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Abstract Debris-flow activity in the Alps is anticipated to undergo pronounced changes in response to a warming climate. Yet, a fundamental challenge in comprehensively assessing changes in process activity is the systematic lack of long-term observational debris-flow records. Here, we reconstruct the longest, continuous time series (1626-2020) of debris flows at Multetta, a supply-limited torrential system in the Eastern Swiss Alps. Relying on growth-ring records of trees that were damaged by debris flows, we do not detect significant changes in the frequency or magnitude over time. This seeming absence of a direct climatic influence on debris-flow initiation aligns with the regular distribution of repose time patterns, indicating a dependence of local process activity on sediment discharge and recharge. This stark difference in process behavior between our supply-limited site and transport-limited catchments has implications for assessing torrential hazard and risk mitigation in a context of global warming.

Abstract This pilot study focusing on Sickle Cell Anemia (SCA) patients offers a comprehensive and integrative evaluation of respiratory, cardiovascular, hemodynamic, and metabolic variables during exercise. Knowing that diastolic dysfunction is frequent in this population, we hypothesize that a lack of cardiac adaptation through exercise might lead to premature increase in blood lactate concentrations in SCA patients, a potential trigger for acute disease complication. SCA patients were prospectively included in PHYSIO-EXDRE study and underwent a comprehensive stress test with a standardized incremental exercise protocol up to 4 mmol L−1 blood lactate concentration (BL4). Gas exchange, capillary lactate concentration and echocardiography were performed at baseline, during stress test (at ∼ 2 mmol L−1) and BL4. The population was divided into two groups and compared according to the median value of percentage of theoretical peak oxygen uptake (% $${\dot{\text{V}}\text{O}}_{2peakth}$$ V ˙ O 2 p e a k t h ) at BL4. Twenty-nine patients were included (42 ± 12 years old, 48% of women). Most patients reached BL4 at low-intensity exercise [median value of predicted power output (W) was 37%], which corresponds to daily life activities. The median value of % $${\dot{\text{V}}\text{O}}_{2peakth}$$ V ˙ O 2 p e a k t h at BL4 was 39%. Interestingly, diastolic maladaptation using echocardiography during stress test along with hemoglobin concentration were independently associated to early occurrence of BL4. As BL4 occurs for low-intensity exercises, SCA patients may be subject to acidosis-related complications even during their daily life activities. Beyond assessing physical capacities, our study underlines that diastolic maladaptation during exercise is associated with an early increase in blood lactate concentration.

Abstract The structures, strain fields, and defect distributions in solid materials underlie the mechanical and physical properties across numerous applications. Many modern microstructural microscopy tools characterize crystal grains, domains and defects required to map lattice distortions or deformation, but are limited to studies of the (near) surface. Generally speaking, such tools cannot probe the structural dynamics in a way that is representative of bulk behavior. Synchrotron X-ray diffraction based imaging has long mapped the deeply embedded structural elements, and with enhanced resolution, dark field X-ray microscopy (DFXM) can now map those features with the requisite nm-resolution. However, these techniques still suffer from the required integration times due to limitations from the source and optics. This work extends DFXM to X-ray free electron lasers, showing how the $$10^{12}$$ 10 12 photons per pulse available at these sources offer structural characterization down to 100 fs resolution (orders of magnitude faster than current synchrotron images). We introduce the XFEL DFXM setup with simultaneous bright field microscopy to probe density changes within the same volume. This work presents a comprehensive guide to the multi-modal ultrafast high-resolution X-ray microscope that we constructed and tested at two XFELs, and shows initial data demonstrating two timing strategies to study associated reversible or irreversible lattice dynamics.

Abstract Xenopus egg extract is a powerful material to modify cultured cells fate and to induce cellular reprogramming in mammals. In this study, the response of goldfish fin cells to in vitro exposure to Xenopus egg extract, and subsequent culture, was studied using a cDNA microarray approach, gene ontology and KEGG pathways analyses, and qPCR validation. We observed that several actors of the TGFβ and Wnt/β-catenin signaling pathways, as well as some mesenchymal markers, were inhibited in treated cells, while several epithelial markers were upregulated. This was associated with morphological changes of the cells in culture, suggesting that egg extract drove cultured fin cells towards a mesenchymal-epithelial transition. This indicates that Xenopus egg extract treatment relieved some barriers of somatic reprogramming in fish cells. However, the lack of re-expression of pou2 and nanog pluripotency markers, the absence of DNA methylation remodeling of their promoter region, and the strong decrease in de novo lipid biosynthesis metabolism, indicate that reprogramming was only partial. The observed changes may render these treated cells more suitable for studies on in vivo reprogramming after somatic cell nuclear transfer.

BackgroundA sedentary lifestyle is commonly associated with a higher risk of chronic disease development. Among school-aged children from European countries, screen-time represents a significant portion of sedentary time with 39.8% of children spending more than 2h/day in front of a screen on average. Therefore, effective solutions to reduce sedentary behavior (SB) must be found. Multilevel interventions based on the socio-ecological model (SEM) are particularly relevant to take into account influences of the social environment on individuals' SB. Moreover, the trans-contextual model (TCM) can offer complementary levers for individuals' behavior change. The CIPRES study is a theory-based multilevel intervention designed to decrease the SB in French primary school children aged 8-10 years. The present paper describes the protocol of a randomized controlled study to evaluate the effectiveness of the CIPRES multilevel intervention on SB.MethodsThe CIPRES study is a cluster-randomized controlled trial comparing intervention vs control groups. A total of 700 children are targeted for inclusion, distributed in four municipalities considered as clusters. The study consists of two successive phases: 1) co-building of a SB prevention intervention by using a participatory approach involving representatives of each level of the SEM (e.g., children, parents, staff from municipalities, teachers) and 2) implementation and evaluation of the intervention. The intervention will last for 6 weeks in each involved class. Primary outcome will be the sedentary time of children per week, assessed by accelerometry. In addition, children and their parents will be asked to fill out questionnaires concerning children's physical activity level, screen time, quality-of-life and variables of the TCM.DiscussionThis study will give information on the effectiveness of a theory-based intervention, involving multiple levels of actors in the co-construction and the implementation of the intervention, that may interest schools and public health officers looking for innovative sedentary prevention programs.

