Search

Solar activity is an important driver of long-term climate trends and must be accounted for in climate models. Unfortunately, direct measurements of this quantity over long periods do not exist. The only observation related to solar activity whose records reach back to the seventeenth century are sunspots. Surprisingly, determining the number of sunspots consistently over time has remained until today a challenging statistical problem. It arises from the need of consolidating data from multiple observing stations around the world in a context of low signal-to-noise ratios, non-stationarity, missing data, non-standard distributions and errors of different kind. The data from some stations experience therefore severe and various deviations over time. In this paper, we apply a systematic statistical approach for monitoring these complex and important series. It consists of three steps essential for successful treatment of the data: smoothing on multiple time-scales, monitoring using block bootstrap calibrated CUSUM charts and classifying of out-of-control situations by support vector techniques. This approach allows us to detect a wide range of anomalies (such as sudden jumps or more progressive drifts), unseen in previous analyses. It helps us to identify the causes of major deviations, which are often observer or equipment related. Their detection and identification will contribute to improve future observations. Their elimination or correction in past data will lead to a more precise reconstruction of the world reference index for solar activity: the International Sunspot Number.

The human gut microbiota can acquire new catabolic functions by integrating genetic material coming from bacteria associated to the food. The most illustrative example is the acquisition of genes by the gut microbiota of Asian populations coming from marine bacteria living at the surface of algae incorporated in diet. In order to interrogate the pace of acquisition of algal polysaccharide utilizing loci (PUL) and their diffusion rate inside populations, we investigated the PUL dedicated to degradation of porphyran, the main polysaccharide of the red algaePorphyra sp. used to prepare maki-sushi. We demonstrated that both methylated and unmethylated fractions were catabolized without the help of external enzymes. The PUL organization was conserved in several Bacteroidetes strains, highlighting lateral transfers inside the microbiota, but we point out various conserved mutations, deletion and insertions. Geographic distribution of the variants showed that specific mutation and recombination events appeared independently in geographically distant populations.

Building from Blum and Dobrotić’s conceptual framework, this paper shows that the decisions to reopen childcare centres and schools in the Canadian province of Quebec in 2020 were influenced by four goals: (1) protecting public health, (2) promoting academic success / fostering early education, (3) addressing social inequalities, and (4) helping parents to reconcile employment and care activities. Although the first three objectives were considered in the sequence of reopening, the government quickly chose to prioritize work-family reconciliation above other objectives. Quebec’s tight sequence of reopening childcare centres and schools is not simply a consequence of evolving research showing lower risks associated with COVID-19 for young children, it also reflects the province’s cultural norms toward mothers’ employment and the high legitimacy of the state in subsidizing childcare.

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.

Background The heart rate increases by 10–20 beats per minute (bpm) throughout pregnancy in women, reaching maximum heart rate in the third trimester. During pregnancy, important changes in thyroid hormones also occur, with increases of up to 50% in the levels of triiodothyronine (T3), the biological active thyroid hormone. In addition, T3 has been shown to regulate cardiac electrophysiology. Objective Thus, in the present study the potential contribution of T3 in pregnancy-induced increased heart rate was explored. Methods We compared the heart rate between nonpregnant and pregnant mice under control conditions and after altering thyroid hormone levels with T3 and propylthiouracil (PTU, an antithyroid drug) treatments. Results Consistent with the clinical data, we found a 58% rise in T3 levels during pregnancy in mice. Although pregnant mice had a higher baseline heart rate (607 ± 8 bpm, P = .004) and higher T3 levels (1.9 ± 0.4 nM, P = .0005) than nonpregnant mice (heart rate: 546 ± 16 bpm; T3 levels: 1.2 ± 0.1 nM), their heart rate responded similarly to T3 treatment as nonpregnant mice (nonpregnant: Δ130 ± 22 bpm; pregnant: Δ126 ± 17 bpm, P = .858). Additionally, the heart rate remained significantly elevated (607 ± 11 bpm, P = .038) and comparable to untreated pregnant mice, after the use of the antithyroid drug PTU, although T3 levels (1.3 ± 0.2 nM, P = .559) returned to nonpregnant values. Conclusion Based on these results, it is unlikely that T3 contributes significantly to the pregnancy-induced increased heart rate.

