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The study of iron reinforcements used in the construction of Notre-Dame de Paris offers a glimpse into the innovation that took place on this building site in the mid-12th century, adapting metal to create a novel architecture. The restoration of the monument after the 2019 fire offered unique possibilities to investigate its iron armatures and to sample 12 iron staples from different locations (tribunes, nave aisles and upper walls). Six of them were dated thanks to the development of an innovative methodology based on radiocarbon dating. They reveal that Notre-Dame is the first known Gothic cathedral where iron was massively used as a proper construction material to bind stones throughout its entire construction, leading to a better understanding of the master masons’ thinking. Moreover, a metallographic study and slag inclusion chemical analyses of the staples provide the first study of iron supply for a great medieval Parisian building yard, renewing our understanding of iron circulation, trade and forging in the 12th and 13th century capital of the French kingdom. The highlighting of numerous welds in all iron staples and the multiple provenances sheds light on the activity of the iron market in this major medieval European city and the nature of the goods that circulated, and questions the possible importance of recycling.

The presence of glass beads in West African archaeological sites provides important evi- dence of long-distance trade between this part of the continent and the rest of the world. Until recently, most of these items came from historical Sub-Saharan urban centers, well known for their role in the medieval trans-Saharan trade. We present here the chemical analysis by Laser Ablation-Inductively Coupled Plasma-Mass Spectrometry (LA-ICP-MS) of 16 glass beads found in three rural sites excavated during the past decade: the funerary site of Dourou-Boro and settlement sites of Sadia, in central Mali, as well as the settlement site of Djoutoubaya, in eastern Senegal, in contexts dated between the 7th-9th and the 11th-13th centuries CE. Results show that the raw materials used to manufacture the majority of the glass most probably originated in Egypt, the Levantine coast and the Middle East. One bead is of uncertain provenance and shows similarities with glass found in the Iberian Peninsula and in South Africa. One bead fragment found inside a tomb is a modern production, proba- bly linked to recent plundering. All of these ancient beads were exchanged along the trans- Saharan trade routes active during the rise of the first Sahelian states, such as the Ghana and the Gao kingdoms, and show strong similarities with the other West African bead assemblages that have been analysed. Despite the remoteness of their location in the Dogon Country and in the Fale ́ me ́ River valley, the beads studied were therefore included in the long-distance trade network, via contacts with the urban commercial centers located at the edge of the Sahara along the Niger River and in current southern Mauretania. These results bring a new light on the relationships between international and regional trade in Africa and highlight the complementarity between centres of political and economic power and their peripheries, important because of resources like gold for eastern Senegal.

The Core Scientific Dataset (CSD) model with JavaScript Object Notation (JSON) serialization is presented as a lightweight, portable, and versatile standard for intra- and interdisciplinary scientific data exchange. This model supports datasets with a p-component dependent variable, {U 0, . . ., U q, . . ., U p− 1}, discretely sampled at M unique points in a d-dimensional independent variable (X 0, . . ., X k, . . ., X d− 1) space. Moreover, this sampling is over an orthogonal grid, regular or rectilinear, where the principal coordinate axes of the grid are the independent variables. It can also hold correlated datasets assuming the different physical quantities (dependent variables) are sampled on the same orthogonal grid of independent variables. The model encapsulates the dependent variables’ sampled data values and the minimum metadata needed to accurately represent this data in an appropriate coordinate system of independent variables. The CSD model can serve as a re-usable building block in the development of more sophisticated portable scientific dataset file standards.

In the past few decades, a diverse array of research has emphasized the precocity of technically advanced and symbolic practices occurring during the southern African Middle Stone Age. However, uncertainties regarding the regional chrono-cultural framework constrain models and identification of the cultural and ecological mechanisms triggering the development of such early innovative behaviours. Here, we present new results and a refined chronology for the Pietersburg, a techno-complex initially defined in the late 1920's, which has disappeared from the literature since the 1980's. We base our revision of this techno-complex on ongoing excavations at Bushman Rock Shelter (BRS) in Limpopo Province, South Africa, where two Pietersburg phases (an upper phase called '21' and a lower phase called '28') are recognized. Our analysis focuses on the '28' phase, characterized by a knapping strategy based on Levallois and semi-prismatic laminar reduction systems and typified by the presence of end-scrapers. Luminescence chronology provides two sets of ages for the upper and lower Pietersburg of BRS, dated respectively to 73±6ka and 75±6ka on quartz and to 91±10ka and 97±10ka on feldspar, firmly positioning this industry within MIS5. Comparisons with other published lithic assemblages show technological differences between the Pietersburg from BRS and other southern African MIS5 traditions, especially those from the Western and Eastern Cape. We argue that, at least for part of MIS5, human populations in South Africa were regionally differentiated, a process that most likely impacted the way groups were territorially and socially organized. Nonetheless, comparisons between MIS5 assemblages also indicate some typological similarities, suggesting some degree of connection between human groups, which shared similar innovations but manipulated them in different ways. We pay particular attention to the end-scrapers from BRS, which represent thus far the earliest documented wide adoption of such tool-type and provide further evidence for the innovative processes characterizing southern Africa from the MIS5 onwards.

