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 série d’articles scientifiques, des modèles alternatifs pour la détection de (QTLs chez les animaux de ferme sont proposés et leurs propriétés sont évaluées par simulation. Ce premier article décrit le modèle de base utilisé, qui concerne des familles indépendantes de demi-germains de père, avec des phénotypes marqueurs mesurés sur deux ou trois générations et des phénotypes quantitatifs mesurés seulement sur la dernière génération. Les hypothèses sont données et l’expression de la vraisemblance décrite en détail. À partir de ce modèle de base, différentes alternatives ont été étudiées, incluant diverses modélisations des performances et la prise en compte de structures familiales avec de vrais germains. Leurs principales caractéristiques sont décrites et une illustration est donné

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 décrit deux types de modèles alternatifs pour la détection de QTL dans les populations animales : un modèle hétéroscédastique d’une part, et des modèles correspondants à différentes hypothèses sur la distribution de l’effet de substitution du QTL pour chaque mâle : un nombre fixe et limité d’allèles ou au contraire un nombre infini d’allèles. Les puissances des différents tests construits avec ces hypothèses sont calculées dans différentes situations. L’estimation de la variance génétique liée au QTL est donnée dans certaines situations. Les résultats montrent de faibles différences de puissance entre les différents modèles, mais des différences importantes dans la qualité des estimations. De plus, on construit un modèle dans une situation simplifiée pour étudier le gain que l’on peut obtenir en utilisant un éventuel déséquilibre 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 κB 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

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

Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity

BackgroundAgonistic anti-CD40 monoclonal antibodies (mAbs) have emerged as promising immunotherapeutic compounds with impressive antitumor effects in mouse models. However, preclinical and clinical studies faced dose-limiting toxicities mediated by necroinflammatory liver disease. An effective prophylactic treatment for liver immune-related adverse events that does not suppress specific antitumor immunity remains to be found.MethodsWe used different mouse models and time-resolved single-cell RNA-sequencing to characterize the pathogenesis of anti-CD40 mAb induced liver toxicity. Subsequently, we developed an antibody-based treatment protocol to selectively target red blood cells (RBCs) for erythrophagocytosis in the liver, inducing an anti-inflammatory liver macrophage reprogramming.ResultsWe discovered that CD40 signaling in Clec4f$^{+}$Kupffer cells is the non-redundant trigger of anti-CD40 mAb-induced liver toxicity. Taking advantage of the highly specific functionality of liver macrophages to clear antibody-tagged RBCs from the blood, we hypothesized that controlled erythrophagocytosis and the linked anti-inflammatory signaling by the endogenous metabolite heme could be exploited to reprogram liver macrophages selectively. Repeated low-dose administration of a recombinant murine Ter119 antibody directed RBCs for selective phagocytosis in the liver and skewed the phenotype of liver macrophages into a Hmox$^{high}$/Marco$^{high}$/MHCII$^{low}$anti-inflammatory phenotype. This unique mode of action prevented necroinflammatory liver disease following high-dose administration of anti-CD40 mAbs. In contrast, extrahepatic inflammation, antigen-specific immunity, and antitumor activity remained unaffected in Ter119 treated animals.ConclusionsOur study offers a targeted approach to uncouple CD40-augmented antitumor immunity in peripheral tissues from harmful inflammatoxicity in the liver

Novel Insights into the Bovine Polled Phenotype and Horn Ontogenesis in Bovidae

Despite massive research efforts, the molecular etiology of bovine polledness and the developmental pathways involved in horn ontogenesis are still poorly understood. In a recent article, we provided evidence for the existence of at least two different alleles at the Polled locus and identified candidate mutations for each of them. None of these mutations was located in known coding or regulatory regions, thus adding to the complexity of understanding the molecular basis of polledness. We confirm previous results here and exhaustively identify the causative mutation for the Celtic allele (PC) and four candidate mutations for the Friesian allele (PF). We describe a previously unreported eyelash-and-eyelid phenotype associated with regular polledness, and present unique histological and gene expression data on bovine horn bud differentiation in fetuses affected by three different horn defect syndromes, as well as in wild-type controls. We propose the ectopic expression of a lincRNA in PC/p horn buds as a probable cause of horn bud agenesis. In addition, we provide evidence for an involvement of OLIG2, FOXL2 and RXFP2 in horn bud differentiation, and draw a first link between bovine, ovine and caprine Polled loci. Our results represent a first and important step in understanding the genetic pathways and key process involved in horn bud differentiation in Bovidae