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Purpose\ud \ud Research demonstrates a strong socioeconomic gradient in health and well-being. However, many studies rely on unidimensional measures of socioeconomic status (SES) (e.g. educational qualifications, household income), and there is often a more limited consideration of how facets of SES combine to impact well-being. This paper develops a multidimensional measure of SES, drawing on family and school-level factors, to provide more nuanced understandings of socioeconomic patterns in adolescent substance use and mental well-being.\ud Methods\ud \ud Data from the Student Health and Wellbeing Survey from Wales, UK was employed. The sample compromised 22,372 students and we used latent class analysis to identify distinct groups using three measures of SES. These classes were then used to estimate mental well-being, internalizing symptoms, and substance use.\ud Results\ud \ud The five-class solution offered the best fit. Findings indicated distinct classes of families as follows: “nonworking,” “deprived working families,” “affluent families in deprived schools,” “lower affluence,” and “higher affluence.” There was a clear relationship among the classes and mental well-being, internalizing symptoms, smoking, and cannabis use; alcohol was the exception to this.\ud Conclusions\ud \ud The identification of these classes led to a fuller understanding of the health and well-being effects of SES, showing clearer patterning in health behaviors that often is not captured in research. The implications for adolescent health and well-being are discussed, including considerations for future research.

Childhood conduct problems (eg, defiance, anger, and aggression) compromise child and family well-being and development.

Background: The role of children and young people (CYP) in transmission of SARS-CoV-2 in household and educational settings remains unclear. We undertook a systematic review and meta-analysis of contact-tracing and population-based studies at low risk of bias. Methods: We searched 4 electronic databases on 5 April for contact-tracing studies and population-based studies informative about transmission of SARS-CoV-2 from 0-19 year olds in household or educational settings. We excluded studies at high risk of bias, including from under-ascertainment of asymptomatic infections. We undertook multilevel random effects meta-analyses of secondary attack rates (SAR: contact-tracing studies) and school infection prevalence, and used meta-regression to examine the impact of community SARS-CoV-2 incidence, mitigations and attendance on school infection prevalence. Findings: 4179 abstracts were reviewed, resulting in 37 included studies (17 contact-tracing; 18 population studies; 2 mixed studies). The pooled relative transmissibility of CYP compared with adults was 1.00 (0.73, 1.37) in adjusted household studies. The pooled SAR from 0CYP was significantly lower in school studies (0.5% (0.1, 1.6) than household studies (7.3% (2.5, 21.8) – p

Schools have closed worldwide as part of measures to prevent SARS-CoV-2 transmission but are beginning to reopen in some countries. Various measures are being pursued to minimise transmission but existing guidance has not developed a comprehensive framework or theory of change. We present a framework informed by the occupational health hierarchy of control and a theory of change informed by realist approaches. We present measures focused on elimination, substitution, engineering, administration, education and personal protective equipment. We theorise that such measures offer a means of disrupting SARS-CoV-2 transmission via routes involving fomites, faeco-oral routes, droplets and aerosols., Highlights • Schools have been closed worldwide as part of lock-down measures to prevent SARS-CoV-2 transmission but are beginning to reopen in a number of countries. • Various measures are being pursued to minimise transmission but existing guidance has not aimed to develop a comprehensive framework or theory of change. • We present a framework for measures informed by the occupational health hierarchy of control (elimination, substitution, engineering, administration, education and personal protective equipment) and a theory of change. • We theorise that, together, such measures offer a means of disrupting SARS-CoV-2 transmission via routes involving fomites, faeco-oral routes, droplets and aerosols.

XAF1 is a tumor suppressor gene with low or absent expression in cancer. Since transcriptional reactivation or ectopic-mediated expression of XAF1 inhibits tumor growth, it is of great interest to elucidate the molecular mechanisms leading to XAF1 silencing. YY1 is a transcription factor that acts as a repressor or an activator to modulate several cancer-associated cellular processes. Both YY1 and XAF1 have key roles in prostate cancer (PCa) progression and are associated with worse clinical outcomes. To assess whether YY1 regulates the transcriptional activation of the XAF1 gene, we performed gene-reporter assays coupled with site-directed mutagenesis, which showed that YY1 is able to mediate XAF1 silencing. Concordantly, ChIP-qPCR assays showed that YY1 interacts with the XAF1 promoter in PC3 cells that lacks XAF1 expression. This association was lost after exposure to epigenetic modulators that induce XAF1 expression. Further supporting the YY1's repressive role, we found transcriptional reactivation of the XAF1 gene by YY1 downregulation. As expected by previous reports showing that HDAC1 is needed for YY1-mediated repressive actions, we observed XAF1 re-expression after either inhibition or downregulation of the HDAC1 gene. Finally, expression data retrieved from the TCGA consortium showed that PCa samples presented lower XAF1 and higher HDAC expression levels than normal tissues. Thus, our results support a model in which YY1 is able to silence tumor suppressor genes such as XAF1 through HDAC1 in PCa.

A multiaxial fatigue criterion is proposed, which can be seen as a modification of a previous criterion presented by the authors. The influence of the unique material state can be taken into consideration, as well as the range and mean value of the variables involved in the fatigue parameter for depicting the influence of the loading condition. Definitions of the out-of-phase failure and out-of-phase failure angle are proposed, as well as an out-of-phase failure parameter that can be used to express the interdependent relationship with the out-of-phase failure, in both normal-type and shear-type failure. An explicit physical interpretation of different failure types is proposed. After validation and comparison with experimental results for different loading conditions and materials, it is concluded that the prediction ability of this modified multiaxial fatigue criterion is better than that of the original Lu’s criterion, as well as than those of the other commonly used multiaxial fatigue criteria.

A multiaxial fatigue criterion recently developed by the authors for 2D conditions is extended here to 3D situations and applied to predict fatigue damage in rail welded joints with the help of an explicit finite element model. Contact theory and axle box acceleration response in frequency domain are used to validate the finite element model. The influence of depth and length of the welded joints is analyzed. It is found that fatigue damage is more severe with shorter and deeper welded joints. When the length of the welded joints is less than 150 mm, fatigue damage is greatly increased with the increasing of the depth. When the depth is less than 0.1 mm, fatigue damage is not relevant, regardless of the length. When the depth is greater than 0.3 mm, fatigue damage increases significantly with the decreasing of the joint length, especially when the length is less than 150 mm. When the welded joints are long enough, the depth restriction can be relaxed. This work can provide guidance and theoretical support for maintenance and repair of rail welded joints.

