Despite the popularity in modeling complex and arbitrary crack configurations in solids, phase-field damage models suffer from burdensome computational cost. This issue arises largely due to the ...robust but inefficient alternating minimization (AM) or staggered algorithm usually employed to solve the coupled damage–displacement governing equations. Aiming to tackle this difficulty, we propose in this work, for the first time, to use the Broyden–Fletcher–Goldfarb–Shanno (BFGS) algorithm to solve in a monolithic manner the system of coupled governing equations, rather than the standard Newton one which is notoriously poor for problems involving non-convex energy functional. It is found that, the BFGS algorithm yields identical results to the AM/staggered solver, and is also robust for both brittle fracture and quasi-brittle failure with a single or multiple cracks. However, much less iterations are needed to achieve convergence. Furthermore, as the system matrix is less reformed per increment, the quasi-Newton monolithic algorithm is much more efficient than the AM/staggered solver. Representative numerical examples show that the saving in CPU time is about factor 3∼7, and the larger the problem is, the more saving it gains. As the BFGS monolithic algorithm has been incorporated in many commercial software packages, it can be easily implemented and is thus attractive in the phase-field damage modeling of localized failure in solids.
•A robust and efficient quasi-Newton monolithic algorithm is proposed for phase-field damage models.•The robustness comes from the BFGS method with a symmetric and positive-definite stiffness matrix.•The proposed quasi-Newton monolithic algorithm is about 3∼7 times faster than the staggered solver.•The phase-field regularized cohesive zone model is not numerically affected by the solution algorithm.
•Three different implementation strategies of phase-field damage models in Abaqus are addressed.•The sources codes and input files of all these three implementation schemes can be open ...accessed.•Representative examples validating the implementation strategies and source codes are presented.•The UEL subroutine together with the BFGS monolithic solver is of best numerical performances.•The UMAT subroutine is viable if the BFGS solver is available in coupled thermal–stress analyses.
Despite the versatility in modeling complex crack configurations, phase-field damage models for fracture usually count only on in-house codes, greatly restricting their potential applications. It is thus of vital importance to implement them in those commonly used commercial software packages like Abaqus. However, so far only the less robust Newton’s monolithic algorithm or the inefficient staggered solver has been considered. In this work, taking the unified phase-field damage theory (Wu, 2017) as the particular example, we present three distinct strategies of implementing phase-field damage models into Abaqus: (i) UMAT-Newton-M: a thermo-mechanically coupled user-defined material (UMAT) implementation of the modified Newton monolithic solver; (ii) UEL-Staggered: a novel user-defined element (UEL) implementation of the iterative staggered (alternate minimization) algorithm with dummy dofs; (iii) UEL-BFGS: a UEL implementation of the recently advocated BFGS quasi-Newton monolithic algorithm. The aforesaid implementation strategies are then validated against several representative benchmark problems of brittle fracture and quasi-brittle failure. It is found that, the UMAT-Newton-M implementation is the simplest but not robust enough, while the UEL-Staggered implementation is robust but extremely inefficient. Comparatively, in all cases the UEL-BFGS scheme is of the best numerical performance with lest iterations and sufficient robustness. For the sake of reproducibility of the presented numerical results and the promotion of phase-field damage models, the source codes (programmed in the free format syntax of FORTRAN90) are also provided and interested users can download them at https://github.com/jianyingwu/pfczm-abaqus.
In the phase-field modeling of fracture in brittle and quasi-brittle solids, it is crucial to represent the asymmetric tensile/compressive material behavior. Existing phase-field models generally ...adopt either an intuitive split of the free energy density without capturing the crack boundary conditions properly or an ad hoc hybrid formulation at the loss of variational consistency. To address this issue, this work presents a variationally consistent phase-field anisotropic damage model within the framework of the unified phase-field theory for brittle fracture and quasi-brittle failure Wu 1, 2. Consistent with the variational approach to fracture, the positive/negative projection of the effective stress in energy norm Wu and Cervera 3 is adopted, minimizing the tensile part of the stored energy that drives crack evolution. A rounded-Rankine criterion naturally emerges to realistically characterize localized failure of brittle and quasi-brittle solids, with no need of ad hoc assumptions. A mixed-mode cohesive zone model is recovered upon strain localization, with the involved parameters determined from the analytical solution of a softening bar under constrained stretching. Representative numerical examples show that the proposed model can capture arbitrary cracks propagation in solids independently of the mesh discretization and length scale parameter. Remarkably, the spurious stress locking, which is notoriously accompanied with classical anisotropic damage models, is not exhibited.
•A variationally and thermodynamically consistent phase-field anisotropic damage model is presented.•Unilateral effects are dealt with by a positive/negative projection of the effective stress in energy norm.•A rounded-Rankine criterion is obtained to describe localized failure in brittle and quasi-brittle solids.•A mixed-mode cohesive zone model is recovered from strain localization for a vanishing length scale.•Representative numerical examples are presented to validate the mesh and length scale independence.
