Showing papers by "Paul Sabatier University published in 2015"

Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota

Abstract: Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis–specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.

Tropospheric ozone and its precursors from the urban to the global scale from air quality to short-lived climate forcer

Abstract: Ozone holds a certain fascination in atmospheric science. It is ubiquitous in the atmosphere, central to tropospheric oxidation chemistry, yet harmful to human and ecosystem health as well as being an important greenhouse gas. It is not emitted into the atmosphere but is a by-product of the very oxidation chemistry it largely initiates. Much effort is focussed on the reduction of surface levels of ozone owing to its health impacts but recent efforts to achieve reductions in exposure at a country scale have proved difficult to achieve due to increases in background ozone at the zonal hemispheric scale. There is also a growing realisation that the role of ozone as a short-lived climate pollutant could be important in integrated air quality climate-change mitigation. This review examines current understanding of the processes regulating tropospheric ozone at global to local scales from both measurements and models. It takes the view that knowledge across the scales is important for dealing with air quality and climate change in a synergistic manner.

The steady-state visual evoked potential in vision research: A review.

Abstract: Periodic visual stimulation and analysis of the resulting steady-state visual evoked potentials were first introduced over 80 years ago as a means to study visual sensation and perception. From the first single-channel recording of responses to modulated light to the present use of sophisticated digital displays composed of complex visual stimuli and high-density recording arrays, steady-state methods have been applied in a broad range of scientific and applied settings.The purpose of this article is to describe the fundamental stimulation paradigms for steady-state visual evoked potentials and to illustrate these principles through research findings across a range of applications in vision science.

Long-term decline of the Amazon carbon sink

Abstract: Atmospheric carbon dioxide records indicate that the land surface has acted as a strong global carbon sink over recent decades, with a substantial fraction of this sink probably located in the tropics, particularly in the Amazon. Nevertheless, it is unclear how the terrestrial carbon sink will evolve as climate and atmospheric composition continue to change. Here we analyse the historical evolution of the biomass dynamics of the Amazon rainforest over three decades using a distributed network of 321 plots. While this analysis confirms that Amazon forests have acted as a long-term net biomass sink, we find a long-term decreasing trend of carbon accumulation. Rates of net increase in above-ground biomass declined by one-third during the past decade compared to the 1990s. This is a consequence of growth rate increases levelling off recently, while biomass mortality persistently increased throughout, leading to a shortening of carbon residence times. Potential drivers for the mortality increase include greater climate variability, and feedbacks of faster growth on mortality, resulting in shortened tree longevity. The observed decline of the Amazon sink diverges markedly from the recent increase in terrestrial carbon uptake at the global scale, and is contrary to expectations based on models.

Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis

Abstract: BackgroundEarly clinical studies suggested that the anti–interleukin-17 receptor A monoclonal antibody brodalumab has efficacy in the treatment of psoriasis. MethodsIn two phase 3 studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomly assigned to receive brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with a body weight ≤100 kg and 90 mg for patients >100 kg), or placebo. At week 12, patients receiving brodalumab were randomly assigned again to receive a brodalumab maintenance dose of 210 mg every 2 weeks or 140 mg every 2 weeks, every 4 weeks, or every 8 weeks; patients receiving ustekinumab continued to receive ustekinumab every 12 weeks, and patients receiving placebo received 210 mg of brodalumab every 2 weeks. The primary aims were to evaluate the superiority of brodalumab over placebo at week 12 with respect to at least a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physician’s global assessment ...

67P/Churyumov-Gerasimenko, a Jupiter family comet with a high D/H ratio

Abstract: The provenance of water and organic compounds on Earth and other terrestrial planets has been discussed for a long time without reaching a consensus. One of the best means to distinguish between different scenarios is by determining the deuterium-to-hydrogen (D/H) ratios in the reservoirs for comets and Earth’s oceans. Here, we report the direct in situ measurement of the D/H ratio in the Jupiter family comet 67P/Churyumov-Gerasimenko by the ROSINA mass spectrometer aboard the European Space Agency’s Rosetta spacecraft, which is found to be (5.3 ± 0.7) × 10−4—that is, approximately three times the terrestrial value. Previous cometary measurements and our new finding suggest a wide range of D/H ratios in the water within Jupiter family objects and preclude the idea that this reservoir is solely composed of Earth ocean–like water.

