Non-alcoholic fatty liver disease (NAFLD), a common prelude to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. Defining the molecular mechanisms underlying the pathogenesis of NAFLD has been hampered by a lack of animal models that closely recapitulate the severe end of the human disease spectrum, including bridging hepatic fibrosis. Here, we demonstrate that a novel experimental model employing thermoneutral housing, as opposed to standard housing, resulted in lower stress-driven production of corticosterone, augmented mouse proinflammatory immune responses and markedly exacerbated high fat diet (HFD)-induced NAFLD pathogenesis. Disease exacerbation at thermoneutrality was conserved across multiple mouse strains and was associated with augmented intestinal permeability, an altered microbiome and activation of inflammatory pathways associated with human disease. Depletion of Gram-negative microbiota, hematopoietic cell deletion of Toll-like receptor 4 (TLR4) and inactivation of the interleukin-17 (IL-17) axis resulted in altered immune responsiveness and protection from thermoneutral housing-driven NAFLD amplification. Finally, female mice, typically resistant to HFD-induced obesity and NAFLD, develop full-blown disease at thermoneutrality. Thus, thermoneutral housing provides a sex-independent model of exacerbated NAFLD in mice and represents a novel approach for interrogation of the cellular and molecular mechanisms underlying disease pathogenesis.
Preterm birth (PTB) is a leading worldwide cause of morbidity and mortality in infants. Maternal inflammation induced by microbial infection is a critical predisposing factor for PTB. However, biological processes associated with competency of pathogens, including viruses, to induce PTB or sensitize for secondary bacterial infection-driven PTB are unknown. We show that pathogen/pathogen-associated molecular pattern-driven activation of type I IFN/IFN receptor (IFNAR) was sufficient to prime for systemic and uterine proinflammatory chemokine and cytokine production and induction of PTB. Similarly, treatment with recombinant type I IFNs recapitulated such effects by exacerbating proinflammatory cytokine production and reducing the dose of secondary inflammatory challenge required for induction of PTB. Inflammatory challenge-driven induction of PTB was eliminated by defects in type I IFN, TLR, or IL-6 responsiveness, whereas the sequence of type I IFN sensing by IFNAR on hematopoietic cells was essential for regulation of proinflammatory cytokine production. Importantly, we also show that type I IFN priming effects are conserved from mice to nonhuman primates and humans, and expression of both type I IFNs and proinflammatory cytokines is upregulated in human PTB. Thus, activation of the type I IFN/IFNAR axis in pregnancy primes for inflammation-driven PTB and provides an actionable biomarker and therapeutic target for mitigating PTB risk.
High-contrast, high-resolution imaging of biomedical specimens is indispensable for studying organ function and pathologies. Conventional histology, the gold standard for soft-tissue visualization, is limited by its anisotropic spatial resolution, elaborate sample preparation, and lack of quantitative image information. X-ray absorption or phase tomography have been identified as promising alternatives enabling non-destructive, distortion-free three-dimensional (3D) imaging. However, reaching sufficient contrast and resolution with a simple experimental procedure remains a major challenge. Here, we present a solution based on x-ray phase tomography through speckle-based imaging (SBI). We demonstrate on a mouse kidney that SBI delivers comprehensive 3D maps of hydrated, unstained soft tissue, revealing its microstructure and delivering quantitative tissue-density values at a density resolution of better than 2 mg/cm 3 and spatial resolution of better than 8 µm. We expect that SBI virtual histology will find widespread application in biomedicine and will open up new possibilities for research and histopathology.
Methods for automatically isolating and extracting biblio graphic references from the full texts of patents are described and evaluated; these include citations both to patents and to other bibliographic sources. Patents are unusual as citing documents in that citations occur princi pally in the text of the abstracts or description parts of the documents, rather than as footnotes or in separate sections. A template mining approach has been developed for this purpose, to relieve patent examiners of the chore of doing this manually.