Abstract
The mixed linear model has been widely used in genome-wide association studies (GWAS), but its application to multi-locus GWAS analysis has not been explored and assessed. Here, we ...implemented a fast multi-locus random-SNP-effect EMMA (FASTmrEMMA) model for GWAS. The model is built on random single nucleotide polymorphism (SNP) effects and a new algorithm. This algorithm whitens the covariance matrix of the polygenic matrix K and environmental noise, and specifies the number of nonzero eigenvalues as one. The model first chooses all putative quantitative trait nucleotides (QTNs) with ≤ 0.005 P-values and then includes them in a multi-locus model for true QTN detection. Owing to the multi-locus feature, the Bonferroni correction is replaced by a less stringent selection criterion. Results from analyses of both simulated and real data showed that FASTmrEMMA is more powerful in QTN detection and model fit, has less bias in QTN effect estimation and requires a less running time than existing single- and multi-locus methods, such as empirical Bayes, settlement of mixed linear model under progressively exclusive relationship (SUPER), efficient mixed model association (EMMA), compressed MLM (CMLM) and enriched CMLM (ECMLM). FASTmrEMMA provides an alternative for multi-locus GWAS.
One major merit of phase-field models for fracture is that cracks nucleation, propagation, branching, merging, coalescence and even fragmentation, etc., can be accounted for seamlessly within a ...standalone regularized variational framework. This fascinating feature overcomes the cumbersomeness in the characterization of non-smooth crack surfaces and the tracking of complex crack paths. However, the numerical algorithms frequently adopted in solving the coupled governing equations are not robust or efficient enough, together with the high computational cost in resolving the fracture process zone, largely hindering application of these models to general 3D problems. In this work, several 3D benchmark problems involving mode I, I+II or I+III failure in brittle and quasi-brittle solids is addressed based on our recent theoretical and numerical progresses on the unified phase-field theory for damage and fracture (Wu, 2017). Complex 3D fracture problems with over 2 million elements and more than 6 million degrees of freedom (dofs) can be tackled using normal computation facilities within acceptable computational time. Moreover, we are able to not only reproduce qualitatively evolution of the complex fracture pattern, but also compare quantitatively the global responses against experimental results. With the need neither to characterize the non-smooth crack surface nor to track the twisting crack path, the 3D computer implementation is almost the same as the 2D counterpart, paving the way to the phase-field modeling of large scale engineering problems.
•The phase-field regularized cohesive zone model is applied to mixed-mode 3D fracture problems in solids.•An improved BFGS monolithic algorithm is used to solve efficiently the discretized governing equations.•Complex 3D problems with over 2 million elements can be considered using normal computer facilities.•Both the qualitative crack patterns and the quantitative global responses can be well captured in 3D cases.•Application of the proposed phase-field approach to large scale engineering structures is straightforward.
This is the first randomised controlled trial for assessment of the immunogenicity and safety of a candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine, aiming to determine an ...appropriate dose of the candidate vaccine for an efficacy study.
This randomised, double-blind, placebo-controlled, phase 2 trial of the Ad5-vectored COVID-19 vaccine was done in a single centre in Wuhan, China. Healthy adults aged 18 years or older, who were HIV-negative and previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-free, were eligible to participate and were randomly assigned to receive the vaccine at a dose of 1 × 1011 viral particles per mL or 5 × 1010 viral particles per mL, or placebo. Investigators allocated participants at a ratio of 2:1:1 to receive a single injection intramuscularly in the arm. The randomisation list (block size 4) was generated by an independent statistician. Participants, investigators, and staff undertaking laboratory analyses were masked to group allocation. The primary endpoints for immunogenicity were the geometric mean titres (GMTs) of specific ELISA antibody responses to the receptor binding domain (RBD) and neutralising antibody responses at day 28. The primary endpoint for safety evaluation was the incidence of adverse reactions within 14 days. All recruited participants who received at least one dose were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, NCT04341389.
603 volunteers were recruited and screened for eligibility between April 11 and 16, 2020. 508 eligible participants (50% male; mean age 39·7 years, SD 12·5) consented to participate in the trial and were randomly assigned to receive the vaccine (1 × 1011 viral particles n=253; 5 × 1010 viral particles n=129) or placebo (n=126). In the 1 × 1011 and 5 × 1010 viral particles dose groups, the RBD-specific ELISA antibodies peaked at 656·5 (95% CI 575·2–749·2) and 571·0 (467·6–697·3), with seroconversion rates at 96% (95% CI 93–98) and 97% (92–99), respectively, at day 28. Both doses of the vaccine induced significant neutralising antibody responses to live SARS-CoV-2, with GMTs of 19·5 (95% CI 16·8–22·7) and 18·3 (14·4–23·3) in participants receiving 1 × 1011 and 5 × 1010 viral particles, respectively. Specific interferon γ enzyme-linked immunospot assay responses post vaccination were observed in 227 (90%, 95% CI 85–93) of 253 and 113 (88%, 81–92) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Solicited adverse reactions were reported by 183 (72%) of 253 and 96 (74%) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Severe adverse reactions were reported by 24 (9%) participants in the 1 × 1011 viral particles dose group and one (1%) participant in the 5 × 1010 viral particles dose group. No serious adverse reactions were documented.