European S3‐Guidelines on the systemic treatment of psoriasis vulgaris – Update 2015 – Short version – EDF in cooperation with EADV and IPC

Abstract: European S3-Guidelines on the systemic treatment of psoriasis vulgaris – Update 2015 – Short version – EDF in cooperation with EADV and IPC A. Nast,* P. Gisondi, A.D. Ormerod, P. Saiag, C. Smith, P.I. Spuls, P. Arenberger, H. Bachelez, J. Barker, E. Dauden, E.M. de Jong, E. Feist, A. Jacobs, R. Jobling, L. Kem eny, M. Maccarone, U. Mrowietz, K.A. Papp, C. Paul, K. Reich, S. Rosumeck, T. Talme, H.B. Thio, P. van de Kerkhof, R.N. Werner, N. Yawalkar Division of Evidence Based Medicine, Department of Dermatology, Charit e – Universit€ atsmedizin Berlin, Berlin, Germany Section of Dermatology and Venereology, Department of Medicine, University of Verona, Verona, Italy Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, UK Service de Dermatologie, Hôpital Ambroise Par e Universit e Paris V, Boulogne, France Clinical Lead for Dermatology, St Johns Institute of Dermatology, St Thomas’ Hospital, London, UK Department of Dermatology, Academic Medical Center, Amsterdam, The Netherlands Third Faculty of Medicine, Department of Dermatology, Charles University, Prague, Czech Republic Department of Dermatology, Hôpital Saint-Louis, Paris, France St. Johns Institute of Dermatology, St. Thomas’ Hospital, London, UK Hospital Universitario de la Princesa, Madrid, Spain University Medical Center Nijmegen St Radboud, Nijmegen, The Netherlands Medizinische Klinik mit Schwerpunkt Rheumatologie u. klinische Immonologie, Charit e – Universit€atsmedizin Berlin, Berlin, Germany Cambridge, UK SZTE Borgyogyaszati Klinika, Szeged, Hungary Roma, Italy Department of Dermatology, Psoriasis-Center University Medical Center Schleswig Holstein, Kiel, Germany Waterloo, Canada Department of Dermatology, Paul Sabatier University, Toulouse, France Dermatologikum Hamburg, Hamburg, Germany Section of Dermatology and Venereology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden Department of Dermatology, Erasmus University, Rotterdam, The Netherlands Department of Dermatology, University Hospital Nijmegen, Nijmegen, The Netherlands Department of Dermatology, Inselspital, Universit€ atsklinik f€ ur Dermatologie, Bern, Switzerland *Correspondence: A. Nast. E-mail: alexander.nast@charite.de Received: 22 June 2015; Accepted: 7 July 2015

Two-Dimensional Vanadium Carbide (MXene) as Positive Electrode for Sodium-Ion Capacitors

Abstract: Ion capacitors store energy through intercalation of cations into an electrode at a faster rate than in batteries and within a larger potential window. These devices reach a higher energy density compared to electrochemical double layer capacitor. Li-ion capacitors are already produced commercially, but the development of Na-ion capacitors is hindered by lack of materials that would allow fast intercalation of Na-ions. Here we investigated the electrochemical behavior of 2D vanadium carbide, V2C, from the MXene family. We investigated the mechanism of Na intercalation by XRD and achieved capacitance of ∼100 F/g at 0.2 mV/s. We assembled a full cell with hard carbon as negative electrode, a known anode material for Na ion batteries, and achieved capacity of 50 mAh/g with a maximum cell voltage of 3.5 V.