In this article, a universally applicable multiaxial fatigue criterion in 2D cyclic loading is proposed, which can be used for a great variety of materials and loading conditions. A strain-based fatigue parameter is defined and, at the same time, a new failure model is proposed to overcome the weaknesses of other mechanisms used previously. In addition, the influence of non-proportional loading, maximum, minimum and mean loading, the influence of both normal and shear components, Poisson effect, different failure types, etc. can also be taken into consideration. A huge number of materials and loading conditions are used to validate the capabilities of the proposed methodology. The results show that the new multiaxial fatigue criterion provides excellent life predictions for all the materials and loading conditions used in this work. The proposed approach can be regarded as a universally applicable multiaxial fatigue criterion in 2D cyclic loading.

A new multiaxial fatigue criterion is proposed that takes into account the influence of material properties and loading conditions on the direction of the critical fatigue plane. Poisson’s effect, normal and shear strain energies, both elastic and plastic, and material hardening can be taken into account in this criterion. Ten different materials subjected to various loading paths with different test-sample geometries are used to validate the capabilities of the proposed approach. The comparison with other commonly used energy-based criteria is also presented. The results show that the proposed criterion provides very good predictions for all the analysed materials and loading conditions (within a factor of two) used in this work. The error in life prediction with the present approach also compares favourably with respect to other criteria available in the literature.

Background Establishing typologies of drug use among gay and bisexual men who have sex with men (GBMSM) who are living with HIV, as well as differences in health outcomes between them, is important in addressing health inequalities within this population. We sought to determine how use of non-prescription drugs is clustered for these individuals and to establish differences in their broader health and well-being, including STI diagnosis, mental health, and physical health. Method We examined past-year drug use reported by 747 GBMSM in Australia as part of the HIV Futures 8 survey, a large cross-sectional survey of people living with HIV. We tested between two and five latent class models of specific drug use and conducted cross-class comparisons of past-year STI diagnosis and self-reported mental and physical health. Results We identified four distinct drug use typologies: ‘chemsex-related use’, ‘minimal use’, ‘analgesic and sedative use’, and ‘diverse use’. The ‘chemsex use’ and ‘diverse use’ classes had a markedly higher likelihood of STI diagnosis relative to the other two classes, while the ‘analgesic and sedative use’ class reported markedly poorer physical and mental health scores than the other classes. Conclusions While GBMSM living with HIV in Australia have higher rates of drug use compared to other GBMSM, and the general population, our analysis indicates that patterns of drug use are not uniform within this group. Specific patterns of drug use are related to distinct health inequalities, and this should be accounted for when addressing the needs of men who use drugs differently.

This study aimed to identify critical features of successful lifestyle weight management interventions for overweight children (0-11years). Eleven qualitative UK-based studies examining children's, parents' and providers' perspectives and experiences of programmes were synthesised to identify components felt to be critical. Studies for this views synthesis were identified from existing reviews and an update of one review's search, which was run in December 2015. The identified components were then explored in a synthesis of intervention evaluations (five 'most effective' and 15 'least effective') conducted in western Europe, North America, Australia or New Zealand. The intervention evaluations were identified from existing reviews and an update of one review's search, which was run in March 2016. This evaluation synthesis was carried out using Qualitative Comparative Analysis. Three important mechanisms were present in all the most effective interventions but absent in all the least effective: 1/ showing families how to change: a) providing child physical activity sessions, b) delivering practical behaviour change strategy sessions, c) providing calorie intake advice; 2/ ensuring all the family are on board: a) delivering discussion/education sessions for both children and parents, b) delivering child-friendly sessions, c) aiming to change behaviours across the whole family; 3/ enabling social support for both parents and children by delivering both child group sessions and parent group sessions. To conclude, programmes should ensure the whole family is on board the programme, that parents and children can receive social support and are not just told what to change, but shown how.

Background Sexual violence (defined as any attempted or completed sexual act obtained by force, violence, or coercion) among higher education students is a public health problem. Determing the prevalence of sexual violence is key to understanding the scope of this issue. This systematic review and meta-analysis aimed to estimate the global prevalence of sexual violence among higher education students. Methods In this systematic review and meta-analysis, we searched Medline, EMBASE, Global Health, PsycINFO, Web of Science, ERIC, and CINHAL for studies published in English, French, Italian, and Spanish from database inception to Aug 12, 2020. We screened studies (10% were double screened) using prespecified inclusion criteria for the population (higher education students), self-reported sexual violence victimisation as a higher eduction student (excluding sexual harassment), context (higher education institution), and study design (ie, quantitative or cross-sectional survey). Quality assessment was conducted using The Joanna Briggs Institure Critical Appraisal Checklist for Studies Reporting Prevalence Data. Prevalence estimates, disagregated by severity and gender identity, were meta-analysed using a random-effects model. This study is registered with PROSPERO, CRD42020171142. Findings We identified 104 studies, from 16 different countries, measuring sexual violence victimisation. 75 (72%) of 104 studies were based in the USA. The risk of bias among studies varied substantially given the sampling methods and sample sizes. Included studies had an overall low risk of bias (81 studies had low risk of bias and 23 studies were at high risk of bias) due to the rigorous inclusion criteria of only including studies using self-reported sexual violence surveys among higher education students. The overall meta-analysed prevalence rate for sexual violence victimisation was 17·4% (95% CI 15·2–19·8) for women and 7·8% (5·7–10·5) for men. When disaggregated by severity, 11·4% of women experienced coercive sex, 14·5% forced sexual touching, 8·2% attempted rape, and 5·9% rape. Comparatively, 6·8% of men experienced coercive sex, 6·4% experienced forced sexual touching, 1·1% experienced attempted rape, and 2·4% rape. Interpretation Prevalence estimates in studies of sexual violence among higher education students vary considerably because of inconsistencies in how sexual violence is defined and measured, and the sampling methods used. The meta-analysed victimisation estimates provide insight into how sexual violence among higher education students manifests itself among this population. Funding Social Science and Humanities Research Council, Canada.

