Co-benefits of global, domestic, and sectoral greenhouse gas mitigation for US air quality and human health in 2050

Policies to reduce greenhouse gas (GHG) emissions can bring ancillary benefits of improved air quality and reduced premature mortality, in addition to slowing climate change. Here we study the co-benefits of global and domestic GHG mitigation on US air quality and human health in 2050 at fine resolution using dynamical downscaling, and quantify for the first time the co-benefits from foreign GHG mitigation. Relative to a reference scenario, global GHG reductions in RCP4.5 avoid 16000 PM2.5-related all-cause deaths yr-1 (90% confidence interval, 11700-20300), and 8000 (3600-12400) O3-related respiratory deaths yr-1 in the US in 2050. Foreign GHG mitigation avoids 15% and 62% of PM2.5- and O3-related total avoided deaths, highlighting the importance of foreign GHG mitigation on US human health benefits. GHG mitigation in the US residential sector brings the largest co-benefits for PM2.5-related deaths (21% of total domestic co-benefits), and industry for O3 (17%). Monetized benefits, for avoided deaths from ozone, PM2.5, and heat stress from a related study, are $148 ($96-201) per ton CO2 at high valuation and $49 ($32-67) at low valuation, of which 36% are from foreign GHG reductions. These benefits likely exceed the marginal cost of GHG reductions in 2050. The US gains significantly greatermore » co-benefits when coordinating GHG reductions with foreign countries. Similarly, previous studies estimating co-benefits locally or regionally may greatly underestimate the full co-benefits of coordinated global actions.« les

Risk-conscious correction of batch effects: maximising information extraction from high-throughput genomic datasets

Contains additional information and discussion on gPCA (Reese et al., 2013). Table S1. Demonstrates the inverse proportionality between gPCA p-value and the associated ‘delta’ score, reflecting unadjusted relative magnitude of batch effects (Reese et al., 2013). The table shows the scores for all three datasets. Figure S1. Contains an Illustration to further help interpret gPCA p-value vs preserved data variance plots. (DOCX 60 kb

Gambling problems, traumatic life events and the perpetration of violence

There have been suggestions that violence and victimisation are associated with gambling problems. However, despite the global expansion of the gambling industry, there have been very few studies investigating this phenomenon in the general population. The aim of this study was to examine the relationship between gambling problems and violence (as a victim and perpetrator), including IPV (Intimate partner violence) and traumatic life events in a nationally representative sample of men. Regression analysis revealed that problem/pathological gambling was associated with increased odds of the perpetration of violence, using a weapon, hitting a child and being injured in a violent incident. Moreover, pathological gambling was associated with increased odds of the perpetration of IPV and fighting whilst intoxicated. A comorbid alcohol dependence diagnosis further increased the likelihood of IPV perpetration. The findings also indicated that there was a significant relationship between problem gambling and victimisation including direct and indirect IPV, and other childhood and adulthood traumatic episodes (e.g. assault, injury, homelessness and relationship breakdown). The links between violence and gambling are not fully established, but it is possible that the strain and tension associated with problem gambling (exacerbated by a traumatic history and alcohol use in some cases) can lead to antagonism that is directed towards others, particularly those in immediate surroundings including spouses, partners and children. The current findings highlight the need for problem gambling treatment services to undertake routine screening for alcohol, violence, IPV and traumatic life events and to tailor treatment for clients who present with such issues

Co-benefits of global and regional greenhouse gas mitigation for US air quality in 2050

