2,242 research outputs found
Alternative models for QTL detection in livestock. I. General introduction
In a series of papers, alternative models for QTL detection in livestock are proposed and their properties evaluated using simulations. This first paper describes the basic model used, applied to independent half-sib families, with marker phenotypes measured for a two or three generation pedigree and quantitative trait phenotypes measured only for the last generation. Hypotheses are given and the formulae for calculating the likelihood are fully described. Different alternatives to this basic model were studied, including variation in the performance modelling and consideration of full-sib families. Their main features are discussed here and their influence on the result illustrated by means of a numerical exampleDans une sĂ©rie dâarticles scientifiques, des modĂšles alternatifs pour la dĂ©tection de (QTLs chez les animaux de ferme sont proposĂ©s et leurs propriĂ©tĂ©s sont Ă©valuĂ©es par simulation. Ce premier article dĂ©crit le modĂšle de base utilisĂ©, qui concerne des familles indĂ©pendantes de demi-germains de pĂšre, avec des phĂ©notypes marqueurs mesurĂ©s sur deux ou trois gĂ©nĂ©rations et des phĂ©notypes quantitatifs mesurĂ©s seulement sur la derniĂšre gĂ©nĂ©ration. Les hypothĂšses sont donnĂ©es et lâexpression de la vraisemblance dĂ©crite en dĂ©tail. Ă partir de ce modĂšle de base, diffĂ©rentes alternatives ont Ă©tĂ© Ă©tudiĂ©es, incluant diverses modĂ©lisations des performances et la prise en compte de structures familiales avec de vrais germains. Leurs principales caractĂ©ristiques sont dĂ©crites et une illustration est donnĂ©
Alternative models for QTL detection in livestock. III. Heteroskedastic model and models corresponding to several distributions of the QTL effect
This paper describes two kinds of alternative models for QTL detection in livestock: an heteroskedastic model, and models corresponding to several hypotheses concerning the distribution of the QTL substitution effect among the sires: a fixed and limited number of alleles or an infinite number of alleles. The power of different tests built with these hypotheses were computed under different situations. The genetic variance associated with the QTL was shown in some situations. The results showed small power differences between the different models, but important differences in the quality of the estimations. In addition, a model was built in a simplified situation to investigate the gain in using possible linkage disequilibrium.Ce papier dĂ©crit deux types de modĂšles alternatifs pour la dĂ©tection de QTL dans les populations animales : un modĂšle hĂ©tĂ©roscĂ©dastique dâune part, et des modĂšles correspondants Ă diffĂ©rentes hypothĂšses sur la distribution de lâeffet de substitution du QTL pour chaque mĂąle : un nombre fixe et limitĂ© dâallĂšles ou au contraire un nombre infini dâallĂšles. Les puissances des diffĂ©rents tests construits avec ces hypothĂšses sont calculĂ©es dans diffĂ©rentes situations. Lâestimation de la variance gĂ©nĂ©tique liĂ©e au QTL est donnĂ©e dans certaines situations. Les rĂ©sultats montrent de faibles diffĂ©rences de puissance entre les diffĂ©rents modĂšles, mais des diffĂ©rences importantes dans la qualitĂ© des estimations. De plus, on construit un modĂšle dans une situation simplifiĂ©e pour Ă©tudier le gain que lâon peut obtenir en utilisant un Ă©ventuel dĂ©sĂ©quilibre de liaison
Macrophage Migration Inhibitory Factor Deficiency Is Associated With Impaired Killing of Gram-Negative Bacteria by Macrophages and Increased Susceptibility to Klebsiella pneumoniae Sepsis
The cytokine macrophage migration inhibitory factor (MIF) is an important component of the early proinflammatory response of the innate immune system. However, the antimicrobial defense mechanisms mediated by MIF remain fairly mysterious. In the present study, we examined whether MIF controls bacterial uptake and clearance by professional phagocytes, using wild-type and MIF-deficient macrophages. MIF deficiency did not affect bacterial phagocytosis, but it strongly impaired the killing of gram-negative bacteria by macrophages and host defenses against gram-negative bacterial infection, as shown by increased mortality in a Klebsiella pneumonia model. Consistent with MIF's regulatory role of Toll-like 4 expression in macrophages, MIF-deficient cells stimulated with lipopolysaccharide or Escherichia coli exhibited reduced nuclear factor ÎșB activity and tumor necrosis factor (TNF) production. Addition of recombinant MIF or TNF corrected the killing defect of MIF-deficient macrophages. Together, these data show that MIF is a key mediator of host responses against gram-negative bacteria, acting in part via a modulation of bacterial killing by macrophage
trained immunity confers broad spectrum protection against bacterial infections
Abstract
Background
The innate immune system recalls a challenge to adapt to a secondary challenge, a phenomenon called trained immunity. Training involves cellular metabolic, epigenetic and functional reprogramming, but how broadly trained immunity protects from infections is unknown. For the first time, we addressed whether trained immunity provides protection in a large panel of preclinical models of infections.