Although the coronavirus disease 2019 (COVID-19) pandemic has spurred critical and much-needed attention to re-thinking policy approaches to child care and long-term elder care, little focus has been given to its implications for parental leave policies and parental benefits for the care of infants and young children. This article is about reconceptualizing and reconfiguring employment-based parental leave policies in Canada both during and after COVID-19. Informed by theoretical insights from the fields of care economies, feminist political economy, and care and social reproduction and by national and international parental leave research, we argue that it is time to reconceptualize parental leave benefits not only as employment policy but also as a care and social protection policy. To make this shift, we explore three topic areas: a mixed system of parental benefits that combine employment-based and citizenship-based entitlements, connections between policy design and gender equality, and the need for robust intersectional data to track which Canadian families are receiving parental benefits.

This paper compares access to parental leave benefits in the four largest Canadian provinces –Québec, Ontario, Alberta and British Columbia between 2000 and 2016, using quantitative data from the Employment Insurance Coverage Survey. We show that inequalities in the receipt of benefits mirror and reinforce the structure of income and gender inequalities. We argue that Alberta and Québec represent two regimes of parental benefits. In Alberta the take-up of parental benefits is low, and is closely related to income and gender. Conversely, the vast majority of mothers and fathers have access to parental benefits in Québec. We argue that Alberta is closer to a liberal regime of parental benefits, while Québec is closer to a social-democratic model.

Observing and counting sunspots constitutes one of the longest-running scientific experiment, with first observations dating back to Galileo and the invention of the telescope around 1610. Today the sunspot number (SN) time series acts as a benchmark of solar activity in a large range of physical models. An appropriate statistical modelling, adapted to the time series' complex nature, is however still lacking. In this work, we provide the first comprehensive uncertainty quantification analysis of sunspot counts. Our interest lies in the following three components: the number of spots ($N_s$), the number of sunspot groups ($N_g$), and the composite $N_c$, defined as $N_c:=N_s+10N_g$. Those are reported by a network of observatories around the world, and are corrupted by errors of various types. We use a multiplicative framework to provide, for each of the three components, an estimation of their error distribution in various regimes (short-term, long-term, minima of solar activity). We also propose a robust estimator for the underlying solar signal and fit a density distribution that takes into account intrinsic characteristics such as over-dispersion, excess of zeros, and multiple modes. The estimation of the solar signal underlying the composite $N_c$ may be seen as a robust version of the International Sunspot Number (ISN), a quantity widely used as a proxy of solar activity. Therefore our results on $N_c$ may serve to characterize the uncertainty on ISN as well. Our results paves the way for a future monitoring of the observatories in quasi-real time, with the aim to alert the observers when they start deviating from the network and prevent large drifts from occurring in the network., 19 pages, 14 figures, journal paper

Cichorium intybus is a biennal species storing inulin in taproot during the first year and flowering after vernalization. Heat impact on sugar distribution and inulin yield remains poorly documented. Plants were cultivated under ambient or high (ambient+5 °C) temperature for 27 weeks. Plants were monthly harvested and morphological parameters, bolting rate, sugar translocation, soluble sugars and inulin content were determined. Heat reduced shoot and root growth and unexpectedly induced precocious bolting. It increased fructose contents in roots and leaves, increased root myo-inositol and reduced leaf sucrose content. At harvest, inulin content was higher in heat-treated than in control roots but total amount of inulin produced per plant was lower. Heat inhibited sugar translocation from leaves to secondary roots. Total soluble sugar content was lower in leaves but higher in roots of bolted plants compared to non-bolted ones. Bolting induced an increase in the mean degree of polymerization of inulin and root lignification. High temperatures impaired inulin production as a result of root growth inhibition and reduced sugar translocation from the leaves to the roots. Heat induced precocious bolting on non-vernalized plants. Bolting reinforced root growth inhibition and thus inulin yield decrease.

