Adsorption of CO in amorphous water-ice surfaces

Wetensch. publicatieFaculteit der Wiskunde en Natuurwetenschappe

Discovery of new therapeutic targets in ovarian cancer through identifying significantly non-mutated genes

Background: Mutated and non-mutated genes interact to drive cancer growth and metastasis. While research has focused on understanding the impact of mutated genes on cancer biology, understanding non-mutated genes that are essential to tumor development could lead to new therapeutic strategies. The recent advent of high-throughput whole genome sequencing being applied to many different samples has made it possible to calculate if genes are significantly non-mutated in a specific cancer patient cohort. Methods: We carried out random mutagenesis simulations of the human genome approximating the regions sequenced in the publicly available Cancer Growth Atlas Project for ovarian cancer (TCGA-OV). Simulated mutations were compared to the observed mutations in the TCGA-OV cohort and genes with the largest deviations from simulation were identified. Pathway analysis was performed on the non-mutated genes to better understand their biological function. We then compared gene expression, methylation and copy number distributions of non-mutated and mutated genes in cell lines and patient data from the TCGA-OV project. To directly test if non-mutated genes can affect cell proliferation, we carried out proof-of-concept RNAi silencing experiments of a panel of nine selected non-mutated genes in three ovarian cancer cell lines and one primary ovarian epithelial cell line. Results: We identified a set of genes that were mutated less than expected (non-mutated genes) and mutated more than expected (mutated genes). Pathway analysis revealed that non-mutated genes interact in cancer associated pathways. We found that non-mutated genes are expressed significantly more than mutated genes while also having lower methylation and higher copy number states indicating that they could be functionally important. RNAi silencing of the panel of non-mutated genes resulted in a greater significant reduction of cell viability in the cancer cell lines than in the non-cancer cell line. Finally, as a test case, silencing ANKLE2, a significantly non-mutated gene, affected the morphology, reduced migration, and increased the chemotherapeutic response of SKOV3 cells. Conclusion: We show that we can identify significantly non-mutated genes in a large ovarian cancer cohort that are well-expressed in patient and cell line data and whose RNAi-induced silencing reduces viability in three ovarian cancer cell lines. Targeting non-mutated genes that are important for tumor growth and metastasis is a promising approach to expand cancer therapeutic options.We would like to thank Weill Cornell Medicine in Qatar (WCM-Q) and the Qatar National Leadership Program (QNLP) for research support. We would also like to thank the WCM-Q Advanced Computing Division for computing time and software support. Finally, we would like to thank colleagues and reviewers for experimental support and critical discussions. This study was made possible by JSREP grant 4-011-1-003 from the Qatar National Research Fund (a member of Qatar Foundation) and the QF Leadership program. The statements made herein are solely the responsibility of the author[s]. The funders had no role in the design of the study or in the collection, analysis, and interpretation of data and in writing the manuscript.Scopu

Reactive scattering of H2 from Cu(100): comparison of dynamics calculations based on the specific reaction parameter approach to density functional theory with experiment

We present new experimental and theoretical results for reactive scattering of dihydrogen from Cu(100). In the new experiments, the associative desorption of H2 is studied in a velocity resolved and final rovibrational state selected manner, using time-of-flight techniques in combination with resonance-enhanced multi-photon ionization laser detection. Average desorption energies and rota- tional quadrupole alignment parameters were obtained in this way for a number of (v = 0, 1) ro- tational states, v being the vibrational quantum number. Results of quantum dynamics calculations based on a potential energy surface computed with a specific reaction parameter (SRP) density func- tional, which was derived earlier for dihydrogen interacting with Cu(111), are compared with the results of the new experiments and with the results of previous molecular beam experiments on sticking of H2 and on rovibrationally elastic and inelastic scattering of H2 and D2 from Cu(100). The calculations use the Born-Oppenheimer and static surface approximations. With the functional derived semi-empirically for dihydrogen + Cu(111), a chemically accurate description is obtained of the molecular beam experiments on sticking of H2 on Cu(100), and a highly accurate descrip- tion is obtained of rovibrationally elastic and inelastic scattering of D2 from Cu(100) and of the orientational dependence of the reaction of (v = 1, j = 2 − 4) H2 on Cu(100). This suggests that a SRP density functional derived for H2 interacting with a specific low index face of a metal will yield accurate results for H2 reactively scattering from another low index face of the same metal, and that it may also yield accurate results for H2 interacting with a defected (e.g., stepped) surface of that same metal, in a system of catalytic interest. However, the description that was obtained of the average desorption energies, of rovibrationally elastic and inelastic scattering of H2 from Cu(100), and of the orientational dependence of reaction of (v = 0, j = 3 − 5, 8) H2 on Cu(100) compares less well with the available experiments. More research is needed to establish whether more accurate SRP-density functional theory dynamics results can be obtained for these observables if surface atom motion is added to the dynamical model. The experimentally and theoretically found dependence of the rotational quadrupole alignment parameter on the rotational quantum number provides evidence for rotational enhancement of reaction at low translational energies.Fil: Sementa, L.. Leiden University; Países Bajos. Istituto per i Processi Chimico-Fisici of the Consiglio Nazionale delle Ricerche; ItaliaFil: Wijzenbroek, M.. Leiden University; Países BajosFil: Van Kolck, B. J.. Leiden University; Países BajosFil: Somers, M. F.. Leiden University; Países BajosFil: Al-Halabi, A.. Leiden University; Países BajosFil: Busnengo, Heriberto Fabio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Física de Rosario (i); ArgentinaFil: Olsen, R. A.. Leiden University; Países Bajos. SINTEF Materials and Chemistry; NoruegaFil: Kroes, G. J.. Leiden University; Países BajosFil: Rutkowski, M.. Westfalische Wilhelms Universitat; AlemaniaFil: Thewes, C.. Westfalische Wilhelms Universitat; AlemaniaFil: Kleimeier, N. F.. Westfalische Wilhelms Universitat; AlemaniaFil: Zacharias, H.. Westfalische Wilhelms Universitat; Alemani