International audience; Active cellular transporters of harmful agents-multidrug resistance (mdr) proteins-are present in tumor, stem and endothelial cells, among others. While mdr proteins are broadly studied in tumor cells, their role in non-tumor cells and the significance of their action not connected with removal of harmful xenobiotics is less extensively documented. Proper assessment of mdr proteins expression is difficult. Mdr mRNA presence is most often evaluated but that does not necessarily correlate with the protein level. The protein expression itself is difficult to determine; usually cells with mdr overexpression are studied, not cells under physiological conditions, in which a low expression level of mdr protein is often insufficient for detection in vitro. Various methods are used to identify mdr mRNA and protein expression, together with functional tests demonstrating their biological drug transporting activities. Data comparing different methods of investigating expression of mdr mRNAs and their corresponding proteins are still scarce. In this article we present the results of a study concerning mdr mRNA and protein expression. Our goal was to search for the best method to investigate the expression level and functional activity of five selected mdr proteins-MDR1, BCRP, MRP1, MRP4 and MRP5-in established in vitro cell lines of human endothelial cells (ECs) and their progenitors. Endothelial cells demonstrated mdr presence at the mRNA level, which was not always confirmed at the protein level or in functional tests. Therefore, several different assays had to be applied for evaluation of mdr proteins expression and functions in endothelial cells. Among them functional tests seemed to be the most conclusive, although not very specific.

Goda Buticha is a cave site near Dire Dawa in southeastern Ethiopia that contains an archaeological sequence sampling the late Pleistocene and Holocene of the region. The sedimentary sequence displays complex cultural, chronological and sedimentological histories that seem incongruent with one another. A first set of radiocarbon ages suggested a long sedimentological gap from the end of Marine Isotopic Stage (MIS) 3 to the mid-Holocene. Macroscopic observations suggest that the main sedimentological change does not coincide with the chronostratigraphic hiatus. The cultural sequence shows technological continuity with a late persistence of artifacts that are usually attributed to the Middle Stone Age into the younger parts of the stratigraphic sequence, yet become increasingly associated with lithic artifacts typically related to the Later Stone Age. While not a unique case, this combination of features is unusual in the Horn of Africa. In order to evaluate the possible implications of these observations, sedimentological analyses combined with optically stimulated luminescence (OSL) were conducted. The OSL data now extend the radiocarbon chronology up to 63 ± 7 ka; they also confirm the existence of the chronological gap between 24.8 ± 2.6 ka and 7.5 ± 0.3 ka. The sedimentological analyses suggest that the origin and mode of deposition were largely similar throughout the whole sequence, although the anthropic and faunal activities increased in the younger levels. Regional climatic records are used to support the sedimentological observations and interpretations. We discuss the implications of the sedimentological and dating analyses for understanding cultural processes in the region., This research benefited from funding of the National Geographic Society (http:// nationalgeographic.org/), grants # 8110-06 and 8510-08 (ZA), of the Wenner-Gren Foundation (http://www.wennergren.org/), grant # ICRG e 102, (ZA and DP), of the Hebrew University of Jerusalem (http://new.huji.ac.il/en) (EH), of the French National Research Agency (http://www.agence-nationale-recherche.fr), projects # ANR-09- JCJC-0123-01 (CT), # ANR-14-CE31-0023-03, and # ANR-10-LABX-52, of the Regional Priority Program « Heritage, Resources, Governance » (HEREGO, coordinated by the Institut de Recherche pour le Developpement) (DP), the Doctoral School of the Museum National d’Histoire Naturelle in Paris (France) and UMR CNRS 7194 (AL), the Smithsonian NMNH small grants, and the European Union’s Horizon 2020 research and innovation program under the Marie SklodowskaCurie grant (https://ec.europa.eu/programmes/ horizon2020/en/h2020-section/marie-sklodowskacurie-actions), agreement #655459. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

One hundred and forty-one glass fragments from medieval Ciudad de Vascos (Toledo, Spain) were analysed by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The glasses fall into three types according to the fluxing agents used: mineral natron, soda-rich plant ash, and a combination of soda ash and lead. The natron glasses can be assigned to various established primary production groups of eastern Mediterranean provenance. Different types of plant ash glasses indicate differences in the silica source as well as the plant ash component, reflecting changing supply mechanisms. While the earlier plant ash groups can be related to Islamic glasses from the Near East, both in terms of typology and composition, the chemical signature of the later samples appear to be specific to glass from the Iberian Peninsula. This has important implications for our understanding of the emerging glass industry in Spain and the distribution patterns of glass groups and raw materials. The plant ash that was used for the Vascos glasses is rich in soda with low levels of potash, similar to ash produced in the eastern Mediterranean. It could therefore be possible that Levantine plant ash was imported and used in Islamic period glass workshops in Spain. Unlike central and northern Europe where an independent glass industry based on potassium-rich wood ash developed during the Carolingian period, the prevalence of soda ash and soda ash lead glass on the Iberian Peninsula indicates its commercial and technological interconnection with the Islamic east. Our study thus traces several stages leading to the development of a specifically Spanish primary glassmaking industry.

