Effects of internal fluctuations on the spreading of Hantavirus

We study the spread of Hantavirus over a host population of deer mice using a population dynamics model. We show that taking into account the internal fluctuations in the mouse population due to its discrete character strongly alters the behaviour of the system. In addition to the familiar transition present in the deterministic model, the inclusion of internal fluctuations leads to the emergence of an additional deterministically hidden transition. We determine parameter values that lead to maximal propagation of the disease, and discuss some implications for disease prevention policies

A Multiorgan Trafficking Circuit Provides Purifying Selection of Listeria monocytogenes Virulence Genes.

Listeria monocytogenes can cause a life-threatening illness when the foodborne pathogen spreads beyond the intestinal tract to distant organs. Many aspects of the intestinal phase of L. monocytogenes pathogenesis remain unknown. Here, we present a foodborne infection model using C57BL/6 mice that have been pretreated with streptomycin. In this model, as few as 100 L. monocytogenes CFU were required to cause self-limiting enterocolitis, and systemic dissemination followed previously reported routes. Using this model, we report that listeriolysin O (LLO) and actin assembly-inducing protein (ActA), two critical virulence determinants, were necessary for intestinal pathology and systemic spread but were dispensable for intestinal growth. Sequence tag-based analysis of microbial populations (STAMP) was used to investigate the within-host population dynamics of wild-type and LLO-deficient strains. The wild-type bacterial population experienced severe bottlenecks over the course of infection, and by 5 days, the intestinal population was highly enriched for bacteria originating from the gallbladder. In contrast, LLO-deficient strains did not efficiently disseminate and gain access to the gallbladder, and the intestinal population remained diverse. These findings suggest that systemic spread and establishment of a bacterial reservoir in the gallbladder imparts an intraspecies advantage in intestinal occupancy. Since intestinal L. monocytogenes is ultimately released into the environment, within-host population bottlenecks may provide purifying selection of virulence genes.IMPORTANCE Listeria monocytogenes maintains capabilities for free-living growth in the environment and for intracellular replication in a wide range of hosts, including livestock and humans. Here, we characterized an enterocolitis model of foodborne L. monocytogenes infection. This work highlights a multiorgan trafficking circuit and reveals a fitness advantage for bacteria that successfully complete this cycle. Because virulence factors play critical roles in systemic dissemination and multiple bottlenecks occur as the bacterial population colonizes different tissue sites, this multiorgan trafficking circuit likely provides purifying selection of virulence genes. This study also serves as a foundation for future work using the L. monocytogenes-induced enterocolitis model to investigate the biology of L. monocytogenes in the intestinal environment

A Zebrafish Model of Mycobacterium leprae Granulomatous Infection.

Understanding the pathogenesis of leprosy granulomas has been hindered by a paucity of tractable experimental animal models. Mycobacterium leprae, which causes leprosy, grows optimally at approximately 30°C, so we sought to model granulomatous disease in the ectothermic zebrafish. We found that noncaseating granulomas develop rapidly and eventually eradicate infection. rag1 mutant zebrafish, which lack lymphocytes, also form noncaseating granulomas with similar kinetics, but these control infection more slowly. Our findings establish the zebrafish as a facile, genetically tractable model for leprosy and reveal the interplay between innate and adaptive immune determinants mediating leprosy granuloma formation and function

Minimal long-term neurobehavioral impairments after endovascular perforation subarachnoid hemorrhage in mice

AbstractCognitive deficits are among the most severe and pervasive consequences of aneurysmal subarachnoid hemorrhage (SAH). A critical step in developing therapies targeting such outcomes is the characterization of experimentally-tractable pre-clinical models that exhibit multi-domain neurobehavioral deficits similar to those afflicting humans. We therefore searched for neurobehavioral abnormalities following endovascular perforation induction of SAH in mice, a heavily-utilized model. We instituted a functional screen to manage variability in injury severity, then assessed acute functional deficits, as well as activity, anxiety-related behavior, learning and memory, socialization, and depressive-like behavior at sub-acute and chronic time points (up to 1 month post-injury). Animals in which SAH was induced exhibited reduced acute functional capacity and reduced general activity to 1 month post-injury. Tests of anxiety-related behavior including central area time in the elevated plus maze and thigmotaxis in the open field test revealed increased anxiety-like behavior at subacute and chronic time-points, respectively. Effect sizes for subacute and chronic neurobehavioral endpoints in other domains, however, were small. In combination with persistent variability, this led to non-significant effects of injury on all remaining neurobehavioral outcomes. These results suggest that, with the exception of anxiety-related behavior, alternate mouse models are required to effectively analyze cognitive outcomes after SAH.</jats:p

Structured learning of assignment models for neuron reconstruction to minimize topological errors

© 20xx IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works.Structured learning provides a powerful framework for empirical risk minimization on the predictions of structured models. It allows end-to-end learning of model parameters to minimize an application specific loss function. This framework is particularly well suited for discrete optimization models that are used for neuron reconstruction from anisotropic electron microscopy (EM) volumes. However, current methods are still learning unary potentials by training a classifier that is agnostic about the model it is used in. We believe the reason for that lies in the difficulties of (1) finding a representative training sample, and (2) designing an application specific loss function that captures the quality of a proposed solution. In this paper, we show how to find a representative training sample from human generated ground truth, and propose a loss function that is suitable to minimize topological errors in the reconstruction. We compare different training methods on two challenging EM-datasets. Our structured learning approach shows consistently higher reconstruction accuracy than other current learning methods.Peer ReviewedPostprint (author's final draft

Exercise epigenetics and the foetal origins of disease

Exercise epigenetics is a nascent area of research with vast health implications (e.g., from the treatment of obesity-related diseases to beneficially decoupling epigenetic and chronological age). Evidence is accumulating [1] that exercise can acutely modify the epigenome (e.g., via DNA methylation) for short-term regulatory purposes (e.g., mRNA expression). More speculatively perhaps, maternal exercise during the pre and post–partum period could cause epigenetic changes in offspring. It is generally believed that there are benefits of regular moderate exercise during pregnancy [2]. The phenotypic benefits of maternal exercise notwithstanding, exercise can be viewed as a type of organismal stressor [1]. There are a myriad of ways in which environmental perturbations can affect foetal development. For example gestational stress could alter the epigenome and subsequent physical development. We suggest that maternal exercise -- like most gestational stressors -- will have a dose-response relationship on an offspring’s epigenome (i.e., negative effects at high doses), akin to the phenomenon of hormesis. Interestingly there is no research investigating the epigenetic effects of maternal exercise in humans. This editorial is a call for research on the subject