3D chromatin-based variant-to-gene maps across 57 human cell types reveal the cellular and genetic architecture of autoimmune disease susceptibility.

A portion of the genetic basis for many common autoimmune disorders has been uncovered by genome-wide association studies (GWAS), but GWAS do not reveal causal variants, effector genes, or the cell types impacted by disease-associated variation. We have generated 3D genomic datasets consisting of promoter-focused Capture-C, Hi-C, ATAC-seq, and RNA-seq and integrated these data with GWAS of 16 autoimmune traits to physically map disease-associated variants to the effector genes they likely regulate in 57 human cell types. These 3D maps of gene cis-regulatory architecture are highly powered to identify the cell types most likely impacted by disease-associated genetic variation compared to 1D genomic features, and tend to implicate different effector genes than eQTL approaches in the same cell types. Most of the variants implicated by these cis-regulatory architectures are highly trait-specific, but nearly half of the target genes connected to these variants are shared across multiple autoimmune disorders in multiple cell types, suggesting a high level of genetic diversity and complexity among autoimmune diseases that nonetheless converge at the level of target gene and cell type. Substantial effector gene sharing led to the common enrichment of similar biological networks across disease and cell types. However, trait-specific pathways representing potential areas for disease-specific intervention were identified. To test this, we pharmacologically validated squalene synthase, a cholesterol biosynthetic enzyme encoded by the FDFT1 gene implicated by our approach in MS and SLE, as a novel immunomodulatory drug target controlling inflammatory cytokine production by human T cells. These data represent a comprehensive resource for basic discovery of gene cis-regulatory mechanisms, and the analyses reported reveal mechanisms by which autoimmune-associated variants act to regulate gene expression, function, and pathology across multiple, distinct tissues and cell types.

Respirable dust and crystalline silica exposure among rice mill workers of northeast India.

Crystalline silica is a Group I lung carcinogen primarily known as a causative agent for silicosis. A study was performed to quantify respirable dust, and respirable crystalline silica (RCS) in the rice mills of northeast India. Seventy-two respirable dust samples were collected from the worker's breathing zone from four rice mills at three locations: feeding, sieving, and polishing sections for two paddy varieties: Ranjit and Sali. The National Institute of Occupational Safety and Health (NIOSH), method #7602, was used to determine RCS. The results show that geometric mean TWA dust and RCS emissions in the rice mills varied from 3.97 to 455.00 mg/m3 and 0.02 to 5.38 mg/m3, respectively. RCS exposures were higher during milling of the Sali variety paddy (GM: 0.76 mg/m3) than the Ranjit variety paddy (GM: 0.25 mg/m3). Respirable dust and RCS emissions were considerably higher in the feeding and sieving sections than in the polishing section. Respirable dust and RCS exposure varied significantly (p < 0.001) with paddy variety. Respirable dust and RCS were highly correlated for different rice mills; however, the proportion of RCS in the dust was higher in the Sali variety paddy than in the Ranjit variety paddy. RCS exposure to the workers at the feeding and sieving sections was observed to be higher than the occupational exposure limits (OELs) published by Safe Work Australia, American Conference of Governmental Industrial Hygienists (ACGIH), National Institute for Occupational Safety and Health (NIOSH), Health and Safety Executive (HSE), and Factories Amendment Act, 1987, Government of India.

Mixed methods study on latent tuberculosis among agate stone workers and advocacy for testing silica dust exposed individuals in India.

The 2021 tuberculosis (TB) preventive treatment guidelines in India included silicosis as a screening group, yet latent TB infection (LTBI) testing for silica-dust-exposed individuals is underemphasized. Focusing on an estimated 52 million silica-dust-exposed workers, particularly agate-stone workers in Khambhat, Gujarat, our study aims to estimate LTBI prevalence, identify predictors, and gather insights from TB and silicosis experts. Employing a sequential explanatory mixed-methods approach, a cross-sectional study involved 463 agate-stone workers aged ≥ 20 years in Khambhat, using IGRA kits for LTBI testing. In-depth interviews with experts complemented quantitative findings. Among agate-stone workers, 58% tested positive for LTBI, with predictors including longer exposure, type of work, and BCG vaccination. Our findings reveal a nearly double burden of LTBI compared to the general population, particularly in occupations with higher silica dust exposure. Experts advocate for including silica-dust-exposed individuals in high-risk groups for LTBI testing, exploring cost-effective alternatives like improved skin sensitivity tests, and shorter TB preventive treatment regimens to enhance compliance. Future research should explore upfront TB preventive treatment for silica-dust-exposed individuals with high LTBI prevalence and optimal exposure duration. This study underscores the urgent need for policy changes and innovative approaches to TB prevention among silica-dust-exposed populations, impacting global occupational health strategies.