Islands as model systems in ecology and evolution: prospects fifty years after MacArthur‐Wilson

Abstract: The study of islands as model systems has played an important role in the development of evolutionary and ecological theory. The 50th anniversary of MacArthur and Wilson's (December 1963) article, ‘An equilibrium theory of insular zoogeography’, was a recent milestone for this theme. Since 1963, island systems have provided new insights into the formation of ecological communities. Here, building on such developments, we highlight prospects for research on islands to improve our understanding of the ecology and evolution of communities in general. Throughout, we emphasise how attributes of islands combine to provide unusual research opportunities, the implications of which stretch far beyond islands. Molecular tools and increasing data acquisition now permit re‐assessment of some fundamental issues that interested MacArthur and Wilson. These include the formation of ecological networks, species abundance distributions, and the contribution of evolution to community assembly. We also extend our prospects to other fields of ecology and evolution – understanding ecosystem functioning, speciation and diversification – frequently employing assets of oceanic islands in inferring the geographic area within which evolution has occurred, and potential barriers to gene flow. Although island‐based theory is continually being enriched, incorporating non‐equilibrium dynamics is identified as a major challenge for the future.

Globally significant greenhouse-gas emissions from African inland waters

Abstract: Carbon dioxide emissions to the atmosphere from inland waters—streams, rivers, lakes and reservoirs—are nearly equivalent to ocean and land sinks globally. Inland waters can be an important source of methane and nitrous oxide emissions as well, but emissions are poorly quantified, especially in Africa. Here we report dissolved carbon dioxide, methane and nitrous oxide concentrations from 12 rivers in sub-Saharan Africa, including seasonally resolved sampling at 39 sites, acquired between 2006 and 2014. Fluxes were calculated from published gas transfer velocities, and upscaled to the area of all sub-Saharan African rivers using available spatial data sets. Carbon dioxide-equivalent emissions from river channels alone were about 0.4 Pg carbon per year, equivalent to two-thirds of the overall net carbon land sink previously reported for Africa. Including emissions from wetlands of the Congo river increases the total carbon dioxide-equivalent greenhouse-gas emissions to about 0.9 Pg carbon per year, equivalent to about one quarter of the global ocean and terrestrial combined carbon sink. Riverine carbon dioxide and methane emissions increase with wetland extent and upland biomass. We therefore suggest that future changes in wetland and upland cover could strongly affect greenhouse-gas emissions from African inland waters. Inland waters are important sources of greenhouse gases. Measurements over eight years suggest that African inland waters are a substantial source of greenhouse gases, equivalent to a quarter of the global land and ocean carbon sink.

How many dimensions are needed to accurately assess functional diversity? A pragmatic approach for assessing the quality of functional spaces

Abstract: Aim Functional diversity is a key facet of biodiversity that is increasingly being measured to quantify its changes following disturbance and to understand its effects on ecosystem functioning. Assessing the functional diversity of assemblages based on species traits requires the building of a functional space (dendrogram or multidimensional space) where indices will be computed. However, there is still no consensus on the best method for measuring the quality of functional spaces. Innovation Here we propose a framework for evaluating the quality of a functional space (i.e. the extent to which it is a faithful representation of the initial functional trait values). Using simulated datasets, we analysed the influence of the number and type of functional traits used and of the number of species studied on the identity and quality of the best functional space. We also tested whether the quality of the functional space affects functional diversity patterns in local assemblages, using simulated datasets and a real study case. Main conclusions The quality of functional space strongly varied between situations. Spaces having at least four dimensions had the highest quality, while functional dendrograms and two-dimensional functional spaces always had a low quality. Importantly, we showed that using a poor-quality functional space could led to a biased assessment of functional diversity and false ecological conclusions. Therefore, we advise a pragmatic approach consisting of computing all the possible functional spaces and selecting the most parsimonious one.

