The Scenario Model Intercomparison Project (ScenarioMIP) for CMIP6

Model experiment description paperProjections of future climate change play a fundamental role in improving understanding of the climate system as well as characterizing societal risks and response options. The Scenario Model Intercomparison Project (ScenarioMIP) is the primary activity within Phase 6 of the Coupled Model Intercomparison Project (CMIP6) that will provide multi-model climate projections based on alternative scenarios of future emissions and land use changes produced with integrated assessment models. In this paper, we describe ScenarioMIP's objectives, experimental design, and its relation to other activities within CMIP6. The ScenarioMIP design is one component of a larger scenario process that aims to facilitate a wide range of integrated studies across the climate science, integrated assessment modeling, and impacts, adaptation, and vulnerability communities, and will form an important part of the evidence base in the forthcoming Intergovernmental Panel on Climate Change (IPCC) assessments. At the same time, it will provide the basis for investigating a number of targeted science and policy questions that are especially relevant to scenario-based analysis, including the role of specific forcings such as land use and aerosols, the effect of a peak and decline in forcing, the consequences of scenarios that limit warming to below 2 °C, the relative contributions to uncertainty from scenarios, climate models, and internal variability, and long-term climate system outcomes beyond the 21st century. To serve this wide range of scientific communities and address these questions, a design has been identified consisting of eight alternative 21st century scenarios plus one large initial condition ensemble and a set of long-term extensions, divided into two tiers defined by relative priority. Some of these scenarios will also provide a basis for variants planned to be run in other CMIP6-Endorsed MIPs to investigate questions related to specific forcings. Harmonized, spatially explicit emissions and land use scenarios generated with integrated assessment models will be provided to participating climate modeling groups by late 2016, with the climate model simulations run within the 2017-2018 time frame, and output from the climate model projections made available and analyses performed over the 2018-2020 period.CRESCENDO project members (V. Eyring, P. Friedlingstein, E. Kriegler, R. Knutti, J. Lowe, K. Riahi, D. van Vuuren) acknowledge funding received from the Horizon 2020 European Union’s Framework Programme for Research and Innovation under grant agreement no. 641816. C. Tebaldi, G. A. Meehl and B. M. Sanderson acknowledge the support of the Regional and Global Climate Modeling Program (RGCM) of the U.S. Department of Energy’s, Office of Science (BER), Cooperative Agreement DE-FC02-97ER6240

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Markers of serotonergic function in the orbitofrontal cortex and dorsal raphé nucleus predict individual variation in spatial-discrimination serial reversal learning.

Dysfunction of the orbitofrontal cortex (OFC) impairs the ability of individuals to flexibly adapt behavior to changing stimulus-reward (S-R) contingencies. Impaired flexibility also results from interventions that alter serotonin (5-HT) and dopamine (DA) transmission in the OFC and dorsomedial striatum (DMS). However, it is unclear whether similar mechanisms underpin naturally occurring variations in behavioral flexibility. In the present study, we used a spatial-discrimination serial reversal procedure to investigate interindividual variability in behavioral flexibility in rats. We show that flexibility on this task is improved following systemic administration of the 5-HT reuptake inhibitor citalopram and by low doses of the DA reuptake inhibitor GBR12909. Rats in the upper quintile of the distribution of perseverative responses during repeated S-R reversals showed significantly reduced levels of the 5-HT metabolite, 5-hydroxy-indoleacetic acid, in the OFC. Additionally, 5-HT2A receptor binding in the OFC of mid- and high-quintile rats was significantly reduced compared with rats in the low-quintile group. These perturbations were accompanied by an increase in the expression of monoamine oxidase-A (MAO-A) and MAO-B in the lateral OFC and by a decrease in the expression of MAO-A, MAO-B, and tryptophan hydroxylase in the dorsal raphé nucleus of highly perseverative rats. We found no evidence of significant differences in markers of DA and 5-HT function in the DMS or MAO expression in the ventral tegmental area of low- vs high-perseverative rats. These findings indicate that diminished serotonergic tone in the OFC may be an endophenotype that predisposes to behavioral inflexibility and other forms of compulsive behavior.This work was supported by Medical Research Council Grants (G0701500; G0802729), a 503 Wellcome Trust Programme Grant (grant number 089589/Z/09/Z), and by a Core Award 504 from the Medical Research Council and the Wellcome Trust to the Behavioural and Clinical 505 21 Neuroscience Institute (MRC Ref G1000183; WT Ref 093875/Z/10/Z). RLB was supported 506 by a studentship from the Medical Research Council. JA was supported by a Fellowship from 507 the Swedish Research Council (350-2012-230). BJ was supported by Fellowships from the 508 AXA Research Fund and the National Health and Medical Research Council of Australia. 509 Financial support from the Fredrik and Ingrid Thuring Foundation is also acknowledged.This is the accepted manuscript. The final version is available from Nature Publishing at http://www.nature.com/npp/journal/vaop/ncurrent/full/npp2014335a.html