Cichorium intybus is a biennial plant species forming a taproot and a leaf rosette during the first year and which requires low temperature during vernalization to flower during the second year of its cycle. Heat stress, however, is known to induce premature flowering during the first year. The present work aims to compare the effect of heat treatment (38 °C during 3 days) and vernalization (4 °C during 6 weeks) on the phytohormonal profile and the expression of two chicory genes (CiFL1 and CiFT) homologous to the Arabidopsis flowering genes FLOWERING LOCUS C (FLC) and FLOWERING LOCUS T (FT). In Arabidopsis, FLC and FT code, respectively, for a repressor and an activator of flowering. Although CiFL1 was inhibited by vernalization, its expression was increased by heat treatment in both vernalized and non-vernalized seedlings while high temperature unexpectedly inhibited FT expression in vernalized seedlings. Vernalization induced a modification in the hormonal profile of C. intybus (cv. Melci) in a sense of a decrease in ethylene production, abscisic acid and total jasmonates content, while the level of salicylic and benzoic acids as well as polyamine spermidine increased. A limited effect on the gibberellins’ profile was observed. The subsequent impact of heat stress on phytohormone content was different in non-vernalized and vernalized seedlings, with a higher abscisic acid and jasmonates and a lower 1-aminocyclopropane-1-carboxylic acid concentration in the former than in the latter. These data are discussed in relation to the putative involvement of phytohormones in stress-induced flowering. It appears that heat stress implies different pathways than vernalization to hasten flowering process.

In 1997, the government of Québec instituted a low-cost and universal childcare services program most commonly available through the "centres de la petite enfance (CPE)" (early chilldhood centers). Since 2003, this model is being slowly dismantled on account of an explosion in the number of commercial daycare centers and, since 2015, an adjustment of rates according to family revenues. This research article gathers scattered information about the childcare services offer changes in Québec to demonstrate that tearing down a section of the Québécois family policy lowers the collectivization of social reproductive work.En 1997, le gouvernement du Québec élabore un réseau de services de garde (SDG) à la petite enfance-au tarif faible et universel-dont l'offre se fait principalement dans les centres de la petite enfance (CPE). Depuis 2003, ce modèle fait l'objet d'un démantèlement avec l'explosion du nombre de garderies commerciales et, depuis 2015, de la modulation des tarifs selon le revenu familial. Cette article de recherche synthétise des connaissances éparses sur la transformation de l'offre de SDG au Québec pour démontrer que la déconstruction d'un pan de la politique familiale québécoise entraine une diminution de la collectivisation du travail de reproduction sociale.

This article adds to the debate on how to “genderize” comparative analysis of welfare states by building from mainstream and feminist research. It introduces a new conceptual tool—the “demotherization” of care work—to convey the extent to which mothers can transfer part of their caregiving responsibilities to the state, grand-parents, their partner, or paid caregivers. The concept of demotherization allows shifting the focus of the analysis from the role of “families” to the role of “mothers” in social reproductive work. The combination of motherization/demo-therization and familialization/defamilialization yields four types of maternalism: “implicit,” “traditional,” “state-funded dematernalism,” and “familialized dematernalism.” Although the demotherization of care work leads to increased gender equality, it does not systematically challenge the gendered division of care work.

Canada has two parental leave benefit programs for the care of a newborn or adopted child: a federal program, and, since 2006, a provincial program in Québec. Informed by a social reproduction framework, this article compares access to parental leave benefits between Québec and the rest of Canada by family income and by its two different programs. Our analysis of quantitative data reveals that maternal access to leave benefits has improved dramatically over the past decade in the province of Québec, especially for low-income households. By contrast, on average 38% of mothers in the rest of Canada are consistently excluded from maternity or parental benefits under the federal program. We argue that one key explanation for the gap in rates of access to benefits between the two programs and between families by income is difference in eligibility criteria. In Canada, parental leaves paid for by all employers and employees are unevenly supporting the social reproduction of higher earners. Our article draws attention to the need for greater public and scholarly scrutiny of social class inequality effects of parental leave policy.

