Hypoxia promotes chemoresistance in acute lymphoblastic leukemia cell lines by modulating death signaling pathways

International audienceBackground: Several studies show that bone marrow (BM) microenvironment and hypoxia condition can promote the survival of leukemic cells and induce resistance to anti-leukemic drugs. However, the molecular mechanism for chemoresistance by hypoxia is not fully understood.Methods: In the present study, we investigated the effect of hypoxia on resistance to two therapies, methotrexate (MTX) and prednisolone (PRD), in two cell models for acute lymphoblastic leukemia (ALL). To look for an implication of hypoxia in chemoresistance, cell viability, total cell density and cell proliferation were analyzed. Survival and death signaling pathways were also screened by "reverse phase protein array" (RPPA) and western blotting experiments conducted on selected proteins to confirm the results.Results: We found that hypoxia promotes chemoresistance in both ALL cell lines. The induction of drug-resistance by hypoxia was not associated with an increase in total cell density nor an increase in cell proliferation. Using RPPA, we show that chemoresistance induced by hypoxia was mediated through an alteration of cell death signaling pathways. This protective effect of hypoxia seems to occur via a decrease in pro-apoptotic proteins and an increase in anti-apoptotic proteins. The results were confirmed by immunoblotting. Indeed, hypoxia is able to modulate the expression of anti-apoptotic proteins independently of chemotherapy while a pro-apoptotic signal induced by a chemotherapy is not modulated by hypoxia.Conclusions: Hypoxia is a factor in leukemia cell resistance and for two conventional chemotherapies modulates cell death signaling pathways without affecting total cell density or cell proliferation

Gravity Currents in Aquatic Canopies

A lock exchange experiment is used to investigate the propagation of gravity currents through a random array of rigid, emergent cylinders which represents a canopy of aquatic plants. As canopy drag increases, the propagating front varies from the classic profile of an unobstructed gravity current to a triangular profile. Unlike the unobstructed lock exchange, the gravity current in the canopy decelerates with time as the front lengthens. Two drag-dominated regimes associated with linear and nonlinear drag laws are identified. The theoretical expression for toe velocity is supported by observed values. Empirical criteria are developed to predict the current regime from the cylinder Reynolds number and the array density.National Science Foundation (U.S.) (grant EAR0309188)National Science Foundation (U.S.) (grant EAR0509658)Massachusetts Institute of Technology (Presidential Graduate Fellowship

Actuator Saturation in Individual Blade Control of Rotorcraft

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97053/1/AIAA2012-1477.pd

A Survey of Volunteered Open Geo-Knowledge Bases in the Semantic Web

Over the past decade, rapid advances in web technologies, coupled with innovative models of spatial data collection and consumption, have generated a robust growth in geo-referenced information, resulting in spatial information overload. Increasing 'geographic intelligence' in traditional text-based information retrieval has become a prominent approach to respond to this issue and to fulfill users' spatial information needs. Numerous efforts in the Semantic Geospatial Web, Volunteered Geographic Information (VGI), and the Linking Open Data initiative have converged in a constellation of open knowledge bases, freely available online. In this article, we survey these open knowledge bases, focusing on their geospatial dimension. Particular attention is devoted to the crucial issue of the quality of geo-knowledge bases, as well as of crowdsourced data. A new knowledge base, the OpenStreetMap Semantic Network, is outlined as our contribution to this area. Research directions in information integration and Geographic Information Retrieval (GIR) are then reviewed, with a critical discussion of their current limitations and future prospects

Dog Burials Associated with Human Burials in the West Indies during the Early Pre-Columbian Ceramic Age (500 BC-600 AD)