The Ad5-vectored COVID-19 vaccine at 5 × 1010 viral particles is safe, and induced significant immune responses in the majority of recipients after a single immunisation.
National Key R&D Programme of China, National Science and Technology Major Project, and CanSino Biologics.
Genome-wide association studies (GWAS) have been widely used in genetic dissection of complex traits. However, common methods are all based on a fixed-SNP-effect mixed linear model (MLM) and single ...marker analysis, such as efficient mixed model analysis (EMMA). These methods require Bonferroni correction for multiple tests, which often is too conservative when the number of markers is extremely large. To address this concern, we proposed a random-SNP-effect MLM (RMLM) and a multi-locus RMLM (MRMLM) for GWAS. The RMLM simply treats the SNP-effect as random, but it allows a modified Bonferroni correction to be used to calculate the threshold p value for significance tests. The MRMLM is a multi-locus model including markers selected from the RMLM method with a less stringent selection criterion. Due to the multi-locus nature, no multiple test correction is needed. Simulation studies show that the MRMLM is more powerful in QTN detection and more accurate in QTN effect estimation than the RMLM, which in turn is more powerful and accurate than the EMMA. To demonstrate the new methods, we analyzed six flowering time related traits in Arabidopsis thaliana and detected more genes than previous reported using the EMMA. Therefore, the MRMLM provides an alternative for multi-locus GWAS.
The large-scale hydrogen production and application through electrocatalytic water splitting depends crucially on the development of highly efficient, cost-effective electrocatalysts for oxygen ...evolution reaction (OER), which, however, remains challenging. Here, a new electrocatalyst of trimetallic Fe-Co-Ni hydroxide (denoted as FeCoNiO
H
) with a nanotubular structure is developed through an enhanced Kirkendall process under applied potential. The FeCoNiO
H
features synergistic electronic interaction between Fe, Co, and Ni, which not only notably increases the intrinsic OER activity of FeCoNiO
H
by facilitating the formation of *OOH intermediate, but also substantially improves the intrinsic conductivity of FeCoNiO
H
to facilitate charge transfer and activate catalytic sites through electrocatalyst by promoting the formation of abundant Co
. Therefore, FeCoNiO
H
delivers remarkably accelerated OER kinetics and superior apparent activity, indicated by an ultra-low overpotential potential of 257 mV at a high current density of 200 mA cm
. This work is of fundamental and practical significance for synergistic catalysis related to advanced energy conversion materials and technologies.
Nonclinical testing has served as a foundation for evaluating potential risks and effectiveness of investigational new drugs in humans. However, the current two‐dimensional (2D) in vitro cell culture ...systems cannot accurately depict and simulate the rich environment and complex processes observed in vivo, whereas animal studies present significant drawbacks with inherited species‐specific differences and low throughput for increased demands. To improve the nonclinical prediction of drug safety and efficacy, researchers continue to develop novel models to evaluate and promote the use of improved cell‐ and organ‐based assays for more accurate representation of human susceptibility to drug response. Among others, the three‐dimensional (3D) cell culture models present physiologically relevant cellular microenvironment and offer great promise for assessing drug disposition and pharmacokinetics (PKs) that influence drug safety and efficacy from an early stage of drug development. Currently, there are numerous different types of 3D culture systems, from simple spheroids to more complicated organoids and organs‐on‐chips, and from single‐cell type static 3D models to cell co‐culture 3D models equipped with microfluidic flow control as well as hybrid 3D systems that combine 2D culture with biomedical microelectromechanical systems. This article reviews the current application and challenges of 3D culture systems in drug PKs, safety, and efficacy assessment, and provides a focused discussion and regulatory perspectives on the liver‐, intestine‐, kidney‐, and neuron‐based 3D cellular models.
Emodin (1, 3, 8-trihydroxy-6-methylanthraquinone) is a derived anthraquinone compound extracted from roots and barks of pharmaceutical plants, including Rheum palmatum, Aloe vera, Giant knotweed, ...Polygonum multiflorum and Polygonum cuspidatum. The review aims to provide a scientific summary of emodin in pharmacological activities and toxicity in order to identify the therapeutic potential for its use in human specific organs as a new medicine. Based on the fundamental properties, such as anticancer, anti-inflammatory, antioxidant, antibacterial, antivirs, anti-diabetes, immunosuppressive and osteogenesis promotion, emodin is expected to become an effective preventive and therapeutic drug of cancer, myocardial infarction, atherosclerosis, diabetes, acute pancreatitis, asthma, periodontitis, fatty livers and neurodegenerative diseases. This article intends to provide a novel insight for further development of emodin, hoping to reveal the potential of emodin and necessity of further studies in this field.
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