Crack initiation in uniaxial compressive loading of rocks occurs well before the peak strength is reached. The factors that may influence the onset of cracking and possible initiating mechanisms were ...explored using a discrete element numerical approach. The numerical approach was based on grain-based model that utilized the Voronoi tessellation scheme to represent low porosity crystalline rocks such as granite. The effect of grain size distribution (sorting coefficient ranging from 1.5 to 1.03), grain size (average grain size ranging from 0.75 to 2.25 mm), and the heterogeneities of different mineral grains (quartz, K-feldspar, plagioclase) on the onset of cracking were examined. The modelling revealed that crack initiation appears to be a tensile mechanism in low porosity rocks, and that shear cracking along grain boundaries is only a prominent mechanism near the peak strength. It was also shown that the heterogeneity introduced by the grain size distribution had the most significant effect on peak strength and crack initiation stress. The peak strength ranges from 140 to 208 MPa as the grain size distribution varies from heterogeneous to uniform, respectively. However, the ratio of crack initiation to peak stress showed only minor variation, as the heterogeneity decreases. The other factors investigated had only minor effects on crack initiation and peak strength, and crack initiation ratio.
Chordomas are rare, malignant bone tumors of the skull-base and axial skeleton. Until recently, there was no consensus among experts regarding appropriate clinical management of chordoma, resulting ...in inconsistent care and suboptimal outcomes for many patients. To address this shortcoming, the European Society of Medical Oncology (ESMO) and the Chordoma Foundation, the global chordoma patient advocacy group, convened a multi-disciplinary group of chordoma specialists to define by consensus evidence-based best practices for the optimal approach to chordoma. In January 2015, the first recommendations of this group were published, covering the management of primary and metastatic chordomas. Additional evidence and further discussion were needed to develop recommendations about the management of local-regional failures. Thus, ESMO and CF convened a second consensus group meeting in November 2015 to address the treatment of locally relapsed chordoma. This meeting involved over 60 specialists from Europe, the United States and Japan with expertise in treatment of patients with chordoma. The consensus achieved during that meeting is the subject of the present publication and complements the recommendations of the first position paper.
Stress-induced brittle failure (spalling) is probable at a deep geological repository for nuclear waste in crystalline rock. In the early stages of repository design it is unlikely that orientation ...and magnitudes of the principal stresses and the rock mass strength will be accurately known. A simple methodology is developed for estimating if spalling will occur and the severity of the hazard. The methodology is calibrated to case studies and applied to a site in Sweden. Results from the methodology are expressed in terms of a factor of safety for the mean input values and the probability of spalling based on input parameter distributions. It is shown based on the calibration studies that a factor of safety of 1.25 using the mean values should be adequate to reduce the probability of yielding to negligible levels. The methodology is proposed as a screening tool in the early design stages of a project to identify potential spalling problems.
Moyamoya disease (MMD) is a progressive vasculopathy characterized by occlusion of the terminal portion of the internal carotid arteries and its branches, and the formation of compensatory moyamoya ...collateral vessels. Homozygous mutations in GUCY1A3 have been reported as a cause of MMD and achalasia. Probands (n = 96) from unrelated families underwent sequencing of GUCY1A3. Functional studies were performed to confirm the pathogenicity of identified GUCY1A3 variants. Two affected individuals from the unrelated families were found to have compound heterozygous mutations in GUCY1A3. MM041 was diagnosed with achalasia at 4 years of age, hypertension and MMD at 18 years of age. MM149 was diagnosed with MMD and hypertension at the age of 20 months. Both individuals carry one allele that is predicted to lead to haploinsufficiency and a second allele that is predicted to produce a mutated protein. Biochemical studies of one of these alleles, GUCY1A3 Cys517Tyr, showed that the mutant protein (a subunit of soluble guanylate cyclase) has a significantly blunted signaling response with exposure to nitric oxide (NO). GUCY1A3 missense and haploinsufficiency mutations disrupt NO signaling leading to MMD and hypertension, with or without achalasia.
Photoionisation time delays carry structural and dynamical information on the target system, including electronic correlation effects in atoms and molecules and electron transport properties at ...interfaces. In molecules, the electrostatic potential experienced by an outgoing electron depends on the emission direction, which should thus lead to anisotropic time delays. To isolate this effect, information on the orientation of the molecule at the photoionisation instant is required. Here we show how attosecond time delays reflect the anisotropic molecular potential landscape in CF
molecules. The variations in the measured delays can be directly related to the different heights of the potential barriers that the outgoing electrons see in the vicinity of shape resonances. Our results indicate the possibility to investigate the spatial characteristics of the molecular potential by mapping attosecond photoionisation time delays in the recoil-frame.