Accurate estimates of glacier surface elevation changes are paramount for various aspects of the study of the cryosphere, from glacier flow and thickness estimates to hydrological forecasts and projections of sea-level-rise. We present a novel probabilistic framework to filter outliers and estimate uncertainties in glacier surface elevation changes computed from the subtraction of digital elevation models (DEM). Our methodology frames outlier filtering as a Bayesian inference problem, thus characterizing the state of knowledge on glacier surface elevation changes through the posterior distribution as the combination of glacier volume variation observations and prior knowledge arising from previously collected data and/or modeled results. We validate this technique with experiments using Gaussian random fields to generate artificial noise in glacier surface elevation variation observations and show that the model satisfactorily culls the simulated outliers. Surface elevation change estimates are consistent with results computed from widely-used outlier filtering and uncertainty estimation techniques. The Bayesian framework allows unifying DEM error models with physical considerations on glacier surface elevation changes within a simple, statistically coherent model preventing temporal correlation and additional biases in other techniques. On the basis of these results, we discuss the implications of DEM uncertainty and offer suggestions for the glaciological community.

Abstract In this study, a training simulator for the examination of dizzy patients based on a virtual-reality-enhanced mannequin (VREM) was developed to evaluate the detection of catch-up saccades during head impulse test (HIT) and the effect of training in VREM. For novices (n = 35), 2 trials were conducted before and after a training session. Experts (n = 7) were submitted to an evaluation session. In each trial, a left or a right horizontal canal deficit with an overt catch-up saccade (delay between 110 and 320 ms) was randomly presented. Participants scored the difficulty in performing the maneuver, in recognizing the saccades, and the self-confidence in the diagnosis using a visual analogue scale (VAS). Saccade delay significantly influenced the performance. Training significantly improved the sensitivity in the residents (69.1% before to 97.9% after the training, p

Many recent studies have explored the response of magnetic systems to circularly polarised light. To achieve this, typically experiments use a birefringent crystal. Here, Yang et al show that any small error in the alignment of the crystal can result in a beam shift, and this shift can lead to spurious signals similar yet unrelated to the electron spin.

A 7,638 yr summer temperature reconstruction based on subfossil trees buried in the Siberian Arctic shows that recent warming is unprecedented and interrupted a multi-millennial cooling trend.

Toxin-antitoxin systems are widespread in bacteria. Here the authors present structures of M. tuberculosis HigBTAC alone and bound to the ribosome in the presence of native cspA mRNA, shedding light on its mechanism of translation inhibition.

While metal organic frameworks offer highly tunable materials for photocatalytic applications, catalytic site accessibility is a crucial parameter. Here, authors demonstrate selective ligand removal to introduce new active sites and mesopores and to enhance photocatalytic H2 evolution.

We present a microscopic magnetic domain imaging study of single-shot all-optical magnetic toggle switching of a ferrimagnetic Gd26Fe74 film with out-of-plane easy axis of magnetization by X-ray magnetic circular dichroism photoelectron emission microscopy. Individual linearly polarized laser pulses of 800 nm wavelength and 100 fs duration above a certain threshold fluence reverse the sample magnetization, independent of the magnetization direction, the so-called toggle switching. Local deviations from this deterministic behavior close to magnetic domain walls are studied in detail. Reasons for nondeterministic toggle switching are related to extrinsic effects, caused by pulse-to-pulse variations of the exciting laser system, and to intrinsic effects related to the magnetic domain structure of the sample. The latter are, on the one hand, caused by magnetic domain wall elasticity, which leads to a reduction of the domain-wall length at features with sharp tips. These features appear after the optical switching at positions where the line of constant threshold fluence in the Gaussian footprint of the laser pulse comes close to an already existing domain wall. On the other hand, we identify the presence of laser-induced domain-wall motion in the toggle-switching event as a further cause for local deviations from purely deterministic toggle switching.

Tree rings are a crucial archive for Common Era climate reconstructions, but the degree to which methodological decisions influence outcomes is not well known. Here, the authors show how different approaches taken by 15 different groups influence the ensemble temperature reconstruction from the same data.

Abstract This paper reports investigations led on the combination of the refractive index and morphological dilation to enhance performances towards breast tumour margin delineation during conserving surgeries. The refractive index map of invasive ductal and lobular carcinomas were constructed from an inverse electromagnetic problem. Morphological dilation combined with refractive index thresholding was conducted to classify the tissue regions as malignant or benign. A histology routine was conducted to evaluate the performances of various dilation geometries associated with different thresholds. It was found that the combination of a wide structuring element and high refractive index was improving the correctness of tissue classification in comparison to other configurations or without dilation. The method reports a sensitivity of around 80% and a specificity of 82% for the best case. These results indicate that combining the fundamental optical properties of tissues denoted by their refractive index with morphological dilation may open routes to define supporting procedures during breast-conserving surgeries.

