Intracule functional models. II. Analytically integrable kernels

We present, within the framework of intracule functional theory (IFT), a class of kernels whose correlation integrals can be found in closed form. This approach affords three major advantages over other kernels that we have considered previously; ease of implementation, computational efficiency, and numerical stability. We show that even the simplest member of the class yields reasonable estimates of the correlation energies of 18 atomic and 56 molecular systems and we conclude that this kernel class will prove useful in the development of future IFT models

Mast cell tryptase stimulates myoblast proliferation; a mechanism relying on protease-activated receptor-2 and cyclooxygenase-2

<p>Abstract</p> <p>Background</p> <p>Mast cells contribute to tissue repair in fibrous tissues by stimulating proliferation of fibroblasts through the release of tryptase which activates protease-activated receptor-2 (PAR-2). The possibility that a tryptase/PAR-2 signaling pathway exists in skeletal muscle cell has never been investigated. The aim of this study was to evaluate whether tryptase can stimulate myoblast proliferation and determine the downstream cascade.</p> <p>Methods</p> <p>Proliferation of L6 rat skeletal myoblasts stimulated with PAR-2 agonists (tryptase, trypsin and SLIGKV) was assessed. The specificity of the tryptase effect was evaluated with a specific inhibitor, APC-366. Western blot analyses were used to evaluate the expression and functionality of PAR-2 receptor and to assess the expression of COX-2. COX-2 activity was evaluated with a commercial activity assay kit and by measurement of PGF₂α production. Proliferation assays were also performed in presence of different prostaglandins (PGs).</p> <p>Results</p> <p>Tryptase increased L6 myoblast proliferation by 35% above control group and this effect was completely inhibited by APC-366. We confirmed the expression of PAR-2 receptor <it>in vivo </it>in skeletal muscle cells and in satellite cells and <it>in vitro </it>in L6 cells, where PAR-2 was found to be functional. Trypsin and SLIGKV increased L6 cells proliferation by 76% and 26% above control, respectively. COX-2 activity was increased following stimulation with PAR-2 agonist but its expression remained unchanged. Inhibition of COX-2 activity by NS-398 abolished the stimulation of cell proliferation induced by tryptase and trypsin. Finally, 15-deoxy-Δ-^12,14-prostaglandin J₂(15Δ-PGJ₂), a product of COX-2-derived prostaglandin D₂, stimulated myoblast proliferation, but not PGE₂and PGF₂α.</p> <p>Conclusions</p> <p>Taken together, our data show that tryptase can stimulate myoblast proliferation and this effect is part of a signaling cascade dependent on PAR-2 activation and on the downstream activation of COX-2.</p

Identification of common genetic risk variants for autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD

A genetic investigation of sex bias in the prevalence of attention-deficit/hyperactivity disorder

Background Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is 2-7 times more common in males than females. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. Methods We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (20,183 cases, 35,191 controls) and Swedish populationregister data (N=77,905 cases, N=1,874,637 population controls). Results Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that females with ADHD may be at especially high risk of certain comorbid developmental conditions (i.e. autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score (PRS) analysis did not support a higher burden of ADHD common risk variants in female cases (OR=1.02 [0.98-1.06], p=0.28). In contrast, epidemiological sibling analyses revealed that the siblings of females with ADHD are at higher familial risk of ADHD than siblings of affected males (OR=1.14, [95% CI: 1.11-1.18], p=1.5E-15). Conclusions Overall, this study supports a greater familial burden of risk in females with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence

Mapping DNA lesions in and out the nucleosome: insights from molecular dynamics simulations

International audienceI will present our recent efforts to achieve a robust, computationally-driven assessment of the structure and dynamics of damaged oligonucleotides. Molecular modeling indeed offers a same-footing description to compare the effects of various DNA defects on structural properties and repair propensities [1]. The computational efficiency of GPU-accelerated molecular dynamics codes allows to dissect the impact of abasic and 6-4 PP lesions within a nucleosome core particle, for which interactions between DNA defects and histone tails become crucial. References[1] E. Bignon, H. Gattuso, C. Morell, F. Dehez, A. Georgakilas, A. Monari, E. Dumont, Nucl. Acids Res. 2016, 44, 8588-859