Background Ventricular arrhythmias and sudden cardiac deaths are among the leading causes of mortality in patients with heart failure, and the underlying mechanisms remain incompletely understood. Chronic elevation of angiotensin II (ANGII) is known to be one of the main contributors to heart failure. Objective We tested whether ANGII can alter ventricular conduction and Na + current using transgenic mice with cardiomyocyte-restricted overexpression of ANGII type 1 receptor (AT1R). Methods We used surface electrocardiograms along with current- and voltage-clamp techniques to characterize the electrophysiological properties of AT1R mice while the underlying regulatory mechanisms were explored using reverse transcription/quantitative polymerase chain reaction, Western blots, and immunofluorescence techniques. Results Electrophysiological data indicated that chronic AT1R activation in ventricular myocytes caused a 60% reduction in Na + current density that slowed the maximal velocity of the action potential upstroke, leading to a prolongation of the QRS complex. These changes occur independently of cardiac hypertrophy, suggesting a direct role for ANGII/AT1R in slowing ventricular conduction. Western blots demonstrated a selective increase in sarcolemmal protein kinase Cα (PKCα) in AT1R mice, indicating PKCα activation. Furthermore, immunofluorescence analysis showed reorganization of PKCα expression to sarcolemma and colocalization with Na V 1.5 in AT1R myocytes. The involvement of PKCα in regulating Na + current was subsequently demonstrated in human-induced pluripotent stem cell–derived cardiomyocytes where ANGII treatment reduced Na + current density. Concomitant treatment with αV5-3, a PKCα translocation inhibitor peptide, blocked the ANGII effect. Conclusion Overall, this study suggests that in mouse and human cardiomyocytes, PKCα is an important mediator of the ANGII-induced reduction in Na + current and may contribute to ventricular arrhythmias.

Cleaning products have long been a focus of efforts to improve sustainability and assure safety for the aquatic environment when disposed of after use. The latter is addressed at ingredient level through environmental risk assessment, including in formal frameworks such as REACH. Nevertheless, in the context of programs to improve overall sustainability, stakeholders demand both environmental safety assurance and progress at product level. Current product-level approaches for aquatic toxicity (e.g., USEtox™, Critical Dilution Volume) can be seen as predominantly hazard-based. The more logical approach would be risk-based, because ecotoxicity is generally threshold-dependent and hazard-based assessment produces conflicts with risk-based learnings. The development of a risk-based approach to assess formulated products is described: the International Association for Soaps, Detergents and Maintenance Products (A.I.S.E.) Charter Environmental Safety Check (ESC), which is consistent with the scientific principles underlying REACH. This is implemented through a simple spreadsheet tool and internal database of ingredient parameters including predicted no-effect concentration (PNEC) and removal rate. A novel feature is applying market volume information for both product types and ingredients to permit a risk-based calculation. To pass the ESC check, the projected environmental safety ratio (PESR) for each ingredient as formulated and dosed (unless cleared by a published risk assessment or exempted as inherently low risk) must be less than 1. The advantages of a risk-based approach are discussed. The strengths and limitations of various possible approaches to standard-setting, product-ranking and driving continuous improvement in respect of potential ecotoxic impacts on the aquatic environment are considered. It is proposed that as ecotoxicity is generally accepted to be threshold-dependent, with no effect below the threshold, the most constructive approach to continuous improvement of sustainability with regard to ecotoxicity is to focus efforts on instances where the safety margins for ingredients as used in specific products are narrow. This necessitates a risk-based approach. Integr Environ Assess Manag 2017;13:127-138. © 2016 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of SETAC.

Single-agent regorafenib is approved in Canada and in the US for patients with metastatic colorectal cancer (mCRC) who have failed previous lines of therapy1. Identification of prognostic biomarkers is crucial to ensure the best therapeutic strategies for mCRC patients. The goal of this clinical study (NCT01949194) was to explore putative molecular signatures of response and resistance to regorafenib in metastatic tumors and serial blood samples. We used a multi-omics approach to profile metastatic tumor tissues and serial blood samples from 47 mCRC patients who received single-agent regorafenib as second-line therapy after failing first-line therapy with an oxaliplatin or irinotecan-containing regimen with or without bevacizumab. Whole exome sequencing was performed to assess both the mutational and copy number (CN) landscapes of metastatic tissues from 29 patients and the transcriptome was interrogated using RNA sequencing. A 14-gene panel was used to profile serial plasma samples. Molecular aberrations were then correlated with lesion-specific treatment response using RECIST 1.1 and progression free survival (PFS) to investigate potential associations.The copy number aberration (CNA) landscape of metastatic tumors was assessed using Nexus Copy Number Software and 20 significant focal aberrations were identified using Genomic Identification of Significant Target in Cancer (GISTIC) test (q-bound Citation Format: Karen Gambaro, Maud Marques, Suzan McNamara, Mathilde Couetoux du Tertre, Cyrla Hoffert, Archana Srivastava, Sophie Mathieu, Anna schab, Thierry Alcindor, Adrian Langleben, Lucas Sideris, Mahmoud Adbelsalam, Mustapha Tehfe, Gerald Batist, Petr Kavan. A Phase II exploratory study to identify biomarkers prognostic of clinical response to regorafenib in patients with metastatic colorectal cancer who have failed first-line therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4325.