The detection and quantification of fractures in rocks, as well as the detection of lithological changes, are of particular interest in scientific fields, such as construction materials, geotechnics, reservoirs and the diagnostics of dielectric composite materials and cultural heritage objects. Therefore, different methods and techniques have been developed and improved over the years to provide solutions, e.g., seismic, ground-penetrating radar and X-ray microtomography. However, there are always trade-offs, such as spatial resolution, investigated volume and rock penetration depth. At present, high-frequency radars (>60 GHz) are available on the market, which are compact in size and capable of imaging large areas in short periods of time. However, the few rock applications that have been carried out have not provided any information on whether these radars would be useful for detecting fractures and lithological changes in rocks. Therefore, in this work, we performed different experiments on construction and reservoir rocks using a frequency-modulated continuous wave radar working at 300 GHz to evaluate its viability in this type of application. The results showed that the radar quantified millimeter fractures at a 1 cm rock penetration depth with a sensitivity of 500 μm. Furthermore, lithological changes were identified, even when detecting interfaces generated by the artificial union of two samples from the same rock.

Real-time dynamic Fourier analysis of high-speed signals is difficult using either digital or analog schemes. Here, the authors present a universal analog approach that can track the changing frequency spectrum of waveforms in a real-time fashion at the nanosecond level, continuously and with no gaps.

Atomically thin transition metal dichalcogenides possess a valley degree of freedom, which could enrich the physics underpinning the conventional Nernst effect observed in traditional solids. Here, the authors report experimental evidence of the valley Nernst effect in WSe2 at room temperature.

Summary: Computed tomography is a powerful medical imaging modality for longitudinal studies in cancer to follow neoplasia progression and evaluate anticancer therapies. Here, we report the generation of a photon-counting micro-computed tomography (PC-CT) method based on hybrid pixel detectors with enhanced sensitivity and precision of tumor imaging. We then applied PC-CT for longitudinal imaging in a clinically relevant liver cancer model, the Alb-R26Met mice, and found a remarkable heterogeneity in the dynamics for tumors at the initiation phases. Instead, the growth curve of evolving tumors exhibited a comparable exponential growth, with a constant doubling time. Furthermore, longitudinal PC-CT imaging in mice treated with a combination of MEK and BCL-XL inhibitors revealed a drastic tumor regression accompanied by a striking remodeling of macrophages in the tumor microenvironment. Thus, PC-CT is a powerful system to detect cancer initiation and progression, and to monitor its evolution during treatment. : Optics; Optical Imaging; Cancer Subject Areas: Optics, Optical Imaging, Cancer

Full spectral and temporal control of light has a multitude of applications but is often limited in frequency resolution. The authors implement a scheme using a frequency shifting optical loop for optical field spectral shaping with a high degree of control and megahertz resolution

SecB homologs can be associated with stress-responsive type II toxin–antitoxin (TA) systems and form tripartite toxin-antitoxin-chaperone systems (TAC). Here the authors provide structural insights into TACs by presenting the crystal structure of the M. tuberculosis TA-associated SecB chaperone in complex with the C-terminal ChAD (chaperone addiction) extension of the antitoxin HigA1.

Producing versatile radio-frequency chirped waveforms often requires complicated techniques. The authors use a fiber-optic frequency-shifting loop to create a low-complexity photonic chirp generator with high bandwidth and fully flexible properties for application in radar, spectroscopy, and imaging.

The Cytolethal Distending Toxin (CDT) is produced by many pathogenic bacteria. CDT is known to induce genomic DNA damage to host eukaryotic cells through its catalytic subunit, CdtB. CdtB is structurally homologous to DNase I and has a nuclease activity, dependent on several key residues. Yet some differences between various CdtB subunit activities, and discrepancies between biochemical and cellular data, have been observed. To better characterise the role of CdtB in the induction of DNA damage, we affinity-purified wild-type and mutants of CdtB, issued from E. coli and H. ducreyi, under native and denaturing conditions. We then compared their nuclease activity by a classic in vitro assay using plasmid DNA, and two different eukaryotic assays-the first assay where host cells were transfected with a plasmid encoding CdtB, the second assay where host cells were directly transfected with purified CdtB. We show here that in vitro nuclease activities are difficult to quantify, whereas CdtB activities in host cells can be easily interpreted and confirmed the loss of function of the catalytic mutant. Our results highlight the importance of performing multiple assays while studying the effects of bacterial genotoxins, and indicate that the classic in vitro assay should be complemented with cellular assays.

X-ray free electron lasers are increasingly available for use in macromolecular structure determination. Here, the authors describe the successful use of selenium single-wavelength anomalous diffraction data to calculate experimentally derived phases.

Some bacterial toxin-antitoxin systems consist of a labile antitoxin that inhibits a toxin, and a chaperone that stabilizes the antitoxin. Here, Bordes et al. identify a sequence within the antitoxin to which the chaperone binds and which can be transferred to other proteins to make them chaperone-dependent.

Podosomes are adhesive cytoskeletal structures found in several cell types, but whether or how they are interconnected is not known. Here the authors demonstrate mesoscale connectivity of podosome clusters by imaging directional flow patterns of podosome components vinculin, talin and F-actin.

