The STAT3/SETDB2 axis dictates NF-κB-mediated inflammation in macrophages during wound repair.

Macrophage transition from an inflammatory to reparative phenotype after tissue injury is controlled by epigenetic enzymes that regulate inflammatory gene expression. We have previously identified that the histone methyltransferase SETDB2 in macrophages drives tissue repair by repressing NF-κB-mediated inflammation. Complementary ATAC-Seq and RNA-Seq of wound macrophages isolated from mice deficient in SETDB2 in myeloid cells revealed that SETDB2 suppresses the inflammatory gene program by inhibiting chromatin accessibility at NF-κB-dependent gene promoters. We found that STAT3 was required for SETDB2 expression in macrophages, yet paradoxically, it also functioned as a binding partner of SETDB2 where it repressed SETDB2 activity by inhibiting its interaction with the NF-κB component, RELA, leading to increased RELA/NF-κB-mediated inflammatory gene expression. Furthermore, RNA-Seq in wound macrophages from STAT3-deficient mice corroborated this and revealed STAT3 and SETDB2 transcriptionally coregulate overlapping genes. Finally, in diabetic wound macrophages, STAT3 expression and STAT3/SETDB2 binding were increased. We have identified what we believe to be a novel STAT3/SETDB2 axis that modulates macrophage phenotype during tissue repair and may be an important therapeutic target for nonhealing diabetic wounds.

Identifying Barriers to the Adoption of Digital Contact Tracing Apps in England: Semistructured Interview Study With Professionals Involved in the Pandemic Response.

BACKGROUND: The NHS (National Health Service) COVID-19 app was a digital contact tracing app (DCTA) used in England in response to the COVID-19 pandemic. The aim of which was to limit the spread of COVID-19 by providing exposure alerts. At the time of the pandemic, questions were raised regarding the effectiveness and cost of the NHS COVID-19 app and whether DCTAs have a role in future pandemics. OBJECTIVE: This study aims to explore key barriers to DCTAs in England during the COVID-19 pandemic. METHODS: This is a qualitative study using semistructured video interviews conducted with professionals in public health, digital health, clinicians, health care law, and health executives who had an active role in the COVID-19 pandemic. These interviews aimed to explore the perspective of different experts involved in the pandemic response and gauge their opinions on the key barriers to DCTAs in England during the COVID-19 pandemic. The initial use of maximum variation sampling combined with a snowball sampling approach ensured diversity within the cohort of interviewees. Interview transcripts were then analyzed using Braun and Clarke's 6 steps for thematic analysis. RESULTS: Key themes that acted as barriers to DCTAs were revealed by interviewees such as privacy concerns, poor communication, technological accessibility, digital literacy, and incorrect use of the NHS COVID-19 app. Interviewees believed that some of these issues stemmed from poor governmental communication and a lack of transparency regarding how the NHS COVID-19 app worked, resulting in decreased public trust. Moreover, interviewees highlighted that a lack of social support integration within the NHS COVID-19 app and delayed app notification period also contributed to the poor adoption rates. CONCLUSIONS: Qualitative findings from interviews highlighted barriers to the NHS COVID-19 app, which can be applied to DCTAs more widely and highlight some important implications for the future use of DCTAS. There was no consensus among interviewees as to whether the NHS COVID-19 app was a success; however, all interviewees provided recommendations for improvements in creating and implementing DCTAs in the future.

Epigenetic Alteration of Smooth Muscle Cells Regulates Endothelin-Dependent Blood Pressure and Hypertensive Arterial Remodeling.