Heart failure (HF) is associated with high mortality and affects men and women differently. The underlying mechanisms for these sex-related differences remain largely unexplored. Accordingly, using mice with cardiac-specific overexpression of the angiotensin II (ANGII) type 1 receptor (AT1R), we explored male-female differences in the manifestations of hypertrophy and HF. AT1R mice of both sexes feature electrical and Ca2+ handling alterations, systolic dysfunction, hypertrophy and develop HF. However, females had much higher mortality (21.0%) rate than males (5.5%). In females, AT1R stimulation leads to more pronounced eccentric hypertrophy (larger increase in LV mass/body weight ratio [+31%], in cell length [+27%], in LV internal end-diastolic [LVIDd, +34%] and systolic [LVIDs, +67%] diameter) and dilation (larger decrease in LV posterior wall thickness, +17%) than males. In addition, in female AT1R mice the cytosolic Ca2+ extrusion mechanisms were more severely compromised and were associated with a specific increased in Ca2+ sparks (by 187%) and evidence of SR Ca2+ leak. Altogether, these results suggest that female AT1R mice have more severe eccentric hypertrophy, dysfunction and compromised Ca2+ dynamics. These findings indicate that females are more susceptible to the adverse effects of AT1R stimulation than males favouring the development of HF and increased mortality.

International audience; 10 Alginate oligosaccharides (AOS) with a weight average molecular weight of 5 kDa were 11 efficiently amidated with amino acids and carbohydrates in aqueous media in the presence of 12 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM). Here, 13 alanine, leucine, serine, as well as mannose and rhamnose, were amidated at high yields with a 14 good control of the degree of substitution (DS). Amino acid-and carbohydrate-grafted AOS 15 showed improved stability against degradation by alginate lyases having different specificities. 16 This enzyme resistance was correlated with the DS: hydrolysis was reduced by 60 to 70% for 17 low DS (0.1), whereas AOS with DS ranging from 0.4 to 0.6 remained unhydrolyzed. 18 Competitive inhibition assays demonstrated multivalent binding of mannose-amidated AOS to 19 concanavalin A lectin. A 178-fold affinity enhancement was observed for AOSMan-0.38 (DS 0.38) 20 over -methyl-mannoside with an IC50 of 5.6 M, lending further evidence for the promising 21 potential of AOS as multivalent scaffolds. 22 23 24 25 2 Highlights: 26  DMTMM promoted efficient amidation of alginate oligosaccharides (AOS) 27  AOS were functionalized with amino acids and carbohydrates 28  Grafting conferred improved stability to AOS against alginate lyases 29  Mannose-grafted AOS exhibited multivalent inhibition of ConA lectin 30 31

Breeding for resistance to Fe toxicity in rice remains challenging because of the complex nature of this trait. In the past 15 years, several QTL studies have been conducted using different combinations of crosses and environments. The aim of this study was to compile these data in a unique QTL map to identify candidate regions (CR) and, subsequently, candidate genes involved in rice resistance to Fe toxicity. The integrated QTL map was constructed by aligning the flanking markers on the annotated physical map of the rice reference variety Nipponbare. The heat map of QTL density was developed, highlighting four candidate regions (i.e. genomic regions of high QTL density): CR1 on chromosome 1 between markers RM246 and RM443; CR2 on chromosome 2 between markers RM526 and R758; CR3 on chromosome 3 between markers C515 and C25; and CR4 on chromosome 7 between markers R1245 and RM429. The mining of the two genomic regions harbouring the highest QTL density (CR1 and CR3) allowed the identification of 31 and 23 candidate genes in the first and second regions, respectively, based on their known function and/or on the differences in their expression between control and high Fe2+ conditions. The integrated map is a useful tool for breeders, highlighting the positions of reliable QTLs and helping to narrow the target candidate regions for marker-assisted selection. This map also provides a strong starting point for the identification of genes underlying the reported QTLs through the candidate gene approach.

An increase in mean and extreme summer temperatures is expected as a consequence of climate changes and this might have an impact on plant development in numerous species. Root chicory (Cichorium intybus L.) is a major crop in northern Europe, and it is cultivated as a source of inulin. This polysaccharide is stored in the tap root during the first growing season when the plant grows as a leafy rosette, whereas bolting and flowering occur in the second year after winter vernalisation. The impact of heat stress on plant phenology, water status, photosynthesis-related parameters, and inulin content was studied in the field and under controlled phytotron conditions. In the field, plants of the Crescendo cultivar were cultivated under a closed plastic-panelled greenhouse to investigate heat-stress conditions, while the control plants were shielded with a similar, but open, structure. In the phytotrons, the Crescendo and Fredonia cultivars were exposed to high temperatures (35°C day/28°C night) and compared to control conditions (17°C) over 10 weeks. In the field, heat reduced the root weight, the inulin content of the root and its degree of polymerisation in non-bolting plants. Flowering was observed in 12% of the heat stressed plants during the first growing season in the field. In the phytotron, the heat stress increased the total number of leaves per plant, but reduced the mean leaf area. Photosynthesis efficiency was increased in these plants, whereas osmotic potential was decreased. High temperature was also found to induced flowering of up to 50% of these plants, especially for the Fredonia cultivar. In conclusion, high temperatures induced a reduction in the growth of root chicory, although photosynthesis is not affected. Flowering was also induced, which indicates that high temperatures can partly substitute for the vernalisation requirement for the flowering of root chicory.

Background and aims Flooding stress is known to affect root growth and sugar metabolism in plants, but data are crucially missing for Cichorium intybus which stores inulin in its tap root. The aim of the present study was to quantify the impact of recurrent episodes of flooding stress on plant growth, water status, photosynthesis and sugar metabolism in relation to inulin synthesis and accumulation in roots of this species.

International audience; FUR (Ferric Uptake Regulator) protein is a global transcriptional regulator that senses iron status and controls the expression of genes involved in iron homeostasis, virulence, and oxidative stress. Ubiquitous in Gram-negative bacteria and absent in eukaryotes, FUR is an attractive antivirulence target since the inactivation of the fur gene in various pathogens attenuates their virulence. The characterization of 13-aa-long anti-FUR linear peptides derived from the variable part of the anti-FUR peptide aptamers, that were previously shown to decrease pathogenic E. coli strain virulence in a fly infection model, is described herein. Modeling, docking, and experimental approaches in vitro (activity and interaction assays, mutations) and in cells (yeast two-hybrid assays) were combined to characterize the interactions of the peptides with FUR, and to understand their mechanism of inhibition. As a result, reliable structure models of two peptide–FUR complexes are given. Inhibition sites are mapped in the groove between the two FUR subunits where DNA should also bind. Another peptide behaves differently and interferes with the dimerization itself. These results define these novel small peptide inhibitors as lead compounds for inhibition of the FUR transcription factor.

Background Hepatitis C virus (HCV) is underdiagnosed and therefore increasing the opportunities for HCV testing without venipuncture may be useful. Objectives We evaluated the analytical performance of a modified, commercially available, combined HCV antigen–antibody assay (cEIA) (Monolisa ® HCV-Ag-Ab-ULTRA) and a commercially available point-of-care (POC) device (OraQuick ® HCV) on fingerstick blood (FSB) and oral mucosal transudate (OMT). Study design FSB, OMT and serum samples were collected from 113 cases of HCV-antibody-positive patients and 88 HCV-antibody-negative controls. The HCV-antibody-positive group included 63 patients with quantifiable HCV-RNA (56%) and 17 HIV/HCV co-infected patients (15%). FSB and OMT specimens were collected as dried blood spots (DBSs) or with the OraSure collection system, before testing with cEIA. Results With FSB specimens, the cEIA and the POC device exhibited 100% specificity and 98.2% and 97.4% sensitivity, respectively. The specificity of the cEIA in FSB sharply decreased if stored 3 days at room temperature. With OMT specimens, the cEIA sensitivity (71.7%) and specificity (94.3%) were significantly lower than the performance of OraQuick ® HCV (sensitivity, 94.6%; specificity, 100%). The optical densities obtained with the cEIA in FSB and OMT were lower in HIV/HCV co-infected patients compared with HCV monoinfected patients. Conclusion The cEIA using FSB specimens collected on DBSs preserved in appropriate storage conditions was a reliable alternative, equivalent to the POC assay, for HCV testing without venipuncture. The cEIA was not adapted for HCV testing on OMT.

Enzymes used in cleaning products have an excellent safety profile, with little ability to cause adverse responses in humans. For acute toxicity, genotoxicity, sub-acute and repeated dose toxicity, enzymes are unremarkable. Reproductive toxicity and carcinogenicity are also not endpoints of concern. Exceptions are the ability of some proteases to produce irritating effects at high concentrations and more importantly, the intrinsic potential of these bacterial/fungal proteins to act as respiratory sensitizers. It is a reasonable assumption that the majority of enzyme proteins possess this hazard. However, methods for characterising the respiratory sensitisation hazard of enzymes are lacking and the information required for risk assessment and risk management, although sufficient, remains limited. Previously, most data was generated in animal models and in in vitro immunoassays that assess immunological cross-reactivity. Nevertheless, by the establishment of strict limits on airborne exposure (based on a defined minimal effect limit of 60 ng active enzyme protein/m3) and air and health monitoring, occupational safety can be assured. Similarly, by ensuring that airborne exposure is kept similarly low, coupled with knowledge of the fate of these enzymes on skin and fabrics, it has proven possible to establish a long history of safe consumer use of enzyme containing products.

International audience; Today the migration situation in France is largely reported through media and political speeches from a biased point of view. We frequently hear about a “migrant crisis”, and the danger for the economy, the French values and especially the security, that the Syrian refugees would represent when reaching Europe massively. This situation seems to create an unprecedented modern issue. To a certain extent, it is yet the update of old representational forms which have marked the History of France. What are the changes in the relation between France and its foreigners? And what are, on the contrary, the logical and integrated continuities that partly determine the migrant policies currently?; Le contexte migratoire en France aujourd’hui est relaté dans les médias et les discours politiques sous un angle peu objectif. On entend souvent parler d’une « crise des migrants » et du danger pour l’économie, les valeurs françaises et à plus forte raison la sécurité, que représenteraient les réfugiés syriens arrivant « en masse » vers l’Europe. Cette situation semble former un problème moderne sans précédent. Pourtant, elle est, dans une certaine mesure, l’actualisation de formes représentationnelles anciennes et jalonnant l’histoire de la France. Quelles sont les évolutions dans le rapport que la France entretient avec ses étrangers ? Et quelles sont au contraire les continuités logiques et intégrées qui déterminent en partie les politiques en matière d’immigration aujourd’hui ?

International audience; Severe hemophilia A is an X-linked bleeding disorder. Immune tolerance induction (ITI) is the best strategy of treatment when patients develop inhibitors. The objective is to illustrate the benefit of a high-purity human factor VIII/von Willebrand factor (VWF) concentrate (Octanate) in the management of ITI. We also wanted to raise the potential interest of laboratory assays such as thrombin-generation test (TGT) and epitope mapping. Two patients were treated during ITI, first with a recombinant FVIII and then with plasma-derived factor VIII without success, and, finally, with Octanate. Bypassing agents were used based on the results of TGT. Epitope mapping was performed during ITI therapy. These observations suggest the potential contribution of Octanate in the management of ITI in difficult cases. The use of bypassing agents can be necessary in prophylaxis or to treat bleedings, and may be guided by TGT results. Epitope mapping is used to describe the inhibitor. This article shows a decrease of the inhibitor directed against the C2 domain after initiation of Octanate. A high-purity human factor VIII/von Willebrand factor concentrate (Octanate) may be a valuable therapeutical option for ITI therapy. TGT and epitope mapping could be of help in the management of ITI.

Background and objective We have previously shown that androgens upregulate cardiac K+ channels and shorten repolarization. However, the effects that estrogens (E2) and estrogen receptors (ER) might have on the various repolarizing K+ currents and underlying ion channels remain incompletely understood. Accordingly, our objective was to verify whether and how E2 and its ERs subtypes influence these K+ currents. Methods and results In order to examine the influence of E2 and ERs on K+ currents we drastically lowered the E2 level through ovariectomy (OVX; 74% reduction vs CTL) and in parallel, we used female mice lacking either ERα (ERαKO) or ERβ (ERβKO). In OVX mice, results showed a specific increase of 35% in the density of the Ca2 +-independent transient outward K+ current (Ito) compared to CTL. Western blots showed increase in Kv4.2 and Kv4.3 sarcolemmal protein expression while qPCR revealed higher mRNA expression of only Kv4.3 in OVX mice. This upregulation of Ito was correlated with a shorter ventricular action potential duration and QTc interval. In ERαKO but not ERβKO mice, the mRNA of Kv4.3 was selectively increased. Furthermore, when ventricular myocytes obtained from ERαKO and ERβKO were cultured in the presence of E2, results showed that E2 reduced Ito density only in ERβKO myocytes confirming the repressive role of E2-ERα in regulating Ito. Conclusion Altogether, these results suggest that E2 negatively regulates the density of Ito through ERα, this highlights a potential role for this female hormone and its α-subtype receptor in modulating cardiac electrical activity.

International audience; The FUR protein (ferric uptake regulator) is an iron-dependent global transcriptional regulator. Specific to bacteria, FUR is an attractive antibacterial target since virulence is correlated to iron bioavailability. Recently, four anti-FUR peptide aptamers, composed of 13 amino acid variable loops inserted into a thioredoxinA scaffold, were identified, which were able to interact with Escherichia coli FUR (EcFUR), inhibit its binding to DNA and to decrease the virulence of pathogenic E. coli in a fly infection model. The first characterization of anti-FUR linear peptides (pF1 6 to 13 amino acids) derived from the variable part of the F1 anti-FUR peptide aptamer is described herein. Theoretical and experimental approaches, in original combination, were used to study interactions of these peptides with FUR in order to understand their mechanism of inhibition. After modeling EcFUR by homology, docking with Autodock was combined with molecular dynamics simulations in implicit solvent to take into account the flexibility of the partners. All calculations were cross-checked either with other programs or with experimental data. As a result, reliable structures of EcFUR and its complex with pF1 are given and an inhibition pocket formed by the groove between the two FUR subunits is proposed. The location of the pocket was validated through experimental mutation of key EcFUR residues at the site of proposed peptide interaction. Cyclisation of pF1, mimicking the peptide constraint in F1, improved inhibition. The details of the interactions between peptide and protein were analyzed and a mechanism of inhibition of these anti-FUR molecules is proposed.

Inflammation is now widely recognized as a key component of heart disease. Patients suffering from arrhythmias and heart failure have increased levels of tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β). Evidence suggests that these cytokines are important mediators of cardiac remodeling; however, their effects on ion channels and arrhythmogenesis remain incompletely understood. The L-type Ca(2+) current (ICaL) is a major determinant of the plateau phase of cardiac action potential and has a critical excitation-contraction coupling role. Thus, altering its properties could have detrimental effects on cardiac electrical and contractile functions. Accordingly, the objective of this study was to elucidate the effect of TNFα and IL-1β on ICaL, while exploring the underlying regulatory mechanisms. Neonatal mouse ventricular myocytes were treated with a pathophysiological concentration (30 pg/ml) of TNFα and IL-1β for 24 h. Voltage-clamp recordings showed that TNFα had no effect on ICaL, whereas IL-1β decreased the current density by 36%. Although both IL-1β- and TNFα-treated myocytes showed significant increase in reactive oxidative species (ROS), Western blot experiments revealed that only IL-1β increased PKCϵ membrane translocation. The antioxidant N-acetyl-L-cysteine normalized ROS levels and restored ICaL density. Furthermore, the PKCϵ translocation inhibitor ϵ-V1-2 blocked the effect of IL-1β on ICaL. The reduction of ICaL by IL-1β was also seen in cultured adult ventricular myocytes. Overall, chronic IL-1β treatment decreased ICaL density in cardiomyocytes. These effects implicated ROS signaling and PKCϵ activation. These findings could contribute to explain the role of IL-1β in the development of arrhythmia and heart failure.