Dissolved organic matter (DOM) is an important component in the global carbon cycle and knowledge of its chemical composition is crucial for understanding its role in biogeochemical cycles and its interaction with pollutants in aquatic systems. Changes in DOM could drastically affect carbon fluxes, and the toxicity and distribution of pollutants. This study reports DOM characterization and comparison by ultra-high resolution and accuracy Fourier transformed ion cyclotron resonance mass spectrometry (FT-ICR-MS) of samples from an estuarine, a marine, a riverine and a lacustrine system of southeastern Brazil (SE Brazil). The MS screening of DOM showed ions corresponding to several classes of constituents such as synthetic surfactants, lignins, lipids and sulfur polyoxygenated (CHOS) constituents. The CHOS constituents and the synthetic surfactants displayed higher abundance for riverine and lacustrine samples which have higher human impact than the marine and estuarine samples. We hypothesized that these CHOS compounds are formed in situ by the addition of inorganic sulfur anions such as sulfide or bisulfide to lignin derived compounds via Kraft reactions.

Alzheimer's disease (AD) is a neurodegenerative disorder caused by the aggregation of the amyloid-beta peptide (Aβ) in senile plaques and cerebral vasculature. The Aβ25-35 fraction has shown the most toxicity; its neurotoxic mechanisms are associated with the generation of oxidative stress and reactive astrogliosis that induce neuronal death and memory impairment. Studies indicate that pharmacological treatment with flavonoids reduces the rate of AD, in particular, it has been shown that antioxidants are compounds that could interact with this peptide due to their antioxidant proprieties. In this study, experimental and computational tools were used to calculate the molecular electrostatic potential and the Fukui function with the Gaussian 09 computational program, to predict the most reactive parts of these molecules and make the complex between Aβ25-35 and two flavonoids (catechin and epicatechin) in the absolute gas-phase, where a possible interaction between them was observed. This is important for understanding the Aβ25-35-Flavonoid (A-F) interaction as a therapeutic strategy to inhibit the neurotoxic effects that this peptide causes in AD, which currently is still considered an ambiguous process.

The extent of unsaturation level in a compound, commonly measured in terms of its number of double bond equivalents (DBEs), reflects the total number of π bonds plus rings and can be calculated if the molecular formula is known. The extent of unsaturation can also be calculated via DBE/C, where C is the number of carbon atoms. For hydrocarbons, if DBE/C is > 0.67, the structure corresponds unequivocally to a condensed aromatic (CA) compound, but this criterion cannot be applied directly to heteroatom containing compounds. A new parameter, the aromaticity index (AI) was recently proposed to solve this problem, and has been applied to establish a region of CA compounds in high resolution mass spectrometry (MS) van Krevelen diagrams to characterize natural organic matter (NOM), such as humic acids (HAs). In this study, we report a reformulated AI (rAI) that also considers formulae that accommodate non-aromatic (NA) and non-condensed aromatic (NCA) cyclic carbonyl compounds. We also propose a correction for AI with respect to N and P containing formulae and show an application of the rAI index for the analysis and data treatment of a certified reference material (CRM) of NOM.

Latent EBV infection can lead to EBV-PTLD when proliferating, EBV+ B cells are insufficiently controlled by cellular immunity. At the National Institutes of Health (NIH), all HCT recipients are monitored weekly from day 0-100 with whole blood EBV qPCR. We evaluated the cumulative incidence (CI) of EBV-related events across 4 T-cell manipulation strategies (posttransplantation cyclophosphamide (PTCy), proximal serotherapy, ex vivo T cell depletion (TCD), and calcineurin/mTOR inhibitor (CNI/mTORi)-based), across all graft sources (marrow (BM), peripheral blood (PBSC), and umbilical cord blood (UCB)), and across regimens with and without mTORi drugs. The CI of EBV events (detection of any EBV in blood (Any-EBV), detection of EBV > 3 log10 IU/mL (>3-EBV), pre-emptive therapy for EBV (EBV-Tx), and EBV-PTLD) were determined, with death as a competing risk. EBV-tx included rituximab and/or EBV-specific T-cells. Any-EBV and >3-EBV events were captured through day +100 and EBV-Tx and EBV-PTLD events were captured through 1-year post-HCT. Included are 356 consecutive patients receiving 1st HCT at NIH from 2011-2017 with sufficient weekly day 0-100 EBV qPCRs (> 63% of specimens) and 1 year of follow-up of survivors. Fig 1 shows cohort characteristics. Among T-cell manipulation strategies, the CI of Any-EBV and >3-EBV was lowest for serotherapy, p=0.0007 and p=0.0006, with no difference among strategies in the CI of EBV-Tx or EBV-PTLD. By graft source, UCB had the highest CI of Any-EBV at day +100, p=0.001, with no difference in the CI of >3-EBV owing to higher CI of EBV-Tx among UCB recipients compared to BM and PBSC grafts, p 3-EBV, but no difference in the CI of EBV-Tx or EBV-PTLD. Within CNI/mTORi-based approaches, the CI of Any-EBV and >3-EBV was lower for CNI+mTORi vs CNI without mTORi, p=0.004 and p=0.002, and the CI of EBV-Tx was 3% for CNI+mTORi vs 14% for CNI without mTORi, p=0.009, with no difference in the CI of EBV-PTLD. Among PTCy-containing approaches, with or without serotherapy, there were no differences in the CI of Any-EBV, >3-EBV, EBV-Tx, or EBV-PTLD. The CI of EBV events are summarized in Fig 2. While EBV detection in blood was common post-HCT, the clinical significance of detection and the role of pre-emptive therapy seem to vary by T-cell manipulation strategy, graft source, and use of mTORi. The finding of less EBV detection with mTORi-containing regimens across approaches warrants further investigation into the clinical significance and underlying mechanisms.

Objectives To explore user perspectives on applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to systematic reviews of complex interventions. Study Design and Setting Thirty-three authors of recent (2013 onward) systematic reviews were contacted regarding their perspectives on using GRADE from three Cochrane review groups: Cochrane Developmental, Psychosocial, and Learning Problems Group; Cochrane Public Health Group; and Cochrane Depression, Anxiety, and Neurosis Group. Framework Analysis was applied to the data to identify the challenges in applying GRADE and suggestions for its extension, that is, adaptation. These two themes were cross-compared between the groups of answers from “simple” vs. “complex” intervention review authors to identify the specific perspectives on using GRADE in reviews of complex interventions. Results Specific challenges were identified in applying GRADE to reviews of complex interventions. These were related to the assessment of nonrandomized studies and performance bias in GRADE. Authors perceived these challenges to contribute to frequent downgrading of the “best evidence possible” for complex interventions. Meanwhile, GRADE was found to lack an analytic approach to enable adequate evidence synthesis and assessment of intervention implementation elements. Conclusion Users suggest that the GRADE guidance be extended to address-specific considerations for complex interventions.

