BACKGROUND—Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) vary in volume and quality. We evaluated whether fat volume or attenuation (indirect measure of quality) predicts ...metabolic risk factor changes.
METHODS AND RESULTS—Framingham Heart Study Multi-detector Computed Tomography Substudy participants (n=1730, 45% women) were followed up over a mean of 6.2 years. Baseline VAT and SAT volume (in cm) and attenuation (in Hounsfield units) were assessed. Outcomes included blood pressure, lipids, and glucose. We constructed multivariable regression models predicting change from baseline to follow-up. Baseline VAT was associated with metabolic risk factors at follow-up. Per 500-cm increase in baseline VAT, glucose was 2.34 mg/dL higher (95% confidence interval, 1.71–2.97) and high-density lipoprotein was 1.62 mg/dL lower (95% confidence interval, 0.97–2.28) in women (P<0.0001 for both). These findings remained significant after adjustment for body mass index. Results for SAT were similar although less striking. Lower (more negative) fat attenuation was associated with more adverse metabolic profiles at follow-up. For example, per 5-unit decrease in baseline VAT Hounsfield units, log triglycerides increased by 0.08 mg/dL (95% confidence interval, 0.05–0.12; P=0.005), which remained significant after adjustment for baseline VAT. Among men, VAT and SAT Hounsfield units were associated with changes in cardiovascular disease risk factors but were mostly attenuated after baseline volume adjustment.
CONCLUSIONS—VAT volume and SAT volume are associated with incident metabolic risk factors beyond overall adiposity. Decreases in fat attenuation are also associated with incident risk factors. These findings suggest that both volume and quality of VAT and SAT contribute to metabolic risk.
Summary
Background
Human skin is populated by diverse bacteria and there is increasing evidence that resident bacteria play a key role initiating immune responses in cutaneous diseases such as atopic ...dermatitis, psoriasis and hidradenitis suppurativa. Bacteria are present at all layers of the skin but many studies have relied on swabs to profile the skin microbiota.
Objectives
As the pathogenesis of many skin conditions is dermal, we wanted to compare the microbiota obtained in swabs (surface) and biopsies (dermis).
Methods
Using 16S rRNA gene sequencing we established the microbial profiles of skin swabs and skin biopsies in 16 patients.
Results
We found differences in both diversity and taxonomic composition of the microbiome obtained from swabs and biopsies of the same individual. Several taxa were found to be more abundant in the swabs, which displayed significantly higher community richness, but Clostridiales and Bacteroidetes were significantly enriched in the biopsies. Most published research on cutaneous microbiota has been based on skin swabs, which represent the surface of the skin.
Conclusions
Our study demonstrated a clear difference between the microbiome observed from skin swabs and skin biopsies. These findings may be highly relevant in disorders such as psoriasis where pathogenesis arises in the dermis.
What's already known about this topic?
16S RNA gene sequencing has facilitated study of the skin microbiome.
Several studies have sequenced the microbiome sampled by skin swabs.
What does this study add?
The microbiome data obtained using swabs and biopsies were different.
Diseases that are predominantly dermal should be studied using both swabs and biopsies.
Linked Comment: Bernigaud and Chosidow. Br J Dermatol 2019; 181:444–445.
Plain language summary available online
Respond to this article
Transgenic labeling of innate immune cell lineages within the larval zebrafish allows for real-time, in vivo analyses of microbial pathogenesis within a vertebrate host. To date, labeling of ...zebrafish macrophages has been relatively limited, with the most specific expression coming from the mpeg1 promoter. However, mpeg1 transcription at both endogenous and transgenic loci becomes attenuated in the presence of intracellular pathogens, including Salmonella typhimurium and Mycobacterium marinum. Here, we describe mfap4 as a macrophage-specific promoter capable of producing transgenic lines in which transgene expression within larval macrophages remains stable throughout several days of infection. Additionally, we have developed a novel macrophage-specific Cre transgenic line under the control of mfap4, enabling macrophage-specific expression using existing floxed transgenic lines. These tools enrich the repertoire of transgenic lines and promoters available for studying zebrafish macrophage dynamics during infection and inflammation and add flexibility to the design of future macrophage-specific transgenic lines.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Macrophages play a central role in mycobacterial pathogenesis. Recent work has highlighted the importance of diverse macrophage types and phenotypes that depend on local environment and developmental ...origins. In this review, we highlight how distinct macrophage phenotypes may influence disease progression in tuberculosis. In addition, we draw on work investigating specialized macrophage populations important in cancer biology and atherosclerosis in order to suggest new areas of investigation relevant to mycobacterial pathogenesis. Understanding the mechanisms controlling the repertoire of macrophage phenotypes and behaviors during infection may provide opportunities for novel control of disease through modulation of macrophage form and function.