Policies to mitigate greenhouse gas (GHG) emissions will not only slow climate change but can also have ancillary benefits of improved air quality. Here we examine the co-benefits of both global and regional GHG mitigation for US air quality in 2050 at fine resolution, using dynamical downscaling methods, building on a previous global co-benefits study (West et al., 2013). The co-benefits for US air quality are quantified via two mechanisms: through reductions in co-emitted air pollutants from the same sources and by slowing climate change and its influence on air quality, following West et al. (2013). Additionally, we separate the total co-benefits into contributions from domestic GHG mitigation vs. mitigation in foreign countries. We use the Weather Research and Forecasting (WRF) model to dynamically downscale future global climate to the regional scale and the Sparse Matrix Operator Kernel Emissions (SMOKE) program to directly process global anthropogenic emissions to the regional domain, and we provide dynamical boundary conditions from global simulations to the regional Community Multi-scale Air Quality (CMAQ) model. The total co-benefits of global GHG mitigation from the RCP4.5 scenario compared with its reference are estimated to be higher in the eastern US (ranging from 0.6 to 1.0 µg m−3) than the west (0–0.4 µg m−3) for fine particulate matter (PM2.5), with an average of 0.47 µg m−3 over the US; for O3, the total co-benefits are more uniform at 2–5 ppb, with a US average of 3.55 ppb. Comparing the two mechanisms of co-benefits, we find that reductions in co-emitted air pollutants have a much greater influence on both PM2.5 (96 % of the total co-benefits) and O3 (89 % of the total) than the second co-benefits mechanism via slowing climate change, consistent with West et al. (2013). GHG mitigation from foreign countries contributes more to the US O3 reduction (76 % of the total) than that from domestic GHG mitigation only (24 %), highlighting the importance of global methane reductions and the intercontinental transport of air pollutants. For PM2.5, the benefits of domestic GHG control are greater (74 % of total). Since foreign contributions to co-benefits can be substantial, with foreign O3 benefits much larger than those from domestic reductions, previous studies that focus on local or regional co-benefits may greatly underestimate the total co-benefits of global GHG reductions. We conclude that the US can gain significantly greater domestic air quality co-benefits by engaging with other nations to control GHGs.</html

The role of acid ceramidase in the radiotherapy response of an in vitro model of rectal cancer

Abstract The role of acid ceramidase in the radiotherapy response of an in vitro model of rectal cancer N Govindarajah, P Sutton, D Bowden, JL Parsons, D Vimalachandran. Background: Chemo radiotherapy (CRT) is often employed to treat locally advanced rectal cancer with highly variable response, emphasizing the necessity for predictive response biomarkers. Our initial proteomic and immune-histochemical work demonstrated that acid ceramidase (AC) expression correlated with poorer CRT responses in rectal cancer. We described that higher AC expression correlates with radio resistance in colorectal cancer cells and improved radio sensitivity through siRNA inhibition of AC. The mechanisms behind AC expression, radio resistance and apoptosis remain unknown in colorectal cancer. AC is known to affect apoptosis and the enzyme poly (ADP-ribose) polymerase-1 (PARP-1) is a DNA repair enzyme that is also cleaved into specific fragments during apoptosis. Aims: To elucidate a potential mechanism linking AC expression with radio resistance in colorectal cancer cells. Methods: Differential AC protein expression of four colorectal cell lines was confirmed by Western blotting. Radio sensitivity of these cell lines was examined using standard clonogenic assays by counting individual colony survival post-exposure to increasing doses of ionizing radiation. siRNA knockdown of AC was performed with further clonogenic assays to establish the impact of AC inhibition on radio sensitivity. HT29 and HCT cells were then treated with non-targeting control siRNA and AC siRNA, irradiated at increased doses of radiation then harvested at specific time points (2,6,24h). Western blotting was then performed to detect and measure for specific PARP-1 cleavage fragments as specific apoptotic markers. Results: Clonogenic assays confirmed that cell lines with greater cellular AC protein expression (LIM1215/MDST8) demonstrated higher colony survival compared to those with lower AC expression (HT29/HCT 116) post irradiation. siRNA AC knockdown improved radio sensitivity by reducing colony formation efficiency (CFE) in three cell lines: HT29(0.52 CFE control vs 0.13 CFE knockdown at 1Gyp=0.00004); HCT116(0.24 CFEcontrolvs0.09 CFE knockdown at 1Gyp=0.026); LIM1215 (0.88 CFE control vs 0.43 CFE knockdown at 0.25Gyp=0.001).Western blotting confirmed that HT29,HCT116 and LIM1215cells treated with AC siRNA displayed significantly higher levels of the 24kD PARP-1 cleavage fragments compared to control therefore indicating increased apoptosis. Conclusion: Higher AC expression correlates with radio resistance in several colorectal cell lines and radio sensitivity was successfully improved through biological (siRNA) inhibition of AC. Initial mechanistic work has confirmed that siRNA inhibition of AC causes increased apoptosi