In situ NMR and electrochemical quartz crystal microbalance techniques reveal the structure of the electrical double layer in supercapacitors

Abstract: Supercapacitors store charge through the electrosorption of ions on microporous electrodes. Despite major efforts to understand this phenomenon, a molecular-level picture of the electrical double layer in working devices is still lacking as few techniques can selectively observe the ionic species at the electrode/electrolyte interface. Here, we use in situ NMR to directly quantify the populations of anionic and cationic species within a working microporous carbon supercapacitor electrode. Our results show that charge storage mechanisms are different for positively and negatively polarized electrodes for the electrolyte tetraethylphosphonium tetrafluoroborate in acetonitrile; for positive polarization charging proceeds by exchange of the cations for anions, whereas for negative polarization, cation adsorption dominates. In situ electrochemical quartz crystal microbalance measurements support the NMR results and indicate that adsorbed ions are only partially solvated. These results provide new molecular-level insight, with the methodology offering exciting possibilities for the study of pore/ion size, desolvation and other effects on charge storage in supercapacitors.

Ammoniated phyllosilicates with a likely outer Solar System origin on (1) Ceres

Abstract: Studies of the dwarf planet (1) Ceres using ground-based and orbiting telescopes have concluded that its closest meteoritic analogues are the volatile-rich CI and CM carbonaceous chondrites. Water in clay minerals, ammoniated phyllosilicates, or a mixture of Mg(OH)2 (brucite), Mg2CO3 and iron-rich serpentine have all been proposed to exist on the surface. In particular, brucite has been suggested from analysis of the mid-infrared spectrum of Ceres. But the lack of spectral data across telluric absorption bands in the wavelength region 2.5 to 2.9 micrometres--where the OH stretching vibration and the H2O bending overtone are found--has precluded definitive identifications. In addition, water vapour around Ceres has recently been reported, possibly originating from localized sources. Here we report spectra of Ceres from 0.4 to 5 micrometres acquired at distances from ~82,000 to 4,300 kilometres from the surface. Our measurements indicate widespread ammoniated phyllosilicates across the surface, but no detectable water ice. Ammonia, accreted either as organic matter or as ice, may have reacted with phyllosilicates on Ceres during differentiation. This suggests that material from the outer Solar System was incorporated into Ceres, either during its formation at great heliocentric distance or by incorporation of material transported into the main asteroid belt.

Algal ancestor of land plants was preadapted for symbiosis

Abstract: Colonization of land by plants was a major transition on Earth, but the developmental and genetic innovations required for this transition remain unknown. Physiological studies and the fossil record strongly suggest that the ability of the first land plants to form symbiotic associations with beneficial fungi was one of these critical innovations. In angiosperms, genes required for the perception and transduction of diffusible fungal signals for root colonization and for nutrient exchange have been characterized. However, the origin of these genes and their potential correlation with land colonization remain elusive. A comprehensive phylogenetic analysis of 259 transcriptomes and 10 green algal and basal land plant genomes, coupled with the characterization of the evolutionary path leading to the appearance of a key regulator, a calcium- and calmodulin-dependent protein kinase, showed that the symbiotic signaling pathway predated the first land plants. In contrast, downstream genes required for root colonization and their specific expression pattern probably appeared subsequent to the colonization of land. We conclude that the most recent common ancestor of extant land plants and green algae was preadapted for symbiotic associations. Subsequent improvement of this precursor stage in early land plants through rounds of gene duplication led to the acquisition of additional pathways and the ability to form a fully functional arbuscular mycorrhizal symbiosis.

Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: a randomized, controlled trial (JUNCTURE)

Abstract: Background Secukinumab is a fully human anti–interleukin-17A monoclonal antibody. Objective Determine the efficacy, safety and usability of secukinumab administered via autoinjector/pen. Methods This phase III trial randomized subjects with moderate to severe plaque psoriasis to secukinumab 300 mg, 150 mg or placebo self-injection once weekly to Week 4, then every 4 weeks. Co-primary end points at Week 12 were ≥75% improvement in Psoriasis Area and Severity Index (PASI 75) and clear/almost clear skin by investigator's global assessment 2011 modified version (IGA mod 2011 0/1). Secondary end points included autoinjector usability, assessed by successful, hazard-free self-injection and subject-reported acceptability on Self-Injection Assessment Questionnaire. Results Week 12 PASI 75 and IGA mod 2011 0/1 responses were superior with secukinumab 300 mg (86.7% and 73.3%, respectively) and 150 mg (71.7% and 53.3%, respectively) vs. placebo (3.3% and 0%, respectively) (P < 0.0001 for all). All subjects successfully self-administered treatment at Week 1, without critical use-related hazards. Subject acceptability of autoinjector was high throughout 12 weeks. Adverse events were higher with secukinumab (300 mg, 70.0%; 150 mg, 63.9%) vs. placebo (54.1%), with differences largely driven by mild/moderate nasopharyngitis. Conclusion Secukinumab delivered by autoinjector/pen is efficacious, well-tolerated and associated with high usability in moderate to severe plaque psoriasis.

Reactivity of Gold Complexes towards Elementary Organometallic Reactions

Abstract: For a while, the reactivity of gold complexes was largely dominated by their Lewis acid behavior. In contrast to the other transition metals, the elementary steps of organometallic chemistry—oxidative addition, reductive elimination, transmetallation, migratory insertion—have scarcely been studied in the case of gold or even remained unprecedented until recently. However, within the last few years, the ability of gold complexes to undergo these fundamental reactions has been unambiguously demonstrated, and the reactivity of gold complexes was shown to extend well beyond π-activation. In this Review, the main achievements described in this area are presented in a historical context. Particular emphasis is set on mechanistic studies and structure determination of key intermediates. The electronic and structural parameters delineating the reactivity of gold complexes are discussed, as well as the remaining challenges.

Hyperdominance in Amazonian forest carbon cycling

Abstract: While Amazonian forests are extraordinarily diverse, the abundance of trees is skewed strongly towards relatively few 'hyperdominant' species. In addition to their diversity, Amazonian trees are a key component of the global carbon cycle, assimilating and storing more carbon than any other ecosystem on Earth. Here we ask, using a unique data set of 530 forest plots, if the functions of storing and producing woody carbon are concentrated in a small number of tree species, whether the most abundant species also dominate carbon cycling, and whether dominant species are characterized by specific functional traits. We find that dominance of forest function is even more concentrated in a few species than is dominance of tree abundance, with only ≈1% of Amazon tree species responsible for 50% of carbon storage and productivity. Although those species that contribute most to biomass and productivity are often abundant, species maximum size is also influential, while the identity and ranking of dominant species varies by function and by region.

Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial.