Long-standing hypertension (HTN) affects multiple organ systems and leads to pathologic arterial remodeling, which is driven largely by smooth muscle cell (SMC) plasticity. Although genome wide association studies (GWAS) have identified numerous variants associated with changes in blood pressure in humans, only a small percentage of these variants actually cause HTN. In order to identify relevant genes important in SMC function in HTN, we screened three separate human GWAS and Mendelian randomization studies to identify SNPs located within non-coding gene regions, focusing on genes encoding epigenetic enzymes, as these have been recently identified to control SMC fate in cardiovascular disease. We identified SNPs rs62059712 and rs74480102 in the promoter of the human JMJD3 gene and show that the minor C allele increases JMJD3 transcription in SMCs via increased SP1 binding to the JMJD3 promoter. Using our novel SMC-specific Jmjd3-deficient murine model ( Jmjd3 flox/flox Myh11 CreERT ), we show that loss of Jmjd3 in SMCs results in HTN, mechanistically, due to decreased EDNRB expression and a compensatory increase in EDNRA expression. As a translational corollary, through single cell RNA-sequencing (scRNA-seq) of human arteries, we found strong correlation between JMJD3 and EDNRB expression in SMCs. Further, we identified that JMJD3 is required for SMC-specific gene expression, and loss of JMJD3 in SMCs in the setting of HTN results in increased arterial remodeling by promoting the SMC synthetic phenotype. Our findings link a HTN-associated human DNA variant with regulation of SMC plasticity, revealing therapeutic targets that may be used in the screening and/or personalized treatment of HTN.

Diabetic Wound Keratinocytes Induce Macrophage JMJD3-Mediated Nlrp3 Expression via IL-1R Signaling.

Macrophage (Mφ) plasticity is critical for normal wound repair; however, in type 2 diabetic wounds, Mφs persist in a low-grade inflammatory state that prevents the resolution of wound inflammation. Increased NLRP3 inflammasome activity has been shown in diabetic wound Mφs; however, the molecular mechanisms regulating NLRP3 expression and activity are unclear. Here, we identified that diabetic wound keratinocytes induce Nlrp3 gene expression in wound Mφs through IL-1 receptor-mediated signaling, resulting in enhanced inflammasome activation in the presence of pathogen-associated molecular patterns and damage-associated molecular patterns. We found that IL-1α is increased in human and murine wound diabetic keratinocytes compared with nondiabetic controls and directly induces Mφ Nlrp3 expression through IL-1 receptor signaling. Mechanistically, we report that the histone demethylase, JMJD3, is increased in wound Mφs late post-injury and is induced by IL-1α from diabetic wound keratinocytes, resulting in Nlrp3 transcriptional activation through an H3K27me3-mediated mechanism. Using genetically engineered mice deficient in JMJD3 in myeloid cells (Jmjd3f/flyz2Cre+), we demonstrate that JMJD3 controls Mφ-mediated Nlrp3 expression during diabetic wound healing. Thus, our data suggest a role for keratinocyte-mediated IL-1α/IL-1R signaling in driving enhanced NLRP3 inflammasome activity in wound Mφs. These data also highlight the importance of cell cross-talk in wound tissues and identify JMJD3 and the IL-1R signaling cascade as important upstream therapeutic targets for Mφ NLRP3 inflammasome hyperactivity in nonhealing diabetic wounds.

GZMK+CD8+ T cells Target A Specific Acinar Cell Type in Sjögren's Disease.

Sjögren's Disease (SjD) is a systemic autoimmune disease without a clear etiology or effective therapy. Utilizing unbiased single-cell and spatial transcriptomics to analyze human minor salivary glands in health and disease we developed a comprehensive understanding of the cellular landscape of healthy salivary glands and how that landscape changes in SjD patients. We identified novel seromucous acinar cell types and identified a population of PRR4+CST3+WFDC2- seromucous acinar cells that are particularly targeted in SjD. Notably, GZMK+CD8 T cells, enriched in SjD, exhibited a cytotoxic phenotype and were physically associated with immune-engaged epithelial cells in disease. These findings shed light on the immune response's impact on transitioning acinar cells with high levels of secretion and explain the loss of this specific cell population in SjD. This study explores the complex interplay of varied cell types in the salivary glands and their role in the pathology of Sjögren's Disease.

Emerging Biosensing Methods to Monitor Lung Cancer Biomarkers in Biological Samples: A Comprehensive Review.