Ammonium nitrate fuel oil (ANFO) is an explosive used in many civil applications. In Brazil, ANFO has unfortunately also been used in criminal attacks, mainly in automated teller machine (ATM) explosions. In this paper, we describe a detailed characterization of the ANFO composition and its two main constituents (diesel and a nitrate explosive) using high resolution and accuracy mass spectrometry performed on an FT-ICR-mass spectrometer with electrospray ionization (ESI(±)–FTMS) in both the positive and negative ion modes. Via ESI(−)–MS, an ion marker for ANFO was characterized. Using a direct and simple ambient desorption/ionization technique, i.e., easy ambient sonic-spray ionization mass spectrometry (EASI–MS), in a simpler, lower accuracy but robust single quadrupole mass spectrometer, the ANFO ion marker was directly detected from the surface of banknotes collected from ATM explosion theft.

Most of the naturally occurring steroidal sapogenins (C-23 non-substituted frameworks), possess an R configuration at the spiro C-22 center. Their C-22 epimers have become important targets in biological research. This paper describes a procedure to obtain 22S-spirostans from 22R-sapogenins and pseudosapogenin skeletons, without affecting the chirality at either C-25 or C-20. An optimal way to synthesize the pair of C-22 stereoisomers of 23-acetyldiosgenin is also reported. The latter was obtained from a 22,26-epoxycholestane or from 23-acetylfurostene compounds.

Mercury stored in forests can be volatilized to the atmosphere during fires. Many factors influence this process such as mercury concentration, vegetation loading and the soil temperature reached during the fire. We quantified mercury emissions from biomass and soil during a prescribed fire in Brazil using the difference in mercury burden in vegetation and soil before and after burning, and data were critically compared with those previously obtained in a similar experiment in another part of the Amazonia. The calculated mercury emission factor was 4.1 ± 1.4 g Hg ha −1 , with the main part (78%) originating from litterfall and O-horizon, and only 14% associated with live biomass. When considering the fuel burned loading, the emission factor ranged from 40 to 53 μg Hg kg −1 . Data were also obtained on soil temperature profile and on Hg speciation in soil in an effort to relate these parameters to Hg emissions.

The molecular structures, IR spectroscopy, 1 H, 13 C and 51 V NMR spectroscopy of three bis-peroxo-oxovanadate species containing histidine peptides were studies on theoretical grounds. The geometry optimizations and IR spectra in gas phase were carried out with the DFT (B3LYP functional) method and the spectra of the peptides under study were obtained with the gauche-including atomic orbital (GIAO) method as implemented in the GAUSSIAN 09 package. The standard 6-31+G ∗ basis set and core-valence effective core potential Lanl2dz were employed. New coordination modes were found in the potential curves for the rotation through the V−N coordination bond. They bent up and down (Bu, Bd) with the imidazole ring aligned with the V–O(peroxo) bond and also bent with respect to the V O group. In addition, the parameters describing quadrupolar and chemical shift anisotropy interactions are determined theoretically. In particular, this results help to solve apparent inconsistencies found in the 51 V NMR solution spectroscopy of the three bis-peroxo-oxovanadate complexes. The gathered evidence furthers the understanding of the electronic implications and structure–activity relationships in the case of histidine peptide-containing bis-peroxo-oxovanadate structures.

Four (dimethylamino)arylacrylonitrile derivatives in the solid state are presented. The compounds were characterized by single crystal X-ray diffraction to investigate the effects of substituents on the resulting crystals lattices and to examine the effects of the factors controlling their solid state on photochemical behavior. The molecules included 2-(phenyl)-3-(4-dimethylaminophenyl)acrylonitrile (I) 2-(2′-pyridyl)-3-(4-dimethylaminophenyl)-acrylonitrile (II), 2-(3′-pyridyl)-3-(4-dimethyl-aminophenyl)acrylonitrile (III) and 2-(3′-pyridyl)-3-(4-dimethylaminophenyl)acrylonitrile (IV). The dimethyl-, CN groups and the position of nitrogen atom in the pyridyl groups affected the nature of the molecular packing and consequently their fluorescence properties. The lattice of each compound is compared with acrylonitriles previously reported and the effect of substitution on the crystal properties with the strongest emission in solid state is examined. Based on analyses of molecular packing in the single crystals, the differences in the fluorescence could be attributed to aggregates that showed non-classical herringbone packing with π–π overlap between neighbor molecules. Also the crystal structure studies showed that the N atom position is located anti to the CN group, giving a more planar geometry. This N-dimethyl substituent for I–IV appears to be general for more planar ground-state geometry about the nitrogen atom and consistent with an “amino conjugation effect” to obtain sufficient quinoid structures.

A highly Z -selective isomerization (double bond migration) was observed when oxazolidinone vinylogous glycolate was exposed to a strong base to give N -acyl oxazolidinone, bearing an electron rich olefin. The corresponding enolate was exposed to alkyl halides to provide alkylated compounds on the γ-position with respect to OBn group, with high regioselectivity and moderate diastereoselectivity. However, the nature of the chiral oxazolidinone leads to a significant increase in the reaction diastereoselectivity. A stereospecific formation of cis -olefin was also observed in these alkylated compounds.

Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic substances which are resistant to environmental degradation due to their highly hydrophobic nature. Soils contaminated with PAHs pose potential risks to human and ecological health, therefore concern over their adverse effects have resulted in extensive studies on their removal from contaminated soils. The main purpose of this study was to compare experimental results of PAHs removal, from a natural certified soil polluted with PAHs, by biological methods (using bioaugmentation and biostimulation in a solid-state culture) with those from supercritical fluid extraction (SFE), using supercritical ethane as solvent. The comparison of results between the two methods showed that maximal removal of naphthalene, acenaphthene, fluorene, and chrysene was performed using bioremediation; however, for the rest of the PAHs considered (fluoranthene, pyrene, and benz(a)anthracene) SFE resulted more efficient. Although bioremediation achieved higher removal ratios for certain hydrocarbons and takes advantage of the increased rate of natural biological processes, it takes longer time (i.e. 36 d vs. half an hour) than SFE and it is best for 2-3 PAHs rings.