Abstract: Summary Background The Hedgehog pathway inhibitor vismodegib has shown clinical benefit in patients with advanced basal cell carcinoma and is approved for treatment of patients with advanced basal cell carcinoma for whom surgery is inappropriate. STEVIE was designed to assess the safety of vismodegib in a situation similar to routine practice, with a long follow-up. Methods In this multicentre, open-label trial, adult patients with histologically confirmed locally advanced basal cell carcinoma or metastatic basal cell carcinoma were recruited from regional referral centres or specialist clinics. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and adequate organ function. Patients with locally advanced basal cell carcinoma had to have been deemed ineligible for surgery. All patients received 150 mg oral vismodegib capsules once a day on a continuous basis in 28-day cycles. The primary objective was safety (incidence of adverse events until disease progression or unacceptable toxic effects), with assessments on day 1 of each treatment cycle (28 days) by principal investigator and coinvestigators at the site. Efficacy variables were assessed as secondary endpoints. The safety evaluable population included all patients who received at least one dose of study drug. Patients with histologically confirmed basal cell carcinoma who received at least one dose of study drug were included in the efficacy analysis. An interim analysis was pre-planned after 500 patients achieved 1 year of follow-up. This trial is registered with ClinicalTrials.gov, number NCT01367665. The study is still ongoing. Findings Between June 30, 2011, and Nov 6, 2014, we enrolled 1227 patients. At clinical cutoff (Nov 6, 2013), 499 patients (468 with locally advanced basal cell carcinoma and 31 with metastatic basal cell carcinoma) had received study drug and had the potential to be followed up for 12 months or longer. Treatment was discontinued in 400 (80%) patients; 180 (36%) had adverse events, 70 (14%) had progressive disease, and 51 (10%) requested to stop treatment. Median duration of vismodegib exposure was 36·4 weeks (IQR 17·7–62·0). Adverse events happened in 491 (98%) patients; the most common were muscle spasms (317 [64%]), alopecia (307 [62%]), dysgeusia (269 [54%]), weight loss (162 [33%]), asthenia (141 [28%]), decreased appetite (126 [25%]), ageusia (112 [22%]), diarrhoea (83 [17%]), nausea (80 [16%]), and fatigue (80 [16%]). Most adverse events were grade 1 or 2. We recorded serious adverse events in 108 (22%) of 499 patients. Of the 31 patients who died, 21 were the result of adverse events. As assessed by investigators, 302 (66·7%, 62·1–71·0) of 453 patients with locally advanced basal cell carcinoma had an overall response (153 complete responses and 149 partial responses); 11 (37·9%; 20·7–57·7) of 29 patients with metastatic basal cell carcinoma had an overall response (two complete responses, nine partial responses). Interpretation This study assessed the use of vismodegib in a setting representative of routine clinical practice for patients with advanced basal cell carcinoma. Our results show that treatment with vismodegib adds a novel therapeutic modality from which patients with advanced basal cell carcinoma can benefit substantially. Funding F Hoffmann-La Roche.

Prevalence of undiagnosed psoriatic arthritis among psoriasis patients: Systematic review and meta-analysis

Abstract: Background Skin psoriasis precedes the onset of psoriatic arthritis (PsA) in 84% of patients with psoriasis. Dermatologists have an important role to screen psoriasis patients for PsA. The efficiency of PsA screening remains unknown. Objective We sought to determine the point prevalence of undiagnosed PsA in patients with psoriasis using a systematic search of the literature and meta-analysis. Methods PubMed, Cochrane, and Embase database searches yielded 394 studies for review. No study aimed to determine the prevalence of undiagnosed PsA in patients with psoriasis. We assumed that the prevalence of newly diagnosed PsA in patients with psoriasis at the time they seek medical care could be a sound estimate of this value. Seven epidemiological studies and 5 studies on PsA screening questionnaires allowed us to clearly identify patients with newly diagnosed PsA and were selected for review. Results The prevalence of undiagnosed PsA was 15.5% when all studies were considered and 10.1% when only epidemiological studies were considered. Limitations Data were obtained from studies not designed to address the question at hand. Heterogeneity was high (I2 = 96.86%), and therefore a random effects model was used. Conclusion The high prevalence of undiagnosed PsA in patients with psoriasis adds to the recommendation that dermatologists need to screen all patients with psoriasis for PsA.

Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination

Abstract: How chromatin shapes pathways that promote genome–epigenome integrity in response to DNA damage is an issue of crucial importance. We report that human bromodomain (BRD)-containing proteins, the primary “readers” of acetylated chromatin, are vital for the DNA damage response (DDR). We discovered that more than one-third of all human BRD proteins change localization in response to DNA damage. We identified ZMYND8 (zinc finger and MYND [myeloid, Nervy, and DEAF-1] domain containing 8) as a novel DDR factor that recruits the nucleosome remodeling and histone deacetylation (NuRD) complex to damaged chromatin. Our data define a transcription-associated DDR pathway mediated by ZMYND8 and the NuRD complex that targets DNA damage, including when it occurs within transcriptionally active chromatin, to repress transcription and promote repair by homologous recombination. Thus, our data identify human BRD proteins as key chromatin modulators of the DDR and provide novel insights into how DNA damage within actively transcribed regions requires chromatin-binding proteins to orchestrate the appropriate response in concordance with the damage-associated chromatin context.

