Plasmodium falciparum parasite population structure and gene flow associated to anti-malarial drugs resistance in Cambodia

Background: Western Cambodia is recognized as the epicentre of emergence of Plasmodium falciparum multi-drug resistance. The emergence of artemisinin resistance has been observed in this area since 2008–2009 and molecular signatures associated to artemisinin resistance have been characterized in k13 gene. At present, one of the major threats faced, is the possible spread of Asian artemisinin resistant parasites over the world threatening millions of people and jeopardizing malaria elimination programme efforts. To anticipate the diffusion of artemisinin resistance, the identification of the P. falciparum population structure and the gene flow among the parasite population in Cambodia are essential. Methods: To this end, a mid-throughput PCR-LDR-FMA approach based on LUMINEX technology was developed to screen for genetic barcode in 533 blood samples collected in 2010–2011 from 16 health centres in malaria endemics areas in Cambodia. Results: Based on successful typing of 282 samples, subpopulations were characterized along the borders of the country. Each 11-loci barcode provides evidence supporting allele distribution gradient related to subpopulations and gene flow. The 11-loci barcode successfully identifies recently emerging parasite subpopulations in western Cambodia that are associated with the C580Y dominant allele for artemisinin resistance in k13 gene. A subpopulation was identified in northern Cambodia that was associated to artemisinin (R539T resistant allele of k13 gene) and mefloquine resistance. Conclusions: The gene flow between these subpopulations might have driven the spread of artemisinin resistance over Cambodia

Observatoire Scientifique en Appui à la GEstion de la Santé sur un territoire (OSAGE-S)

Dans le contexte « environnement-santé », l’équipe interdisciplinaire (biologistes, médecins, épidémiologistes, modélisateurs, écologues, géographes, informaticiens) qui travaille sur la dynamique de maladies infectieuses dans le Sud-Est asiatique, propose de mettre en commun la connaissance qu’elle a des agents biologiques pathogènes et des processus qui interviennent dans les milieux et les sociétés et de partager expériences de terrain, de laboratoire, clinique pour aborder les questions de recherche, de suivi des maladies et de gestion de la santé. Pour ce faire, l’idée d’une plateforme intégrative a été avancée et nous a permis de décliner la proposition de mise en œuvre d’un Observatoire Scientifique en Appui à la GEstion de la Santé sur un territoire (OSAGE-S). Les prémices de ce travail sont d’une part d’ordre générique et épistémologique : ils explicitent formellement la formule « environnement-santé » pour y positionner le pathosystème, l’environnement et l’observatoire ; d’autre part d’ordre opérationnel par explicitation du concept d’observatoire en appui à la gestion de la Santé. Par la suite nous illustrerons nos propos autour d’OSAGE-S, à partir d’une étude de cas, la maladie du Chikungunya en Indonésie.Within the “Health and Environment” framework, a group of scientists in disciplinary fields as diverse as biology, medical sciences, modelling, ecology, geography, computer sciences, are collaborating to study the dynamics of infectious diseases in Southeast Asia. In this paper they propose to pool their knowledge on biological pathogens, environment and societies and to share their field, laboratory and clinical expertise to address questions on research, disease monitoring and health management. An integrative platform has been suggested and organised in order to implement a Scientific Observatory (OSAGE-S), dedicated to supporting Health Management in a Territory. The first part of this work addresses generic and epistemological questions, formally explicits the formula “Health and Environment” in order to relate it to concepts such as « pathological system », « environment » and « observatory » ; the second part relates to further operational issues for the observatory concept dedicated to the support of Health management. Thereafter we illustrate our proposition with a case study, the Chikungunya disease in Indonesia

HLA-DPB1 and HLA Class I Confer Risk of and Protection from Narcolepsy

Correction: AMERICAN JOURNAL OF HUMAN GENETICS Volume: 96 Issue: 5 Pages: 852-852 DOI: 10.1016/j.ajhg.2015.04.001 Published:MAY 7 2015Peer reviewe

Design and selection of optimal ErbB-targeting bispecific antibodies in pancreatic cancer

The ErbB family of receptor tyrosine kinases is a primary target for small molecules and antibodies for pancreatic cancer treatment. Nonetheless, the current treatments for this tumor are not optimal due to lack of efficacy, resistance, or toxicity. Here, using the novel BiXAb™ tetravalent format platform, we generated bispecific antibodies against EGFR, HER2, or HER3 by considering rational epitope combinations. We then screened these bispecific antibodies and compared them with the parental single antibodies and antibody pair combinations. The screen readouts included measuring binding to the cognate receptors (mono and bispecificity), intracellular phosphorylation signaling, cell proliferation, apoptosis and receptor expression, and also immune system engagement assays (antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity). Among the 30 BiXAbs™ tested, we selected 3Patri-1Cetu-Fc, 3Patri-1Matu-Fc and 3Patri-2Trastu-Fc as lead candidates. The in vivo testing of these three highly efficient bispecific antibodies against EGFR and HER2 or HER3 in pre-clinical mouse models of pancreatic cancer showed deep antibody penetration in these dense tumors and robust tumor growth reduction. Application of such semi-rational/semi-empirical approach, which includes various immunological assays to compare pre-selected antibodies and their combinations with bispecific antibodies, represents the first attempt to identify potent bispecific antibodies against ErbB family members in pancreatic cancer

American Gut: an Open Platform for Citizen Science Microbiome Research

McDonald D, Hyde E, Debelius JW, et al. American Gut: an Open Platform for Citizen Science Microbiome Research. mSystems. 2018;3(3):e00031-18

Compaction behavior and deformation mechanism of directly compressible textured mannitol in a rotary tablet press simulator

International audienceTextured mannitol powder is widely used as a pharmaceutical excipient for tablet compaction. In order to choose the right tableting parameters, it is necessary to understand its mechanical behavior during deformation under industrial tableting conditions. The aim of this study was to evaluate the mechanical behavior during deformation of a textured mannitol using a rotary tablet press simulator. Mean yield pressure (Py) obtained by Heckel modeling, Walker coefficients (W) and Stress Rate Sensitivity (SRS) were compared to reference excipients, known for either their plastic (microcrystalline cellulose) or fragmentary (lactose and dibasic calcium phosphate) deformation behavior. Py, W and SRS values showed that the studied textured mannitol has a fragmentary deformation mechanism. Furthermore, this mechanical behavior was not sensitive to lubrication, which is characteristic of fragmentary excipients