Intimate Partner Violence in Treatment Seeking Problem Gamblers

The co-occurrence of Intimate Partner Violence (IPV) and gambling disorder is an emerging area of research but no studies, as yet, have examined these within a gambling treatment-seeking population from the UK. In a sample of 204 patients, the study utilised routine clinical data and the Jellinek–Inventory for assessing Partner Violence (J-IPV) to determine the prevalence of IPV perpetration and victimisation. 20.1% of participants reported any IPV in the past year; 12.3% reported perpetration and 14.1% reported victimisation in the past year. Clinical scores were greater among patients disclosing IPV; higher anxiety and depression scores coupled with victimisation, alongside greater problem gambling severity; age, anxiety, depression and debt scores among those reporting IPV perpetration. There is need for enhanced vigilance and first-line responses to IPV in problem gambling treatment services. There is also a need for professional support for the clinicians working with these clients

Visible light carrier generation in co-doped epitaxial titanate films

Perovskite titanates such as SrTiO$_{3}$ (STO) exhibit a wide range of important functional properties, including high electron mobility, ferroelectricity, and excellent photocatalytic performance. The wide optical band gap of titanates limits their use in these applications, however, making them ill-suited for integration into solar energy harvesting technologies. Our recent work has shown that by doping STO with equal concentrations of La and Cr we can enhance visible light absorption in epitaxial thin films while avoiding any compensating defects. In this work, we explore the optical properties of photoexcited carriers in these films. Using spectroscopic ellipsometry, we show that the Cr$^{3+}$ dopants, which produce electronic states immediately above the top of the O 2p valence band in STO reduce the direct band gap of the material from 3.75 eV to between 2.4 and 2.7 eV depending on doping levels. Transient reflectance spectroscopy measurements are in agreement with the observations from ellipsometry and confirm that optically generated carriers are present for longer than 2 ns. Finally, through photoelectrochemical methylene blue degradation measurements, we show that these co-doped films exhibit enhanced visible light photocatalysis when compared to pure STO.Comment: 19 pages including supplement, 8 figures (3 main, 5 supplement

Targeting Acid Ceramidase to Improve the Radiosensitivity of Rectal Cancer.

Previous work utilizing proteomic and immunohistochemical analyses has identified that high levels of acid ceramidase (AC) expression confers a poorer response to neoadjuvant treatment in locally advanced rectal cancer. We aimed to assess the radiosensitising effect of biological and pharmacological manipulation of AC and elucidate the underlying mechanism. AC manipulation in three colorectal cancer cell lines (HT29, HCT116 and LIM1215) was achieved using siRNA and plasmid overexpression. Carmofur and a novel small molecular inhibitor (LCL521) were used as pharmacological AC inhibitors. Using clonogenic assays, we demonstrate that an siRNA knockdown of AC enhanced X-ray radiosensitivity across all colorectal cancer cell lines compared to a non-targeting control siRNA, and conversely, AC protein overexpression increased radioresistance. Using CRISPR gene editing, we also generated AC knockout HCT116 cells that were significantly more radiosensitive compared to AC-expressing cells. Similarly, two patient-derived organoid models containing relatively low AC expression were found to be comparatively more radiosensitive than three other models containing higher levels of AC. Additionally, AC inhibition using carmofur and LCL521 in three colorectal cancer cell lines increased cellular radiosensitivity. Decreased AC protein led to significant poly-ADP ribose polymerase-1 (PARP-1) cleavage and apoptosis post-irradiation, which was shown to be executed through a p53-dependent process. Our study demonstrates that expression of AC within colorectal cancer cell lines modulates the cellular response to radiation, and particularly that AC inhibition leads to significantly enhanced radiosensitivity through an elevation in apoptosis. This work further solidifies AC as a target for improving radiotherapy treatment of locally advanced rectal cancer

