Mercury DPM: fast, flexible particle simulations in complex geometries part II: applications

MercuryDPM is a particle-simulation software developed open-source by a global network of researchers. It was designed ​ab initio to simulate realistic geometries and materials, thus it contains several unique features not found in any other particle simulation software. These features have been discussed in a companion paper published in the DEM7 conference proceedings; here we present several challenging setups implemented in MercuryDPM ​ . Via these setups, we demonstrate the unique capability of the code to simulate and analyse highly complex geotechnical and industrial applications.These tups implemented include complex geometries such as (i) a screw conveyor, (ii) steady-state inflow conditions for chute flows, (iii) a confined conveyor belt to simulate a steady-state breaking wave, and(iii)aquasi-2D cylindrical slice to efficiently study shear flows.​MercuryDPM is also parallel, which we showcase via a multi-million particle simulations of a rotating drum. We further demonstrate how to simulate complex particle interactions, including: (i)deformable, charged clay particles; and (ii) liquid bridges and liquid migration in wet particulates, (iii) non-spherical particles implemented via superquadrics. Finally, we show how to analyse and complex systems using the unique micro-macro mapping (coarse-graining) tool MercuryCG

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies

Comparative return of imports into the state of Negri Sembilan during the years, 1916 and 1915.

Supplement to the F.M.S Government Gazette, May 11th, 1917. It also contains 'Comparative return of exports into the state of Negri Sembilan during the years, 1916 and 1915'

MicroRNA profiling in ischemic injury of the gracilis muscle in rats

<p>Abstract</p> <p>Background</p> <p>To profile the expression of microRNAs (miRNAs) and their potential target genes in the gracilis muscles following ischemic injury in rats by monitoring miRNA and mRNA expression on a genome-wide basis.</p> <p>Methods</p> <p>Following 4 h of ischemia and subsequent reperfusion for 4 h of the gracilis muscles, the specimens were analyzed with an Agilent rat miRNA array to detect the expressed miRNAs in the experimental muscles compared to those from the sham-operated controls. Their expressions were subsequently quantified by real-time reverse transcription polymerase chain reaction (real-time RT-PCR) to determine their expression pattern after different durations of ischemia and reperfusion. In addition, the expression of the mRNA in the muscle specimens after 4 h of ischemia and reperfusion for 1, 3, 7, and 14 d were detected with the Agilent Whole Rat Genome 4 × 44 k oligo microarray. A combined approach using a computational prediction algorithm that included miRanda, PicTar, TargetScanS, MirTarget2, RNAhybrid, and the whole genome microarray experiment was performed by monitoring the mRNA:miRNA association to identify potential target genes.</p> <p>Results</p> <p>Three miRNAs (miR-21, miR-200c, and miR-205) of 350 tested rat miRNAs were found to have an increased expression in the miRNA array. Real-time RT-PCR demonstrated that, with 2-fold increase after 4 h of ischemia, a maximum 24-fold increase at 7 d, and a 7.5-fold increase at 14 d after reperfusion, only the miR-21, but not the miR-200c or miR-205 was upregulated throughout the experimental time. In monitoring the target genes of miR-21 in the expression array at 1, 3, 7, 14 d after reperfusion, with persistent expression throughout the experiment, we detected the same 4 persistently downregulated target genes (<it>Nqo1</it>, <it>Pdpn</it>, <it>CXCL3</it>, and <it>Rad23b</it>) with the prediction algorithms miRanda and RNAhybrid, but no target gene was revealed with PicTar, TargetScanS, and MirTarget2.</p> <p>Conclusions</p> <p>This study revealed 3 upregulated miRNAs in the gracilis muscle following ischemic injury and identified 4 potential target genes of miR-21 by examining miRNAs and mRNAs expression patterns in a time-course fashion using a combined approach with prediction algorithms and a whole genome expression array experiment.</p