In this review, we highlight the influence of distinct macrophage phenotypes on disease progression in tuberculosis, including similarities to findings about macrophages in cancer biology and atherosclerosis.
Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium ...marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A4 hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B4. We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation.
Display omitted
► Conserved eicosanoids are regulated by LTA4H activity and impact inflammatory state ► Genotype-directed modulation of TNF improves outcomes in a zebrafish tuberculosis model ► Drug therapies tailored to lta4h genotype improve infection outcome in zebrafish ► In humans, LTA4H genotype associates with responsiveness to therapy for TB meningitis
A polymorphism in a locus that controls the balance between pro- and anti-inflammatory mediators is predictive of response to anti-inflammatory therapy in tuberculous meningitis.
During the current COVID-19 pandemic, there has been renewed scientific and public focus on understanding the pathogenesis of infectious diseases and investigating vaccines and therapies to combat ...them. In addition to the tragic toll of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we also recognize increased threats from antibiotic-resistant bacterial strains, the effects of climate change on the prevalence and spread of human pathogens, and the recalcitrance of other infectious diseases – including tuberculosis, malaria, human immunodeficiency virus (HIV) and fungal infections – that continue to cause millions of deaths annually. Large amounts of funding have rightly been redirected toward vaccine development and clinical trials for COVID-19, but we must continue to pursue fundamental and translational research on other pathogens and host immunity. Now more than ever, we need to support the next generation of researchers to develop and utilize models of infectious disease that serve as engines of discovery, innovation and therapy.
Mycobacterium tuberculosis infection in humans triggers formation of granulomas, which are tightly organized immune cell aggregates that are the central structure of tuberculosis. Infected and ...uninfected macrophages interdigitate, assuming an altered, flattened appearance. Although pathologists have described these changes for over a century, the molecular and cellular programs underlying this transition are unclear. Here, using the zebrafish-Mycobacterium marinum model, we found that mycobacterial granuloma formation is accompanied by macrophage induction of canonical epithelial molecules and structures. We identified fundamental macrophage reprogramming events that parallel E-cadherin-dependent mesenchymal-epithelial transitions. Macrophage-specific disruption of E-cadherin function resulted in disordered granuloma formation, enhanced immune cell access, decreased bacterial burden, and increased host survival, suggesting that the granuloma can also serve a bacteria-protective role. Granuloma macrophages in humans with tuberculosis were similarly transformed. Thus, during mycobacterial infection, granuloma macrophages are broadly reprogrammed by epithelial modules, and this reprogramming alters the trajectory of infection and the associated immune response.
Display omitted
•Macrophages mobilize classical epithelial modules during granuloma formation•Macrophage reprogramming shares features of mesenchymal-epithelial transitions•Inhibition of macrophage epithelialization leads to disordered granulomas•Granuloma disruption increases immune access and promotes host survival
A hallmark of tuberculosis is aggregation of macrophages into a structure termed the granuloma. Cronan et al. show that macrophages deploy classical epithelialization pathways to construct mycobacterial granulomas. This reprogramming is host detrimental, as macrophage-specific inhibition of the process enhances host survival and immune cell access and reduces bacterial burden.
Summary
Chronic rhinosinusitis (CRS) has been known as a disease with strong infectious and inflammatory components for decades. The recent advancement in methods identifying microbes has helped ...implicate the airway microbiome in inflammatory respiratory diseases such as asthma and COPD. Such studies support a role of resident microbes in both health and disease of host tissue, especially in the case of inflammatory mucosal diseases. Identifying interactive events between microbes and elements of the immune system can help us to uncover the pathogenic mechanisms underlying CRS. Here we provide a review of the findings on the complex upper respiratory microbiome in CRS in comparison with healthy controls. Furthermore, we have reviewed the defects and alterations of the host immune system that interact with microbes and could be associated with dysbiosis in CRS.
Conjugated porous polymers (CPPs) are a class of fully crosslinked polymers defined by high surface area and porosity in the nanometer range, having been traditionally developed for applications such ...as gas storage, sensing and (photo)catalysis. As these materials are comprised of extended π-conjugation, their ability to act as light harvesters, and in turn photocatalysts, has come to prominence. The insoluble nature of CPPs allows them to be employed as photocatalysts under heterogeneous conditions, replacing traditional homogeneous systems. This Perspective highlights the current state-of-the-art CPPs along with a view to their applications as heterogeneous photocatalysts for a wide range of chemical transformations including hydrogen production, organic synthesis and photopolymerization, just to name but a few.
Conjugated porous polymers (CPPs), a class of fully crosslinked polymers, as heterogeneous photocatalysts are reviewed revealing a wide range of chemical transformations including hydrogen production, organic synthesis and photopolymerization.
PDF