Experiments are carried to investigate free dendritic growth of succinonitrile–acetone alloys in an undercooled melt. The measurements include the steady dendrite tip velocity and radius, the non-axisymmetric amplitude coefficient of the fins near the tip, and the envelope width, projection area, and contour length of the sidebranch structure far from the tip. It is found that the measured dendrite tip growth Peclet numbers agree well with the predictions from a stagnant film model that accounts for thermosolutal convection in the melt. The measured tip selection parameter, σ ⁎ , is verified to be independent of the alloy composition, but shows a strong dependence on the imposed undercooling. The universal amplitude coefficient, A 4 , is measured to be equal to 0.004, independent of the undercooling, but the early onset of sidebranching prevents its accurate determination for more concentrated alloys. For the self-similar sidebranch structure far from the tip, scaling laws are obtained for the measured geometrical parameters. While melt convection causes some widening of the sidebranch envelope, and the early onset of sidebranching for alloy dendrites results in a 25% upward shift of the envelope width, the projection area and, hence, the mean width of a sidebranching dendrite, as well as its contour length in the sidebranch plane, obey universal power laws that are independent of the convection intensity and the alloy composition.

Transient cerebral ischemia often results in secondary ischemic/reperfusion injury, the pathogenesis of which remains unclear. This study provides a comprehensive, temporal description of the molecular events contributing to neuronal injury after transient cerebral ischemia. Intraluminal middle cerebral artery occlusion (MCAO) was performed to induce a 2-h ischemia with reperfusion. Microarray analysis was then performed on the infarct cortex of wild-type (WT) and glutathione peroxidase-1 (a major antioxidant enzyme) knockout (Gpx1(-/-)) mice at 8 and 24h postreperfusion to identify differential gene expression profile patterns and potential alternative injury cascades in the absence of Gpx1, a crucial antioxidant enzyme, in cerebral ischemia. Genes with at least ±1.5-fold change in expression at either time point were considered significant. Global transcriptomic analyses demonstrated that 70% of the WT-MCAO profile overlapped with that of Gpx1(-/-)-MCAO, and 28% vice versa. Critical analysis of the 1034 gene probes specific to the Gpx1(-/-)-MCAO profile revealed regulation of additional novel pathways, including the p53-mediated proapoptotic pathway and Fas ligand (CD95/Apo1)-mediated pathways; downplay of the Nrf2 antioxidative cascade; and ubiquitin-proteasome system dysfunction. Therefore, this comparative study forms the foundation for the establishment of screening platforms for target definition in acute cerebral ischemia intervention.

The transfection of siRNA in vivo is essential for the study of gene functions, target validation, and for gene therapy. However, the successful delivery of siRNA in whole organisms is still very difficult to achieve. A high-pressure delivery technique, called the "hydrodynamics" method, has been used for siRNA transfection in mice. However, it is a method based on a high-speed and high-volume of i.v. injection, which makes it very difficult to implement in vivo, due to vascular breakage. Here, we systematically investigated ways to optimize the siRNA delivery, in order to avoid strong side effects, while achieving a high-efficiency siRNA-gene knockdown. We show here that the amount of siRNA delivered is crucial, as using too little or too much siRNA minimizes the knockdown effect. We demonstrate that by carefully identifying an optimal-minimal volume, and an optimal amount of siRNA, we achieve a high knockdown effect, with a 100% survival rate. We have previously shown that SphK1 plays a key role in anaphylatoxin (C5a) signaling in neutrophils and macrophages. Our approach, optimizing the dosage of siRNA, allowed us to successfully silence our target gene-product (SphK1) in vivo, and enabled us to validate SphK1 as a key player in our in vivo model of C5a-induced acute peritonitis and systemic inflammation including multi-organ damage, demonstrating that this improved siRNA-silencing method not only allowed us to identify SphK1 as a key therapeutic target, but brings us a step closer to the usage of siRNA for therapeutic intervention.

During the last few years, it has become clear that sphingolipids are sources of important signalling molecules. Particularly, the sphingolipid metabolites, ceramide and S1P, have emerged as a new class of potent bioactive molecules, implicated in a variety of cellular processes such as cell differentiation, apoptosis, and proliferation. Sphingomyelin (SM) is the major membrane sphingolipid and is the precursor for the bioactive products. Ceramide is formed from SM by the action of sphingomyelinases (SMase), however, ceramide can be very rapidly hydrolysed, by ceramidases to yield sphingosine, and sphingosine can be phosphorylated by sphingosine kinase (SphK) to yield S1P. In immune cells, the sphingolipid metabolism is tightly related to the main stages of immune cell development, differentiation, activation, and proliferation, transduced into physiological responses such as survival, calcium mobilization, cytoskeletal reorganization and chemotaxis. Several biological effectors have been shown to promote the synthesis of S1P, including growth factors, cytokines, and antigen and G-protein-coupled receptor agonists. Interest in S1P focused recently on two distinct cellular actions of this lipid, namely its function as an intracellular second messenger, capable of triggering calcium release from internal stores, and as an extracellular ligand activating specific G protein-coupled receptors. Inhibition of SphK stimulation strongly reduced or even prevented cellular events triggered by several proinflammatory agonists, such as receptor-stimulated DNA synthesis, Ca(2+) mobilization, degranulation, chemotaxis and cytokine production. Another very important observation is the direct role played by S1P in chemotaxis, and cellular escape from apoptosis. As an extracellular mediator, several studies have now shown that S1P binds a number of G-protein-coupled receptors (GPCR) encoded by endothelial differentiation genes (EDG), collectively known as the S1P-receptors. Binding of S1P to these receptors trigger an wide range of cellular responses including proliferation, enhanced extracellular matrix assembly, stimulation of adherent junctions, formation of actin stress fibres, and inhibition of apoptosis induced by either ceramide or growth factor withdrawal. Moreover, blocking S1P1-receptor inhibits lymphocyte egress from lymphatic organs. This review summarises the evidence linking SphK signalling pathway to immune-cell activation and based on these data discuss the potential for targeting SphKs to suppress inflammation and other pathological conditions.

