Les pratiques pastorales d'un berger sur l'alpage de la Vieille Selle: un modèle reproductible?

Des critères de structuration et de gestion de l’espace sont retenus pour caractériser les pratiques pastorales d’un berger sur un alpage

Verticalization of bacterial biofilms

Biofilms are communities of bacteria adhered to surfaces. Recently, biofilms of rod-shaped bacteria were observed at single-cell resolution and shown to develop from a disordered, two-dimensional layer of founder cells into a three-dimensional structure with a vertically-aligned core. Here, we elucidate the physical mechanism underpinning this transition using a combination of agent-based and continuum modeling. We find that verticalization proceeds through a series of localized mechanical instabilities on the cellular scale. For short cells, these instabilities are primarily triggered by cell division, whereas long cells are more likely to be peeled off the surface by nearby vertical cells, creating an "inverse domino effect". The interplay between cell growth and cell verticalization gives rise to an exotic mechanical state in which the effective surface pressure becomes constant throughout the growing core of the biofilm surface layer. This dynamical isobaricity determines the expansion speed of a biofilm cluster and thereby governs how cells access the third dimension. In particular, theory predicts that a longer average cell length yields more rapidly expanding, flatter biofilms. We experimentally show that such changes in biofilm development occur by exploiting chemicals that modulate cell length.Comment: Main text 10 pages, 4 figures; Supplementary Information 35 pages, 15 figure

Pharmacological levels of withaferin A (Withania somnifera) trigger clinically relevant anticancer effects specific to triple negative breast cancer cells

Withaferin A (WA) isolated from Withania somnifera (Ashwagandha) has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to different concentrations of WA which can be detected systemically in in vivo experiments. Whereas WA treatment demonstrated attenuation of multiple cancer hallmarks, the withanolide analogue Withanone (WN) did not exert any of the described effects at comparable concentrations. Pathway enrichment analysis revealed that WA targets specific cancer processes related to cell death, cell cycle and proliferation, which could be functionally validated by flow cytometry and real-time cell proliferation assays. WA also strongly decreased MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This was further supported by decreased gene expression of extracellular matrix-degrading proteases (uPA, PLAT, ADAM8), cell adhesion molecules (integrins, laminins), pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R) and concomitant increased expression of the validated breast cancer metastasis suppressor gene (BRMS1). In line with the transcriptional changes, nanomolar concentrations of WA significantly decreased protein levels and corresponding activity of uPA in MDA-MB-231 cell supernatant, further supporting its anti-metastatic properties. Finally, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking into account that sub-cytotoxic concentrations of WA target multiple metastatic effectors in therapy-resistant triple negative breast cancer, WA-based therapeutic strategies targeting the uPA pathway hold promise for further (pre)clinical development to defeat aggressive metastatic breast cancer

Immunogenicity and safety of a quadrivalent high-dose inactivated influenza vaccine compared with a standard-dose quadrivalent influenza vaccine in healthy people aged 60 years or older: a randomized Phase III trial

A quadrivalent high-dose inactivated influenza vaccine (IIV4-HD) is licensed for adults 6565 y of age based on immunogenicity and efficacy studies. However, IIV4-HD has not been evaluated in adults aged 60\u201364 y. This study compared immunogenicity and safety of IIV4-HD with a standard-dose quadrivalent influenza vaccine (IIV4-SD) in adults aged 6560 y. This Phase III, randomized, modified double-blind, active-controlled study enrolled 1,528 participants aged 6560 y, randomized 1:1 to a single injection of IIV4-HD or IIV4-SD. Hemagglutination inhibition (HAI) geometric mean titers (GMTs) were measured at baseline and D 28 and seroconversion assessed. Safety was described for 180 d after vaccination. The primary immunogenicity objective was superiority of IIV4-HD versus IIV4-SD, for all four influenza strains 28 d post vaccination in participants aged 60\u201364 and 6565 y. IIV4-HD induced a superior immune response versus IIV4-SD in terms of GMTs in participants aged 60\u201364 y and those aged 6565 y for all four influenza strains. IIV4-HD induced higher GMTs in those aged 60\u201364 y than those aged 6565 y. Seroconversion rates were higher for IIV4-HD versus IIV4-SD in each age-group for all influenza strains. Both vaccines were well tolerated in participants 6560 y of age, with no safety concerns identified. More solicited reactions were reported with IIV4-HD than with IIV4-SD. IIV4-HD provided superior immunogenicity versus IIV4-SD and was well tolerated in adults aged 6560 y. IIV4-HD is assumed to offer improved protection against influenza compared with IIV4-SD in adults aged 6560 y, as was previously assessed for adults aged 6565 y

Pediatric brain tumor cancer stem cells: cell cycle dynamics, DNA repair, and etoposide extrusion

Reliable model systems are needed to elucidate the role cancer stem cells (CSCs) play in pediatric brain tumor drug resistance. The majority of studies to date have focused on clinically distinct adult tumors and restricted tumor types. Here, the CSC component of 7 newly established primary pediatric cell lines (2 ependymomas, 2 medulloblastomas, 2 gliomas, and a CNS primitive neuroectodermal tumor) was thoroughly characterized. Comparison of DNA copy number with the original corresponding tumor demonstrated that genomic changes present in the original tumor, typical of that particular tumor type, were retained in culture. In each case, the CSC component was approximately 3–4-fold enriched in neurosphere culture compared with monolayer culture, and a higher capacity for multilineage differentiation was observed for neurosphere-derived cells. DNA content profiles of neurosphere-derived cells expressing the CSC marker nestin demonstrated the presence of cells in all phases of the cell cycle, indicating that not all CSCs are quiescent. Furthermore, neurosphere-derived cells demonstrated an increased resistance to etoposide compared with monolayer-derived cells, having lower initial DNA damage, potentially due to a combination of increased drug extrusion by ATP-binding cassette multidrug transporters and enhanced rates of DNA repair. Finally, orthotopic xenograft models reflecting the tumor of origin were established from these cell lines. In summary, these cell lines and the approach taken provide a robust model system that can be used to develop our understanding of the biology of CSCs in pediatric brain tumors and other cancer types and to preclinically test therapeutic agents