International audience; The understanding of the glass trade in the first millennium CE relies on the characterisation of well-dated compositional groups and the identification of their primary production sites. 275 Byzantine glass weights from the British Museum and the Bibliothèque nationale de France dating to the sixth and seventh century were analysed by LA-ICP-MS. Multivariate statistical and graphical data analysis discriminated between six main primary glass types. Primary glass sources were differentiated based on multi-dimensional comparison of silica-derived elements (MgO, Al2O3, CaO, TiO2, Fe2O3, ZrO2) and components associated with the alkali source (Li2O, B2O3). Along with Egyptian and Levantine origins of the glassmaking sands, variations in the natron source possibly point to the exploitation of two different natron deposits. Differences in strontium to calcium ratios revealed variations in the carbonate fractions in the sand. At least two cobalt sources were employed as colouring agents, one of which shows strong correlations with nickel, indicating a specific post-Roman cobalt source. Typological evidence identified chronological developments in the use of the different glass groups. Throughout the sixth century, Byzantine glass weights were predominately produced from two glasses that are probably of an Egyptian origin (Foy-2 and Foy-2 high Fe). Towards the second half of the sixth century a new but related plant-ash glass type emerged (Magby). Levantine I was likewise found among the late sixth- to early seventh-century samples. The use of different dies for the same batch testifies to large-scale, centralised production of the weights, while the same die used for different primary production groups demonstrates the co-existence of alternative sources of supply. Given the comprehensive design of our study, these results can be extrapolated to the wider early Byzantine glass industry and its changes at large.

Ca(2+) signaling plays an important role in the function of dendritic cells (DC), the professional antigen presenting cells. Here, we described the role of Calcium released activated (CRAC) channels in the maturation and cytokine secretion of human DC. Recent works identified STIM1 and Orai1 in human T lymphocytes as essential for CRAC channel activation. We investigated Ca(2+) signaling in human DC maturation by imaging intracellular calcium signaling and pharmalogical inhibitors. The DC response to inflammatory mediators or PAMPs (Pathogen-associated molecular patterns) is due to a depletion of intracellular Ca(2+) stores that results in a store-operated Ca(2+) entry (SOCE). This Ca(2+) influx was inhibited by 2-APB and exhibited a Ca(2+)permeability similar to the CRAC (Calcium-Released Activated Calcium), found in T lymphocytes. Depending on the PAMPs used, SOCE profiles and amplitudes appeared different, suggesting the involvement of different CRAC channels. Using siRNAi, we identified the STIM1 and Orai1 protein complex as one of the main pathways for Ca(2+) entry for LPS- and TNF-α-induced maturation in DC. Cytokine secretions also seemed to be SOCE-dependent with profile differences depending on the maturating agents since IL-12 and IL10 secretions appeared highly sensitive to 2-APB whereas IFN-γ was less affected. Altogether, these results clearly demonstrate that human DC maturation and cytokine secretions depend on SOCE signaling involving STIM1 and Orai1 proteins.

The Arabian Peninsula is a key region for understanding climate change and human occupation history in a marginal environment. The Mundafan palaeolake is situated in southern Saudi Arabia, in the Rub’ al-Khali (the ‘Empty Quarter’), the world’s largest sand desert. Here we report the first discoveries of Middle Palaeolithic and Neolithic archaeological sites in association with the palaeolake. We associate the human occupations with new geochronological data, and suggest the archaeological sites date to the wet periods of Marine Isotope Stage 5 and the Early Holocene. The archaeological sites indicate that humans repeatedly penetrated the ameliorated environments of the Rub’ al-Khali. The sites probably represent short-term occupations, with the Neolithic sites focused on hunting, as indicated by points and weaponry. Middle Palaeolithic assemblages at Mundafan support a lacustrine adaptive focus in Arabia. Provenancing of obsidian artifacts indicates that Neolithic groups at Mundafan had a wide wandering range, with transport of artifacts from distant sources., peer-reviewed

International audience; Bartonella henselae, a zoonotic agent, induces tumors of endothelial cells (ECs), namely bacillary angiomatosis and peliosis in immunosuppressed humans but not in cats. In vitro studies on ECs represent to date the only way to explore the interactions between Bartonella henselae and vascular endothelium. However, no comparative study of the interactions between Bartonella henselae and human (incidental host) ECs vs feline (reservoir host) ECs has been carried out because of the absence of any available feline endothelial cell lines. To this purpose, we have developed nine feline EC lines which allowed comparing the effects of Bartonella strains on human and feline micro-vascular ECs representative of the infection development sites such as skin, versus macro-vascular ECs, such as umbilical vein. Our model revealed intrinsic differences between human (Human Skin Microvascular ECs -HSkMEC and Human Umbilical Vein ECs - iHUVEC) and feline ECs susceptibility to Bartonella henselae infection. While no effect was observed on the feline ECs upon Bartonella henselae infection, the human ones displayed accelerated angiogenesis and wound healing. Noticeable differences were demonstrated between human micro-and macro-vasculature derived ECs both in terms of pseudotube formation and healing. Interestingly, Bartonella henselae effects on human ECs were also elicited by soluble factors. Neither Bartonella henselae-infected Human Skin Microvascular ECs clinically involved in bacillary angiomatosis, nor feline ECs increased cAMP production, as opposed to HUVEC. Bartonella henselae could stimulate the activation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) in homologous cellular systems and trigger VEGF production by HSkMECs only, but not iHUVEC or any feline ECs tested. These results may explain the decreased pathogenic potential of Bartonella henselae infection for cats as compared to humans and strongly suggest that an autocrine secretion of VEGF by human skin endothelial cells might induce their growth and ultimately lead to bacillary angiomatosis formation.