Diagnosis of Parkinson's disease on the basis of clinical and genetic classification: a population-based modelling study

Abstract: Summary Background Accurate diagnosis and early detection of complex diseases, such as Parkinson's disease, has the potential to be of great benefit for researchers and clinical practice. We aimed to create a non-invasive, accurate classification model for the diagnosis of Parkinson's disease, which could serve as a basis for future disease prediction studies in longitudinal cohorts. Methods We developed a model for disease classification using data from the Parkinson's Progression Marker Initiative (PPMI) study for 367 patients with Parkinson's disease and phenotypically typical imaging data and 165 controls without neurological disease. Olfactory function, genetic risk, family history of Parkinson's disease, age, and gender were algorithmically selected by stepwise logistic regression as significant contributors to our classifying model. We then tested the model with data from 825 patients with Parkinson's disease and 261 controls from five independent cohorts with varying recruitment strategies and designs: the Parkinson's Disease Biomarkers Program (PDBP), the Parkinson's Associated Risk Study (PARS), 23andMe, the Longitudinal and Biomarker Study in PD (LABS-PD), and the Morris K Udall Parkinson's Disease Research Center of Excellence cohort (Penn-Udall). Additionally, we used our model to investigate patients who had imaging scans without evidence of dopaminergic deficit (SWEDD). Findings In the population from PPMI, our initial model correctly distinguished patients with Parkinson's disease from controls at an area under the curve (AUC) of 0·923 (95% CI 0·900–0·946) with high sensitivity (0·834, 95% CI 0·711–0·883) and specificity (0·903, 95% CI 0·824–0·946) at its optimum AUC threshold (0·655). All Hosmer-Lemeshow simulations suggested that when parsed into random subgroups, the subgroup data matched that of the overall cohort. External validation showed good classification of Parkinson's disease, with AUCs of 0·894 (95% CI 0·867–0·921) in the PDBP cohort, 0·998 (0·992–1·000) in PARS, 0·955 (no 95% CI available) in 23andMe, 0·929 (0·896–0·962) in LABS-PD, and 0·939 (0·891–0·986) in the Penn-Udall cohort. Four of 17 SWEDD participants who our model classified as having Parkinson's disease converted to Parkinson's disease within 1 year, whereas only one of 38 SWEDD participants who were not classified as having Parkinson's disease underwent conversion (test of proportions, p=0·003). Interpretation Our model provides a potential new approach to distinguish participants with Parkinson's disease from controls. If the model can also identify individuals with prodromal or preclinical Parkinson's disease in prospective cohorts, it could facilitate identification of biomarkers and interventions. Funding National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J Fox Foundation.

Sex Differences in Plasmacytoid Dendritic Cell Levels of IRF5 Drive Higher IFN-α Production in Women.

Abstract: Increased IFN-α production contributes to the pathogenesis of infectious and autoimmune diseases. Plasmacytoid dendritic cells (pDCs) from females produce more IFN-α upon TLR7 stimulation than pDCs from males, yet the mechanisms underlying this difference remain unclear. In this article, we show that basal levels of IFN regulatory factor (IRF) 5 in pDCs were significantly higher in females compared with males and positively correlated with the percentage of IFN-α-secreting pDCs. Delivery of recombinant IRF5 protein into human primary pDCs increased TLR7-mediated IFN-α secretion. In mice, genetic ablation of the estrogen receptor 1 (Esr1) gene in the hematopoietic compartment or DC lineage reduced Irf5 mRNA expression in pDCs and IFN-α production. IRF5 mRNA levels furthermore correlated with ESR1 mRNA levels in human pDCs, consistent with IRF5 regulation at the transcriptional level by ESR1. Taken together, these data demonstrate a critical mechanism by which sex differences in basal pDC IRF5 expression lead to higher IFN-α production upon TLR7 stimulation in females and provide novel targets for the modulation of immune responses and inflammation.

