APOE Protects Against Severe Infection with by Restraining Production of Neutrophil Extracellular Traps.

While neutrophils are the predominant cell type in the lungs of humans with active tuberculosis (TB), they are relatively scarce in the lungs of most strains of mice that are used to study the disease. However, similar to humans, neutrophils account for approximately 45% of CD45+ cells in the lungs of mice on a high-cholesterol (HC) diet following infection with (Mtb). We hypothesized that the susceptibility of HC mice might arise from an unrestrained feed-forward loop in which production of neutrophil extracellular traps (NETs) stimulates production of type I interferons by pDCs which in turn leads to the recruitment and activation of more neutrophils, and demonstrated that depleting neutrophils, depleting plasmacytoid dendritic cells (pDCs), or blocking type I interferon signaling, improved the outcome of infection.

Oxysterol binding protein regulates the resolution of TLR-induced cytokine production in macrophages.

Toll-like receptors (TLRs) on macrophages sense microbial components and trigger the production of numerous cytokines and chemokines that mediate the inflammatory response to infection. Although many of the components required for the activation of the TLR pathway have been identified, the mechanisms that appropriately regulate the magnitude and duration of the response and ultimately restore homeostasis are less well understood. Furthermore, a growing body of work indicates that TLR signaling reciprocally interacts with other fundamental cellular processes, including lipid metabolism but only a few specific molecular links between immune signaling and the macrophage lipidome have been studied in detail.

Host and pathogen genetic diversity shape vaccine-mediated protection to .

To investigate how host and pathogen diversity govern immunity against (Mtb), we performed a large-scale screen of vaccine-mediated protection against aerosol Mtb infection using three inbred mouse strains [C57BL/6 (B6), C3HeB/FeJ (C3H), Balb/c x 129/SvJ (C129F1)] and three Mtb strains (H37Rv, CDC1551, SA161) representing two lineages and distinct virulence properties. We compared three protective modalities, all of which involve inoculation with live mycobacteria: Bacillus Calmette-Guérin (BCG), the only approved TB vaccine, delivered either subcutaneously or intravenously, and concomitant Mtb infection (CoMtb), a model of pre-existing immunity in which a low-level Mtb infection is established in the cervical lymph node following intradermal inoculation. We examined lung bacterial burdens at early (Day 28) and late (Day 98) time points after aerosol Mtb challenge and histopathology at Day 98.

Encephaloduroarteriosynangiosis Procedure: A Treatment Option for Patients With Moyamoya Disease.

Moyamoya disease is a progressive cerebrovascular disorder for which there is no cure. It is characterized by narrowing of and occlusions in the blood vessels that supply the brain, which causes a fine vascular network to develop to serve as collateral pathways. Moyamoya disease can lead to a reduction of blood flow to the brain and increase the risk of stroke.

AgRP neuron activity promotes associations between sensory and nutritive signals to guide flavor preference.

Objective: The learned associations between sensory cues (e.g., taste, smell) and nutritive value (e.

AgRP neuron activity promotes associations between sensory and nutritive signals to guide flavor preference.

Objective: The learned associations between sensory cues (e.g., taste, smell) and nutritive value (e.

How financial mechanisms can incentivize provision of ecosystem services from land restoration: A systematic review protocol.

The current food chain both contributes to, and is affected by, climate change. While GHG emissions and emissions to water and soil are a problem for the whole food chain, the majority of such emissions and the major solutions to them can be found in the farming and land use sector. The farming system needs to reduce its greenhouse-gas emissions and adapt its supply chain to cope with climate change.

Type I interferon decreases macrophage energy metabolism during mycobacterial infection.

Metabolic reprogramming powers and polarizes macrophage functions, but the nature and regulation of this response during infection with pathogens remain controversial. In this study, we characterize the metabolic and transcriptional responses of murine macrophages to Mycobacterium tuberculosis (Mtb) in order to disentangle the underlying mechanisms. We find that type I interferon (IFN) signaling correlates with the decreased glycolysis and mitochondrial damage that is induced by live, but not killed, Mtb.

Use of a Contained Mycobacterium tuberculosis Mouse Infection Model to Predict Active Disease and Containment in Humans.

Previous studies have identified whole-blood transcriptional risk and disease signatures for tuberculosis; however, several lines of evidence suggest that these signatures primarily reflect bacterial burden, which increases before symptomatic disease. We found that the peripheral blood transcriptome of mice with contained Mycobacterium tuberculosis infection (CMTI) has striking similarities to that of humans with active tuberculosis and that a signature derived from these mice predicts human disease with accuracy comparable to that of signatures derived directly from humans. A set of genes associated with immune defense are up-regulated in mice with CMTI but not in humans with active tuberculosis, suggesting that their up-regulation is associated with bacterial containment.

Contained Mycobacterium tuberculosis infection induces concomitant and heterologous protection.

Progress in tuberculosis vaccine development is hampered by an incomplete understanding of the immune mechanisms that protect against infection with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. Although the M72/ASOE1 trial yielded encouraging results (54% efficacy in subjects with prior exposure to Mtb), a highly effective vaccine against adult tuberculosis remains elusive. We show that in a mouse model, establishment of a contained and persistent yet non-pathogenic infection with Mtb ("contained Mtb infection", CMTB) rapidly and durably reduces tuberculosis disease burden after re-exposure through aerosol challenge.

PPARα exacerbates necroptosis, leading to increased mortality in postinfluenza bacterial superinfection.

Patients infected with influenza are at high risk of secondary bacterial infection, which is a major proximate cause of morbidity and mortality. We have shown that in mice, prior infection with influenza results in increased inflammation and mortality upon infection, recapitulating the human disease. Lipidomic profiling of the lungs of superinfected mice revealed an increase in CYP450 metabolites during lethal superinfection.

Alveolar macrophages generate a noncanonical NRF2-driven transcriptional response in vivo.

Alveolar macrophages (AMs) are the first cells to be infected during (M.tb.) infection.

Using mathematical modeling to inform health policy: A case study from voluntary medical male circumcision scale-up in eastern and southern Africa and proposed framework for success.

Background: Modeling contributes to health program planning by allowing users to estimate future outcomes that are otherwise difficult to evaluate. However, modeling results are often not easily translated into practical policies. This paper examines the barriers and enabling factors that can allow models to better inform health decision-making.

Scaling Up Voluntary Medical Male Circumcision for Human Immunodeficiency Virus Prevention for Adolescents and Young Adult Men: A Modeling Analysis of Implementation and Impact in Selected Countries.

Background: The new World Health Organization and Joint United Nations Programme on HIV/AIDS strategic framework for voluntary medical male circumcision (VMMC) aims to increase VMMC coverage among males aged 10-29 years in priority settings to 90% by 2021. We use mathematical modeling to assess the likelihood that selected countries will achieve this objective, given their historical VMMC progress and current implementation options.

Methods: We use the Decision Makers' Program Planning Toolkit, version 2, to examine 4 ambitious but feasible scenarios for scaling up VMMC coverage from 2017 through 2021, inclusive in Lesotho, Malawi, Mozambique, Namibia, South Africa, Swaziland, Tanzania, Uganda, and Zimbabwe.

Correction: Modeling Impact and Cost-Effectiveness of Increased Efforts to Attract Voluntary Medical Male Circumcision Clients Ages 20-29 in Zimbabwe.

[This corrects the article DOI: 10.1371/journal.pone.

Correction: Voluntary Medical Male Circumcision for HIV Prevention in Swaziland: Modeling the Impact of Age Targeting.

[This corrects the article DOI: 10.1371/journal.pone.

Modeling Impact and Cost-Effectiveness of Increased Efforts to Attract Voluntary Medical Male Circumcision Clients Ages 20-29 in Zimbabwe.

Background: Zimbabwe aims to increase circumcision coverage to 80% among 13- to 29-year-olds. However, implementation data suggest that high coverage among men ages 20 and older may not be achievable without efforts specifically targeted to these men, incurring additional costs per circumcision. Scale-up scenarios were created based on trends in implementation data in Zimbabwe, and the cost-effectiveness of increasing efforts to recruit clients ages 20-29 was examined.

Scaling Up and Sustaining Voluntary Medical Male Circumcision: Maintaining HIV Prevention Benefits.