Preterm birth (PTB) is the leading cause of neonatal mortality worldwide. Infection and inflammation are considered main causes of PTB. Among multiple pathogens, Gram‐positive bacteria are commonly linked with induction of PTB. Although activation of innate immune responses, via TLR2 engagement, by Gram‐positive bacteria is a likely cause, whether induction of PTB depends on the potency of specific microbial components to induce Toll‐like receptor (TLR)2‐driven inflammation has not been elucidated. Here, we show that TLR2 activation by synthetic lipopeptides, Pam2Cys, and Pam3Cys specifically, variably influenced inflammation and subsequent induction of PTB. Pam2Cys challenge, compared to Pam3Cys, induced PTB and promoted significantly higher expression of inflammatory cytokines, specifically IL‐6 and IFN‐β, both in vivo and in vitro. Notably, antibody‐mediated neutralization of IL‐6 or genetic deletion of type I IFN receptor (IFNAR) was sufficient to protect from Pam2Cys‐driven PTB and to temper excessive proinflammatory cytokine production. Conversely, IFN‐β or IL‐6 was not sufficient to promote induction of PTB by Pam3Cys. In summary, our data implies a divergent function of TLR2‐activating lipopeptides in the magnitude and type of ligand‐driven inflammatory vigor in induction of PTB.
Svalbard is an arctic archipelago where coal mining generates all electricity via the local coal-fired power station. Coal combustion produces a waste product in the form of particulate matter (PM) coal fly ash (CFA), derived from incombustible minerals present in the feed coal. PM ≤10 µm (diameter) may be “inhaled” into the human respiratory system, and particles ≤2.5 µm may enter the distal alveoli to disrupt normal pulmonary functions and trigger disease pathways. This study discovered that Svalbard CFA contained unusually high levels of iron-rich magnetic minerals that induced adverse effects upon human lungs cells. Iron is a well-characterised driver of reactive oxygen species (ROS) generation, a driving force for cell death and disease. CFA physicochemical characterisation showed non-uniform particle morphologies indicative of coal burnt at inefficient combustion temperatures. The bioreactivity (ROS generation) of PM2.5/10 fractions was measured using plasmid scission assay (PSA, DNA damage) and haemolysis assays (erythrocyte lysis), with PM2.5 CFA showing significant bioreactivity. CFA leached in mild acid caused a significant increase in toxicity, which could occur in CFA waste-stores. The CFA and leachates were exposed to a surrogate model of human bronchial epithelia that confirmed that CFA induced apoptosis in bronchial cells. This study shows that CFA containing magnetic iron-rich minerals mediated adverse reactions in the human lung, and thus CFA should be considered to be an environmental inhalation hazard.
Fetal exposure to betamethasone (BMX) as a consequence of glucocorticoid administration to women threatening premature delivery may lead to long-term deleterious effects on the cardiovascular system and dysregulation of blood pressure in exposed adults. Indeed, adult offspring of BMX sheep exhibit increased mean arterial pressure (MAP) and attenuated baroreflex sensitivity (BRS) that are associated with lower medullary and cerebrospinal fluid (CSF) angiotensin-(1–7) [(ANG-(1–7)] content. Thus we determined the effects of ANG-(1–7) supplementation in the CSF on MAP, BRS, blood pressure (BPV) and heart rate variability (HRV) in conscious animals. The peptide or artificial CSF (aCSF) was infused continuously into the lateral ventricle (intracerebroventricular) of 4-mo-old male and female BMX sheep for 2 wk. Analysis of data from males and females combined revealed that intracerebroventricular ANG-(1–7) significantly lowered MAP and heart rate and improved BRS as compared with baseline; intracerebroventricular aCSF did not change these indexes. Similar patterns were observed for altered hemodynamics and autonomic function produced by intracerebroventricular ANG-(1–7) in both sexes. Oxidative stress and MAP kinase (MAPK) activation were lower in tissues from the dorsomedial medulla (DMM) of ANG-(1–7)-treated males but were unchanged in the treated females, when assessed at the end of the treatment period. We conclude that in the face of ANG-(1–7) deficiency in CSF and medullary tissue in BMX sheep intracerebroventricular supplementation of ANG-(1–7) lowers MAP and restores the impaired autonomic function to a similar degree in both males and females; however, the attenuation of MAPK and oxidative stress within the DMM was evident only in males. NEW & NOTEWORTHY We demonstrate that intracerebroventricular angiotensin-(1–7) [(ANG-(1–7)] treatment for 2 wk in antenatal betamethasone-exposed sheep provides beneficial effects on blood pressure and autonomic function. The physiological improvements are accompanied by an attenuation of oxidative stress in males but not females. The finding that ANG-(1–7) supplementation lowers blood pressure and restores the impaired autonomic function in a model of fetal programming previously shown to exhibit a deficiency in cerebrospinal fluid and brain tissue illustrates the potential for new therapeutic strategies for reducing cardiovascular dysfunction arising from prenatal events.
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