Novel MicroRNA Candidates and miRNA-mRNA Pairs in Embryonic Stem (ES) Cells

MicroRNAS (miRNAS: a class of short non-coding RNAs) are emerging as important agents of post transcriptional gene regulation and integral components of gene networks. MiRNAs have been strongly linked to stem cells, which have a remarkable dual role in development. They can either continuously replenish themselves (self-renewal), or differentiate into cells that execute a limited number of specific actions (pluripotence).In order to identify novel miRNAs from narrow windows of development we carried out an in silico search for micro-conserved elements (MCE) in adult tissue progenitor transcript sequences. A plethora of previously unknown miRNA candidates were revealed including 545 small RNAs that are enriched in embryonic stem (ES) cells over adult cells. Approximately 20% of these novel candidates are down-regulated in ES (Dicer(-/-)) ES cells that are impaired in miRNA maturation. The ES-enriched miRNA candidates exhibit distinct and opposite expression trends from mmu-mirs (an abundant class in adult tissues) during retinoic acid (RA)-induced ES cell differentiation. Significant perturbation of trends is found in both miRNAs and novel candidates in ES (GCNF(-/-)) cells, which display loss of repression of pluripotence genes upon differentiation.Combining expression profile information with miRNA target prediction, we identified miRNA-mRNA pairs that correlate with ES cell pluripotence and differentiation. Perturbation of these pairs in the ES (GCNF(-/-)) mutant suggests a role for miRNAs in the core regulatory networks underlying ES cell self-renewal, pluripotence and differentiation

Regulation of early steps of GPVI signal transduction by phosphatases: a systems biology approach

We present a data-driven mathematical model of a key initiating step in platelet activation, a central process in the prevention of bleeding following Injury. In vascular disease, this process is activated inappropriately and causes thrombosis, heart attacks and stroke. The collagen receptor GPVI is the primary trigger for platelet activation at sites of injury. Understanding the complex molecular mechanisms initiated by this receptor is important for development of more effective antithrombotic medicines. In this work we developed a series of nonlinear ordinary differential equation models that are direct representations of biological hypotheses surrounding the initial steps in GPVI-stimulated signal transduction. At each stage model simulations were compared to our own quantitative, high-temporal experimental data that guides further experimental design, data collection and model refinement. Much is known about the linear forward reactions within platelet signalling pathways but knowledge of the roles of putative reverse reactions are poorly understood. An initial model, that includes a simple constitutively active phosphatase, was unable to explain experimental data. Model revisions, incorporating a complex pathway of interactions (and specifically the phosphatase TULA-2), provided a good description of the experimental data both based on observations of phosphorylation in samples from one donor and in those of a wider population. Our model was used to investigate the levels of proteins involved in regulating the pathway and the effect of low GPVI levels that have been associated with disease. Results indicate a clear separation in healthy and GPVI deficient states in respect of the signalling cascade dynamics associated with Syk tyrosine phosphorylation and activation. Our approach reveals the central importance of this negative feedback pathway that results in the temporal regulation of a specific class of protein tyrosine phosphatases in controlling the rate, and therefore extent, of GPVI-stimulated platelet activation

Measurement of the W-boson mass in pp collisions at √s=7 TeV with the ATLAS detector

A measurement of the mass of the W boson is presented based on proton–proton collision data recorded in 2011 at a centre-of-mass energy of 7 TeV with the ATLAS detector at the LHC, and corresponding to 4.6 fb−1 of integrated luminosity. The selected data sample consists of 7.8×106 candidates in the W→μν channel and 5.9×106 candidates in the W→eν channel. The W-boson mass is obtained from template fits to the reconstructed distributions of the charged lepton transverse momentum and of the W boson transverse mass in the electron and muon decay channels, yielding mW=80370±7 (stat.)±11(exp. syst.) ±14(mod. syst.) MeV =80370±19MeV, where the first uncertainty is statistical, the second corresponds to the experimental systematic uncertainty, and the third to the physics-modelling systematic uncertainty. A measurement of the mass difference between the W+ and W−bosons yields mW+−mW−=−29±28 MeV

Open data from the third observing run of LIGO, Virgo, KAGRA and GEO

The global network of gravitational-wave observatories now includes five detectors, namely LIGO Hanford, LIGO Livingston, Virgo, KAGRA, and GEO 600. These detectors collected data during their third observing run, O3, composed of three phases: O3a starting in April of 2019 and lasting six months, O3b starting in November of 2019 and lasting five months, and O3GK starting in April of 2020 and lasting 2 weeks. In this paper we describe these data and various other science products that can be freely accessed through the Gravitational Wave Open Science Center at https://gwosc.org. The main dataset, consisting of the gravitational-wave strain time series that contains the astrophysical signals, is released together with supporting data useful for their analysis and documentation, tutorials, as well as analysis software packages.Comment: 27 pages, 3 figure

2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

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The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care