Fabric anisotropy & DEM informed two-surface hyperplasticity : constitutive formulation, asymptotic states & experimental validation.

In geotechnical analysis continuum idealisations of the bulk material still provide the most appropriate approach for engineers designing large-scale structures. In this area, the most successful framework for describing the behaviour of soils is Critical State (CS) soil mechanics. However, the findings from discrete element method (DEM) analysis, such as the uniqueness of the CS, can provide invaluable information in the development such models. This paper details the key concepts behind a two-surface hyperplasticity model (?) whose development was informed by recent DEM findings on the uniqueness of the CS. Asymptotic states of the model will be confirmed and the DEM-continuum-experimental loop will be closed through comparison of the developed model with experimental data on coarse-grained particulate media. This will demonstrate, that providing the previous stress history is accounted for, the proposed model is suitable for a variety of particulate media

Validation of a nowcasting technique from a hydrological perspective

Nowcasting precipitation is a key point to anticipate risks in flood warning systems. In this environment, weather radars are very useful because of the high resolution of their measurements both in time and space. The aim of this study is to assess the performance of a recently proposed nowcasting technique (SPROG) from a hydrological point of view. This technique is based on the advection of radar precipitation fields and its main point is that the forecasted fields get smoothed as the forecasting time increases, to filter out the smallest scales of the field when they become unpredictable. The evaluation of the forecasted precipitation fields is done in two different ways: a) comparing them against the actually measured precipitation fields and b) according to the concept of “hydrological validation”, comparing the hydrographs calculated by a distributed rainfall-runoff model simulating operational conditions (using the forecasted precipitation fields) against the hydrographs calculated by the model with the entire series of radar measurements. This part of the study has been carried out in the framework of the Besos basin flood forecasting system.Postprint (published version

Role of spatial anisotropy in design storm generation: Experiment and interpretation

Rainfall accumulation depths over a given area are strongly dependent on the shape of the storm together with its direction of advection. A method to produce design storms exhibiting anisotropic spatial scaling is presented by combining a state-of-the-art stochastic rainfall generator STEPS with the linear generalized scale invariance (GSI) notation. The enhanced model is used to create ensembles of design storms based on an extreme storm with a distinct rainband shape observed in Melbourne, Australia. Design storms are generated both with and without accounting for anisotropy. Effect of anisotropy on precipitation characteristics is studied using the entire region covered by the radar (radar scale) and at a significantly smaller catchment scale. A rainfall-runoff model is applied to route the rainfall through the catchment into streamflow. Accounting for anisotropy allows for a more realistic description of precipitation features at the radar scale. At the catchment scale, anisotropy increases the probability of high rainfall accumulations, which translates into greater flood volumes. No discernible difference was observed in streamflow characteristics after controlling for the accumulation over the catchment. This could be explained by a lower importance of anisotropy relative to other factors affecting streamflow generation, and by the difficulties in creating representative rainfall temporal properties at the catchment scale when the radar scale is used for model calibration. The proposed method provides a tool to create ensembles of design storms when the anisotropic shape of the fields is of importance.Peer reviewe

Exceptional uranium(VI)-nitride triple bond covalency from ¹⁵N nuclear magnetic resonance spectroscopy and quantum chemical analysis.

From Europe PMC via Jisc Publications RouterHistory: ppub 2021-09-01, epub 2021-09-24Publication status: PublishedFunder: RCUK | Engineering and Physical Sciences Research Council (EPSRC); Grant(s): EP/M027015/1, EP/K024000/1, EP/S033181/1Funder: European Research Council; Grant(s): 612724Determining the nature and extent of covalency of early actinide chemical bonding is a fundamentally important challenge. Recently, X-ray absorption, electron paramagnetic, and nuclear magnetic resonance spectroscopic studies have probed actinide-ligand covalency, largely confirming the paradigm of early actinide bonding varying from ionic to polarised-covalent, with this range sitting on the continuum between ionic lanthanide and more covalent d transition metal analogues. Here, we report measurement of the covalency of a terminal uranium(VI)-nitride by 15N nuclear magnetic resonance spectroscopy, and find an exceptional nitride chemical shift and chemical shift anisotropy. This redefines the 15N nuclear magnetic resonance spectroscopy parameter space, and experimentally confirms a prior computational prediction that the uranium(VI)-nitride triple bond is not only highly covalent, but, more so than d transition metal analogues. These results enable construction of general, predictive metal-ligand 15N chemical shift-bond order correlations, and reframe our understanding of actinide chemical bonding to guide future studies

Prostate-specific Membrane Antigen Heterogeneity and DNA Repair Defects in Prostate Cancer.

