2,230 research outputs found
Gastrointestinal parasites in an isolated Norwegian population of wild red deer (Cervus elaphus)
The CECAM Electronic Structure Library and the modular software development paradigm
First-principles electronic structure calculations are very widely used thanks to the many successful software packages available. Their traditional coding paradigm is monolithic, i.e., regardless of how modular its internal structure may be, the code is built independently from others, from the compiler up, with the exception of linear-algebra and message-passing libraries. This model has been quite successful for decades. The rapid progress in methodology, however, has resulted in an ever increasing complexity of those programs, which implies a growing amount of replication in coding and in the recurrent re-engineering needed to adapt to evolving hardware architecture. The Electronic Structure Library (\esl) was initiated by CECAM (European Centre for Atomic and Molecular Calculations) to catalyze a paradigm shift away from the monolithic model and promote modularization, with the ambition to extract common tasks from electronic structure programs and redesign them as free, open-source libraries. They include ``heavy-duty'' ones with a high degree of parallelisation, and potential for adaptation to novel hardware within them, thereby separating the sophisticated computer science aspects of performance optimization and re-engineering from the computational science done by scientists when implementing new ideas. It is a community effort, undertaken by developers of various successful codes, now facing the challenges arising in the new model. This modular paradigm will improve overall coding efficiency and enable specialists (computer scientists or computational scientists) to use their skills more effectively. It will lead to a more sustainable and dynamic evolution of software as well as lower barriers to entry for new developers
A Novel Compound C12 Inhibits Inflammatory Cytokine Production and Protects from Inflammatory Injury In Vivo
Inflammation is a hallmark of many diseases. Although steroids and cyclooxygenase inhibitors are main anti-inflammatory therapeutical agents, they may cause serious side effects. Therefore, developing non-steroid anti-inflammatory agents is urgently needed. A novel hydrosoluble compound, C12 (2,6-bis(4-(3-(dimethylamino)-propoxy)benzylidene)cyclohexanone), has been designed and synthesized as an anti-inflammatory agent in our previous study. In the present study, we investigated whether C12 can affect inflammatory processes in vitro and in vivo. In mouse primary peritoneal macrophages, C12 potently inhibited the production of the proinflammatory gene expression including TNF-α, IL-1β, IL-6, iNOS, COX-2 and PGE synthase. The activity of C12 was partly dependent on inhibition of ERK/JNK (but p38) phosphorylation and NF-κB activation. In vivo, C12 suppressed proinflammatory cytokine production in plasma and liver, attenuated lung histopathology, and significantly reduced mortality in endotoxemic mice. In addition, the pre-treatment with C12 reduced the inflammatory pain in the acetic acid and formalin models and reduced the carrageenan-induced paw oedema and acetic acid-increased vascular permeability. Taken together, C12 has multiple anti-inflammatory effects. These findings, coupled with the low toxicity and hydrosolubility of C12, suggests that this agent may be useful in the treatment of inflammatory diseases
Vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic stress
The intermediate filament (IF) cytoskeleton has been proposed to regulate morphogenic processes by integrating the cell fate signaling machinery with mechanical cues. Signaling between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) through the Notch pathway regulates arterial remodeling in response to changes in blood flow. Here we show that the IF-protein vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic forces. Vimentin is important for Notch transactivation by ECs and vimentin knockout mice (VimKO) display disrupted VSMC differentiation and adverse remodeling in aortic explants and in vivo. Shear stress increases Jagged1 levels and Notch activation in a vimentin-dependent manner. Shear stress induces phosphorylation of vimentin at serine 38 and phosphorylated vimentin interacts with Jagged1 and increases Notch activation potential. Reduced Jagged1-Notch transactivation strength disrupts lateral signal induction through the arterial wall leading to adverse remodeling. Taken together we demonstrate that vimentin forms a central part of a mechanochemical transduction pathway that regulates multilayer communication and structural homeostasis of the arterial wall
Mitochondria function associated genes contribute to Parkinson's Disease risk and later age at onset
Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson’s disease (PD). Yet the role that
mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we
comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the
scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We
calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our
primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the
secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional
genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial functionassociated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes
are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting
mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early
stage of PD
Study of the photon strength functions and level density in the gamma decay of the n+U-234 reaction
The accurate calculations of neutron-induced reaction cross sections are relevant for many nuclear applications. The photon strength functions and nuclear level densities are essential inputs for such calculations. These quantities for U-235 are studied using the measurement of the gamma de-excitation cascades in radiative capture on U-234 with the Total Absorption Calorimeter at n_TOF at CERN. This segmented 4 pi gamma calorimeter is designed to detect gamma rays emitted from the nucleus with high efficiency. This experiment provides information on gamma multiplicity and gamma spectra that can be compared with numerical simulations. The code DICEBOXC is used to simulate the gamma cascades while GEANT4 is used for the simulation of the interaction of these gammas with the TAC materials. Available models and their parameters are being tested using the present data. Some preliminary results of this ongoing study are presented and discussed
First results of the140ce(N,ү)141ce cross-section measurement at n_tof
An accurate measurement of the140Ce(n,ү) energy-dependent cross-section was performed at the n_TOF facility at CERN. This cross-section is of great importance because it represents a bottleneck for the s-process nucleosynthesis and determines to a large extent the cerium abundance in stars. The measurement was motivated by the significant difference between the cerium abundance measured in globular clusters and the value predicted by theoretical stellar models. This discrepancy can be ascribed to an overestimation of the140Ce capture cross-section due to a lack of accurate nuclear data. For this measurement, we used a sample of cerium oxide enriched in140Ce to 99.4%. The experimental apparatus consisted of four deuterated benzene liquid scintillator detectors, which allowed us to overcome the difficulties present in the previous measurements, thanks to their very low neutron sensitivity. The accurate analysis of the p-wave resonances and the calculation of their average parameters are fundamental to improve the evaluation of the140Ce Maxwellian-averaged cross-section
Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets
Importance Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. / Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. / Design and Setting This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. / Main Outcomes and Measures It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. / Results Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. / Conclusions and Relevance Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies
Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability
Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types
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