A minimum-dissipation time-integration strategy for large-eddy simulation of incompressible turbulent flows

Adaptive time stepping can significantly enhance the accuracy and the efficiency of computational methods. In this work, a time-integration strategy with adaptive time step control is proposed for large-eddy simulation of turbulent flows. The algorithm is based on Runge-Kutta methods and consists in adjusting the time-step size dynamically to ensure that the numerical dissipation rate due to the temporal scheme is smaller than the molecular and subgrid-scale ones within a desired tolerance. The effectiveness of the method, as compared to standard CFL-like criteria, is assessed by large-eddy simulations of the three-dimensional Taylor-Green Vortex

Comparing Petri Net and Activity Diagram Variants for Workflow Modelling:A Quest for Reactive Petri Nets

Petri net variants are widely used as a workflow modelling technique. Recently, UMLa ctivity diagrams have been used for the same purpose, even though the syntax and semantics of activity diagrams has not been yet fully worked out. Nevertheless, activity diagrams seem very similar to Petri nets and on the surface, one may think that they are variants of each other. To substantiate or deny this claim, we need to formalise the intended semantics of activity diagrams and then compare this with various Petri net semantics. In previous papers we have defined two formal semantics for UMLact ivity diagrams that are intended for workflow modelling. In this paper, we discuss the design choices that underlie these two semantics and investigate whether these design choices can be met in low-level and high-level Petri net semantics. We argue that the main difference between the Petri net semantics and our semantics of UML act ivity diagrams is that the Petri net semantics models resource usage of closed, active systems that are non-reactive, whereas our semantics of UMLact ivity diagrams models open, reactive systems. Since workflow systems are open, reactive systems, we conclude that Petri nets cannot model workflows accurately, unless they are extended with a syntax and semantics for reactivity

Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors

Reduced SLIT2 is associated with increased cell proliferation and arsenic trioxide resistance in acute promyelocytic Leukemia

The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate SLIT2 expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with SLIT2high transcript levels were associated with cell cycle arrest, while SLIT2low APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high SLIT2 expression was correlated with reduced leukocyte count (p = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92–0.97; p < 0.001). Functionally, SLIT2-knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count (p = 0.001) and decreased overall survival (p = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated

WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene

Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother’s, and, to a lesser extent, with father’s TL having the strongest influence on the offspring. In this cohort, mother’s, but not father’s age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait

Beyond the Global Brain Differences:Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers

BACKGROUND: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and globalbrain differences compared with noncarriers. However, interpreting regional differences is challenging if a globaldifference drives the regional brain differences. Intraindividual variability measures can be used to test for regionaldifferences beyond global differences in brain structure.METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n =30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matchednoncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual’sregional difference and global difference, were used to test for regional differences that diverge from the globaldifference.RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differedmore than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thicknessin regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal andsomatosensory cortex differed more than the global difference in cortical thickness.CONCLUSIONS: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distaland 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distaland 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanismsinvolved in altered neurodevelopment

Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets

Search for leptophobic Z ' bosons decaying into four-lepton final states in proton-proton collisions at root s=8 TeV

Peer reviewe

Search for black holes and other new phenomena in high-multiplicity final states in proton-proton collisions at root s=13 TeV

Peer reviewe