A time discretization scheme for a nonlocal degenerate problem modelling resistance spot welding

This is the author's PDF version of an article published in Mathematical Modelling of Natural Phenomena© 2015. The definitive version is available at http://www.mmnp-journal.org/articles/mmnp/abs/2015/06/mmnp2015106p90/mmnp2015106p90.htmlIn the current work we construct a nonlocal mathematical model describing the phase transition occurs during the resistance spot welding process in the industry of metallurgy. We then consider a time discretization scheme for solving the resulting nonlocal moving boundary problem. The scheme consists of solving at each time step a linear elliptic partial differential equation and then making a correction to account for the nonlinearity. The stability and error estimates of the developed scheme are investigated. Finally some numerical results are presented confirming the efficiency of the developed numerical algorithm

Prevalence and risk of Down syndrome in monozygotic and dizygotic multiple pregnancies in Europe: implications for prenatal screening.

OBJECTIVE: To determine risk of Down syndrome (DS) in multiple relative to singleton pregnancies, and compare prenatal diagnosis rates and pregnancy outcome. DESIGN: Population-based prevalence study based on EUROCAT congenital anomaly registries. SETTING: Eight European countries. POPULATION: 14.8 million births 1990-2009; 2.89% multiple births. METHODS: DS cases included livebirths, fetal deaths from 20 weeks, and terminations of pregnancy for fetal anomaly (TOPFA). Zygosity is inferred from like/unlike sex for birth denominators, and from concordance for DS cases. MAIN OUTCOME MEASURES: Relative risk (RR) of DS per fetus/baby from multiple versus singleton pregnancies and per pregnancy in monozygotic/dizygotic versus singleton pregnancies. Proportion of prenatally diagnosed and pregnancy outcome. STATISTICAL ANALYSIS: Poisson and logistic regression stratified for maternal age, country and time. RESULTS: Overall, the adjusted (adj) RR of DS for fetus/babies from multiple versus singleton pregnancies was 0.58 (95% CI 0.53-0.62), similar for all maternal ages except for mothers over 44, for whom it was considerably lower. In 8.7% of twin pairs affected by DS, both co-twins were diagnosed with the condition. The adjRR of DS for monozygotic versus singleton pregnancies was 0.34 (95% CI 0.25-0.44) and for dizygotic versus singleton pregnancies 1.34 (95% CI 1.23-1.46). DS fetuses from multiple births were less likely to be prenatally diagnosed than singletons (adjOR 0.62 [95% CI 0.50-0.78]) and following diagnosis less likely to be TOPFA (adjOR 0.40 [95% CI 0.27-0.59]). CONCLUSIONS: The risk of DS per fetus/baby is lower in multiple than singleton pregnancies. These estimates can be used for genetic counselling and prenatal screening

Exploring Research Priorities of Parents Who Have Children With Down Syndrome, Cleft Lip With or Without Cleft Palate, Congenital Heart Defects, and Spina Bifida Using ConnectEpeople:A Social Media Coproduction Research Study

