A free surface finite element model for low Froude number mould filling problems on fixed meshes

The simulation of low Froude number mould filling problems on fixed meshes presents significant difficulties. As the Froude number decreases, the coupling between the position of the interface and the resulting flow field increases. The usual two‐phase flow model provides poor results for such flow. In order to overcome the difficulties, a free surface model that applies boundary conditions at the interface accurately is used. Moreover, the use of wall laws on curved boundaries also fails in the case of low Froude number flows. To solve this second problem, we combine wall laws with ‘do nothing’ boundary conditions. A special feature of our approach is that ‘do nothing’ boundary conditions are only applied in the normal direction. These two key ingredients together with the Level Set method allow us to simulate three‐dimensional mould filling problems borrowed directly from the foundry

A finite element model for free surface flows on fixed meshes

In this paper, we present a finite element model for free surface flows on fixed meshes. The main novelty of the approach, compared with typical fixed mesh finite element models for such flows, is that we take advantage of the particularities of free surface flow, instead of considering it a particular case of two‐phase flow. The fact that a given free surface implies a known boundary condition on the interface, allows us to solve the Navier–Stokes equations on the fluid domain uncoupled from the solution on the rest of the finite element mesh. This, together with the use of enhanced integration allows us to model low Froude number flows accurately, something that is not possible with typical two‐phase flow models applied to free surface flow

The Fixed‐Mesh ALE approach for the numerical simulation of floating solids

In this paper, we propose a method to solve the problem of floating solids using always a background mesh for the spatial discretization of the fluid domain. The main feature of the method is that it properly accounts for the advection of information as the domain boundary evolves. To achieve this, we use an arbitrary Lagrangian–Eulerian framework, the distinctive characteristic being that at each time step results are projected onto a fixed, background mesh. We pay special attention to the tracking of the various interfaces and their intersections, and to the approximate imposition of coupling conditions between the solid and the fluid.&nbsp

The fixed-mesh ALE approach for the numerical approximation of flows in moving domains

In this paper we propose a method to approximate flow problems in moving domains using always a given grid for the spatial discretization, and therefore the formulation to be presented falls within the category of fixed-grid methods. Even though the imposition of boundary conditions is a key ingredient that is very often used to classify the fixed-grid method, our approach can be applied together with any technique to impose approximately boundary conditions, although we also describe the one we actually favor. Our main concern is to properly account for the advection of information as the domain boundary evolves. To achieve this, we use an arbitrary Lagrangian–Eulerian framework, the distinctive feature being that at each time step results are projected onto a fixed, background mesh, that is where the problem is actually solved

Numerical comparison of CBS and SGS as stabilization techniques for the incompressible Navier–Stokes equations

In this work, we present numerical comparisons of some stabilization methods for the incompressible Navier–Stokes. The first is the characteristic‐based split (CBS). It combines the characteristic Galerkin method to deal with convection‐dominated flows with a classical splitting technique, which in some cases allows us to use equal velocity–pressure interpolations. The other two approaches are particular cases of the subgrid scale (SGS) method. The first, obtained after an algebraic approximation of the subgrid scales, is very similar to the popular Galerkin/least‐squares (GLS) method, whereas in the second, the subscales are assumed to be orthogonal to the finite element space. It is shown that all these formulations display similar stabilization mechanisms, provided the stabilization parameter of the SGS methods is identified with the time step of the CBS approach. This paper provides the numerical experiments for the comparison of formulations made by Codina and Zienkiewicz in a previous article

The Fixed-Mesh ALE approach for the numerical approximation of flows in moving domains

In this paper we propose a method to approximate flow problems in moving domains using always a given grid for the spatial discretization, and therefore the formulation to be presented falls within the category of fixed-grid methods. Even though the imposition of boundary conditions is a key ingredient that is very often used to classify the fixed-grid method, our approach can be applied together with any technique to impose approximately boundary conditions, although we also describe the one we actually favor. Our main concern is to properly account for the advection of information as the domain boundary evolves. To achieve this, we use an arbitrary Lagrangian- Eulerian framework, the distinctive feature being that at each time step results are projected onto a fixed, background mesh, that is where the problem is actually solved

Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy

BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs).MethodIn this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed.ResultsOur analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP.ConclusionsThrough WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions

Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. We describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of truncating variants with 72% having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human “knockout” variants in protein-coding genes

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead