Dynamic Parametric Sensitivity Optimization Using Simultaneous Discretization in JModelica.org

Dynamic optimization problems involving parametric sensitivities, such as optimal experimental design, are typically solved using shooting-based methods, while leveraging numerical integrators with sensitivity computation capabilities. In this paper we present how simultaneous discretization can be employed to solve these problems, by augmenting the dynamic optimization problems with forward sensitivity equations. We present an implementation of this approach in the open-source, Modelica-based tool JModelica.org, which addresses the need for solving optimal experimental design problems in Modelica tools. The implementation is demonstrated on a fed-batch reactor and a plate-fin heat exchanger

Damage modelling: the current state and the latest progress on the development of creep damage constitutive equations for high Cr steels

This paper reviews the fundamentals of the development of creep damage constitutive equations for high Cr steels including (1) a concise summary of the characteristics of creep deformation and creep damage evolution and their dependence on the stress level and the importance of cavitation for the final fracture; (2) a critical review of the state of art of creep damage equation for high Cr steels; (3) some discussion and comments on the various approaches; (4) consideration and suggestion for future work. It emphasises the need for better understanding the nucleation, cavity growth and coalesces and the theory for coupling method between creep cavity damage and brittle fracture and generalisatio

A genome-wide association study of the frailty index highlights brain pathways in ageing

Frailty is a common geriatric syndrome and strongly associated with disability, mortality and hospitalization. Frailty is commonly measured using the frailty index (FI), based on the accumulation of a number of health deficits during the life course. The mechanisms underlying FI are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 30 and 45%. Understanding the genetic determinants and biological mechanisms underpinning FI may help to delay or even prevent frailty. We performed a genome-wide association study (GWAS) meta-analysis of a frailty index in European descent UK Biobank participants (n = 164,610, 60–70 years) and Swedish TwinGene participants (n = 10,616, 41–87 years). FI calculation was based on 49 or 44 self-reported items on symptoms, disabilities and diagnosed diseases for UK Biobank and TwinGene, respectively. 14 loci were associated with the FI (p < 5*10−8). Many FI-associated loci have established associations with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, one appears to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 11% (0.11, SE 0.005). In enrichment analysis, genes expressed in the frontal cortex and hippocampus were significantly downregulated (adjusted p < 0.05). We also used Mendelian randomization to identify modifiable traits and exposures that may affect frailty risk, with a higher educational attainment genetic risk score being associated with a lower degree of frailty. Risk of frailty is influenced by many genetic factors, including well-known disease risk factors and mental health, with particular emphasis on pathways in the brain

Antiviral Activities and Putative Identification of Compounds in Microbial Extracts from the Hawaiian Coastal Waters

Marine environments are a rich source of significant bioactive compounds. The Hawaiian archipelago, located in the middle of the Pacific Ocean, hosts diverse microorganisms, including many endemic species. Thirty-eight microbial extracts from Hawaiian coastal waters were evaluated for their antiviral activity against four mammalian viruses including herpes simplex virus type one (HSV-1), vesicular stomatitis virus (VSV), vaccinia virus and poliovirus type one (poliovirus-1) using in vitro cell culture assay. Nine of the 38 microbial crude extracts showed antiviral potencies and three of these nine microbial extracts exhibited significant activity against the enveloped viruses. A secosteroid, 5α(H),17α(H),(20R)-beta-acetoxyergost-8(14)-ene was putatively identified and confirmed to be the active compound in these marine microbial extracts. These results warrant future in-depth tests on the isolation of these active elements in order to explore and validate their antiviral potential as important therapeutic remedies

Copy number variation and neuropsychiatric problems in females and males in the general population