Dynamique des lésions de l'ADN

International audienceChaque jour, l'ADN de nos cellules subit pas moins de 10,000 réactions chimiques conduisant à son endommagement. Malgré la photostabilité de cette macromolécule et la remarquable sophistication des mécanismes de réparation présents dans les cellules, les nucléobases peuvent être modifiés pour donner lieur à plus de 70 lésions qui ont chacune été identifiées au niveau cellulaire, principalement par spectrométrie de masse. La chimie mise en jeu lors de ces réactions implique notamment des radicaux, des états excités, et/ou des sensibilisants auxquels nous sommes quotidiennement exposés. Elle reste malgré tout mal comprise car difficile à explorer aussi bien expérimentalement que théoriquement. Dans ce contexte, je montrerai que les simulations de dynamique moléculaires tout-atomes et hybrides (QM/MM-MD) permettent de sonder les mécanismes de formation, l'impact structural d'une ou plusieurs lésion(s), et les interactions potentielles avec les enzymes de réparation. Je discuterai notamment de l'importance de l'environnement biologique sur la réactivité de l'ADN, mais aussi sur la réorganisation structurale induite lors de son endommagement (hélice, puis nucléosome). Grace à nos simulations, nous sommes capables de proposer des structures permettant de rendre compte de données expérimentales, telles que des taux de réparation, effet de séquences, ou encore des taux de formation de lésion complexes. Tandis que l'ADN canonique/non lésé a été intensivement étudié pour sa photochimie 1 et sa dynamique 2 , nos simulations posent la question de la validité du champ de force pour l'ADN lésé. L'enjeu d'une description fidèle de ces lésions est de pouvoir mettre en place un véritable screening pour les lésions combinatoires les plus génotoxiques pour pouvoir ouvrir de nombreuses perspectives dans les domaines de la biologie et de la médecine, notamment dans le cadre du développement de thérapies contre le cancer

Molecular dynamics investigation of DNA tandem lesions repair

International audienceDNA integrity is constantly threatened by radicals and sunlight, leading to chemical modifications of nucleobases. For two neighboring simple DNA defects, the repair turns out to be dramatically lowered [1]. However the field suffers from X-ray or NMR structure to interpret the repair rate measurements of such tandem lesions (10% of the total 8-oxoguanines). Relying on all-atom explicit-solvent molecular dynamics, we explore the structure of oligonucleotides and DNA-enzyme systems featuring two oxidized guanine sites. Our simulations recover sequence effects [2] and provide atomic-scale structural insights into the lack of non-covalent interactions that induce a low repair of 8-oxoguanine and abasic sites with Nfo[2], APE1[3] and Fpg

Mapping DNA-Photosensitizers Interaction In and Out the Nucleosome

International audienceFormation and repair of DNA lesions embraces a rich and combinatorial chemistry, where atomic-scale simulations are most helpful to complement and expand experimental evidences. This biopolymer constitutes a critical testcase at the crossroad of several timely methodological developments of GPU-accelerated MD codes, polarizable force fields and multiscale approaches [1].I will present our recent efforts to achieve a robust, computationally-driven description of photosensitizers interacting with DNA. Intensive molecular dynamics allow to map the hot spots for DNA lesion induction and delineate rule-of-thumbs for the non-covalent forces that drive sequence recognition [2]. This allows to build DNA-photosensitizer structures, palliating the absence of NMR or X-ray data for labile drugs, and investigate triplet-triplet energy transfer [3], probe new excited-state mechanisms for DNA photostability [4] and rationalize the DNA-dependent photochemistry of DNA drugs [4] owing to QM/MM-MD schemes. The computational efficiency of the MD-then/QM/MM schemes allows to tackle to chemistry within the nucleosome that unveil interactions between DNA defects and histone tails. [1] (a) C. Zhang et al., J Chem Theory Comput., 2018, 14:2084-2108 ; (b) I. Ivani et al., Nat. Methods. 2016, 13:55-58[2] E. Bignon et al., Chem. Eur. J., 2017, 23:12845-12852[3] E. Dumont et al., J. Phys. Chem. Lett, 2015, 6:576-580[4] A. Francés-Monerris et al., Chem. Sci., 2018, 9:7902-791