Lung cancer is the most commonly diagnosed of all cancers and one of the leading causes of cancer deaths among men and women worldwide, causing 1.5 million deaths every year. Despite developments in cancer treatment technologies and new pharmaceutical products, high mortality and morbidity remain major challenges for researchers. More than 75% of lung cancer patients are diagnosed in advanced stages, leading to poor prognosis. Lung cancer is a multistep process associated with genetic and epigenetic abnormalities. Rapid, accurate, precise, and reliable detection of lung cancer biomarkers in biological fluids is essential for risk assessment for a given individual and mortality reduction. Traditional diagnostic tools are not sensitive enough to detect and diagnose lung cancer in the early stages. Therefore, the development of novel bioanalytical methods for early-stage screening and diagnosis is extremely important. Recently, biosensors have gained tremendous attention as an alternative to conventional methods because of their robustness, high sensitivity, inexpensiveness, and easy handling and deployment in point-of-care testing. This review provides an overview of the conventional methods currently used for lung cancer screening, classification, diagnosis, and prognosis, providing updates on research and developments in biosensor technology for the detection of lung cancer biomarkers in biological samples. Finally, it comments on recent advances and potential future challenges in the field of biosensors in the context of lung cancer diagnosis and point-of-care applications.

Corrigendum: Reprogramming the immunosuppressive tumor microenvironment: exploiting angiogenesis and thrombosis to enhance immunotherapy.

[This corrects the article DOI: 10.3389/fimmu.2023.1200941.].

Reprogramming the immunosuppressive tumor microenvironment: exploiting angiogenesis and thrombosis to enhance immunotherapy.

This review focuses on the immunosuppressive effects of tumor angiogenesis and coagulation on the tumor microenvironment (TME). We summarize previous research efforts leveraging these observations and targeting these processes to enhance immunotherapy outcomes. Clinical trials have documented improved outcomes when combining anti-angiogenic agents and immunotherapy. However, their overall survival benefit over conventional therapy remains limited and certain tumors exhibit poor response to anti-angiogenic therapy. Additionally, whilst preclinical studies have shown several components of the tumor coagulome to curb effective anti-tumor immune responses, the clinical studies reporting combinations of anticoagulants with immunotherapies have demonstrated variable treatment outcomes. By reviewing the current state of the literature on this topic, we address the key questions and future directions in the field, the answers of which are crucial for developing effective strategies to reprogram the TME in order to further the field of cancer immunotherapy.

Generation of LexA enhancer-trap lines in Drosophila by an international scholastic network.

Conditional gene regulation in Drosophila through binary expression systems like the LexA-LexAop system provides a superb tool for investigating gene and tissue function. To increase the availability of defined LexA enhancer trap insertions, we present molecular, genetic, and tissue expression studies of 301 novel Stan-X LexA enhancer traps derived from mobilization of the index SX4 line. This includes insertions into distinct loci on the X, II, and III chromosomes that were not previously associated with enhancer traps or targeted LexA constructs, an insertion into ptc, and seventeen insertions into natural transposons. A subset of enhancer traps was expressed in CNS neurons known to produce and secrete insulin, an essential regulator of growth, development, and metabolism. Fly lines described here were generated and characterized through studies by students and teachers in an international network of genetics classes at public, independent high schools, and universities serving a diversity of students, including those underrepresented in science. Thus, a unique partnership between secondary schools and university-based programs has produced and characterized novel resources in Drosophila, establishing instructional paradigms devoted to unscripted experimental science.

Building digital escape rooms for learning: From theory to practice.

Digital games are increasingly used to support learning across a diverse range of cognitive, affective and psychomotor domains in health professions education. Game-based learning will likely become an important competency for educators. However, educators can perceive game building as out of their reach due to a lack of expertise in digital technology. This toolbox offers advice to health professions educators who would like to build a simple game for learning known as a digital educational escape room.

Effect of honey on cardiometabolic risk factors: a systematic review and meta-analysis.