Neurodevelopmental problems (NPs) are more common in males, whereas anxiety and depression are more common in females. Rare copy number variants (CNVs) have been implicated in neurodevelopmental disorders. The aim of this study was to characterize the relationship between rare CNVs with NPs, anxiety, and depression in a childhood population sample, as well as to examine sex‐specific effects. We analyzed a sample of N = 12,982 children, of whom 5.3% had narrowly defined NPs (clinically diagnosed), 20.9% had broadly defined NPs (based on validated screening measures, but no diagnosis), and 3.0% had clinically diagnosed anxiety or depression. Rare ( 500 kb), type, and putative relevance to NPs. We tested for association of CNV categories with outcomes and examined sex‐specific effects. Medium deletions (OR[CI] = 1.18[1.05–1.33], p = .0053) and large duplications (OR[CI] = 1.45[1.19–1.75], p = .00017) were associated with broadly defined NPs. Large deletions (OR[CI] = 1.85[1.14–3.01], p = .013) were associated with narrowly defined NPs. There were no significant sex differences in CNV burden in individuals with NPs. Although CNVs were not associated with anxiety/depression in the whole sample, in individuals diagnosed with these disorders, females were more likely to have large CNVs (OR[CI] = 3.75[1.45–9.68], p = .0064). Rare CNVs are associated with both narrowly and broadly defined NPs in a general population sample of children. Our results also suggest that large, rare CNVs may show sex‐specific phenotypic effects

Epilepsy in immigrants and Swedish-born:A cohort study of all adults 18 years of age and older in Sweden

Purpose: We aimed to study the association between country of birth and incident epilepsy in several immigrant groups using Swedish-born individuals as referents. Method: The study population included all adults aged 18 years and older in Sweden, living and deceased, 6,690,598 in the first-generation and 6,683,125 in the second-generation sub-study. Epilepsy was defined as having at least one registered diagnosis of epilepsy in the National Patient Register. The incidence of epilepsy in different immigrant groups, using Swedish-born as referents, was assessed by Cox regression, expressed as hazard ratios (HRs) and 95 % confidence intervals (CI). The models were stratified by sex and adjusted for age, geographical residence in Sweden, educational level, marital status, and neighbourhood socioeconomic status. Results: In the first-generation sub-study, totally 76,541 individuals had at least one registered diagnosis of epilepsy (1.14 % in total; men 1.22 % and women 1.07 %), and in the second-generation study 72,545 (1.09 %; men 1.18 % and women 0.99 %). After adjusting for confounders, in first-generation immigrants compared to their Swedish-born counterparts the incidence was somewhat lower among both men (HR 0.92, 0.90-0.96) and women (HR 0.93, 0.90-0.96), and in the second-generation immigrants among women (HR 0.95, 0.92-0.99) but not men (HR 0.99; 0.96–1.02). Among immigrant groups, a higher incidence of epilepsy was observed among first-generation women from Africa and Iraq, and second-generation men and women from Bosnia, and women from Finland. Conclusions: Risk of epilepsy was lower in immigrants in general compared to the Swedish-born population; but with higher incidence in some specific groups

Rare functional variants in the CRP and G6PC genes modify the relationship between obesity and serum C-reactive protein in white British population

Background: C-reactive protein (CRP) is a sensitive biomarker of inflammation with moderate heritability. The role of rare functional genetic variants in relation to serum CRP is understudied. We aimed to examine gene mutation burden of protein-altering (PA) and loss-of-function (LOF) variants in association with serum CRP, and to further explore the clinical relevance. Methods: We included 161,430 unrelated participants of European ancestry from the UK Biobank. Of the rare (minor allele frequency <0.1%) and functional variants, 1,776,249 PA and 266,226 LOF variants were identified. Gene-based burden tests, linear regressions, and logistic regressions were performed to identify the candidate mutations at the gene and variant levels, to estimate the potential interaction effect between the identified PA mutation and obesity, and to evaluate the relative risk of 16 CRP-associated diseases. Results: At the gene level, PA mutation burdens of the CRP (β = −0.685, p = 2.87e-28) and G6PC genes (β = 0.203, p = 1.50e-06) were associated with reduced and increased serum CRP concentration, respectively. At the variant level, seven PA alleles in the CRP gene decreased serum CRP, of which the per-allele effects were approximately three to seven times greater than that of a common variant in the same locus. The effects of obesity and central obesity on serum CRP concentration were smaller among the PA mutation carriers in the CRP (pinteraction = 0.008) and G6PC gene (pinteraction = 0.034) compared to the corresponding non-carriers. Conclusion: PA mutation burdens in the CRP and G6PC genes are strongly associated with decreased serum CRP concentrations. As serum CRP and obesity are important predictors of cardiovascular risks in clinics, our observations suggest taking rare genetic factors into consideration might improve the delivery of precision medicine.Peer reviewe