We derive exact expressions for the finite-time statistics of extrema (maximum and minimum) of the spatial displacement and the fluctuating entropy flow of biased random walks. Our approach captures key features of extreme events in molecular motor motion along linear filaments. For one-dimensional biased random walks, we derive exact results which tighten bounds for entropy production extrema obtained with martingale theory and reveal a symmetry between the distribution of the maxima and minima of entropy production. Furthermore, we show that the relaxation spectrum of the full generating function, and hence of any moment, of the finite-time extrema distributions can be written in terms of the Marčenko–Pastur distribution of random-matrix theory. Using this result, we obtain efficient estimates for the extreme-value statistics of stochastic transport processes from the eigenvalue distributions of suitable Wishart and Laguerre random matrices. We confirm our results with numerical simulations of stochastic models of molecular motors.

Bacterial antibiotic resistance is an emerging public health problem worldwide; therefore, new therapeutic strategies are needed. Many studies have described antipsychotic compounds that present antibacterial activity. Hence, the aims of this study were to evaluate the in vitro antibacterial activity of antipsychotics belonging to different chemical families, to assess the influence of their association with lipid nanocapsules (LNCs) on their antimicrobial activity as well as drug release and to study the uptake of LNCs by bacterial cells. Antibacterial activity was evaluated against Gram-positive Staphylococcus aureus and Gram negative Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii by minimum inhibitory concentration (MIC) assay, and the capability of killing tested microorganisms was evaluated by time kill assay. LNCs were prepared by phase inversion method, and the antipsychotic agents were incorporated using pre-loading and post-loading strategies. Only phenothiazines and thioxanthenes showed antibacterial activity, which was independent of antibiotic-resistance patterns. Loading the nanocarriers with the drugs affected the properties of the former, particularly their zeta potential. The release rate depended on the drug and its concentration-a maximum of released drug of less than 40% over 24 hours was observed for promazine. The influence of the drug associations on the antibacterial properties was concentration-dependent since, at low concentrations (high nanocarrier/drug ratio), the activity was lost, probably due to the high affinity of the drug to nanocarriers and slow release rate, whereas at higher concentrations, the activity was well maintained for the majority of the drugs. Chlorpromazine and thioridazine increased the uptake of the LNCs by bacteria compared with blank LNCs, even below the minimum inhibitory concentration.

BACKGROUND:Environmental factors play a major role on atopic dermatitis (AD) which shows a constant rise in prevalence in western countries over the last decades. The Hygiene Hypothesis suggesting an inverse relationship between incidence of infections and the increase in atopic diseases in these countries, is one of the working hypothesis proposed to explain this trend. OBJECTIVE:This study tested the efficacy and safety of oral administration of the bacterial lysate OM-85 (Broncho-Vaxom®, Broncho-Munal®, Ommunal®, Paxoral®, Vaxoral®), in the treatment of established AD in children. METHODS:Children aged 6 months to 7 years, with confirmed AD diagnosis, were randomized in a double-blind, placebo-controlled trial to receive, in addition to conventional treatment with emollients and topical corticosteroids, 3.5mg of the bacterial extract OM-85 or placebo daily for 9 months. The primary end-point was the difference between groups in the occurrence of new flares (NF) during the study period, evaluated by Hazard Ratio (HR) derived from conditional Cox proportional hazard regression models accounting for repeated events. RESULTS:Among the 179 randomized children, 170 were analysed, 88 in the OM-85 and 82 in the placebo group. As expected most children in both treatment groups experienced at least 1 NF during the study period (75 (85%) patients in the OM-85 group and 72 (88%) in the placebo group). Patients treated with OM-85 as adjuvant therapy had significantly fewer and delayed NFs (HR of repeated flares = 0.80; 95% confidence interval (CI): 0.67-0.96), also when potential confounding factors, as family history of atopy and corticosteroids use, were taken into account (HR = 0.82; 95% CI: 0.69-0.98). No major side effect was reported, with comparable and good tolerability for OM-85 and placebo. CONCLUSIONS:Results show an adjuvant therapeutic effect of a well standardized bacterial lysate OM-85 on established AD.

Acute-serum Amyloid A (A-SAA), one of the major acute-phase proteins, is mainly produced in the liver but extra-hepatic synthesis involving the skin has been reported. Its expression is regulated by the transcription factors NF-κB, C/EBPβ, STAT3 activated by proinflammatory cytokines.We investigated A-SAA synthesis by resting and cytokine-activated Normal Human Epidermal Keratinocytes (NHEK), and their inflammatory response to A-SAA stimulation. A-SAA expression was also studied in mouse skin and liver in a model mimicking psoriasis and in the skin and sera of psoriatic and atopic dermatitis (AD) patients.NHEK were stimulated by A-SAA or the cytokines IL-1α, IL-17A, IL-22, OSM, TNF-α alone or in combination, previously reported to reproduce features of psoriasis. Murine skins were treated by imiquimod cream. Human skins and sera were obtained from patients with psoriasis and AD. A-SAA mRNA was quantified by RT qPCR. A-SAA proteins were dosed by ELISA or immunonephelemetry assay.IL-1α, TNF-α and mainly IL-17A induced A-SAA expression by NHEK. A-SAA induced its own production and the synthesis of hBD2 and CCL20, both ligands for CCR6, a chemokine receptor involved in the trafficking of Th17 lymphocytes. A-SAA expression was increased in skins and livers from imiquimod-treated mice and in patient skins with psoriasis, but not significantly in those with AD. Correlations between A-SAA and psoriasis severity and duration were observed.Keratinocytes could contribute to psoriasis pathogenesis via A-SAA production, maintaining a cutaneous inflammatory environment, activating innate immunity and Th17 lymphocyte recruitment.

The original version of this Article contained errors in Figures 1 and 4. In Fig. 1b, the Mtb-SecBTA sequence was displayed incorrectly. In the inset panel within Fig. 4c, the y-axis of the graph incorrectly read (Q.Rg)2 × I(Q)//(0), and should have read (Q.R g)2 × I(Q)/I(0). These errors have been corrected in both the PDF and HTML versions of the Article.

Because cytidine deaminase (CDA) is the key enzyme in gemcitabine metabolism, numerous studies have attempted to investigate impact of CDA status (i.e. genotype or phenotype) on clinical outcome. To date, data are still controversial because none of these studies has fully investigated genotype-phenotype CDA status, pharmacokinetics and clinical outcome relationships in gemcitabine-treated patients. Besides, most patients were treated with gemcitabine associated with other drugs, thus adding a confounding factor. We performed a multicenter prospective clinical trial in gemcitabine-treated patients which aimed at investigating the link between CDA deficiency on the occurrence of severe toxicities and on pharmacokinetics, and studying CDA genotype-phenotype relationships.One hundred twenty patients with resected pancreatic adenocarcinoma eligible for adjuvant gemcitabine monotherapy were enrolled in this study promoted and managed by the Fédération Francophone de Cancérologie Digestive. Toxicities were graded according to National Cancer Institute's Common Terminology Criteria for Adverse Events Version 4. They were considered severe for grade ≥ 3, and early when occurring during the first eight weeks of treatment. CDA status was evaluated using a double approach: genotyping for 79A>C and functional testing. Therapeutic drug monitoring of gemcitabine and its metabolite were performed on the first course of gemcitabine.Five patients out of 120 (i.e., 4.6%) were found to be CDA deficient (i.e., CDA activity

Opiate dependence affects about 15,479,000 people worldwide. The effectiveness of opiate substitution treatments (OST) has been widely demonstrated. Buprenorphine plays a particular role in opiate dependence care provision in France. It is widely prescribed by physicians and national opiate substitution treatment guidelines have been available since 2004. In order to study the prescribing of buprenorphine, we used a questionnaire sent by email, to a large sample of physicians. These physicians were either in practice, or belonged to an addiction treatment network or a hospital. The main objective of this work was to measure the extent to which the theoretical, clinical attitude of physicians towards prescribing buprenorphine (BHD) complied with the statutory guidelines. We showed that the physicians we interviewed rarely took into account the guidelines regarding buprenorphine prescription. The actual prescribing of Buprenorphine differed from the guidelines. Only 42% of independent Family Physicians (FPs), working outside the national health care system, had prescribed buprenorphine as a first-time prescription and 40% of FPs do not follow up patients on buprenorphine. In terms of compliance with the guidelines, 55% of FPs gave theoretical answers that only partially complied with the guidelines. The variations in compliance with the guidelines was noted according to different variables and took into particular account whether the physician were affiliated to a network or in training.

Effects of elevated atmospheric CO2 concentrations on plant growth and associated C cycling have intensively been studied, but less is known about effects on the fluxes of radiatively active trace gases other than CO2. Net soil-atmosphere CH4 fluxes are determined by the balance of soil microbially-driven methane (CH4) oxidation and methanogenesis, and both might change under elevated CO2.Here, we studied CH4 dynamics in a permanent grassland exposed to elevated CO2 for 14 years. Soil-atmosphere fluxes of CH4 were measured using large static chambers, over a period of four years. The ecosystem was a net sink for atmospheric CH4 for most of the time except summer to fall when net CH4 emissions occurred. We did not detect any elevated CO2 effects on CH4 fluxes, but emissions were difficult to quantify due to their discontinuous nature, most likely because of ebullition from the saturated zone. Potential methanotrophic activity, determined by incubation of fresh sieved soil under standardized conditions, also did not reveal any effect of the CO2 treatment. Finally, we determined the spatial micro-distribution of methanotrophic activity at less than 5× atmospheric (10 ppm) and elevated (10000 ppm) CH4 concentrations, using a novel auto-radiographic technique. These analyses indicated that domains of net CH4 assimilation were distributed throughout the analyzed top 15 cm of soils, with no dependence on CH4 concentration or CO2 treatment.Our investigations suggest that elevated CO2 exerts no or only minor effects on CH4 fluxes in the type of ecosystem we studied, at least as long as soil moisture differences are small or absent as was the case here. The autoradiographic analyses further indicate that the spatial niche of CH4 oxidation does not shift in response to CO2 enrichment or CH4 concentration, and that the same type of methanotrophs may oxidize CH4 from atmospheric and soil-internal sources.

Brain blood barrier breakdown as assessed by contrast-enhanced (CE) T1-weighted MR imaging is currently the standard radiological marker of inflammatory activity in multiple sclerosis (MS) patients. Our objective was to evaluate the performance of an alternative model assessing the inflammatory activity of MS lesions by texture analysis of T2-weighted MR images. Twenty-one patients with definite MS were examined on the same 3.0T MR system by T2-weighted, FLAIR, diffusion-weighted and CE-T1 sequences. Lesions and mirrored contralateral areas within the normal appearing white matter (NAWM) were characterized by texture parameters computed from the gray level co-occurrence and run length matrices, and by the apparent diffusion coefficient (ADC). Statistical differences between MS lesions and NAWM were analyzed. ROC analysis and leave-one-out cross-validation were performed to evaluate the performance of individual parameters, and multi-parametric models using linear discriminant analysis (LDA), partial least squares (PLS) and logistic regression (LR) in the identification of CE lesions. ADC and all but one texture parameter were significantly different within white matter lesions compared to within NAWM (p < 0.0167). Using LDA, an 8-texture parameter model identified CE lesions with a sensitivity Se = 70% and a specificity Sp = 76%. Using LR, a 10-texture parameter model performed better with Se = 86% / Sp = 84%. Using PLS, a 6-texture parameter model achieved the highest accuracy with Se = 88% / Sp = 81%. Texture parameter from T2-weighted images can assess brain inflammatory activity with sufficient accuracy to be considered as a potential alternative to enhancement on CE T1-weighted images.