Microalgae biorefinery alternatives and hazard evaluation

Biodiesel production based on microalgae and using carbon dioxide as feedstock constitutes an attractive biofuel alternative. Technology development and process optimization are necessary to minimize the overall production cost. Moreover, in the framework of process sustainability, social and environmental impacts should include process safety aspects. In this context, the objective of this work is to develop a biodiesel production process based on microalgae and the subsequent estimation of the associated risks, thus contributing to more sustainable and safe processes. The biodiesel biorefinery is optimized, taking into account alternative configurations for algae cultivation and lipid extraction. Algae cultivation options are open ponds and tubular photobioreactors. Regarding lipid extraction, dewatering and subsequent n-hexane extraction, and combined ethanol/n-hexane extraction are the studied alternatives. Numerical results showed that open ponds and n-hexane extraction provide maximum net present value. However, n-hexane consumption dramatically rises, and industrial hazards have not been considered in the optimization process. To overcome this issue, a preliminary hazard analysis is carried out to identify hazardous materials and operations. Event trees are formulated to derive the frequencies of different accident scenarios, further determining the consequences. The major consequences of accidents involve toxic releases of high quantities of n-hexane. By comparing the proposed alternatives, this work aims to highlight the need to consider not only economic but also safety and environmental objectives in the development of a biodiesel production project.The authors are grateful for the financial support provided by CONICET and the Spanish MICINN under projects CTQ2013-48280-C3-1-R and CTM2014-57833-R. J. Pinedo would also like to thank the financial support provided by “Becas Iberoamérica JPI España 2014”

A sex-chromosome mutation in Silene latifolia

Silene latifolia is dioecious, yet rare hermaphrodites have been found, and such natural mutants can provide valuable insight into genetic mechanisms. Here, we describe a hermaphrodite-inducing mutation that is almost certainly localized to the gynoecium-suppression region of the Y chromosome in S. latifolia. The mutant Y chromosome was passed through the megaspore, and the presence of two X chromosomes was not necessary for seed development in the parent. This result supports a lack of degeneration of the Y chromosome in S. latifolia, consistent with the relatively recent formation of the sex chromosomes in this species. When crossed to wild-type plants, hermaphrodites performed poorly as females, producing low seed numbers. When hermaphrodites were pollen donors, the sex ratio of offspring they produced through crosses was biased towards females. This suggests that hermaphroditic S. latifolia would fail to thrive and potentially explains the rarity of hermaphrodites in natural populations of S. latifolia. These results indicate that the Y chromosome in Silene latifolia remains very similar to the X, perhaps mostly differing in the primary sex determination regions

Non-lethal control of the cariogenic potential of an agent-based model for dental plaque

Dental caries or tooth decay is a prevalent global disease whose causative agent is the oral biofilm known as plaque. According to the ecological plaque hypothesis, this biofilm becomes pathogenic when external challenges drive it towards a state with a high proportion of acid-producing bacteria. Determining which factors control biofilm composition is therefore desirable when developing novel clinical treatments to combat caries, but is also challenging due to the system complexity and the existence of multiple bacterial species performing similar functions. Here we employ agent-based mathematical modelling to simulate a biofilm consisting of two competing, distinct types of bacterial populations, each parameterised by their nutrient uptake and aciduricity, periodically subjected to an acid challenge resulting from the metabolism of dietary carbohydrates. It was found that one population was progressively eliminated from the system to give either a benign or a pathogenic biofilm, with a tipping point between these two fates depending on a multiplicity of factors relating to microbial physiology and biofilm geometry. Parameter sensitivity was quantified by individually varying the model parameters against putative experimental measures, suggesting non-lethal interventions that can favourably modulate biofilm composition. We discuss how the same parameter sensitivity data can be used to guide the design of validation experiments, and argue for the benefits of in silico modelling in providing an additional predictive capability upstream from in vitro experiments

Precursor lesions of early onset pancreatic cancer

Early onset pancreatic cancer (EOPC) constitutes less than 5% of all newly diagnosed cases of pancreatic cancer (PC). Although histopathological characteristics of EOPC have been described, no detailed reports on precursor lesions of EOPC are available. In the present study, we aimed to describe histopathological picture of extratumoral parenchyma in 23 cases of EOPCs (definition based on the threshold value of 45 years of age) with particular emphasis on two types of precursor lesions of PC: pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMNs). The types, grades, and densities of precursor lesions of PC were compared in patients with EOPCs, in young patients with neuroendocrine neoplasms (NENs), and in older (at the age of 46 or more) patients with PC. PanINs were found in 95.6% of cases of EOPCs. PanINs-3 were found in 39.1% of EOPC cases. Densities of all PanIN grades in EOPC cases were larger than in young patients with NENs. Density of PanINs-1A in EOPC cases was larger than in older patients with PC, but densities of PanINs of other grades were comparable. IPMN was found only in a single patient with EOPC but in 20% of older patients with PC. PanINs are the most prevalent precursor lesions of EOPC. IPMNs are rarely precursor lesions of EOPC. Relatively high density of low-grade PanINs-1 in extratumoral parenchyma of patients with EOPC may result from unknown multifocal genetic alterations in pancreatic tissue in patients with EOPCs