International audience; Heme oxygenase-1 (HO-1), a cytoprotective, pro-angiogenic and anti-inflammatory enzyme, is strongly induced in injured tissues. Our aim was to clarify its role in cutaneous wound healing. In wild type mice, maximal expression of HO-1 in the skin was observed on the 2(nd) and 3(rd) days after wounding. Inhibition of HO-1 by tin protoporphyrin-IX resulted in retardation of wound closure. Healing was also delayed in HO-1 deficient mice, where lack of HO-1 could lead to complete suppression of reepithelialization and to formation of extensive skin lesions, accompanied by impaired neovascularization. Experiments performed in transgenic mice bearing HO-1 under control of keratin 14 promoter showed that increased level of HO-1 in keratinocytes is enough to improve the neovascularization and hasten the closure of wounds. Importantly, induction of HO-1 in wounded skin was relatively weak and delayed in diabetic (db/db) mice, in which also angiogenesis and wound closure were impaired. In such animals local delivery of HO-1 transgene using adenoviral vectors accelerated the wound healing and increased the vascularization. In summary, induction of HO-1 is necessary for efficient wound closure and neovascularization. Impaired wound healing in diabetic mice may be associated with delayed HO-1 upregulation and can be improved by HO-1 gene transfer.

International audience; Using three different microscopy techniques (epifluorescence, electronic and atomic force microscopy), we showed that high-Mg calcite grains in calcifying microbial mats from the hypersaline lake " La Salada de Chiprana " , Spain, contain viruses with a diameter of 50–80 nm. Energy-dispersive X-ray spectrometer analysis revealed that they contain nitrogen and phosphorus in a molar ratio of ~9, which is typical for viruses. Nucleic acid staining revealed that they contain DNA or RNA. As characteristic for hypersaline environments, the concentrations of free and attached viruses were high (>10 10 viruses per g of mat). In addition, we showed that acid treatment (dissolution of calcite) resulted in release of viruses into suspension and estimated that there were ~15 × 10 9 viruses per g of calcite. We suggest that virus-mineral interactions are one of the possible ways for the formation of nano-sized structures often described as " nanobacteria " and that viruses may play a role in initiating calcification.

International audience; The Paleocene-Eocene Thermal Maximum (PETM) is correlated with the first occurrences of earliest modern mammals in the Northern Hemisphere. The latest Paleocene Clarkforkian North American Land Mammal Age, that has yielded rodents and carnivorans, is the only exception to this rule. However, until now no pre-PETM localities have yielded modern mammals in Europe or Asia. We report the first Clarkforkian equivalent Land Mammal Age in the latest Paleocene deposits of the basal Sparnacian facies at Rivecourt, in the north-central part of the Paris Basin. The new terrestrial vertebrate and macroflora assemblages are analyzed through a multidisciplinary study including sedimentologic, stratigraphic, isotopic, and palynological aspects in order to reconstruct the paleoenvironment and to evaluate biochronologic and paleogeographic implications. The mammals are moderately diverse and not abundant, contrary to turtles and champsosaurs. The macroflora is exceptional in preservation and diversity with numerous angiosperms represented by flowers, fruits, seeds and wood preserved as lignite material, revealing an abundance of Arecaceae, Betulaceae, Icacinaceae, Menispermaceae, Vitaceae and probably Cornaceae. Results indicate a Late Paleocene age based on carbon isotope data, palynology and vertebrate occurrences such as the choristoderan Champsosaurus, the arctocyonid Arctocyon, and the plesiadapid Plesiadapis tricuspidens. However, several mammal species compare better with the earliest Eocene. Among these, the particular louisinid Teilhardimys musculus, also recorded from the latest Paleocene of the Spanish Pyrenees, suggests a younger age than the typical MP6 reference level. Nevertheless, the most important aspect of the Rivecourt fauna is the presence of dental remains of a rodent and a ''miacid'' carnivoran, attesting to the presence of two modern mammalian orders in the latest Paleocene of Europe. Interestingly, these two groups are also the only modern groups recorded from the latest Paleocene of North America, making Rivecourt the first direct equivalent to the Clarkforkian Land Mammal Age outside of North America.