Methods
Mice were trained and subjected to systemic infections, peritonitis, enteritis, and pneumonia induced by Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, Citrobacter rodentium, and Pseudomonas aeruginosa. Bacteria, cytokines, leukocytes, and hematopoietic precursors were quantified in blood, bone marrow, and organs. The role of monocytes/macrophages, granulocytes, and interleukin 1 signaling was investigated using depletion or blocking approaches.
Results
Induction of trained immunity protected mice in all preclinical models, including when training and infection were initiated in distant organs. Trained immunity increased bone marrow hematopoietic progenitors, blood Ly6Chigh inflammatory monocytes and granulocytes, and sustained blood antimicrobial responses. Monocytes/macrophages and interleukin 1 signaling were required to protect trained mice from listeriosis. Trained mice were efficiently protected from peritonitis and listeriosis for up to 5 weeks.
Conclusions
Trained immunity confers broad-spectrum protection against lethal bacterial infections. These observations support the development of trained immunity-based strategies to improve host defenses
Fully human anti-macrophage migration inhibitory factor antibodies as potential therapeutics for sepsis and septic shock
Alternative models for QTL detection in livestock. II. Likelihood approximations and sire marker genotype estimations
Detecting Actions of Fruit Flies
In this thesis we describe a system that tracks fruit flies in video and automatically detects and classifies their actions. We introduce Caltech Fly-vs-Fly Interactions, a new dataset that contains hours of video showing pairs of fruit flies engaging in social interactions, and is published with complete expert annotations and articulated pose trajectory features. We compare experimentally the value of a frame-level feature representation with the more elaborate notion of bout features that capture the structure within actions. Similarly, we compare a simple sliding window classifier architecture with a more sophisticated structured output architecture, and find that window based detectors outperform the much slower structured counterparts, and approach human performance. In addition we test the top performing detector on the CRIM13 mouse dataset, finding that it matches the performance of the best published method. </p
Role of TLR1, TLR2 and TLR6 in the modulation of intestinal inflammation and Candida albicans elimination
Toll-like receptors (TLRs) are the major pattern recognition receptors that mediate sensing of a wide range of microorganisms. TLR2 forms heterodimers with either TLR1 or TLR6, broadening its ligand diversity against pathogens. TLR1, TLR2 and TLR6 have been implicated in the recognition of Candida albicans, an opportunistic fungal pathogen that colonizes the gastrointestinal tract. In this study, we explored whether the deficiency in TLR1, TLR2 or TLR6 impacts C. albicans colonization and inflammation-associated colonic injury in the dextran sulfate sodium (DSS)-induced colitis in mice.
DSS treatment and C. albicans challenge induced greater weight loss, worse clinical signs of inflammation, higher histopathologic scores, and increased mortality rates in TLR1(-/-) and TLR2(-/-) mice when compared to TLR6(-/-) and wild-type mice. The number of C. albicans colonies in the stomach, colon and feces was decreased in TLR6(-/-) mice as compared to TLR2(-/-), TLR1(-/-) and wild-type mice. Interestingly, the population of E. coli in colonic luminal contents, intestinal permeability to FITC-dextran and cytokine expression were significantly increased in TLR1(-/-) and TLR2(-/-) mice, while they were decreased in TLR6(-/-) mice.