Gambling and negative life events in a nationally representative sample of UK men

Abstract Introduction: The links between gambling problems, trauma and life stressors are known to exist but understanding the extent of these relationships will allow for greater efficacy in early intervention and treatment. We investigated these relationships among men and sought to determine whether links were attenuated by alcohol and drug use problems. Methods: A cross-sectional UK representative general population survey was conducted in 2009 with 3025 men aged 18-64 years. Measurements included self-reported gambling behaviours, as measured by the South Oaks Gambling Scale (SOGS) and traumatic or stressful life events. Covariates included alcohol and drug dependence and socio-demographics. Binary logistic regression models were used to examine associations. Results: Problem gambling (SOGS 3-4) and probable pathological gambling (SOGS 5+) were associated with increased odds of trauma in childhood (e.g. violence in the home (Adjusted Odd Ratios (AOR) 3.0 (CI =1.8-5.0) and 2.6 (CI =1.7-4.1) respectively), and life stressors in adulthood (e.g. intimate partner violence (AORs 4.5 (CI =2.0-10.3) and 4.7 (CI =2.3-9.7) and homelessness (AORs 2.2 (CI 1.1-4.6) and 3.2 (CI =1.9-5.5)). Results were attenuated when adjusted for probable alcohol and drug dependence with the latter having largest effects. Conclusions: Among men in the United Kingdom, disordered gambling remains uniquely associated with trauma and life stressors in childhood and adulthood after adjusting for alcohol and drug dependence. The results support a need for disordered gambling treatment services to undertake routine screening for alcohol, drugs, IPV and traumatic life events and to tailor treatment that specifically targets the effects of stress for clients who present with such a cluster of issues

Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen

Hantaviruses are a group of emerging pathogens capable of causing severe disease upon zoonotic transmission to humans. The mature hantavirus surface presents higher-order tetrameric assemblies of two glycoproteins, Gn and Gc, which are responsible for negotiating host cell entry and constitute key therapeutic targets. Here, we demonstrate that recombinantly derived Gn from Hantaan virus (HTNV) elicits a neutralizing antibody response (serum dilution that inhibits 50% infection [ID50], 1:200 to 1:850) in an animal model. Using antigen-specific B cell sorting, we isolated monoclonal antibodies (mAbs) exhibiting neutralizing and non-neutralizing activity, termed mAb HTN-Gn1 and mAb nn-ITN-Gn2, respectively. Crystallographic analysis reveals that these mAbs target spatially distinct epitopes at disparate sites of the N-terminal region of the HTNV Gn ectodomain. Epitope mapping onto a model of the higher order (Gn-Gc)(4) spike supports the immune accessibility of the mAb HTN-Gn1 epitope, a hypothesis confirmed by electron cryo-tomography of the antibody with virus-like particles. These data define natively exposed regions of the hantaviral Gn that can be targeted in immunogen design. IMPORTANCE The spillover of pathogenic hantaviruses from rodent reservoirs into the human population poses a continued threat to human health. Here, we show that a recombinant form of the Hantaan virus (HTNV) surface-displayed glycoprotein, Gn, elicits a neutralizing antibody response in rabbits. We isolated a neutralizing (HTN-Gn1) and a non-neutralizing (nn-ITN-Gn2) monoclonal antibody and provide the first molecular-level insights into how the Gn glycoprotein may be targeted by the antibody-mediated immune response. These findings may guide rational vaccine design approaches focused on targeting the hantavirus glycoprotein envelope.Peer reviewe