Across the Caribbean, the widespread presence of canine remains at archaeological sites from the Saladoid period raises questions about the role of “man’s best friend.” Dog (Canis familiaris) remains have been found located in both refuse middens and burials adjacent to human graves in a number of sites in the French Antilles and Barbuda, West Indies. This paper will critically examine dog remains and discuss the varied duality of the dog’s role in the Saladoid world: from food source to lifelong companion. The importance of dogs within Amerindian sites from Saint Martin, the Guadeloupe archipelago, Martinique and Barbuda will be explored from a zooarchaeological perspective, concluding with a critical discussion of changes in cultural patterns, as seen through the decline in dog remains during the Troumassoid and Suazoid period at the sites in the French Antilles. Résumé Sépultures de chiens associées à des sépultures humaines dans les Petites Antilles à l’Âge du Néoindien ancien (500 av. – 600 ap. J.-C.). Dans les Antilles, la présence généralisée de restes de chiens sur les sites de la période céramique ancienne Saladoïde soulève des questions sur le rôle de ce « meilleur ami de l’homme ». En effet, des chiens (Canis familiaris) ont été trouvés aussi bien dans des zones de rejets, qu’enterrés aux côtés de sépultures humaines dans un certain nombre de sites des Petites Antilles. Ce document examinera ces restes de chiens de façon critique et décrira les morphologies particulières des chiens des sites amérindiens de l’île de Saint-Martin, l\u27archipel de la Guadeloupe, la Martinique et de l’île de Barbuda, dans une perspective archéozoologique. Une discussion critique portera sur l\u27évolution des changements des modèles culturels, comme celui de la chute drastique des chiens enterrés pendant les périodes archéologiques plus tardives, Troumassoïde et Suazoïde, des sites des Antilles françaises. Enfin, la discussion portera sur la dualité du rôle du chien dans le monde Saladoïde, à la fois source de nourriture et compagnon de vie

Rise and fall of island butterfly diversity : understanding genetic differentiation and extinction in a highly diverse archipelago

Aim. We describe fine-scale diversity patterns of the entire butterfly fauna occurring on the Tuscan Archipelago. By assessing the traits associated with population diversification, haplotype uniqueness and extinction, we aim to identify the factors determining the origin and maintenance of genetic diversity, and population vulnerability to environmental changes. Location. Tuscan Archipelago, Sardinia, Tuscany (Italy) and Corsica (France). Methods. We built a mtDNA dataset (1,303 COI sequences) for the 52 butterfly species reported in the Archipelago, also including specimens from neighbouring areas, and compiled data on 12 species traits and on the apparent extinction of species from the main islands. We calculated indices that measure genetic differentiation, and using phylogenetic regressions we evaluated the relationships between these indices and species traits. Finally, we inferred which traits are associated with disappearance of species on individual islands using phylogenetic regression. Results. The overall spatial pattern of genetic diversity corresponded with the proximity of the areas, but strong contrasts were also identified between geographically close areas. Together with the island endemics, several common and widespread species had a high genetic diversification among islands and mainland. Phylogenetic regressions revealed that smaller-sized, more specialized species, with a preference for drier regions, displayed greater genetic structure and/or haplotype uniqueness. Species that disappeared from islands had a higher population diversification. Capraia has experienced a notable loss of diversity, which significantly affected species with shorter flight periods. Main conclusions. Tuscan island butterflies are characterized by strong genetic contrasts and species differ in their contribution to the overall genetic diversity. By ranking the species for their contribution to genetic diversity and identifying the traits linked to the emergence and maintenance of diversity, we have developed a valuable tool for prioritizing populations as targets for monitoring and conservation action. The dataset constructed also represents a valuable resource for testing biogeographical hypotheses

Deep-sequencing reveals broad subtype-specific HCV resistance mutations associated with treatment failure

A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients. A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) a-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers. Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received. HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of “extra-target” RAS suggests the need for RAS screening in all three DAA target regions

The impact of the Fungus-Host-Microbiota interplay upon Candida albicans infections: current knowledge and new perspectives

This is the final version. Available on open access from Oxford University Press via the DOI in this recordCandida albicans is a major fungal pathogen of humans. It exists as a commensal in the oral cavity, gut or genital tract of most individuals, constrained by the local microbiota, epithelial barriers and immune defences. Their perturbation can lead to fungal outgrowth and the development of mucosal infections such as oropharyngeal or vulvovaginal candidiasis, and patients with compromised immunity are susceptible to life-threatening systemic infections. The importance of the interplay between fungus, host and microbiota in driving the transition from C. albicans commensalism to pathogenicity is widely appreciated. However, the complexity of these interactions, and the significant impact of fungal, host and microbiota variability upon disease severity and outcome, are less well understood. Therefore, we summarise the features of the fungus that promote infection, and how genetic variation between clinical isolates influences pathogenicity. We discuss antifungal immunity, how this differs between mucosae, and how individual variation influences a person's susceptibility to infection. Also, we describe factors that influence the composition of gut, oral and vaginal microbiotas, and how these affect fungal colonisation and antifungal immunity. We argue that a detailed understanding of these variables, which underlie fungal-host-microbiota interactions, will present opportunities for directed antifungal therapies that benefit vulnerable patients