CONTEXT: Excess calories from free sugars are implicated in the epidemics of obesity and type 2 diabetes. Honey is a free sugar but is generally regarded as healthy. OBJECTIVE: The effect of honey on cardiometabolic risk factors was assessed via a systematic review and meta-analysis of controlled trials using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. DATA SOURCES: MEDLINE, Embase, and the Cochrane Library databases were searched up to January 4, 2021, for controlled trials ≥1 week in duration that assessed the effect of oral honey intake on adiposity, glycemic control, lipids, blood pressure, uric acid, inflammatory markers, and markers of nonalcoholic fatty liver disease. DATA EXTRACTION: Independent reviewers extracted data and assessed risk of bias. Data were pooled using the inverse variance method and expressed as mean differences (MDs) with 95%CIs. Certainty of evidence was assessed using GRADE. DATA ANALYSIS: A total of 18 controlled trials (33 trial comparisons, N = 1105 participants) were included. Overall, honey reduced fasting glucose (MD = -0.20 mmol/L, 95%CI, -0.37 to -0.04 mmol/L; low certainty of evidence), total cholesterol (MD = -0.18 mmol/L, 95%CI, -0.33 to -0.04 mmol/L; low certainty), low-density lipoprotein cholesterol (MD = -0.16 mmol/L, 95%CI, -0.30 to -0.02 mmol/L; low certainty), fasting triglycerides (MD = -0.13 mmol/L, 95%CI, -0.20 to -0.07 mmol/L; low certainty), and alanine aminotransferase (MD = -9.75 U/L, 95%CI, -18.29 to -1.21 U/L; low certainty) and increased high-density lipoprotein cholesterol (MD = 0.07 mmol/L, 95%CI, 0.04-0.10 mmol/L; high certainty). There were significant subgroup differences by floral source and by honey processing, with robinia honey, clover honey, and raw honey showing beneficial effects on fasting glucose and total cholesterol. CONCLUSION: Honey, especially robinia, clover, and unprocessed raw honey, may improve glycemic control and lipid levels when consumed within a healthy dietary pattern. More studies focusing on the floral source and the processing of honey are required to increase certainty of the evidence. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42015023580.

Orthopedic Surgery Causes Gut Microbiome Dysbiosis and Intestinal Barrier Dysfunction in Prodromal Alzheimer Disease Patients: A Prospective Observational Cohort Study.

OBJECTIVE: To investigate gut microbiota and intestinal barrier function changes after orthopedic surgery in elderly patients with either normal cognition (NC) or a prodromal Alzheimer disease phenotype (pAD) comprising either subjective cognitive decline (SCD) or amnestic mild cognitive impairment (aMCI). BACKGROUND: Homeostatic disturbances induced by surgical trauma and/or stress can potentially alter the gut microbiota and intestinal barrier function in elderly patients before and after orthopedic surgery. METHODS: In this prospective cohort study, 135 patients were subject to preoperative neuropsychological assessment and then classified into: NC (n=40), SCD (n=58), or aMCI (n=37). Their gut microbiota, bacterial endotoxin (lipopolysaccharide), tight junction (TJ) protein, and inflammatory cytokines in blood were measured before surgery and on postsurgical day 1, 3, and 7 (or before discharge). RESULTS: The short-chain fatty acid (SCFA)-producing bacteria were lower while the gram-negative bacteria, lipopolysaccharide and TJ were higher preoperatively in both the SCD and aMCI (pAD) groups compared with the NC group. After surgery, a decrease in SCFA-producing bacteria, and an increase in both gram-negative bacteria and plasma claudin were significant in the pAD groups relative to the NC group. SCFA-producing bacteria were negatively correlated with TJ and cytokines in pAD patients on postsurgical day 7. Furthermore, surgery-induced perioperative metabolic stress and inflammatory responses were associated with gut microbiota alterations. CONCLUSIONS: Surgery exacerbates both preexisting microbiota dysbiosis and intestinal barrier dysfunction in pAD patients, all of which may be associated with systemic inflammation and, in turn, may lead to further cognitive deterioration.

Jellyfish Collagen: A Biocompatible Collagen Source for 3D Scaffold Fabrication and Enhanced Chondrogenicity.