Rapid and objective assessment of neural function in autism spectrum disorder using transient visual evoked potentials

OBJECTIVE: There is a critical need to identify biomarkers and objective outcome measures that can be used to understand underlying neural mechanisms in autism spectrum disorder (ASD). Visual evoked potentials (VEPs) offer a noninvasive technique to evaluate the functional integrity of neural mechanisms, specifically visual pathways, while probing for disease pathophysiology. METHODS: Transient VEPs (tVEPs) were obtained from 96 unmedicated children, including 37 children with ASD, 36 typically developing (TD) children, and 23 unaffected siblings (SIBS). A conventional contrast-reversing checkerboard condition was compared to a novel short-duration condition, which was developed to enable objective data collection from severely affected populations who are often excluded from electroencephalographic (EEG) studies. RESULTS: Children with ASD showed significantly smaller amplitudes compared to TD children at two of the earliest critical VEP components, P60-N75 and N75-P100. SIBS showed intermediate responses relative to ASD and TD groups. There were no group differences in response latency. Frequency band analyses indicated significantly weaker responses for the ASD group in bands encompassing gamma-wave activity. Ninety-two percent of children with ASD were able to complete the short-duration condition compared to 68% for the standard condition. CONCLUSIONS: The current study establishes the utility of a short-duration tVEP test for use in children at varying levels of functioning and describes neural abnormalities in children with idiopathic ASD. Implications for excitatory/inhibitory balance as well as the potential application of VEP for use in clinical trials are discussed

Integrins as therapeutic targets: lessons and opportunities.

The integrins are a large family of cell adhesion molecules that are essential for the regulation of cell growth and function. The identification of key roles for integrins in a diverse range of diseases, including cancer, infection, thrombosis and autoimmune disorders, has revealed their substantial potential as therapeutic targets. However, so far, pharmacological inhibitors for only three integrins have received marketing approval. This article discusses the structure and function of integrins, their roles in disease and the chequered history of the approved integrin antagonists. Recent advances in the understanding of integrin function, ligand interaction and signalling pathways suggest novel strategies for inhibiting integrin function that could help harness their full potential as therapeutic targets

Participatory peer research exploring the experience of learning during Covid-19 for Allied Health and Healthcare Science Students

INTRODUCTION: The teaching and learning experience of allied health and healthcare science students has altered because of the Covid-19 pandemic. Limited research has explored the experience on the future healthcare workforce using participatory research design. The aim of this study was to explore the impact of a global pandemic on the clinical and academic experiences of healthcare student using a co-production approach with student peer researchers. METHODS: A participatory research approach adopting online focus groups facilitated by students trained as peer researchers was adopted. First, second and final year students from occupational therapy, physiotherapy, podiatry, healthcare science, diagnostic radiography and imaging, radiotherapy and oncology, and speech and language therapy were recruited to six focus groups. Data generated through focus groups were analysed thematically using the DEPICT model to support a partnership approach. RESULTS: Twenty-three participants took part in six focus groups. The themes identified were: rapid changes to learning; living alongside Covid-19 and psychological impact. Students preferred blended learning approaches when available, as reduced peer interaction, studying and sleeping in the same space, and technology fatigue decreased motivation. CONCLUSION: Due to rapid changes in learning and the stress, anxiety and isolation created by the pandemic, managing study, personal life and placement resulted in a gap in confidence in clinical skills development for students. Students took their professional identity seriously, engaged in behaviours to reduce transmission of Covid-19 and employed a range of coping strategies to protect wellbeing. A challenge with the move to online delivery was the absence of informal peer learning and students indicated that moving forward they would value a hybrid approach to delivery. Higher Education should capitalise on innovative learning experiences developed during the pandemic however it is important to research the impact this has on student skill acquisition and learning experience

On the dynamics of the adenylate energy system: homeorhesis vs homeostasis.