Bestrophin-1 is preferentially expressed at the basolateral membrane of the retinal pigmented epithelium (RPE) of the retina. Mutations in the BEST1 gene cause the retinal dystrophies vitelliform ...macular dystrophy, autosomal-dominant vitreochoroidopathy, and autosomal-recessive bestrophinopathy. Here, we describe four missense mutations in bestrophin-1, three that we believe are previously unreported, in patients diagnosed with autosomal-dominant and -recessive forms of retinitis pigmentosa (RP). The physiological function of bestrophin-1 remains poorly understood although its heterologous expression induces a Cl−-specific current. We tested the effect of RP-causing variants on Cl− channel activity and cellular localization of bestrophin-1. Two (p.L140V and p.I205T) produced significantly decreased chloride-selective whole-cell currents in comparison to those of wild-type protein. In a model system of a polarized epithelium, two of three mutations (p.L140V and p.D228N) caused mislocalization of bestrophin-1 from the basolateral membrane to the cytoplasm. Mutations in bestrophin-1 are increasingly recognized as an important cause of inherited retinal dystrophy.
Climate change and its effects on the hydrologic regime of the Amazon basin can impact biogeochemical processes, transportation, flood vulnerability, fisheries and hydropower generation. We examined ...projections of climate change on discharge and inundation extent in the Amazon basin using the regional hydrological model MGB-IPH with 1-dimensional river hydraulic and water storage simulation in floodplains. Future projections (2070–2099) were obtained from five GCMs from IPCC’s Fifth Assessment Report CMIP5. Climate projections have uncertainty and results from different climate models did not agree in total Amazon flooded area or discharge anomalies along the main stem river. Overall, model runs agree better with wetter (drier) conditions over western (eastern) Amazon. Results indicate that increased mean and maximum river discharge for large rivers draining the Andes in the northwest contributes to increased mean and maximum discharge and inundation extent over Peruvian floodplains and Solimões River (annual mean-max: +9 % - +18.3 %) in western Amazonia. Decreased river discharges (mostly dry season) are projected for eastern basins, and decreased inundation extent at low water (annual min) in the central (−15.9 %) and lower Amazon (−4.4 %).
The REgents PARk and Tower Environmental Experiment (REPARTEE) comprised two campaigns in London in October 2006 and October/November 2007. The experiment design involved measurements at a heavily ...trafficked roadside site, two urban background sites and an elevated site at 160-190 m above ground on the BT Tower, supplemented in the second campaign by Doppler lidar measurements of atmospheric vertical structure. A wide range of measurements of airborne particle physical metrics and chemical composition were made as well as measurements of a considerable range of gas phase species and the fluxes of both particulate and gas phase substances. Significant findings include (a) demonstration of the evaporation of traffic-generated nanoparticles during both horizontal and vertical atmospheric transport; (b) generation of a large base of information on the fluxes of nanoparticles, accumulation mode particles and specific chemical components of the aerosol and a range of gas phase species, as well as the elucidation of key processes and comparison with emissions inventories; (c) quantification of vertical gradients in selected aerosol and trace gas species which has demonstrated the important role of regional transport in influencing concentrations of sulphate, nitrate and secondary organic compounds within the atmosphere of London; (d) generation of new data on the atmospheric structure and turbulence above London, including the estimation of mixed layer depths; (e) provision of new data on trace gas dispersion in the urban atmosphere through the release of purposeful tracers; (f) the determination of spatial differences in aerosol particle size distributions and their interpretation in terms of sources and physico-chemical transformations; (g) studies of the nocturnal oxidation of nitrogen oxides and of the diurnal behaviour of nitrate aerosol in the urban atmosphere, and (h) new information on the chemical composition and source apportionment of particulate matter size fractions in the atmosphere of London derived both from bulk chemical analysis and aerosol mass spectrometry with two instrument types.
The use of copper thiocyanate (CuSCN) as a universal solution‐processable and highly transparent hole‐transporting layer in organic bulk‐heterojunction photovoltaic cells is demonstrated. When CuSCN ...is employed as a replacement for the commonly used poly(3,4‐ethylenedioxythiophene):polystyrenesulfonate (PEDOT:PSS), organic solar cells with maximum power conversion efficiency of 8%, are realized; this value is 1.27 times higher than that for optimized control cells based on PEDOT:PSS.
Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other ...psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10(-15)) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ∼1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.
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