Osteoarthritis (OA) is a multifactorial disease leading to degeneration of articular cartilage, causing morbidity in approximately 8.5 million of the UK population. As the dense extracellular matrix of articular cartilage is primarily composed of collagen, cartilage repair strategies have exploited the biocompatibility and mechanical strength of bovine and porcine collagen to produce robust scaffolds for procedures such as matrix-induced chondrocyte implantation (MACI). However, mammalian sourced collagens pose safety risks such as bovine spongiform encephalopathy, transmissible spongiform encephalopathy and possible transmission of viral vectors. This study characterised a non-mammalian jellyfish (Rhizostoma pulmo) collagen as an alternative, safer source in scaffold production for clinical use. Jellyfish collagen demonstrated comparable scaffold structural properties and stability when compared to mammalian collagen. Jellyfish collagen also displayed comparable immunogenic responses (platelet and leukocyte activation/cell death) and cytokine release profile in comparison to mammalian collagen in vitro. Further histological analysis of jellyfish collagen revealed bovine chondroprogenitor cell invasion and proliferation in the scaffold structures, where the scaffold supported enhanced chondrogenesis in the presence of TGFß1. This study highlights the potential of jellyfish collagen as a safe and biocompatible biomaterial for both OA repair and further regenerative medicine applications.

Estimates of the Potential Impact of the COVID-19 Pandemic on Sexual and Reproductive Health In Low- and Middle-Income Countries.

The novel coronavirus (SARS-CoV-2) that causes COVID-19 has spread rapidly since emerging in late 2019, leading the World Health Organization (WHO) to declare the disease a global pandemic on March 11, 2020. Governments around the world have had to quickly adapt and respond to curb transmission of the virus and to provide care for the many who have been infected. The strain that the outbreak imposes on health systems will undoubtedly impact the sexual and reproductive health of individuals living in low- and middle-income countries (LMICs); however, sexual and reproductive health will also be affected by societal responses to the pandemic, such as local or national lockdowns that force health services to shut down if they are not deemed essential, as well as the consequences of physical distancing, travel restrictions and economic slowdowns.

Impact of a Hypothetical Infectious Disease Outbreak on US Exports and Export-Based Jobs.

We estimated the impact on the US export economy of an illustrative infectious disease outbreak scenario in Southeast Asia that has 3 stages starting in 1 country and, if uncontained, spreads to 9 countries. We used 2014-2016 West Africa Ebola epidemic-related World Bank estimates of 3.3% and 16.1% reductions in gross domestic product (GDP). We also used US Department of Commerce job data to calculate export-related jobs at risk to any outbreak-related disruption in US exports. Assuming a direct correlation between GDP reductions and reduced demand for US exports, we estimated that the illustrative outbreak would cost from $16 million to $27 million (1 country) to $10 million to $18 billion (9 countries) and place 1,500 to almost 1.4 million export-related US jobs at risk. Our analysis illustrates how global health security is enhanced, and the US economy is protected, when public health threats are rapidly detected and contained at their source.

Relevance of Global Health Security to the US Export Economy.

To reduce the health security risk and impact of outbreaks around the world, the US Centers for Disease Control and Prevention and its partners are building capabilities to prevent, detect, and contain outbreaks in 49 global health security priority countries. We examine the extent of economic vulnerability to the US export economy posed by trade disruptions in these 49 countries. Using 2015 US Department of Commerce data, we assessed the value of US exports and the number of US jobs supported by those exports. US exports to the 49 countries exceeded $308 billion and supported more than 1.6 million jobs across all US states in agriculture, manufacturing, mining, oil and gas, services, and other sectors. These exports represented 13.7% of all US export revenue worldwide and 14.3% of all US jobs supported by all US exports. The economic linkages between the United States and these global health security priority countries illustrate the importance of ensuring that countries have the public health capacities needed to control outbreaks at their source before they become pandemics.

lep Expression and Its Role in Obesity and Type-2 Diabetes.

Obesity is metabolic disorder that increases the risk of diabetes, heart disease, and other metabolic syndromes in human beings. One sign of diabetes is increased blood glucose levels in the body. Glucose levels increase due to problems with insulin secretion or insulin resistance. Maturity onset of diabetes of the young is more common in adults and occurs due to insulin resistance. Both diabetes and obesity are major problems that are responsible for the death of millions of individuals every year, worldwide. Leptin, a 164-KDa hormone that is secreted by white adipose tissue, is a product of the lep gene. Mutation in lep decreases leptin concentration and increases obesity and type-2 diabetes mellitus. Leptin has been shown to produce positive effects on hunger, energy expenditure, and behavior and is thus useful in the treatment of obesity and type-2 diabetes. Leptin controls appetite through its effect on the hypothalamus in the brain. Both leptin and insulin regulate appetite, body weight, and glucose levels in the body.