Who's this? Developer identification using IDE event data

This paper presents a technique to identify a developer based on their IDE event data. We exploited the KaVE data set which recorded IDE activities from 85 developers with 11M events. We found that using an SVM with a linear kernel on raw event count outperformed k-NN in identifying developers with an accuracy of 0.52. Moreover, after setting the optimal number of events and sessions to train the classifier, we achieved a higher accuracy of 0.69 and 0.71 respectively. The findings shows that we can identify developers based on their IDE event data. The technique can be expanded further to group similar developers for IDE feature recommendations

Generation and characterisation of Friedreich ataxia YG8R mouse fibroblast and neural stem cell models

This article has been made available through the Brunel Open Access Publishing Fund.Background: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by GAA repeat expansion in the first intron of the FXN gene, which encodes frataxin, an essential mitochondrial protein. To further characterise the molecular abnormalities associated with FRDA pathogenesis and to hasten drug screening, the development and use of animal and cellular models is considered essential. Studies of lower organisms have already contributed to understanding FRDA disease pathology, but mammalian cells are more related to FRDA patient cells in physiological terms. Methodology/Principal Findings: We have generated fibroblast cells and neural stem cells (NSCs) from control Y47R mice (9 GAA repeats) and GAA repeat expansion YG8R mice (190+120 GAA repeats). We then differentiated the NSCs in to neurons, oligodendrocytes and astrocytes as confirmed by immunocytochemical analysis of cell specific markers. The three YG8R mouse cell types (fibroblasts, NSCs and differentiated NSCs) exhibit GAA repeat stability, together with reduced expression of frataxin and reduced aconitase activity compared to control Y47R cells. Furthermore, YG8R cells also show increased sensitivity to oxidative stress and downregulation of Pgc-1α and antioxidant gene expression levels, especially Sod2. We also analysed various DNA mismatch repair (MMR) gene expression levels and found that YG8R cells displayed significant reduction in expression of several MMR genes, which may contribute to the GAA repeat stability. Conclusions/Significance: We describe the first fibroblast and NSC models from YG8R FRDA mice and we confirm that the NSCs can be differentiated into neurons and glia. These novel FRDA mouse cell models, which exhibit a FRDA-like cellular and molecular phenotype, will be valuable resources to further study FRDA molecular pathogenesis. They will also provide very useful tools for preclinical testing of frataxin-increasing compounds for FRDA drug therapy, for gene therapy, and as a source of cells for cell therapy testing in FRDA mice. © 2014 Sandi et al

Laboratory evidence for efficient water formation in interstellar ices

Even though water is the main constituent in interstellar icy mantles, its chemical origin is not well understood. Three different formation routes have been proposed following hydrogenation of O, O2, or O3, but experimental evidence is largely lacking. We present a solid state astrochemical laboratory study in which one of these routes is tested. For this purpose O2 ice is bombarded by H- or D-atoms under ultra high vacuum conditions at astronomically relevant temperatures ranging from 12 to 28 K. The use of reflection absorption infrared spectroscopy (RAIRS) permits derivation of reaction rates and shows efficient formation of H2O (D2O) with a rate that is surprisingly independent of temperature. This formation route converts O2 into H2O via H2O2 and is found to be orders of magnitude more efficient than previously assumed. It should therefore be considered as an important channel for interstellar water ice formation as illustrated by astrochemical model calculations.Comment: 15 pages, 4 figures. ApJ, in pres

The chemistry of multiply deuterated molecules in protoplanetary disks. I. The outer disk

We present new models of the deuterium chemistry in protoplanetary disks, including, for the first time, multiply deuterated species. We use these models to explore whether observations in combination with models can give us clues as to which desorption processes occur in disks. We find, in common with other authors, that photodesorption can allow strongly bound molecules such as HDO to exist in the gas phase in a layer above the midplane. Models including this process give the best agreement with the observations. In the midplane, cosmic ray heating can desorb weakly bound molecules such as CO and N$_2$. We find the observations suggest that N$_2$ is gaseous in this region, but that CO must be retained on the grains to account for the observed DCO$^+$/HCO$^+$. This could be achieved by CO having a higher binding energy than N$_2$ (as may be the case when these molecules are accreted onto water ice) or by a smaller cosmic ray desorption rate for CO than assumed here, as suggested by recent theoretical work. For gaseous molecules the calculated deuteration can be greatly changed by chemical processing in the disk from the input molecular cloud values. On the grains singly deuterated species tend to retain the D/H ratio set in the molecular cloud, whereas multiply deuterated species are more affected by the disk chemistry. Consequently the D/H ratios observed in comets may be partly set in the parent cloud and partly in the disk, depending on the molecule.Comment: Accepted for publication in ApJ. 48 pages, 8 figure

Suicide prevention for youth - a mental health awareness program: lessons learned from the Saving and Empowering Young Lives in Europe (SEYLE) intervention study.

ABSTRACT: BACKGROUND: The Awareness program was designed as a part of the EU-funded Saving and Empowering Young Lives in Europe (SEYLE) intervention study to promote mental health of adolescents in 11 European countries by helping them to develop problem-solving skills and encouraging them to self-recognize the need for help as well as how to help peers in need. METHODS: For this descriptive study all coordinators of the SEYLE Awareness program answered an open-ended evaluation questionnaire at the end of the project implementation. Their answers were synthesized and analyzed and are presented here. RESULTS: The results show that the program cultivated peer understanding and support. Adolescents not only learned about mental health by participating in the Awareness program, but the majority of them also greatly enjoyed the experience. CONCLUSIONS: Recommendations for enhancing the successes of mental health awareness programs are presented. Help and cooperation from schools, teachers, local politicians and other stakeholders will lead to more efficacious future programs

Grain Surface Models and Data for Astrochemistry

AbstractThe cross-disciplinary field of astrochemistry exists to understand the formation, destruction, and survival of molecules in astrophysical environments. Molecules in space are synthesized via a large variety of gas-phase reactions, and reactions on dust-grain surfaces, where the surface acts as a catalyst. A broad consensus has been reached in the astrochemistry community on how to suitably treat gas-phase processes in models, and also on how to present the necessary reaction data in databases; however, no such consensus has yet been reached for grain-surface processes. A team of ∼25 experts covering observational, laboratory and theoretical (astro)chemistry met in summer of 2014 at the Lorentz Center in Leiden with the aim to provide solutions for this problem and to review the current state-of-the-art of grain surface models, both in terms of technical implementation into models as well as the most up-to-date information available from experiments and chemical computations. This review builds on the results of this workshop and gives an outlook for future directions

Mast cells disrupt the function of the esophageal epithelial barrier

Mast cells (MCs) accumulate in the epithelium of patients with eosinophilic esophagitis (EoE), an inflammatory disorder characterized by extensive esophageal eosinophilic infiltration. Esophageal barrier dysfunction plays an important role in the pathophysiology of EoE. We hypothesized that MCs contribute to the observed impaired esophageal epithelial barrier. Herein, we demonstrate that coculture of differentiated esophageal epithelial cells with immunoglobulin E-activated MCs significanly decreased epithelial resistance by 30% and increased permeability by 22% compared with non-activated MCs. These changes were associated with decreased messenger RNA expression of barrier proteins filaggrin, desmoglein-1 and involucrin, and antiprotease serine peptidase inhibitor kazal type 7. Using targeted proteomics, we detected various cytokines in coculture supernatants, most notably granulocyte-macrophage colony-stimulating factor and oncostatin M (OSM). OSM expression was increased by 12-fold in active EoE and associated with MC marker genes. Furthermore, OSM receptor-expressing esophageal epithelial cells were found in the esophageal tissue of patients with EoE, suggesting that the epithelial cells may respond to OSM. Stimulation of esophageal epithelial cells with OSM resulted in a dose-dependent decrease in barrier function and expression of filaggrin and desmoglein-1 and an increase in protease calpain-14. Taken together, these data suggest a role for MCs in decreasing esophageal epithelial barrier function in EoE, which may in part be mediated by OSM