Studies have shown that the lipid peroxidation by-product, 4-hydroxynonenal (HNE), is involved in many pathological events in several neurodegenerative diseases. A number of signaling pathways mediating HNE-induced cell death in the brain have been proposed. However, the exact mechanism remains unknown. In the present study, we have examined the effects of HNE on cultured primary cortical neurons and found that HNE treatment leads to cell death via apoptosis. Both the caspase and calpain proteolytic systems were activated. There were also increased levels of phospho-p53 and cell cycle-related proteins. Gene transcription was further studied using microarray analysis. Results showed that majority of the genes associated with cell cycle regulation, response to stress, and signal transduction were differentially expressed. The various categories of differentially-expressed genes suggested that there are other parallel pathways regulating HNE-induced neuronal apoptosis. Collectively, these might help to elucidate similar molecular mechanisms involved during cell death in neurodegenerative diseases.

14α-demethylation is the reaction which leads directly to norlanosterol from lanosterol, and is carried out exclusively by lanosterol structure. To discover the features, which make lanosterol a unique molecule able to undergo this demethylation, the electronic and energetic parameters of lanosterol and other structurally related steroids, were calculated. Local and global parameters were analyzed, in order to insight into the reactivity and selectivity of every molecule studied. Electrostatic potential maps were used to find differences of selectivity in each molecule, along with total energy and hardness, discovering the differences in reactivity. Lanosterol shows specific orientation and unique shape of electrostatic potential map, which does not appear in other structures, except epilanosterol, because it differs only in the orientation of a hydroxyl group, therefore they present many similarities but many differences also. For this reason, epilanosterol has a similar shape of electrostatic potential map, but not its orientation. Aoyama et al. have found, three essential structural features in lanosterol to be demethylated, which generate a specific electrostatic potential map, the hydroxyl group on C-3, the position of the double bound between C8 and C9 on cycle B, and the side chain double bond. Our study agrees with some biochemical studies, which reveal that there are three key features essential for substrate recognition by the enzyme P-450 14DM . We think the present study is an alternative methodology to find features which are related with some parameters obtained via theoretical calculations.

This work presents a theoretical, unified, study of the conformational distribution of acetylcholine, nicotine and muscarine in vacuum and aqueous solution at physiological temperature. The energetic and geometric data are obtained at the MP2/cc-pVDZ level, whereas the solvent effect is described by means of the PCM continuum model. The population of conformers is derived from a conformational partition function, including the effects of the rotovibrational coupling and the conformational kinetic energy. For muscarine we find, in vacuum and solution, only one significantly populated conformer. In this conformer, muscarine exhibits a gauche conformation. For nicotine, only two conformations are found, similarly populated in vacuum. In solution only one of these conformations remains, corresponding to an almost perpendicular orientation of the pyrrolidine and pyridine rings. On the other hand, acetylcholine in vacuum and solution accumulates its population in a zone where the cationic head is in a gauche conformation. This conformational zone is defined by the orientation of the acetoxy moiety. For the three molecules, the most populated conformers in solution are compared using internuclear distances. The results show that the conformers of acetylcholine and nicotine exhibit a similar pharmacophoric distribution (using the oxygen of the acetylcholine ester group). In addition, this acetylcholine conformer also exhibits a similar pharmacophoric pattern to the conformer of muscarine (using the acetylcholine carbonyl oxygen). Simulation of the effect of the acetylcholine interaction with the receptor site, by using a thermal bath, translates in an increase of the torsional flexibility of the acetoxy moiety.

Anaphylatoxins activate immune cells to trigger the release of proinflammatory mediators that can lead to the pathology of several immune-inflammatory diseases. However, the intracellular signaling pathways triggered by anaphylatoxins are not well understood. Here we report for the first time that sphingosine kinase (SPHK) plays a key role in C5a-triggered signaling, leading to physiological responses of human neutrophils. We demonstrate that C5a rapidly stimulates SPHK activity in neutrophils and differentiated HL-60 cells. Using the SPHK inhibitor N,N-dimethylsphingosine (DMS), we show that inhibition of SPHK abolishes the Ca2+ release from internal stores without inhibiting phospholipase C or protein kinase C activation triggered by C5a but has no effect on calcium signals triggered by other stimuli (FcgammaRII). We also show that DMS inhibits degranulation, activation of the NADPH oxidase, and chemotaxis triggered by C5a. Moreover, an antisense oligonucleotide against SPHK1, in neutrophil-differentiated HL-60 cells, had similar inhibitory properties as DMS, suggesting that the SPHK utilized by C5a is SPHK1. Our data indicate that C5a stimulation decreases cellular sphingosine levels and increases the formation of sphingosine-1-phosphate. Exogenously added sphingosine has a dual effect on C5a-stimulated oxidative burst: it has a priming effect at lower concentrations but a dose-dependent inhibitory effect at higher concentrations; however, C5a-triggered protein kinase C activity was only reduced at high concentration of sphingosine. In contrast, C5a-triggered Ca2+ signals, chemotaxis, and degranulation were not affected by sphingosine at all. Exogenous sphingosine-1-phosphate, by itself, did not induce degranulation or chemotaxis, but it did marginally induce Ca2+ signals and oxidative burst and had a priming effect, enhancing all the C5a-triggered responses. Taken together, these results suggest that SPHK plays an important role in the immune-inflammatory pathologies triggered by anaphylatoxins in human neutrophils and point out SPHK as a potential therapeutic target for the treatment of diseases associated with neutrophil hyperactivation.

Aggregation of receptors for immunoglobulin G (FcgammaRs) on myeloid cells activates a series of events that are key in the inflammatory response and that can ultimately lead to targeted cell killing by antibody-directed cellular cytotoxicity. Generation of lipid-derived proinflammatory mediators is an important component of the integrated cellular response mediated by receptors for the constant region of immunoglobulins (Fc). We have demonstrated previously that, in interferon-gamma-primed U937 cells, the high affinity receptor for IgG, FcgammaRI, is coupled to a novel intracellular signaling pathway that involves the sequential activation of phospholipase D, sphingosine kinase, calcium transients, and protein kinase C isoforms, leading to the activation of the NADPH-oxidative burst. Here, we investigate the nature of the phospholipase that regulates arachidonic acid and eicosanoid production. Our data show that FcgammaRI couples to iPLA(2)beta for the release of arachidonic acid and the generation of leukotriene B(4) and prostaglandin E(2). Activation of iPLA(2)beta was protein kinase C-dependent; on the other hand, platelet-activating factor triggered cPLA(2)alpha by means of the mitogen-activated protein kinase pathway. These studies demonstrate that intracellular PLA(2)s can be selectively regulated by different stimuli and suggest a critical role for iPLA(2)beta in the intracellular signaling cascades initiated by FcgammaRI and its functional role in the generation of key inflammatory mediators.