Background: Using social media for research purposes is novel and challenging in terms of recruitment, participant knowledge about the research process, and ethical issues. This paper provides insight into the recruitment of European parents of children with specific congenital anomalies to engage in coproduction research by using social media. Secret Facebook groups, providing optimal security, were set up for newly recruited research-aware parents (RAPs) to communicate privately and confidentially with each other and for the research team to generate questions and to interpret findings. Objective: This study aimed to use social media for the recruitment and engagement of parents in research and to determine the research priorities of parents who have children with Down syndrome, cleft lip with or without cleft palate, congenital heart defects, and spina bifida. Methods: The design was exploratory and descriptive with 3 phases. Phase 1 included the recruitment of RAPs and generation of research questions important to them; phase 2 was a Web-based survey, designed using Qualtrics software, and phase 3 included analysis and ranking of the top 10 research questions using an adapted James Lind Alliance approach. Simple descriptive statistics were used for analysis, and ethical approval was obtained from the Ethics Filter Committee of the Institute of Nursing and Health Research, Ulster University. Results: The recruitment of 32 RAPs was a sensitive process, varying in the time taken to consent (mean 51 days). However, parents valued the screening approach using the State-Trait Anxiety Inventory as a measure to ensure their well-being (mean 32.5). In phase 1, RAPs generated 98 research questions. In phase 2, 251 respondents accessed the Web-based survey, 248 consented, and 80 completed the survey, giving a completeness rate of 32.3% (80/248). Most parents used social media (74/80, 92%). Social media, online forums, and meeting in person were ranked the most preferable methods for communication with support groups networks and charities. Most respondents stated that they had a good understanding of research reports (71/80, 89%) and statistics (68/80, 85%) and could differentiate among the different types of research methodologies (62/80, 78%). Phase 3 demonstrated consensus among RAPs and survey respondents, with a need to know the facts about their child's condition, future health, and psychosocial and educational outcomes for children with similar issues. Conclusions: Social media is a valuable facilitator in the coproduction of research between parents and researchers. From a theoretical perspective, ocularcentrism can be an applicable frame of reference for understanding how people favor visual contact.This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 733001.info:eu-repo/semantics/publishedVersio

Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes

Structural variants are a common cause of disease and contribute to a large extent to inter-individual variability, but their detection and interpretation remain a challenge. Here, we investigate 11 individuals with complex genomic rearrangements including germline chromothripsis by combining short- and long-read genome sequencing (GS) with Hi-C. Large-scale genomic rearrangements are identified in Hi-C interaction maps, allowing for an independent assessment of breakpoint calls derived from the GS methods, resulting in >300 genomic junctions. Based on a comprehensive breakpoint detection and Hi-C, we achieve a reconstruction of whole rearranged chromosomes. Integrating information on the three-dimensional organization of chromatin, we observe that breakpoints occur more frequently than expected in lamina-associated domains (LADs) and that a majority reshuffle topologically associating domains (TADs). By applying phased RNA-seq, we observe an enrichment of genes showing allelic imbalanced expression (AIG) within 100 kb around the breakpoints. Interestingly, the AIGs hit by a breakpoint (19/22) display both up- and downregulation, thereby suggesting different mechanisms at play, such as gene disruption and rearrangements of regulatory information. However, the majority of interpretable genes located 200 kb around a breakpoint do not show significant expression changes. Thus, there is an overall robustness in the genome towards large-scale chromosome rearrangements

Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes

Here the authors characterize structural variations (SVs) in a cohort of individuals with complex genomic rearrangements, identifying breakpoints by employing short- and long-read genome sequencing and investigate their impact on gene expression and the three-dimensional chromatin architecture. They find breakpoints are enriched in inactive regions and can result in chromatin domain fusions.Structural variants are a common cause of disease and contribute to a large extent to inter-individual variability, but their detection and interpretation remain a challenge. Here, we investigate 11 individuals with complex genomic rearrangements including germline chromothripsis by combining short- and long-read genome sequencing (GS) with Hi-C. Large-scale genomic rearrangements are identified in Hi-C interaction maps, allowing for an independent assessment of breakpoint calls derived from the GS methods, resulting in >300 genomic junctions. Based on a comprehensive breakpoint detection and Hi-C, we achieve a reconstruction of whole rearranged chromosomes. Integrating information on the three-dimensional organization of chromatin, we observe that breakpoints occur more frequently than expected in lamina-associated domains (LADs) and that a majority reshuffle topologically associating domains (TADs). By applying phased RNA-seq, we observe an enrichment of genes showing allelic imbalanced expression (AIG) within 100 kb around the breakpoints. Interestingly, the AIGs hit by a breakpoint (19/22) display both up- and downregulation, thereby suggesting different mechanisms at play, such as gene disruption and rearrangements of regulatory information. However, the majority of interpretable genes located 200 kb around a breakpoint do not show significant expression changes. Thus, there is an overall robustness in the genome towards large-scale chromosome rearrangements

Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report

<p>Abstract</p> <p>Background</p> <p>Brachydactyly type E (BDE; MIM#113300) is characterized by shortening of the metacarpal, metatarsal, and often phalangeal bones, and predominantly affects postaxial ray(s) of the limb. BDE may occur as an isolated trait or as part of a syndrome. Isolated BDE is rare and in the majority of cases the molecular pathogenesis has so far not been resolved. Originally, the molecular cause of isolated BDE has been unravelled in 2 families and shown to result from heterozygous missense mutations in the homeodomain of the <it>HOXD13 </it>gene. Since the initial manuscript, one further <it>HOXD13 </it>mutation has been reported only in a single family manifesting isolated BDE.</p> <p>Case Presentation</p> <p>In this paper, we report on a Polish family exhibiting isolated BDE caused by a novel nonsense heterozygous <it>HOXD13 </it>mutation. We investigated a Polish female proband and her father, both affected by isolated BDE, in whom we identified a nonsense heterozygous mutation c.820C > T(p.R274X) in the <it>HOXD13 </it>gene. So far, only two missense <it>HOXD13 </it>substitutions (p.S308C and p.I314L), localized within the homeodomain of the HOXD13 transcription factor, as well as a single nonsense mutation (p.E181X) were associated with BDE. Both missense changes were supposed to alter DNA binding affinity of the protein.</p> <p>Conclusion</p> <p>The variant p.R274X identified in our proband is the fourth <it>HOXD13 </it>mutation, and the second truncating (nonsense) mutation, reported to result in typical isolated BDE. We refer our clinical and molecular findings to the previously described <it>HOXD13 </it>associated phenotypes and mutations.</p

Mutations in DSTYK and dominant urinary tract malformations.

ABSTRACT Introduction Congenital abnormalities of the kidney of the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and their etiology is poorly understood. Methods We performed genome-wide linkage analysis and whole-exome sequencing in a family with autosomal dominant congenital abnormalities of the kidney of the urinary tract (7 affected family members). We also performed sequence analysis in 311 unrelated patients, as well as histologic and functional studies. Results Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single rare deleterious variant within these linkage intervals, a heterozygous splice-site mutation in dual serine/threonine and tyrosine protein kinase (DSTYK). This variant, which resulted in aberrant gene product splicing, was present in all affected family members. Additional independent DSTYK mutations, including nonsense and splice-site mutations, were detected among 7/311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in multi-organ developmental defects, resembling loss of fibroblast growth factor (FGF) signaling. Consistent with this finding, DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. Finally, DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated ERK-phosphorylation, the principal signal downstream of receptor tyrosine kinases. Conclusions We detected DSTYK mutations in 2.2% of patients with congenital abnormalities of the kidney and urinary tract whom we studied, suggesting that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling

Identification of antisense long noncoding RNAs that function as SINEUPs in human cells

Mammalian genomes encode numerous natural antisense long noncoding RNAs (lncRNAs) that regulate gene expression. Recently, an antisense lncRNA to mouse Ubiquitin carboxyl-terminal hydrolase L1 (Uchl1) was reported to increase UCHL1 protein synthesis, representing a new functional class of lncRNAs, designated as SINEUPs, for SINE element-containing translation UP-regulators. Here, we show that an antisense lncRNA to the human protein phosphatase 1 regulatory subunit 12A (PPP1R12A), named as R12A-AS1, which overlaps with the 5' UTR and first coding exon of the PPP1R12A mRNA, functions as a SINEUP, increasing PPP1R12A protein translation in human cells. The SINEUP activity depends on the aforementioned sense-antisense interaction and a free right Alu monomer repeat element at the 3' end of R12A-AS1. In addition, we identify another human antisense lncRNA with SINEUP activity. Our results demonstrate for the first time that human natural antisense lncRNAs can up-regulate protein translation, suggesting that endogenous SINEUPs may be widespread and present in many mammalian species