Background Knowledge of the normal myocardial–myocyte orientation could theoretically allow the definition of relevant quantitative biomarkers in clinical routine to diagnose heart pathologies. A whole heart diffusion tensor template representative of the global myofiber organization over species is therefore crucial for comparisons across populations. In this study, we developed a groupwise registration and tractography framework to resolve the global myofiber arrangement of large mammalian sheep hearts. To demonstrate the potential application of the proposed method, a novel description of sub-regions in the intraventricular septum is presented. Methods Three explanted sheep (ovine) hearts (size ~12×8×6 cm3, heart weight ~ 150 g) were perfused with contrast agent and fixative and imaged in a 9.4T magnet. A group-wise registration of high-resolution anatomical and diffusion-weighted images were performed to generate anatomical and diffusion tensor templates. Diffusion tensor metrics (eigenvalues, eigenvectors, fractional anisotropy …) were computed to provide a quantitative and spatially-resolved analysis of cardiac microstructure. Then tractography was performed using deterministic and probabilistic algorithms and used for different purposes: i) Visualization of myofiber architecture, ii) Segmentation of sub-area depicting the same fiber organization, iii) Seeding and Tract Editing. Finally, dissection was performed to confirm the existence of macroscopic structures identified in the diffusion tensor template. Results The template creation takes advantage of high-resolution anatomical and diffusion-weighted images obtained at an isotropic resolution of 150 μm and 600 μm respectively, covering ventricles and atria and providing information on the normal myocardial architecture. The diffusion metric distributions from the template were found close to the one of the individual samples validating the registration procedure. Small new sub-regions exhibiting spatially sharp variations in fiber orientation close to the junctions of the septum and ventricles were identified. Each substructure was defined and represented using streamlines. The existence of a fiber-bundles in the posterior junction was validated by anatomical dissection. A complex structural organization of the anterior junction in comparison to the posterior junction was evidenced by the high-resolution acquisition. Conclusions A new framework combining cardiac template generation and tractography was applied on the whole sheep heart. The framework can be used for anatomical investigation, characterization of microstructure and visualization of myofiber orientation across samples. Finally, a novel description of the ventricular junction in large mammalian sheep hearts was proposed.

BackgroundTNF-related lymphotoxin alpha (LTalpha) is essential for the development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). The pathway involved has been attributed to TNFR2. Here we show a second arm of LTalpha-signaling essential for ECM development through LTbeta-R, receptor of LTalpha1beta2 heterotrimer.Methodology/principal findingsLTbetaR deficient mice did not develop the neurological signs seen in PbA induced ECM but died at three weeks with high parasitaemia and severe anemia like LTalphabeta deficient mice. Resistance of LTalphabeta or LTbetaR deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and angiography, associated with lack of microvascular obstruction, while wild-type mice developed distinct microvascular pathology. Recruitment and activation of perforin(+) CD8(+) T cells, and their ICAM-1 expression were clearly attenuated in the brain of resistant mice. An essential contribution of LIGHT, another LTbetaR ligand, could be excluded, as LIGHT deficient mice rapidly succumbed to ECM.Conclusions/significanceLTbetaR expressed on radioresistant resident stromal, probably endothelial cells, rather than hematopoietic cells, are essential for the development of ECM, as assessed by hematopoietic reconstitution experiment. Therefore, the data suggest that both functional LTbetaR and TNFR2 signaling are required and non-redundant for the development of microvascular pathology resulting in fatal ECM.

International audience; Sign Language (SL) is a continuous and complex stream of multiple body movement features. That raises the challenging issue of providing efficient computational models for the description and analysis of these movements. In the present paper, we used Principal Component Analysis (PCA) to decompose SL motion into elementary movements called principal movements (PMs). PCA was applied to the upper-body motion capture data of six different signers freely producing discourses in French Sign Language. Common PMs were extracted from the whole dataset containing all signers, while individual PMs were extracted separately from the data of individual signers. This study provides three main findings: (1) although the data were not synchronized in time across signers and discourses, the first eight common PMs contained 94.6% of the variance of the movements; (2) the number of PMs that represented 94.6% of the variance was nearly the same for individual as for common PMs; (3) the PM subspaces were highly similar across signers. These results suggest that upper-body motion in unconstrained continuous SL discourses can be described through the dynamic combination of a reduced number of elementary movements. This opens up promising perspectives toward providing efficient automatic SL processing tools based on heavy mocap datasets, in particular for automatic recognition and generation.

PurposeAlthough the relationship between body composition and bone mineral density (BMD) is well established, the relative contribution of appendicular lean mass (ALM) and fat mass (FM) to BMD has been rarely evaluated in young men.MethodsWe assessed 100 young men (age: 24.4±2.8 years, BMI: 23.4±2.81 kg/m2). Appendicular lean mass index (ALM/H2) (ALMI), fat mass index (FM/ H2) (FMI), percentage of body fat, BMD at lumbar spine (LS), total hip (TH), femoral neck (FN) and whole body (WB) were measured using DXA. Muscle strength was evaluated by handgrip strength. Pearson's correlations and interactions between all variables were assessed using stepwise regression analyses.ResultsALM index (ALMI) was positively correlated with BMD at all sites (r = 0.62 for WB pConclusionsOur data suggest that BMD was positively associated with ALMI while negatively with FMI. We confirm that ALMI is the strongest factor associated with BMD in a population of young men.