Some of the band systems of several astrophysically important molecules are calculated and compared with the results obtained by calculations based on realistic Klein–Dunham and Rydberg–Klein–Rees potential functions. The Morse potential is approximated by means of a fourth-order anharmonic oscillator model. In the second-quantized formalism, the anharmonic Hamiltonian is diagonalized by using the Bogoliubov–Tyablikov transformation. The diagonalization process gives a shift in the frequency associated with each normal mode of harmonic vibration of the molecules presented here. The Franck–Condon factors are estimated using this new frequency within the framework of a harmonic oscillator.

Immune receptors are coupled to the activation of phosphatidylcholine phospholipase D (PC-PLD) that hydrolyses phosphatidylcholine to generate phosphatidic acid and choline. As these receptors are also coupled to other signalling cascades, it has been difficult to define the precise cell activation events resulting from PLD activation in the absence of specific inhibitors. There is increasing evidence that phosphatidic acid acts as an intracellular signalling molecule regulating release of calcium from intracellular stores, sphingosine kinase and protein kinase C activation and membrane budding. Phosphatidic acid can also be rapidly converted into lysophosphatidic acid, diacylglycerol and arachidonates.

Background The lifetime prevalence of intimate partner violence (IPV), violence committed by a current or former partner, is estimated to be 30% among women worldwide. Effective prevention requires targeting conditions that increase and decrease the risk of IPV—or risk and protective factors, respectively. We aimed to systematically review and quantify the associations between prospective longitudinal risk and protective factors and IPV against women and identify evidence gaps. Methods Systematic searches were conducted in English in 16 databases including Medline and PsycINFO from inception to June 1, 2016, using free-text terms and controlled vocabulary for violence, partner, adults, and study design. English-language studies that prospectively analysed an adjusted association between any risk or protective factor or factors and self-reported IPV victimisation among women were included. Study quality was assessed with the Cambridge Quality Checklists. Studies investigating the same risk or protective factor using similar measures, and with appropriate data available, were combined to compute odds ratios using random-effects meta-analyses. Heterogeneity was indicated by I 2 and τ 2 . All results, including those not meta-analysed, were synthesised with harvest plots to illustrate evidence gaps and trends towards negative or positive associations. This study is registered with PROSPERO, number CRD42016039213. Findings Of 18 608 studies identified, 60 were included, and 35 meta-analysed. The strongest evidence for modifiable risk factors for IPV against women were unplanned pregnancy (odds ratio 1·66, 95% CI 1·20–1·31) and having parents with less than a high school education (1·55, 1·10–2·17). Being older (0·96, 0·93–0·98) and married (0·93, 0·87–0·99) were protective. Interpretation Study limitations include English-language restrictions and low statistical power. Nevertheless, to our knowledge this is the first systematic, meta-analytical review of all risk and protective factors for IPV against women without location, time, or publication restrictions. Education and sexual health interventions may be effective targets for preventing IPV against women, with young, unmarried women most at risk. More prospective evidence for perpetrator-related and context-related risk and protective factors for women's IPV experiences outside the USA is urgently needed to inform global recommendations. Funding Rhodes Trust, Canadian Institutes of Health Research (DFS152265).

Background A third of children in England are overweight or obese (body-mass index >25 kg/m 2 ). Current guidance from the National Institute for Health and Care Excellence recommends that obese adolescents attend a family-based multicomponent lifestyle weight management programme. However, these programmes have low recruitment and high rates of attrition. An understanding of the opinions of adolescents is necessary for planning and developing future interventions. The aim of this systematic review was to explore the viewpoints of overweight–obese adolescents who have attended a lifestyle obesity treatment intervention. Methods Studies of overweight–obese adolescents (aged 12–17 years) who attended a single or multicomponent lifestyle treatment intervention were examined. Only studies that collected and analysed data qualitatively were included. There were no language restrictions. Published literature was identified by searching the following databases: Medline, EMBASE, Web of Science, PsycINFO, ASSIA, and CINAHL between July 27 and 31, 2016. Search terms included obesity, overweight, views, experiences, opinions, attitudes, satisfaction, preferences, adolescents, diet, activity, and behaviour. Reference lists of included studies were screened. Titles and abstracts of identified records were assessed independently by two reviewers. Full texts of all potentially relevant papers were retrieved and assessed independently by two reviewers, reasons for exclusion were recorded, and differences in opinions were resolved by a third reviewer. Methodological quality was assessed by two reviewers independently, in terms of trustworthiness and usefulness of findings, with an EPPI-Centre tool. Full texts were analysed with thematic synthesis. The Confidence in the Evidence from Reviews of Qualitative research approach was used to assess the certainty of review findings. This study is registered with PROSPERO, number CRD42016039588. Findings 19 230 records were identified for title and abstract screening. 284 full -texts were assessed, with 24 included. Thematic synthesis resulted in 178 descriptive codes, which led to the development of 43 analytical themes that have been broadly divided into eight sections: support, motivations, intervention content, maintenance, diet, technology, barriers, and physical activity. Analytical themes included "professional support valued", "tailored intervention", "adolescents enjoy using technology and do so with ease", "prior fears of attending intervention", "enjoyment of sport and physical activity", and "longer term support". Interpretation Our findings may inform local and national policy makers in the development of future interventions for overweight–obese adolescents. Developing interventions with adolescents' opinions in mind, might assist in the improvement of recruitment and attrition rates. Funding NIHR Collaboration for Leadership in Applied Health Research and Care West Midlands (for HJ's PhD).