Keratinocyte differentiation program leading to an organized epidermis plays a key role in maintaining the first line of defense of the skin. Epidermal integrity is regulated by a tight communication between keratinocytes and leucocytes, particularly under cytokine control. Imbalance of the cytokine network leads to inflammatory diseases such as psoriasis. Our attempt to model skin inflammation showed that the combination of IL-17A, IL-22, IL-1α, OSM and TNFα (Mix M5) synergistically increases chemokine and antimicrobial-peptide expression, recapitulating some features of psoriasis. Other characteristics of psoriasis are acanthosis and down-regulation of keratinocyte differentiation markers. Our aim was to characterize the specific roles of these cytokines on keratinocyte differentiation, and to compare with psoriatic lesion features. All cytokines decrease keratinocyte differentiation markers, but IL-22 and OSM were the most powerful, and the M5 strongly synergized the effects. In addition, IL-22 and OSM induced epidermal hyperplasia in vitro and M5 induced epidermal thickening and decreased differentiation marker expression in a mouse model, as observed in human psoriatic skin lesions. This study highlights the precise role of cytokines in the skin inflammatory response. IL-22 and OSM more specifically drive epidermal hyperplasia and differentiation loss while IL-1α, IL-17A and TNFα were more involved in the activation of innate immunity.

INTRODUCTION:In resource limited settings, patients entering an antiretroviral therapy (ART) program comprise ART naive and ART pre-treated patients who may show differential virological outcomes. METHODS:This retrospective study, conducted in 2010-2012 in the HIV clinic of Calmette Hospital located in Phnom Penh (Cambodia) assessed virological failure (VF) rates and patterns of drug resistance of naive and pre-treated patients. Naive and ART pre-treated patients were included when a Viral Load (VL) was performed during the first year of ART for naive subjects or at the first consultation for pre-treated individuals. Patients showing Virological failure (VF) (>1,000 copies/ml) underwent HIV DR genotyping testing. Interpretation of drug resistance mutations was done according to 2013 version 23 ANRS algorithms. RESULTS:On a total of 209 patients, 164 (78.4%) were naive and 45 (21.5%) were ART pre-treated. Their median initial CD4 counts were 74 cells/mm3 (IQR: 30-194) and 279 cells/mm3 (IQR: 103-455) (p

Microtubules are the main constituents of mitotic spindles. They are nucleated in large amounts during spindle assembly, from multiprotein complexes containing γ-tubulin and associated γ-tubulin complex proteins (GCPs). With the aim of developing anti-cancer drugs targeting these nucleating complexes, we analyzed the interface between GCP4 and γ-tubulin proteins usually located in a multiprotein complex named γ-TuRC (γ-Tubulin Ring Complex). 10 ns molecular dynamics simulations were performed on the heterodimers to obtain a stable complex in silico and to analyze the residues involved in persistent protein-protein contacts, responsible for the stability of the complex. We demonstrated in silico the existence of a binding pocket at the interface between the two proteins upon complex formation. By combining virtual screening using a fragment-based approach and biophysical screening, we found several small molecules that bind specifically to this pocket. Sub-millimolar fragments have been experimentally characterized on recombinant proteins using differential scanning fluorimetry (DSF) for validation of these compounds as inhibitors. These results open a new avenue for drug development against microtubule-nucleating γ-tubulin complexes.

The purpose of this study was to investigate the effect of whey supplementation, as compared to the standard casein diet, on the recovery of muscle functional properties after a casting-induced immobilization period. After an initial (I0) evaluation of the contractile properties of the plantarflexors (isometric torque-frequency relationship, concentric power-velocity relationship and a fatigability test), the ankle of 20 male adult rats was immobilized by casting for 8 days. During this period, rats were fed a standard diet with 13% of casein (CAS). After cast removal, rats received either the same diet or a diet with 13% of whey proteins (WHEY). A control group (n = 10), non-immobilized but pair-fed to the two other experimental groups, was also studied and fed with the CAS diet. During the recovery period, contractile properties were evaluated 7 (R7), 21 (R21) and 42 days (R42) after cast removal. The immobilization procedure induced a homogeneous depression of average isometric force at R7 (CAS: - 19.0 ± 8.2%; WHEY: - 21.7 ± 8.4%; P

T-cell responses (proliferation, intracellular cytokine synthesis and IFNγ ELISPOT) against human papillomavirus 16 (HPV16) E2 peptides were tested during 18 months in a longitudinal study in eight women presenting with HPV16-related usual vulvar intraepithelial neoplasia (VIN) and their healthy male partners. In six women, anti-E2 proliferative responses and cytokine production (single IFNγ and/or dual IFNγ/IL2 and/or single IL2) by CD4+ T lymphocytes became detectable after treating and healing of the usual VIN. In the women presenting with persistent lesions despite therapy, no proliferation was observed. Anti-E2 proliferative responses were also observed with dual IFNγ/IL2 production by CD4+ T-cells in six male partners who did not exhibit any genital HPV-related diseases. Ex vivo IFNγ ELISPOT showed numerous effector T-cells producing IFNγ after stimulation by a dominant E2 peptide in all men and women. Since the E2 protein is absent from the viral particles but is required for viral DNA replication, these results suggest a recent infection with replicative HPV16 in male partners. The presence of polyfunctional anti-E2 T-cell responses in the blood of asymptomatic men unambiguously establishes HPV infection even without detectable lesions. These results, despite the small size of the studied group, provide an argument in favor of prophylactic HPV vaccination of young men in order to prevent HPV16 infection and viral transmission from men to women.