NMR Study of Ion Dynamics and Charge Storage in Ionic Liquid Supercapacitors

Abstract: Ionic liquids are emerging as promising new electrolytes for supercapacitors While their higher operating voltages allow the storage of more energy than organic electrolytes, they cannot currently compete in terms of power performance More fundamental studies of the mechanism and dynamics of charge storage are required to facilitate the development and application of these materials Here we demonstrate the application of nuclear magnetic resonance spectroscopy to study the structure and dynamics of ionic liquids confined in porous carbon electrodes The measurements reveal that ionic liquids spontaneously wet the carbon micropores in the absence of any applied potential and that on application of a potential supercapacitor charging takes place by adsorption of counterions and desorption of co-ions from the pores We find that adsorption and desorption of anions surprisingly plays a more dominant role than that of the cations Having elucidated the charging mechanism, we go on to study the factors that affect the rate of ionic diffusion in the carbon micropores in an effort to understand supercapacitor charging dynamics We show that the line shape of the resonance arising from adsorbed ions is a sensitive probe of their effective diffusion rate, which is found to depend on the ionic liquid studied, as well as the presence of any solvent additives Taken as whole, our NMR measurements allow us to rationalize the power performances of different electrolytes in supercapacitors

Decreases in adolescent weekly alcohol use in Europe and North America: evidence from 28 countries from 2002 to 2010.

Abstract: Background: This study examined trends in adolescent weekly alcohol use between 2002 and 2010 in 28 European and North American countries. Methods: Analyses were based on data from 11-, 13- and 15-year-old adolescents who participated in the Health Behaviour in School-Aged Children (HBSC) study in 2002, 2006 and 2010. Results: Weekly alcohol use declined in 20 of 28 countries and in all geographic regions, from 12.1 to 6.1% in Anglo-Saxon countries, 11.4 to 7.8% in Western Europe, 9.3 to 4.1% in Northern Europe and 16.3 to 9.9% in Southern Europe. Even in Eastern Europe, where a stable trend was observed between 2002 and 2006, weekly alcohol use declined between 2006 and 2010 from 12.3 to 10.1%. The decline was evident in all gender and age subgroups. Conclusions: These consistent trends may be attributable to increased awareness of the harmful effects of alcohol for adolescent development and the implementation of associated prevention efforts, or changes in social norms and conditions. Although the declining trend was remarkably similar across countries, prevalence rates still differed considerably across countries.

The Characteristics and Limits of Rapid Visual Categorization

Abstract: Visual categorization appears both effortless and virtually instantaneous, the study by Thorpe et al. (1996) was the first to estimate the processing time necessary to perform fast visual categorization of animals in briefly flashed (20ms) natural photographs. They observed a large differential EEG activity between target and distrater correct trials that developed from 150 ms after stimulus onset. A value that was later shown to be even shorter in monkeys! With such strong processing time constraints, it was difficult to escape the conclusion that rapid visual categorization was relying on massively parallel, essentially feed-forward processing of visual information. Since 1996, we have conducted a large number of studies to determine the characteristics and limits of fast visual categorization. The present chapter will review some of the main results obtained. I will argue that rapid object categorizations in natural scenes can be done without focused attention and are most likely based on coarse and unconscious visual representations activated with the first available (magnocellular) visual information. Fast visual processing proved efficient for the categorization of large superordinate object or scene categories, but shows its limits when more detailed basic representations are required. Basic objects (dogs, cars) or scenes (mountain or sea landscapes) representations need additionnal processing time to be activated. A finding that is at odds with the widely accepted idea that such basic representations are at the entry level of the system. Interestingly, focused attention is still not required to perform such, more time consuming, basic categorizations. Finally we will show that object and context processing can interact very early in an ascending wave of visual information processing. We will discuss how such data could result from our experience with a highly structured and predictable surrounding world that shaped neuronal visual selectivity.