In contrast to TLR6, both TLR1 and TLR2 deficiencies increased intestinal inflammation, and the overgrowth of C. albicans and E. coli populations in the colitis model, suggesting the involvement of TLR1 and TLR2 in epithelial homeostasis, and a role of TLR6 in increasing intestinal inflammation in response to pathogen-sensing
Species-Specific Recognition of Aspergillus fumigatus by Toll-like Receptor 1 and Toll-like Receptor 6
Background.âAspergillus fumigatus causes invasive aspergillosis, a potentially fatal infection in oncohematological patients. Innate immune detection of A. fumigatus involves Toll-like receptor (TLR) 4 and TLR2, which forms a heterodimer with either TLR1 or TLR6. The role of those coreceptors in Aspergillus sensing is unknown. Methods.âCytokine production was measured in bone marrow-derived macrophages (BMDMs) from wild-type (WT) and TLR-deficient mice after incubation with a WT and an immunogenic RodA-deficient (ÎrodA-47) strain of A. fumigatus and in lungs from these mice after intranasal mold inoculation. Aspergillus fumigatus-mediated NF-ÎșB activation was measured in HEK293T cells transfected with plasmids expressing mouse or human TLRs. Results.âBone marrow-derived macrophages from TLR1- and TLR6-deficient mice produced lower amounts of interleukin 12p40, CXCL2, interleukin 6, and tumor necrosis factor α than BMDMs from WT mice after stimulation with A. fumigatus. Lungs from TLR1- and TLR6-deficient mice had diminished CXCL1 and CXCL2 production and increased fungal burden after intranasal inoculation of ÎrodA A. fumigatus compared with lungs from WT mice. ÎrodA strain-mediated NF-ÎșB activation was observed in HEK293T cells expressing mouse TLR2/1, mouse TLR2/6, and human TLR2/1 but not human TLR2/6. Conclusions.âInnate immune detection of A. fumigatus is mediated by TLR4 and TLR2 together with TLR1 or TLR6 in mice and TLR1 but not TLR6 in human
Genetic and Pathogenicity Diversity of Aphanomyces euteiches Populations From Pea-Growing Regions in France
Aphanomyces euteiches is an oomycete pathogen with a broad host-range on legumes that causes devastating root rot disease in many pea-growing countries and especially in France. Genetic resistance is a promising way to manage the disease since consistent QTL controlling partial resistance have been identified in near isogenic lines of pea. However, there are still no resistant pea varieties cultivated in France. This study aimed to evaluate the phenotypic and genetic diversity of A. euteiches populations from the major pea-growing regions in France. A collection of 205 isolates, from soil samples collected in infested pea fields located in five French regions, was established and genotyped using 20 SSR markers. Thirteen multilocus genotypes were found among the 205 isolates which displayed a low genotypic richness (ranged from 0 to 0.333). Two main clusters of isolates were identified using PCoA and STRUCTURE, including a predominant group comprising 88% of isolates and another group representing 12% of isolates mainly from the Bourgogne region. A subset of 34 isolates, representative of the fields sampled, was phenotyped for aggressiveness on a set of resistant and susceptible varieties of four legume hosts (pea, faba bean, vetch, alfalfa). Significant differences in disease severity were found among isolates and three groups of aggressiveness comprising 16, 17, and 2 isolates, respectively, were identified using HCA analysis. A higher diversity in pathogen aggressiveness was observed among isolates from Bourgogne, which included different legumes in its crop history. Little relationship was observed between genetic clusters and pathogenicity in the subset of 34 isolates, as expected using neutral markers. This study provides useful knowledge on the current state of low to moderate diversity among A. euteiches populations before resistant pea varieties are grown in France. New insights and hypotheses about the major factors shaping the diversity and evolution of A. euteiches are also discussed
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