The SlPPC2 phosphoenolpyruvate carboxylase (PEPC; EC 4.1.1.31) gene from tomato (Solanum lycopersicum) is differentially and specifically expressed in expanding tissues of developing tomato fruit. We recently showed that a 1966 bp DNA fragment located upstream of the ATG codon of the SlPPC2 gene (GenBank AJ313434) confers appropriate fruit-specificity in transgenic tomato. In this study, we further investigated the regulation of the SlPPC2 promoter gene by analysing the SlPPC2 cis-regulating region fused to either the firefly luciferase (LUC) or the β-glucuronidase (GUS) reporter gene, using stable genetic transformation and biolistic transient expression assays in the fruit. Biolistic analyses of 5' SlPPC2 promoter deletions fused to LUC in fruits at the 8(th) day after anthesis revealed that positive regulatory regions are mostly located in the distal region of the promoter. In addition, a 5' UTR leader intron present in the 1966 bp fragment contributes to the proper temporal regulation of LUC activity during fruit development. Interestingly, the SlPPC2 promoter responds to hormones (ethylene) and metabolites (sugars) regulating fruit growth and metabolism. When tested by transient expression assays, the chimeric promoter:LUC fusion constructs allowed gene expression in both fruit and leaf, suggesting that integration into the chromatin is required for fruit-specificity. These results clearly demonstrate that SlPPC2 gene is under tight transcriptional regulation in the developing fruit and that its promoter can be employed to drive transgene expression specifically during the cell expansion stage of tomato fruit. Taken together, the SlPPC2 promoter offers great potential as a candidate for driving transgene expression specifically in developing tomato fruit from various tomato cultivars.

Việc hình thành các độ đo hâ?p dâ?n (interestingness measures, quality measures) nhằm đánh giá chất lượng của tri thức dưới dạng luật kết hợp (association rules) đóng một vai trò rất quan trọng trong giai đoạn hậu xử lý (postprocessing) các luật kết hợp của tiến trình khai phá tri thức từ dữ liệu (Knowledge Discovery from Databases - KDD). Cùng với việc ngày càng có nhiều độ đo hâ?p dâ?n được đề xuất trên cả hai tiếp cận đánh giá chủ quan (subjective interestingness measures) và khách quan (objective interestingness measures), việc nghiên cứu các tính chất hay thuộc tính (properties) có được trên các độ đo hâ?p dâ?n sẽ đóng vai trò quan trọng trong việc hiểu được bản chất của những độ đo hâ?p dâ?n khách quan cần quan tâm. Trong bài viết này, chúng tôi tập trung chủ yếu trên các độ đo hâ?p dâ?n khách quan nhằm hệ thống hóa lại một cách tương đối đầy đủ những nghiên cứu gần đây trên các tính chất của các độ đo hâ?p dâ?n khách quan đồng thời hoàn chỉnh một hướng phân lớp mới với khoảng 40 độ đo hâ?p dâ?n khách quan trên cơ sở các tính chất đã nghiên cứu.

OBJECTIVES: Few epidemiological studies have focused on the psychological health of high level athletes. This study aimed to identify the principal psychological problems encountered within French high level athletes, and the variations in their prevalence based on sex and the sport practiced. METHODS: Multivariate analyses were conducted on nationwide data obtained from the athletes' yearly psychological evaluations. RESULTS: A representative sample of 13% of the French athlete population was obtained. 17% of athletes have at least one ongoing or recent disorder, generalized anxiety disorder (GAD) being the most prevalent (6%), followed by non-specific eating disorders (4.2%). Overall, 20.2% of women had at least one psychopathology, against 15.1% in men. This female predominance applied to anxiety and eating disorders, depression, sleep problems and self-harming behaviors. The highest rates of GAD appeared in aesthetic sports (16.7% vs. 6.8% in other sports for men and 38.9% vs. 10.3% for women); the lowest prevalence was found in high risk sports athletes (3.0% vs. 3.5%). Eating disorders are most common among women in racing sports (14% vs. 9%), but for men were found mostly in combat sports (7% vs. 4.8%). DISCUSSION: This study highlights important differences in psychopathology between male and female athletes, demonstrating that the many sex-based differences reported in the general population apply to elite athletes. While the prevalence of psychological problems is no higher than in the general population, the variations in psychopathology in different sports suggest that specific constraints could influence the development of some disorders.