Macrophages play crucial roles in innate immune response and in the priming of adaptive immunity, and are characterized by their phenotypic heterogeneity and plasticity. Reprogramming intracellular metabolism in response to microenvironmental signals is required for M1/M2 macrophage polarization and function. Here we assessed the influence of iron on the polarization of the immune response in vivo and in vitro. Iron-enriched diet increased M2 marker Arg1 and Ym1 expression in liver and peritoneal macrophages, while iron deficiency decreased Arg1 expression. Under LPS-induced inflammatory conditions, low iron diet exacerbated the proinflammatory response, while the IL-12/IL-10 balance decreased with iron-rich diet, thus polarizing toward type 2 response. Indeed, in vitro macrophage iron loading reduced the basal percentage of cells expressing M1 co-stimulatory CD86 and MHC-II molecules. Further, iron loading of macrophages prevented the pro-inflammatory response induced by LPS through reduction of NF-κB p65 nuclear translocation with decreased iNOS, IL-1β, IL-6, IL-12 and TNFα expression. The increase of intracellular iron also reduced LPS-induced hepcidin gene expression and abolished ferroportin down-regulation in macrophages, in line with macrophage polarization. Thus, iron modulates the inflammatory response outcome, as elevated iron levels increased M2 phenotype and negatively regulated M1 proinflammatory LPS-induced response.

International audience; In this work, we developed a device capable to generate a non-thermal plasma discharge inside a sealed bag. The aim of this study was to assess the effectiveness of the oxygen, nitrogen and argon plasma sterilization on Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis spores according to the NF EN 556 Norm. Moreover the bag integrity which is a critical key to maintain the sterile state of items after the end of the process was verified by Fourier Transform Infrared (FTIR) and X-ray Photoelectron Spectrometry (XPS) analyses. After plasma treatments, the bacterial counting showed a 6 log reduction of P. aeruginosa and S. aureus in 45 min and 120 min respectively whatever the gas used and a 4 log reduction of B. subtilis spores in 120 min with only oxygen plasma. These results were confirmed by Scanning Electron Microscopy (SEM) observations showing altered bacteria or spores and numerous debris. Taking into account the studied microorganisms, the oxygen plasma treatment showed the highest efficiency. FTIR and XPS analyses showed that this treatment induced no significant modification of the bags. To conclude this non-thermal plasma sterilization technique could be an opportunity to sterilize heat and chemical-sensitive medical devices and to preserve their sterile state after the end of the process.

International audience; Although the effect of temporal pressure on spatio-temporal aspects of motor coordination and posture is well established in young adults, there is a clear lack of data on elderly subjects. This work examined the aging-related effects of temporal pressure on movement synchronization and dynamic stability. Sixteen young and eleven elderly subjects performed series of simultaneous rapid leg flexions in an erect posture paired with ipsilateral index-finger extensions, minimizing the difference between heel and finger movement onsets. This task was repeated ten times under two temporal conditions (self-initiated [SI] vs. reaction-time [RT]). Results showed that, first, temporal pressure modified movement synchronization; the finger extension preceded swing heel-off in RT, and inversely in SI. Synchronization error and associated standard deviation were significantly greater in elderly than in young adults in SI only, i.e. in the condition where proprioception is thought to be crucial for temporal coordination. Secondly, both groups developed a significantly shorter mediolateral (ML) anticipatory postural adjustment duration in RT (high temporal pressure) than in SI. In both groups, this shortening was compensated by an increase in the anticipatory peak of centre-of-gravity (CoG) acceleration towards the stance-leg so that ML dynamic stability at foot-off, quantified with the "extrapolated centre-of-mass", remained unchanged across temporal conditions. This increased CoG acceleration was associated with an increased anticipatory peak of ML centre-of-pressure shift towards the swing-leg in young adults only. This suggested that the ability to accelerate the CoG with the centre-of-pressure shift was degraded in elderly, probably due to weakness in the lower limb muscles. Dynamic stability at foot-off was also degraded in elderly, with a consequent increased risk of ML imbalance and falling. The present study provides new insights into the ability of elderly adults to deal with temporal pressure constraints in adapting whole-body coordination of postural and focal components of paired movement.

International audience; The aim of the study was to investigate the development of a rhythmical skill of children aged from 5 to 12 years old. Five age groups (5-6, 7-8, 9-10, 11-12, and young adults) performed a virtual ball bouncing task (16 forty-second long test trials). Task performances, racket oscillation, ball-racket impacts as well as the ball-racket coupling were analysed. The results showed a change in both performance and behaviour at the age of 7 years old. Before this age, children exhibited restricted perceptual-motor coordination with a high frequency of racket oscillation and a poor level of performance. After the age of 7, cycle-to-cycle adaptive coordination based on visual information was progressively acquired leading to increasing performance levels with age. Overall these results revealed a rapid change in capability to perform the ball bouncing task across age with a late emergence of the required coordination and significant change in the coordination at the age of 7.