To maintain high circumcision prevalence, voluntary medical male circumcision programs in East and Southern Africa need to plan for sustainability and conduct transition assessments early on, rather than waiting until the saturation of priority targets at the end of the program.

Voluntary Medical Male Circumcision for HIV Prevention in Swaziland: Modeling the Impact of Age Targeting.

Background: Voluntary medical male circumcision (VMMC) for HIV prevention has been a priority for Swaziland since 2009. Initially focusing on men ages 15-49, the Ministry of Health reduced the minimum age for VMMC from 15 to 10 years in 2012, given the existing demand among 10- to 15-year-olds. To understand the implications of focusing VMMC service delivery on specific age groups, the MOH undertook a modeling exercise to inform policy and implementation in 2013-2014.

An LXR-NCOA5 gene regulatory complex directs inflammatory crosstalk-dependent repression of macrophage cholesterol efflux.

LXR-cofactor complexes activate the gene expression program responsible for cholesterol efflux in macrophages. Inflammation antagonizes this program, resulting in foam cell formation and atherosclerosis; however, the molecular mechanisms underlying this antagonism remain to be fully elucidated. We use promoter enrichment-quantitative mass spectrometry (PE-QMS) to characterize the composition of gene regulatory complexes assembled at the promoter of the lipid transporter Abca1 following downregulation of its expression.

Epigenome-guided analysis of the transcriptome of plaque macrophages during atherosclerosis regression reveals activation of the Wnt signaling pathway.

We report the first systems biology investigation of regulators controlling arterial plaque macrophage transcriptional changes in response to lipid lowering in vivo in two distinct mouse models of atherosclerosis regression. Transcriptome measurements from plaque macrophages from the Reversa mouse were integrated with measurements from an aortic transplant-based mouse model of plaque regression. Functional relevance of the genes detected as differentially expressed in plaque macrophages in response to lipid lowering in vivo was assessed through analysis of gene functional annotations, overlap with in vitro foam cell studies, and overlap of associated eQTLs with human atherosclerosis/CAD risk SNPs.

25-Hydroxycholesterol acts as an amplifier of inflammatory signaling.

Cross-talk between sterol regulatory pathways and inflammatory pathways has been demonstrated to significantly impact the development of both atherosclerosis and infectious disease. The oxysterol 25-hydroxycholesterol (25HC) plays multiple roles in lipid biosynthesis and immunity. We recently used a systems biology approach to identify 25HC as an innate immune mediator that had a predicted role in atherosclerosis and we demonstrated a role for 25HC in foam cell formation.

Lessons learned from scale-up of voluntary medical male circumcision focusing on adolescents: benefits, challenges, and potential opportunities for linkages with adolescent HIV, sexual, and reproductive health services.

Background And Methods: By December 2013, it was estimated that close to 6 million men had been circumcised in the 14 priority countries for scaling up voluntary medical male circumcision (VMMC), the majority being adolescents (10-19 years). This article discusses why efforts to scale up VMMC should prioritize adolescent men, drawing from new evidence and experiences at the international, country, and service delivery levels. Furthermore, we review the extent to which VMMC programs have reached adolescents, addressed their specific needs, and can be linked to their sexual and reproductive health and other key services.

Costs and impacts of scaling up voluntary medical male circumcision in Tanzania.

Background: Given the proven effectiveness of voluntary medical male circumcision (VMMC) in preventing the spread of HIV, Tanzania is scaling up VMMC as an HIV prevention strategy. This study will inform policymakers about the potential costs and benefits of scaling up VMMC services in Tanzania.

Methodology: The analysis first assessed the unit costs of delivering VMMC at the facility level in three regions-Iringa, Kagera, and Mbeya-via three currently used VMMC service delivery models (routine, campaign, and mobile/island outreach).

Urokinase plasminogen activator induces pro-fibrotic/m2 phenotype in murine cardiac macrophages.

Objective: Inflammation and fibrosis are intertwined in multiple disease processes. We have previously found that over-expression of urokinase plasminogen activator in macrophages induces spontaneous macrophage accumulation and fibrosis specific to the heart in mice. Understanding the relationship between inflammation and fibrosis in the heart is critical to developing therapies for diverse myocardial diseases.