Association test using copy number profile curves (CONCUR) enhances power in rare copy number variant analysis

Copy number variants (CNVs) are the gain or loss of DNA segments in the genome that can vary in dosage and length. CNVs comprise a large proportion of variation in human genomes and impact health conditions. To detect rare CNV associations, kernel-based methods have been shown to be a powerful tool due to their flexibility in modeling the aggregate CNV effects, their ability to capture effects from different CNV features, and their accommodation of effect heterogeneity. To perform a kernel association test, a CNV locus needs to be defined so that locus-specific effects can be retained during aggregation. However, CNV loci are arbitrarily defined and different locus definitions can lead to different performance depending on the underlying effect patterns. In this work, we develop a new kernel-based test called CONCUR (i.e., copy number profile curve-based association test) that is free from a definition of locus and evaluates CNV-phenotype associations by comparing individuals' copy number profiles across the genomic regions. CONCUR is built on the proposed concepts of "copy number profile curves" to describe the CNV profile of an individual, and the "common area under the curve (cAUC) kernel" to model the multi-feature CNV effects. The proposed method captures the effects of CNV dosage and length, accounts for the numerical nature of copy numbers, and accommodates between- and within-locus etiological heterogeneity without the need to define artificial CNV loci as required in current kernel methods. In a variety of simulation settings, CONCUR shows comparable or improved power over existing approaches. Real data analyses suggest that CONCUR is well powered to detect CNV effects in the Swedish Schizophrenia Study and the Taiwan Biobank

New concept for a regenerative and resorbable prosthesis for tendon and ligament. Physicochemical and biological characterization of PLA-braided biomaterial

We present a concept for a new regenerative and resorbable prosthesis for tendon and ligament and characterize the physicomechanical and biological behavior of one of its components, a hollow braid made of poly-lactide acid (PLA) which is the load-bearing part of the prosthesis concept. The prosthesis consists of a braid, microparticles in its interior serving as cell carriers, and a surface non-adherent coating, all these parts being made of biodegradable materials. The PLA braid has a nonlinear convex stress-strain behavior with a Young modulus of 1370 +/- 90 MPa in the linear, stretched state, and after 12 months of hydrolytic degradation the modulus shows a reduction by a factor of four. Different disinfection methods were tested as to their efficiency in cleansing the braid and preparing it for cell culture. Fibroblasts of L929 line were grown on the PLA braid for 14 days, showing good adherence and proliferation. These studies validate the PLA braid for the intended purpose in the regenerative prosthesis concept. (c) 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 101A: 3228-3237, 2013This work has been developed thanks to the financial support of AITEX (Valencia, Spain). JME thanks Drs. Isabel Pascual, Andres Pena, and their team from Hospital Clinico of Valencia for their fine work.Araque Monrós, MC.; Gamboa Martinez, TC.; Gil Santos, L.; Gironés Bernabé, S.; Monleón Pradas, M.; Más Estellés, J. (2013). New concept for a regenerative and resorbable prosthesis for tendon and ligament. Physicochemical and biological characterization of PLA-braided biomaterial. Journal of Biomedical Materials Research Part A. 101A(11):3228-3237. doi:10.1002/jbm.a.34633S32283237101A11Vieira, A. C., Guedes, R. M., & Marques, A. T. (2009). Development of ligament tissue biodegradable devices: A review. Journal of Biomechanics, 42(15), 2421-2430. doi:10.1016/j.jbiomech.2009.07.019Kuo, C. K., Marturano, J. 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A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005<MAF<0.05) variants. In addition to confirmation of most known CAD loci, we identified 10 novel loci, eight additive and two recessive, that contain candidate genes that newly implicate biological processes in vessel walls. We observed intra-locus allelic heterogeneity but little evidence of low frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect siz