International audience; The Rod and Frame Test has been used to assess the degree to which subjects rely on the visual frame of reference to perceive vertical (visual field dependence-independence perceptual style). Early investigations found children exhibited a wide range of alignment errors, which reduced as they matured. These studies used a mechanical Rod and Frame system, and presented only mean values of grouped data. The current study also considered changes in individual performance. Changes in rod alignment accuracy in 419 school children were measured using a computer-based Rod and Frame test. Each child was tested at school Grade 2 and retested in Grades 4 and 6. The results confirmed that children displayed a wide range of alignment errors, which decreased with age but did not reach the expected adult values. Although most children showed a decrease in frame dependency over the 4 years of the study, almost 20% had increased alignment errors suggesting that they were becoming more frame-dependent. Plots of individual variation (SD) against mean error allowed the sample to be divided into 4 groups; the majority with small errors and SDs; a group with small SDs, but alignments clustering around the frame angle of 18°; a group showing large errors in the opposite direction to the frame tilt; and a small number with large SDs whose alignment appeared to be random. The errors in the last 3 groups could largely be explained by alignment of the rod to different aspects of the frame. At corresponding ages females exhibited larger alignment errors than males although this did not reach statistical significance. This study confirms that children rely more heavily on the visual frame of reference for processing spatial orientation cues. Most become less frame-dependent as they mature, but there are considerable individual differences.

International audience; BACKGROUND: The Drosophila melanogaster gene CG11501 is up regulated after a septic injury and was proposed to act as a negative regulator of the JAK/STAT signaling pathway. Diedel, the CG11501 gene product, is a small protein of 115 residues with 10 cysteines. METHODOLOGY/PRINCIPAL FINDINGS: We have produced Diedel in Drosophila S2 cells as an extra cellular protein thanks to its own signal peptide and solved its crystal structure at 1.15 Å resolution by SIRAS using an iodo derivative. Diedel is composed of two sub domains SD1 and SD2. SD1 is made of an antiparallel β-sheet covered by an α-helix and displays a ferredoxin-like fold. SD2 reveals a new protein fold made of loops connected by four disulfide bridges. Further structural analysis identified conserved hydrophobic residues on the surface of Diedel that may constitute a potential binding site. The existence of two conformations, cis and trans, for the proline 52 may be of interest as prolyl peptidyl isomerisation has been shown to play a role in several physiological mechanisms. The genome of D. melanogaster contains two other genes coding for proteins homologous to Diedel, namely CG43228 and CG34329. Strikingly, apart from Drosophila and the pea aphid Acyrthosiphon pisum, Diedel-related sequences were exclusively identified in a few insect DNA viruses of the Baculoviridae and Ascoviridae families. CONCLUSION/SIGNIFICANCE: Diedel, a marker of the Drosophila antimicrobial/antiviral response, is a member of a small family of proteins present in drosophilids, aphids and DNA viruses infecting lepidopterans. Diedel is an extracellular protein composed of two sub-domains. Two special structural features (hydrophobic surface patch and cis/trans conformation for proline 52) may indicate a putative interaction site, and support an extra cellular signaling function for Diedel, which is in accordance with its proposed role as negative regulator of the JAK/STAT signaling pathway.

International audience; Mycobacteria develop strategies to evade the host immune system. Among them, mycobacterial LAM or PIMs inhibit the expression of pro-inflammatory cytokines by activated macrophages. Here, using synthetic PIM analogues, we analyzed the mode of action of PIM anti-inflammatory effects. Synthetic PIM(1) isomer and PIM(2) mimetic potently inhibit TNF and IL-12 p40 expression induced by TLR2 or TLR4 pathways, but not by TLR9, in murine macrophages. We show inhibition of LPS binding to TLR4/MD2/CD14 expressing HEK cells by PIM(1) and PIM(2) analogues. More specifically, the binding of LPS to CD14 was inhibited by PIM(1) and PIM(2) analogues. CD14 was dispensable for PIM(1) and PIM(2) analogues functional inhibition of TLR2 agonists induced TNF, as shown in CD14-deficient macrophages. The use of rough-LPS, that stimulates TLR4 pathway independently of CD14, allowed to discriminate between CD14-dependent and CD14-independent anti-inflammatory effects of PIMs on LPS-induced macrophage responses. PIM(1) and PIM(2) analogues inhibited LPS-induced TNF release by a CD14-dependent pathway, while IL-12 p40 inhibition was CD14-independent, suggesting that PIMs have multifold inhibitory effects on the TLR4 signalling pathway.

