher values of mean pulmonary artery pressure and PAH (34%, p = 0.003 and PR = 2.43, p = 0.032, respectively) in the multivariable analyses.ConclusionsHigher levels of ET-1 are independently associated with HIV-associated PAH as hemodynamically assessed by RHC. Our findings suggest that excessive ET-1 production in the setting of HIV infection impairs pulmonary endothelial function and contributes to the development of PAH

A common intronic variant of PARP1 confers melanoma risk and mediates melanocyte growth via regulation of MITF

Previous genome-wide association studies have identified a melanoma-associated locus at 1q42.1 that encompasses a ~100-kb region spanning the PARP1 gene. Expression quantitative trait locus (eQTL) analysis in multiple cell types of the melanocytic lineage consistently demonstrated that the 1q42.1 melanoma risk allele (rs3219090[G]) is correlated with higher PARP1 levels. In silico fine-mapping and functional validation identified a common intronic indel, rs144361550 (−/GGGCCC; r2 = 0.947 with rs3219090), as displaying allele-specific transcriptional activity. A proteomic screen identified RECQL as binding to rs144361550 in an allele-preferential manner. In human primary melanocytes, PARP1 promoted cell proliferation and rescued BRAFV600E-induced senescence phenotypes in a PARylation-independent manner. PARP1 also transformed TERT-immortalized melanocytes expressing BRAFV600E. PARP1-mediated senescence rescue was accompanied by transcriptional activation of the melanocyte-lineage survival oncogene MITF, highlighting a new role for PARP1 in melanomagenesis

Shear Capacity of Monolithic Concrete Joints without Transverse Reinforcement.

yesA mechanism analysis based on the upper-bound theorem of concrete plasticity for monolithic concrete joints without transverse reinforcement is presented. Concrete is modelled as a rigid–perfectly plastic material obeying modified Coulomb failure criteria. Existing stress–strain relationships of concrete in compression and tension are comprehensively modified using the crack band theory to allow for concrete type and maximum aggregate size. Simple equations for the effectiveness factor for compression, ratio of effective tensile strength to compressive strength and angle of concrete friction are then mathematically developed using the modified stress–strain relationships of concrete. In addition, 12 push-off specimens made of all-lightweight, sand–lightweight and normal-weight concrete having maximum aggregate size between 4 and 19 mm were physically tested. Test results and mechanism analysis clearly showed that the shear capacity of monolithic concrete joints increased with the increase of the maximum aggregate size and dry density of concrete. The mean and standard deviation of the ratio between experimentally measured and predicted (by the mechanism analysis shear capacities) are 1·01 and 0·16 respectively, showing a closer prediction and less variation than Vecchio and Collins' equation, regardless of concrete type and maximum aggregate size