Ab initio calculations at the RHF/6-31G ∗ level were performed with the spartan program in order to elucidate the best pathway through which norlanosterol could be biosynthesized from lanosterol (demethylation). Two possible main pathways have been reported: the pathway via intermediate carboxylic acid proposed by Olson and Akhtar [J.A. Olson, M. Lindberg, K. Bloch, J. Biol. Chem. 226 (1957) 941–956; M. Akhtar, I.A. Watkinson, A.D. Rahimtula, D.C. Wilton, K.A. Munday, Biochem. J. 111 (1969) 757–761], and the pathway via intermediate formyloxy proposed by Alexander et al. [K. Alexander, M. Akhtar, R.B. Boar, J.F. McGhie, D.H.R. Barton, J. Chem. Soc. Chem. Commun. (1972) 383–386; R.T. Fischer, J.M. Trzaskos, R.L. Magolda, S.S. Koo, C.S. Brosz, B. Larsen, J. Biol. Chem. 266 (10) (1991) 6124–6132]. We conclude that the formyloxy pathway is more feasible than the carboxylic acid pathway based on an analysis of frontier orbitals, hardness/softness and reactivity parameters.

There is accumulating evidence that thrombolytic therapy is underused among eligible patients with acute myocardial infarction. We sought to determine whether potential errors in electrocardiographic diagnosis might be a contributing factor.Seventy-five electrocardiograms were interpreted on 2 separate occasions by 3 cardiologists. Two criteria were compared for thrombolysis eligibility: (1) measurement ofor =1 mm ST-segment elevation in 2 contiguous leads (measured) and (2) criterion 1 plus the subjective opinion that the changes represented acute transmural injury (interpretive). The results were compared with computerized interpretations by the Marquette 12SL system.Raw agreement and agreement corrected for chance between raters for both criteria were excellent and tended to be better for interpretive compared with measured criteria (kappa = 0.89 vs 0.78, respectively). Strict reliance on measured electrocardiographic criteria alone would have resulted in overuse of thrombolysis among all 3 raters. Based on the consensus opinion, the absolute overuse of thrombolysis would have been approximately 15% (P.0034). The computer algorithm had a specificity of 100% and a sensitivity of 61.5%. Reliance on the computerized interpretation alone would have lead to underuse of thrombolytic therapy compared with consensus opinion (21.3% vs 34. 6%; P.005).Agreement for suspected acute myocardial infarction tended to be better when the appearance of the ST segments was added to measurable ST elevation criteria. Strict reliance on measurable criteria may lead to the inappropriate overuse of thrombolysis. Although the Marquette 12SL system has excellent specificity, it has poor sensitivity for the diagnosis of thrombolysis-eligible AMI. Reliance on computerized electrocardiographic interpretation would lead to the inappropriate underuse of thrombolytic therapy in situations in which qualifying electrocardiographic criteria are actually met.

In this paper, conformations of ascorbic acid have been determined from ab initio calculations with full geometry optimization using different levels of theory and basis sets: RHF/6-31G, RHF/6-31G(d,p), RHF/6-311+G(d,p) and MP2/6-31(d,p). The starting point for the optimizations were the A and B X-ray structures of ascorbic acid as determined by crystallography. The molecular energies and optimized structures of 36 conformers of ascorbic acid were obtained. the potential energy surface is mainly dependent on the rotation of the side chain structure. One optimized gas phase conformer is very close to the X-ray structure of the crystal. The largest energy difference between the 36 local minima are 18.641, 6.1 and 7.97 kcal/mol at the four levels of theory, respectively. The three lowest energy, fully optimized conformations are the same for the four levels of theory.

Background Narrative synthesis approaches have been faulted for vote-counting (in which effectiveness is determined by tallying direction and statistical significance of study results) and lack of transparency. Yet narrative syntheses can also highlight trends and explanations for findings in a way that statistical meta-analysis cannot. Debate about the absence of meta-analysis in situations where it could have been done continues in the methodological literature. Using a systematic review of the effects of plain packaging of tobacco products, we compared narrative syntheses and new meta-analyses. We chose this review because its findings, which informed UK public health policy, have been misrepresented by the tobacco industry. Methods We revisited a published systematic review on plain packaging of tobacco products. We compared the findings from the narrative synthesis originally used in the review that accounted for study quality with the findings from a new multilevel meta-analysis that included all available effect sizes. We compared them in terms of their inclusiveness, approach to heterogeneity, and overall findings. Findings Although 21 studies (n=27 166) were included in the narrative synthesis, we included seven studies in our new meta-analysis (56 effect sizes, n=5365). The narrative synthesis found that the 21 studies were "highly consistent" in the decreased attractiveness of plain packaging compared with branded packaging, primarily on the basis of direction and significance of effects as reported in the 21 studies. The pooled effect size for the seven studies in the meta-analysis demonstrated that plain packs were less attractive (Cohen's d =–0·59, 95% CI −0·71 to −0·47). Whereas the narrative synthesis highlighted key generalities across subgroups and study designs, the meta-analysis highlighted possible effect modification by tobacco brand. Interpretation This study adds to existing debates by showing the contribution and implications of each synthesis method, especially with respect to opportunities for exploring heterogeneity. The findings have implications for the credibility of different approaches. Even when narrative synthesis is preferred, a meta-analysis and forest plot can help generate additional hypotheses, test and confirm hypotheses, and understand heterogeneity. In this particular case, use of multilevel meta-analysis helped to make clear aspects of statistical heterogeneity that narrative synthesis alone might not have detected. Funding Medical Research Council.

Mast cell activation triggers Ca(2+) signals and the release of enzyme-containing granules, events that play a major role in allergic/hypersensitivity reactions. However, the precise molecular mechanisms that regulate antigen-triggered degranulation and Ca(2+) fluxes in human mast cells are still poorly understood. Here we show, for the first time, that a receptor can trigger Ca(2+) via two separate molecular mechanisms. Using an antisense approach, we show that IgE-antigen stimulation of human bone marrow-derived mast cells triggers a sphingosine kinase (SPHK) 1-mediated fast and transient Ca(2+) release from intracellular stores. However, phospholipase C (PLC) gamma1 triggers a second (slower) wave of calcium release from intracellular stores, and it is this PLCgamma1-generated signal that is responsible for Ca(2+) entry. Surprisingly, FcepsilonRI (a high affinity receptor for IgE)-triggered mast cell degranulation depends on the first, sphingosine kinase-mediated Ca(2+) signal. These two pathways act independently because antisense knock down of either enzyme does not interfere with the activity of the other enzyme. Of interest, similar to PLCgamma1, SPHK1 translocates rapidly to the membrane after FcepsilonRI cross-linking. Here we also show that SPHK1 activity depends on phospholipase D1 and that FcepsilonRI-triggered mast cell degranulation depends primarily on the activation of both phospholipase D1 and SPHK1.