Guabiraba, Rodrigo Marques, Rafael Elias Besnard, Anne-Gaelle Fagundes, Caio T Souza, Danielle G Ryffel, Bernhard Teixeira, Mauro M PLoS One. 2010 Dec 29;5(12):e15680. doi: 10.1371/journal.pone.0015680.; International audience; Dengue virus (DENV), a mosquito-borne flavivirus, is a public health problem in many tropical countries. Recent clinical data have shown an association between levels of different chemokines in plasma and severity of dengue. We evaluated the role of CC chemokine receptors CCR1, CCR2 and CCR4 in an experimental model of DENV-2 infection in mice. Infection of mice induced evident clinical disease and tissue damage, including thrombocytopenia, hemoconcentration, lymphopenia, increased levels of transaminases and pro-inflammatory cytokines, and lethality in WT mice. Importantly, infected WT mice presented increased levels of chemokines CCL2/JE, CCL3/MIP-1α and CCL5/RANTES in spleen and liver. CCR1⁻/⁻ mice had a mild phenotype with disease presentation and lethality similar to those of WT mice. In CCR2⁻/⁻ mice, lethality, liver damage, levels of IL-6 and IFN-γ, and leukocyte activation were attenuated. However, thrombocytopenia, hemoconcentration and systemic TNF-α levels were similar to infected WT mice. Infection enhanced levels of CCL17/TARC, a CCR4 ligand. In CCR4⁻/⁻ mice, lethality, tissue injury and systemic inflammation were markedly decreased. Despite differences in disease presentation in CCR-deficient mice, there was no significant difference in viral load. In conclusion, activation of chemokine receptors has discrete roles in the pathogenesis of dengue infection. These studies suggest that the chemokine storm that follows severe primary dengue infection associates mostly to development of disease rather than protection.

International audience; Due to the presence of a blastopore as in amphibians, the turtle has been suggested to exemplify a transition form from an amphibian- to an avian-type gastrulation pattern. In order to test this hypothesis and gain insight into the emergence of the unique characteristics of amniotes during gastrulation, we have performed the first molecular characterization of the gastrula in a reptile, the turtle Emys orbicularis. The study of Brachyury, Lim1, Otx2 and Otx5 expression patterns points to a highly conserved dynamic of expression with amniote model organisms and makes it possible to identify the site of mesoderm internalization, which is a long-standing issue in reptiles. Analysis of Brachyury expression also highlights the presence of two distinct phases, less easily recognizable in model organisms and respectively characterized by an early ring-shaped and a later bilateral symmetrical territory. Systematic comparisons with tetrapod model organisms lead to new insights into the relationships of the blastopore/blastoporal plate system shared by all reptiles, with the blastopore of amphibians and the primitive streak of birds and mammals. The biphasic Brachyury expression pattern is also consistent with recent models of emergence of bilateral symmetry, which raises the question of its evolutionary significance.

International audience; Large numbers of protein expression changes are usually observed in mouse models for neurodegenerative diseases, even when only a single gene was mutated in each case. To study the effect of gene dose alterations on the cellular proteome, we carried out a proteomic investigation on murine embryonic stem cells that either overexpressed individual genes or displayed aneuploidy over a genomic region encompassing 14 genes. The number of variant proteins detected per cell line ranged between 70 and 110, and did not correlate with the number of modified genes. In cell lines with single gene mutations, up and down-regulated proteins were always in balance in comparison to parental cell lines regarding number as well as concentration of differentially expressed proteins. In contrast, dose alteration of 14 genes resulted in an unequal number of up and down-regulated proteins, though the balance was kept at the level of protein concentration. We propose that the observed protein changes might partially be explained by a proteomic network response. Hence, we hypothesize the existence of a class of "balancer" proteins within the proteomic network, defined as proteins that buffer or cushion a system, and thus oppose multiple system disturbances. Through database queries and resilience analysis of the protein interaction network, we found that potential balancer proteins are of high cellular abundance, possess a low number of direct interaction partners, and show great allelic variation. Moreover, balancer proteins contribute more heavily to the network entropy, and thus are of high importance in terms of system resilience. We propose that the "elasticity" of the proteomic regulatory network mediated by balancer proteins may compensate for changes that occur under diseased conditions.

International audience; The diffusion of antibiotics in endocarditis vegetation bacterial masses has not been described, although it may influence the efficacy of antibiotic therapy in endocarditis. The objective of this work was to assess the diffusion of ofloxacin in experimental endocarditis vegetation bacterial masses using synchrotron-radiation UV fluorescence microspectroscopy. Streptococcal endocarditis was induced in 5 rabbits. Three animals received an unique IV injection of 150 mg/kg ofloxacin, and 2 control rabbits were left untreated. Two fluorescence microscopes were coupled to a synchrotron beam for excitation at 275 nm. A spectral microscope collected fluorescence spectra between 285 and 550 nm. A second, full field microscope was used with bandpass filters at 510-560 nm. Spectra of ofloxacin-treated vegetations presented higher fluorescence between 390 and 540 nm than control. Full field imaging showed that ofloxacin increased fluorescence between 510 and 560 nm. Ofloxacin diffused into vegetation bacterial masses, although it accumulated in their immediate neighborhood. Fluorescence images additionally suggested an ofloxacin concentration gradient between the vegetation peripheral and central areas. In conclusion, ofloxacin diffuses into vegetation bacterial masses, but it accumulates in their immediate neighborhood. Synchrotron radiation UV fluorescence microscopy is a new tool for assessment of antibiotic diffusion in the endocarditis vegetation bacterial masses.