Intramyocellular lipid accumulation is strongly related to insulin resistance in humans, and we have shown that high glucose concentration induced de novo lipogenesis and insulin resistance in murin muscle cells. Alterations in Wnt signaling impact the balance between myogenic and adipogenic programs in myoblasts, partly due to the decrease of Wnt10b protein. As recent studies point towards a role for Wnt signaling in the pathogenesis of type 2 diabetes, we hypothesized that activation of Wnt signaling could play a crucial role in muscle insulin sensitivity.Here we demonstrate that SREBP-1c and Wnt10b display inverse expression patterns during muscle ontogenesis and regeneration, as well as during satellite cells differentiation. The Wnt/beta-catenin pathway was reactivated in contracting myotubes using siRNA mediated SREBP-1 knockdown, Wnt10b over-expression or inhibition of GSK-3beta, whereas Wnt signaling was inhibited in myoblasts through silencing of Wnt10b. SREBP-1 knockdown was sufficient to induce Wnt10b protein expression in contracting myotubes and to activate the Wnt/beta-catenin pathway. Conversely, silencing Wnt10b in myoblasts induced SREBP-1c protein expression, suggesting a reciprocal regulation. Stimulation of the Wnt/beta-catenin pathway i) drastically decreased SREBP-1c protein and intramyocellular lipid deposition in myotubes; ii) increased basal glucose transport in both insulin-sensitive and insulin-resistant myotubes through a differential activation of Akt and AMPK pathways; iii) restored insulin sensitivity in insulin-resistant myotubes.We conclude that activation of Wnt/beta-catenin signaling in skeletal muscle cells improved insulin sensitivity by i) decreasing intramyocellular lipid deposition through downregulation of SREBP-1c; ii) increasing insulin effects through a differential activation of the Akt/PKB and AMPK pathways; iii) inhibiting the MAPK pathway. A crosstalk between these pathways and Wnt/beta-catenin signaling in skeletal muscle opens the exciting possibility that organ-selective modulation of Wnt signaling might become an attractive therapeutic target in regenerative medicine and to treat obese and diabetic populations.

Aging is associated with a progressive loss of muscle mass, increased adiposity and fibrosis that leads to sarcopenia. At the molecular level, muscle aging is known to alter the expression of a variety of genes but very little is known about the molecular effectors involved. SRF (Serum Response Factor) is a crucial transcription factor for muscle-specific gene expression and for post-natal skeletal muscle growth. To assess its role in adult skeletal muscle physiology, we developed a post-mitotic myofiber-specific and tamoxifen-inducible SRF knockout model. Five months after SRF loss, no obvious muscle phenotype was observed suggesting that SRF is not crucial for myofiber maintenance. However, mutant mice progressively developed IIB myofiber-specific atrophy accompanied by a metabolic switch towards a more oxidative phenotype, muscular lipid accumulation, sarcomere disorganization and fibrosis. After injury, mutant muscles exhibited an altered regeneration process, showing smaller regenerated fibers and persistent fibrosis. All of these features are strongly reminiscent of abnormalities encountered in aging skeletal muscle. Interestingly, we also observed an important age associated decrease in SRF expression in mice and human muscles. Altogether, these results suggest that a naturally occurring SRF down-regulation precedes and contributes to the muscle aging process. Indeed, triggering SRF loss in the muscles of mutant mice results in an accelerated aging process.

The objective was to compare the safety and cellular immunogenicity of intradermal versus intramuscular immunization with an HIV-lipopeptide candidate vaccine (LIPO-4) in healthy volunteers.A randomized, open-label trial with 24 weeks of follow-up was conducted in France at six HIV-vaccine trial sites. Sixty-eight healthy 21- to 55-year-old HIV-uninfected subjects were randomized to receive the LIPO-4 vaccine (four HIV lipopeptides linked to a T-helper-stimulating epitope of tetanus-toxin protein) at weeks 0, 4 and 12, either intradermally (0.1 ml, 100 microg of each peptide) or intramuscularly (0.5 ml, 500 microg of each peptide). Comparative safety of both routes was evaluated. CD8+ T-cell immune responses to HIV epitopes (ELISpot interferon-gamma assay) and tetanus toxin-specific CD4+ T-cell responses (lymphoproliferation) were assessed at baseline, two weeks after each injection, and at week 24.No severe, serious or life-threatening adverse events were observed. Local pain was significantly more frequent after intramuscular injection, but local inflammatory reactions were more frequent after intradermal immunization. At weeks 2, 6, 14 and 24, the respective cumulative percentages of induced CD8+ T-cell responses to at least one HIV peptide were 9, 33, 39 and 52 (intradermal group) or 14, 20, 26 and 37 (intramuscular group), and induced tetanus toxin-specific CD4+ T-cell responses were 6, 27, 33 and 39 (intradermal), or 9, 46, 54 and 63 (intramuscular). In conclusion, intradermal LIPO-4 immunization was well tolerated, required one-fifth of the intramuscular dose, and induced similar HIV-specific CD8+ T-cell responses. Moreover, the immunization route influenced which antigen-specific T-cells (CD4+ or CD8+) were induced.ClinicalTrials.gov NCT00121121.

We employ positron annihilation lifetime spectroscopy (PALS) to measure the temperature dependent fluctuations in a local free volume of water confined in a variety of mesoporous materials with different pore sizes and morphologies. We demonstrate that this unconventional approach can be used to probe the dynamics and glass transition temperature, T _g , of water in confinement. In the simplest case of water confined in a 13X molecular sieve ( d = 7.4 Å), the confinement is so severe that it precludes crystallisation altogether, and we measure a T _g = 190 ± 2 K. We also show that temperature dependent PALS measurements can be used to probe the glass transition of water molecules confined in matrices with larger pore diameters (SBA-15, KIT-6 and Vycor glass), where the confinement is expected to be less severe.