BackgroundProstate-specific membrane antigen (PSMA; folate hydrolase) prostate cancer (PC) expression has theranostic utility.ObjectiveTo elucidate PC PSMA expression and associate this with defective DNA damage repair (DDR).Design, setting, and participantsMembranous PSMA (mPSMA) expression was scored immunohistochemically from metastatic castration-resistant PC (mCRPC) and matching, same-patient, diagnostic biopsies, and correlated with next-generation sequencing (NGS) and clinical outcome data.Outcome measurements and statistical analysisExpression of mPSMA was quantitated by modified H-score. Patient DNA was tested by NGS. Gene expression and activity scores were determined from mCRPC transcriptomes. Statistical correlations utilised Wilcoxon signed rank tests, survival was estimated by Kaplan-Meier test, and sample heterogeneity was quantified by Shannon's diversity index.Results and limitationsExpression of mPSMA at diagnosis was associated with higher Gleason grade (p=0.04) and worse overall survival (p=0.006). Overall, mPSMA expression levels increased at mCRPC (median H-score [interquartile range]: castration-sensitive prostate cancer [CSPC] 17.5 [0.0-60.0] vs mCRPC 55.0 [2.8-117.5]). Surprisingly, 42% (n=16) of CSPC and 27% (n=16) of mCRPC tissues sampled had no detectable mPSMA (H-score ConclusionsMembranous PSMA expression is upregulated in some but not all PCs, with mPSMA expression demonstrating marked inter- and intrapatient heterogeneity. DDR aberrations are associated with higher mPSMA expression and merit further evaluation as predictive biomarkers of response for PSMA-targeted therapies in larger, prospective cohorts.Patient summaryThrough analysis of prostate cancer samples, we report that the presence of prostate-specific membrane antigen (PSMA) is extremely variable both within one patient and between different patients. This may limit the usefulness of PSMA scans and PSMA-targeted therapies. We show for the first time that prostate cancers with defective DNA repair produce more PSMA and so may respond better to PSMA-targeting treatments

The effect of transmucosal 0.2mg/kg Midazolam premedication on dental anxiety, anaesthetic induction and psychological morbidity in children undergoing general anaesthesia for tooth extraction

<b>Background:</b> The project aims were to evaluate the benefit of transmucosal Midazolam 0.2mg/kg pre-medication on anxiety, induction behaviour and psychological morbidity in children undergoing general anaesthesia (GA) extractions. <b>Method:</b> 179 children aged 5-10 years (mean 6.53 years) participated in this randomised, double blind, placebo controlled trial. Ninety children had Midazolam placed in the buccal pouch. Dental anxiety was recorded pre operatively and 48 hours later using a child reported MCDAS-FIS scale. Behaviour at anaesthetic induction was recorded and psychological morbidity was scored by the parent using the Rutter Scale pre-operatively and again one-week later. Subsequent dental attendance was recorded at one, three and six months after GA. <b>Results:</b> Whilst levels of mental anxiety did not reduce overall, the most anxious patients demonstrated a reduction in anxiety after receiving midazolam premedicationmay (p=0.01). Neither induction behaviour nor psychological morbidity improved. Irrespective of group, parents reported less hyperactive (p= 0.002) and more prosocial behaviour (p=0.002) after the procedure:;, older children improved most (p=0.048), Post GA Dental attendance was poor and unrelated to after the procedure and unaffected by premedication. <b>Conclusion:</b> 0.2mg/kg buccal Midazolam provided some evidence for reducing anxiety in the most dentally anxious patients. However, induction behaviour, psychological morbidity and subsequent dental attendance were not found to alter between the premedication groups

Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes

X-linked neutropenia (XLN) is caused by activating mutations in the Wiskott-Aldrich syndrome protein (WASP) that result in aberrant autoinhibition. Although patients with XLN appear to have only defects in myeloid lineages, we hypothesized that activating mutations of WASP are likely to affect the immune system more broadly. We generated mouse models to assess the role of activating WASP mutations associated with XLN (XLN-WASP) in lymphocytes. XLN-WASP is expressed stably in B and T cells and induces a marked increase in polymerized actin. XLN-WASP–expressing B and T cells migrate toward chemokines but fail to adhere normally. In marked contrast to WASP-deficient cells, XLN-WASP–expressing T cells proliferate normally in response to cell-surface receptor activation. However, XLN-WASP–expressing B cells fail to proliferate and secrete lower amounts of antibodies. Moreover, XLN-WASP expression in lymphocytes results in modestly increased apoptosis associated with increased genomic instability. These data indicate that there are unique requirements for the presence and activation status of WASP in B and T cells and that WASP-activating mutations interfere with lymphocyte cell survival and genomic stability

Bayesian echo classification for Australian single-polarization weather radar with application to assimilation of radial velocity observations

The Australian Bureau of Meteorology’s operational weather radar network comprises a heterogeneous radar collection covering diverse geography and climate. A naïve Bayes classifier has been developed to identify a range of common echo types observed with these radars. The success of the classifier has been evaluated against its training dataset and by routine monitoring. The training data indicate that more than 90% of precipitation may be identified correctly. The echo types most difficult to distinguish from rainfall are smoke, chaff, and anomalous propagation ground and sea clutter. Their impact depends on their climatological frequency. Small quantities of frequently misclassified persistent echo (like permanent ground clutter or insects) can also cause quality control issues. The Bayes classifier is demonstrated to perform better than a simple threshold method, particularly for reducing misclassification of clutter as precipitation. However, the result depends on finding a balance between excluding precipitation and including erroneous echo. Unlike many single-polarization classifiers that are only intended to extract precipitation echo, the Bayes classifier also discriminates types of nonprecipitation echo. Therefore, the classifier provides the means to utilize clear air echo for applications like data assimilation, and the class information will permit separate data handling of different echo types

Deep-coverage whole genome sequences and blood lipids among 16,324 individuals.

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia

Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans