van der Waals interactions of the benzene dimer: towards treatment of polycyclic aromatic hydrocarbon dimers

Although density functional theory (DFT) in principle includes even long-range interactions, standard implementations employ local or semi-local approximations of the interaction energy and fail at describing the van der Waals interactions. We show how to modify a recent density functional that includes van der Waals interactions in planar systems [Phys. Rev. Lett. 91, 126402 (2003)] to also give an approximate interaction description of planar molecules. As a test case we use this modified functional to calculate the binding distance and energy for benzene dimers, with the perspective of treating also larger, flat molecules, such as the polycyclic aromatic hydrocarbons (PAH).Comment: 7 pages, 2 figures (3 figure files) submitted to Materials Science and Engineering

Energy Crises and Cooperation: Do International Institutions Matter?

The risk of an oil supply disruption still exists. Oil reserves are increasingly concentrated in a handful of unreliable regimes, plagued by piracy and terrorism. Natural disasters and chokepoint incidents have increased in frequency. In addition, oil is expected to remain a significant part of the energy mix up until 2030. By that time Europe will be importing 90% of its oil. Thus, oil supply security will become an increasingly important feature of European politics. One way to counter the noxious consequences of an oil disruption is to cooperate. International cooperation is a critical factor in any type of crisis, however, it is especially important when it comes to a finite, highly concentrated and critical commodity like oil. The lack of coordination might lead to scrambling and oil hoarding, which dramatically exacerbate the crisis. Yet cooperation in the oil issue-area has been the subject of only a few studies, none of which provides a systematic and comprehensive analysis. They are also limited in their scope and findings. This dissertation aims to partially fill this lacuna. It employs a structured focused comparison to study European consumer countries\u27 cooperation in times of oil supply shortages. There have been fifteen such crises since the Second World War, three of which with dramatic consequences for the world economy. The analysis evaluates European cooperative efforts in seven of these cases, starting with the Abadan crisis in 1951. The cases are selected on the basis of their magnitude and economic impact. In particular, I look at intergovernmental negotiations within existing international bodies prior to, during and immediately after the crisis. The findings suggest that institutions are more likely to facilitate interstate cooperation in the presence of a strong leader (a hegemon) - a role, which in the case of the oil issue-area was assumed by the US until the early 1970s

To Head CT Scan or Not: The Clinical Quandary in Suspected Subarachnoid Hemorrhage; a Validation Study on Ottawa Subarachnoid Hemorrhage Rule

Introduction: The Ottawa Subarachnoid Hemorrhage rule (OSR) is a clinical decision tool identified for ruling out subarachnoid hemorrhage (SAH) in those patient above 15 years of age who present to the emergency department (ED) with acute onset atraumatic headache. Objective: The primary objective of this study was to externally validate the OSR in a single national health service (NHS) setting in the UK and secondly, to compare it with our current practice without using a decision rule. Method: A retrospective review of computerized medical records was done for all patients registered with headaches from January to December 2016. The data were manually charted on a data sheet from individual patient records. Patients fulfilling the preset inclusion and exclusion criteria as per the OSR were enrolled in the analysis. According to the OSR, if patient had any of the 6 criteria enlisted (age > 40 years, neck stiffness/pain, witnessed loss of consciousness, onset during exertion, thunderclap headache, limited neck flexion on examination), further diagnostic decision was required. All patients were followed up for 6 months on the computer system as it gets highlighted if the patient is represented again to the ED or is deceased. Results: A total of 737 ED visits with acute headache were reviewed for potential eligibility. Out of these, 649 were estimated to be eligible. On excluding 485 patients that could not meet the predetermined inclusion criteria and 19 patients as per the exclusion criteria, 145 (19.7%) patients were included in the analysis. There were 5 cases of SAH, yielding an incidence of 3.4 % (95% CI 1.3 % – 8.3 %). The sensitivity for SAH was 100% (95% CI, 46.3 % - 100 %); specificity of 44.2 % (95% CI, 36 % - 53 %); positive predictive value of 6.02 % (95% CI 2.2 % - 14.1 %); and negative predictive value of 100% (95% CI, 92.7 % - 100%). Conclusion: Although being poorly specific, the OSR is a highly sensitive, simple tool for ruling out SAH in alert patients with a headache in ED settings

To Head CT Scan or Not: The Clinical Quandary in Suspected Subarachnoid Hemorrhage; a Validation Study on Ottawa Subarachnoid Hemorrhage Rule

Introduction: The Ottawa Subarachnoid Hemorrhage rule (OSR) is a clinical decision tool identified for ruling out subarachnoid hemorrhage (SAH) in those patient above 15 years of age who present to the emergency department (ED) with acute onset atraumatic headache. Objective: The primary objective of this study was to externally validate the OSR in a single national health service (NHS) setting in the UK and secondly, to compare it with our current practice without using a decision rule. Method: A retrospective review of computerized medical records was done for all patients registered with headaches from January to December 2016. The data were manually charted on a data sheet from individual patient records. Patients fulfilling the preset inclusion and exclusion criteria as per the OSR were enrolled in the analysis. According to the OSR, if patient had any of the 6 criteria enlisted (age > 40 years, neck stiffness/pain, witnessed loss of consciousness, onset during exertion, thunderclap headache, limited neck flexion on examination), further diagnostic decision was required. All patients were followed up for 6 months on the computer system as it gets highlighted if the patient is represented again to the ED or is deceased. Results: A total of 737 ED visits with acute headache were reviewed for potential eligibility. Out of these, 649 were estimated to be eligible. On excluding 485 patients that could not meet the predetermined inclusion criteria and 19 patients as per the exclusion criteria, 145 (19.7%) patients were included in the analysis. There were 5 cases of SAH, yielding an incidence of 3.4 % (95% CI 1.3 % – 8.3 %). The sensitivity for SAH was 100% (95% CI, 46.3 % - 100 %); specificity of 44.2 % (95% CI, 36 % - 53 %); positive predictive value of 6.02 % (95% CI 2.2 % - 14.1 %); and negative predictive value of 100% (95% CI, 92.7 % - 100%). Conclusion: Although being poorly specific, the OSR is a highly sensitive, simple tool for ruling out SAH in alert patients with a headache in ED settings

Mutations in splicing factor PRPF3, causing retinal degeneration, form detrimental aggregates in photoreceptor cells.

PRPF3 is an element of the splicing machinery ubiquitously expressed, yet mutations in this gene are associated with a tissue-specific phenotype: autosomal dominant retinitis pigmentosa (RP). Here, we studied the subcellular localization of endogenous- and mutant-transfected PRPF3. We found that (i) subcellular distribution of the endogenous wild-type protein co-localizes with small nuclear ribonucleoproteins, partially with a nucleolar marker and accumulates in speckles labeled by SC35; (ii) in human retinas, PRPF3 does not show a distinctive abundance in photoreceptors, the cells affected in RP and (iii) the RP causing mutant PRPF3, differently from the wild-type protein, forms abnormally big aggregates in transfected photoreceptor cells. Aggregation of T494M mutant PRPF3 inside the nucleus triggers apoptosis only in photoreceptor cells. On the basis of the observation that mutant PRPF3 accumulates in the nucleolus and that transcriptional, translational and proteasome inhibition can induce this phenomenon in non-photoreceptor cells, we hypothesize that mutation affects splicing factor recycling. Noteworthy, accumulation of the mutant protein in big aggregates also affects distribution of some other splicing factors. Our data suggest that the mutant protein has a cell-specific dominant effect in rod photoreceptors while appears not to be harmful to epithelial and fibroblast cells

Vanadium pentoxide (V2O5): a van der Waals density functional study

The past few years has brought renewed focus on the physics behind the class of materials characterized by long-range interactions and wide regions of low electron density, sparse matter. There is now much work on developing the appropriate algorithms and codes able to correctly describe this class of materials within a parameter-free quantum physical description. In particular, van der Waals (vdW) forces play a major role in building up material cohesion in sparse matter. This work presents an application to the vanadium pentoxide (V2O5) bulk structure of two versions of the vdW-DF method, a first-principles procedure for the inclusion of vdW interactions in the context of density functional theory (DFT). In addition to showing improvement compared to traditional semilocal calculations of DFT, we discuss the choice of various exchange functionals and point out issues that may arise when treating systems with large amounts of vacuum.Comment: 5 pages, 4 figures, 1 tabl

van der Waals density functional calculations of binding in molecular crystals

A recent paper [J. Chem. Phys. 132, 134705 (2010)] illustrated the potential of the van der Waals density functional (vdW-DF) method [Phys. Rev. Lett. 92, 246401 (2004)] for efficient first-principle accounts of structure and cohesion in molecular crystals. Since then, modifications of the original vdW-DF version (identified as vdW-DF1) has been proposed, and there is also a new version called vdW-DF2 [ArXiv 1003.5255], within the vdW-DF framework. Here we investigate the performance and nature of the modifications and the new version for the binding of a set of simple molecular crystals: hexamine, dodecahedrane, C60, and graphite. These extended systems provide benchmarks for computational methods dealing with sparse matter. We show that a previously documented enhancement of non-local correlations of vdW-DF1 over an asymptotic atom-based account close to and a few A, beyond binding separation persists in vdW-DF2. The calculation and analysis of the binding in molecular crystals requires appropriate computational tools. In this paper, we also present details on our real-space parallel implementation of the vdW-DF correlation and on the method used to generate asymptotic atom-based pair potentials based on vdW-DF.Comment: 5 pages, 4 figure

Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins

Background Mutations in pre-mRNA splicing factor PRPF31 can lead to retinitis pigmentosa (RP). Although the exact disease mechanism remains unknown, it has been hypothesized that haploinsufficiency might be involved in the pathophysiology of the disease. Methods In this study, we have analyzed a mouse model containing the p.A216P mutation in Prpf31 gene. Results We found that mutant Prpf31 protein produces cytoplasmic aggregates in the retinal pigment epithelium and decreasing the protein levels of this splicing factor in the nucleus. Additionally, normal protein was recruited in insoluble aggregates when the mutant protein was overexpressed in vitro. In response to protein aggregation, Hspa4l is overexpressed. This member of the HSP70 family of chaperones might contribute to the correct folding and solubilization of the mutant protein, allowing its translocation to the nucleus. Conclusions Our data suggests that a mechanism haploinsufficiency and dominant-negative is involved in retinal degeneration due to mutations in PRPF31. HSP70 over-expression might be a new therapeutic target for the treatment of retinal degeneration due to PRPF31 mutations.This project has been financed through a) The ISCIII (Miguel Servet-I, 2015), co-financed by the European Regional Development Fund (ERDF), No CP15/00071. b) The European Union’s Horizon 2020 research and innovation program, under grant agreement No 634479. c) Regional Ministry of Economy, Innovation and Science of the Junta de Andalucía, No P09-CTS-04967.info:eu-repo/semantics/publishedVersio

Disease mechanism for retinitis pigmentosa (RP11) caused by missense mutations in the splicing factor gene PRPF31

Purpose: Missense mutations in the splicing factor gene PRPF31 cause a dominant form of retinitis pigmentosa (RP11) with reduced penetrance. Missense mutations in PRPF31 have previously been shown to cause reduced protein solubility, suggesting insufficiency of functional protein as the disease mechanism. Here we examine in further detail the effect of the A216P mutation on splicing function. Methods: Splicing activity was assayed using an in vivo assay in transfected mammalian cells with rhodopsin (RHO) and transducin (GNAT1) splicing templates. Pull-down assays were used to study the interaction between PRPF31 and one of its cognate partners in the spliceosome, PRPF6. Results: Splicing of RHO intron 3 and GNAT1 introns 3-5 mini-gene templates was inefficient with both spliced and unspliced products clearly detected. Assays using the RHO minigene template revealed a direct negative effect on splicing efficiency of the mutant. However, no effect of the mutation on splicing efficiency could be detected using the longer GNAT1 minigene template or using a full-length RHO transcript, splicing of which had an efficiency of 100%. No unspliced RHO transcripts could be detected in RNA from human retina. Pull-down assays between PRPF31 and PRPF6 proteins showed a stronger interaction for the mutant than wild type, suggesting a mechanism for the negative effect. Conclusions: Splicing of full-length RHO is more efficient than splicing of the minigene, and assays using a full-length template more accurately mimic splicing in photoreceptors. The RP11 missense mutations exert their pathology mainly via a mechanism based on protein insufficiency due to protein insolubility, but there is also a minor direct negative effect on function