Biochemical energy is the fundamental element that maintains both the adequate turnover of the biomolecular structures and the functional metabolic viability of unicellular organisms. The levels of ATP, ADP and AMP reflect roughly the energetic status of the cell, and a precise ratio relating them was proposed by Atkinson as the adenylate energy charge (AEC). Under growth-phase conditions, cells maintain the AEC within narrow physiological values, despite extremely large fluctuations in the adenine nucleotides concentration. Intensive experimental studies have shown that these AEC values are preserved in a wide variety of organisms, both eukaryotes and prokaryotes. Here, to understand some of the functional elements involved in the cellular energy status, we present a computational model conformed by some key essential parts of the adenylate energy system. Specifically, we have considered (I) the main synthesis process of ATP from ADP, (II) the main catalyzed phosphotransfer reaction for interconversion of ATP, ADP and AMP, (III) the enzymatic hydrolysis of ATP yielding ADP, and (IV) the enzymatic hydrolysis of ATP providing AMP. This leads to a dynamic metabolic model (with the form of a delayed differential system) in which the enzymatic rate equations and all the physiological kinetic parameters have been explicitly considered and experimentally tested in vitro. Our central hypothesis is that cells are characterized by changing energy dynamics (homeorhesis). The results show that the AEC presents stable transitions between steady states and periodic oscillations and, in agreement with experimental data these oscillations range within the narrow AEC window. Furthermore, the model shows sustained oscillations in the Gibbs free energy and in the total nucleotide pool. The present study provides a step forward towards the understanding of the fundamental principles and quantitative laws governing the adenylate energy system, which is a fundamental element for unveiling the dynamics of cellular life

Fine-scale spatial variability of heat-related mortality in Philadelphia County, USA, from 1983-2008: a case-series analysis

<p>Abstract</p> <p>Background</p> <p>High temperature and humidity conditions are associated with short-term elevations in the mortality rate in many United States cities. Previous research has quantified this relationship in an aggregate manner over large metropolitan areas, but within these areas the response may differ based on local-scale variability in climate, population characteristics, and socio-economic factors.</p> <p>Methods</p> <p>We compared the mortality response for 48 Zip Code Tabulation Areas (ZCTAs) comprising Philadelphia County, PA to determine if certain areas are associated with elevated risk during high heat stress conditions. A randomization test was used to identify mortality exceedances for various apparent temperature thresholds at both the city and local scale. We then sought to identify the environmental, demographic, and social factors associated with high-risk areas via principal components regression.</p> <p>Results</p> <p>Citywide mortality increases by 9.3% on days following those with apparent temperatures over 34°C observed at 7:00 p.m. local time. During these conditions, elevated mortality rates were found for 10 of the 48 ZCTAs concentrated in the west-central portion of the County. Factors related to high heat mortality risk included proximity to locally high surface temperatures, low socioeconomic status, high density residential zoning, and age.</p> <p>Conclusions</p> <p>Within the larger Philadelphia metropolitan area, there exists statistically significant fine-scale spatial variability in the mortality response to high apparent temperatures. Future heat warning systems and mitigation and intervention measures could target these high risk areas to reduce the burden of extreme weather on summertime morbidity and mortality.</p

Up-regulation of Toll-like receptors 2, 3 and 4 in allergic rhinitis

BACKGROUND: Toll-like receptors enable the host to recognize a large number of pathogen-associated molecular patterns such as bacterial lipopolysaccharide, viral RNA, CpG-containing DNA and flagellin. Toll-like receptors have also been shown to play a pivotal role in both innate and adaptive immune responses. The role of Toll-like receptors as a primary part of our microbe defense system has been shown in several studies, but their possible function as mediators in allergy and asthma remains to be established. The present study was designed to examine the expression of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with intermittent allergic rhinitis, focusing on changes induced by exposure to pollen. METHODS: 27 healthy controls and 42 patients with seasonal allergic rhinitis volunteered for the study. Nasal biopsies were obtained before and during pollen season as well as before and after allergen challenge. The seasonal material was used for mRNA quantification of Toll-like receptors 2, 3 and 4 with real-time polymerase chain reaction, whereas specimens achieved in conjunction with allergen challenge were used for immunohistochemical localization and quantification of corresponding proteins. RESULTS: mRNA and protein representing Toll-like receptors 2, 3 and 4 could be demonstrated in all specimens. An increase in protein expression for all three receptors could be seen following allergen challenge, whereas a significant increase of mRNA only could be obtained for Toll-like receptor 3 during pollen season. CONCLUSION: The up-regulation of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with symptomatic allergic rhinitis supports the idea of a role for Toll-like receptors in allergic airway inflammation