Multivariate optimization and validation of 200 pesticide residues in the banana matrix by GC-MS/MS.

GC-MS/MS has been observed from past studies to be an appropriate choice for designing a simple, efficient and sensitive analytical technique. Accordingly, the linearity and working range, Method Limit of Detection (MLOD), Method Limit of Quantification (MLOQ), accuracy, precision (intra-day and inter-day), Matrix Effect (ME) and selectivity were analyzed for the assessment of 200 pesticide residues [organophosphorus pesticides (OPP), organochlorine pesticides (OCP), organonitrogen pesticides (ONP), synthetic pyrethroid pesticides (SPP), and herbicide methyl esters (HME)] in the banana matrix. The procedure involved QuEChERS (quick, easy, cheap, effective, rugged, and safe) extraction and clean-up with Multi-Walled Carbon Nanotubes (MWCNTs) and Primary Secondary Amine (PSA) wherein the factors were optimized using the Plackett-Burman and central composite designs. The performance of the method in order to quantitate 200 pesticides at trace levels was evaluated by matrix-matched calibration. The linearity was observed to range from 1 to 100 µg L-1 with determination coefficient (r2) > 0.99. Recovery studies were conducted at 2 levels, 10 µg kg-1 and 25 µg kg-1, and the values obtained were in the range of 71-116% and 72-119%, respectively. The Relative Standard Deviation (RSD) was observed to be less than 20% in line with the recommended guidelines (SANTE/11312/2021). The MLOD and MLOQ were found to be in the range of 0.45-6.33 µg kg-1 and 1.44-9.59 µg kg-1 respectively. The developed method was applied satisfactorily to analyse banana samples cultivated in different regions of Gujarat, India.

Sex Differences in Severity and Risk Factors for Ischemic Stroke in Patients With Hyperlipidemia.

Objective: This study aims to determine sex differences in poststroke hypertriglyceridemia (serum triglyceride levels ⩾ 200 mg/dl) and high stroke severity in ischemic stroke patients. Method: Our study analyzed data from 392 males and 373 females with hypertriglyceridemia. Stroke severity on admission was measured using the National Institute of Health Stroke Scale (NIHSS) with a value ⩽7 indicating a more favorable post-stroke prognosis while a score of >7 indicates poorer post-stroke outcomes. Logistic regression models adjusted for demographic and risk factors. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for each clinical risk factor were used to predict the increasing odds of an association of a specific clinical baseline risk factor with the male or female AIS with hypertriglyceridemia. Results: In the adjusted analysis, male patients with hypertriglyceridemia, diastolic blood pressure (OR = 1.100, 95% CI, 1.034-1.171, P = .002), and Ischemic stroke mortality (OR = 6.474, 95% CI, 3.262-12.847, P < .001) were significantly associated with increased stroke severity. In female patients with hypertriglyceridemia, age (OR = 0.920, 95% CI, 0.866-0.978, P = .008) was associated with reduced stroke severity, while ischemic stroke mortality score (OR = 37.477, 95% CI, 9.636-145.756, P < .001) was associated with increased stroke severity. Conclusion: Increased ischemic stroke mortality risk score was associated with increased severity in both male and female AIS patients with hypertriglyceridemia. Our findings provide information about sex differences in specific risk factors that can be managed to improve the care of male and female ischemic stroke patients with hypertriglyceridemia.

Climate Change, Emerging Vector-Borne Illnesses, and Anesthetic Considerations.

As a result of the widespread prevalence of anesthetic usage, anesthesia-related complications are well studied, ranging from benign postoperative nausea and vomiting to potentially fatal complications, such as paralysis, malignant hyperthermia, and death. However, one intersection that still needs further analysis is the relationship between vector-borne illnesses (VBIs) and anesthetic complications. With the advent of climate change and global warming, what were previously endemic vectors have spread far beyond their typical regions, resulting in the spread of VBI. As the incidence of VBIs rapidly increases in the United States, operations for diagnostic testing, and thus the identification and treatments of these VBIs, have significantly diminished. A literature review was conducted to analyze case reports of patients with VBIs and anesthetic concerns with sources from PubMed and Google Scholar databases, and a wide range of complications were found.

Viral afterlife: SARS-CoV-2 as a reservoir of immunomimetic peptides that reassemble into proinflammatory supramolecular complexes.

It is unclear how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to the strong but ineffective inflammatory response that characterizes severe Coronavirus disease 2019 (COVID-19), with amplified immune activation in diverse cell types, including cells without angiotensin-converting enzyme 2 receptors necessary for infection. Proteolytic degradation of SARS-CoV-2 virions is a milestone in host viral clearance, but the impact of remnant viral peptide fragments from high viral loads is not known. Here, we examine the inflammatory capacity of fragmented viral components from the perspective of supramolecular self-organization in the infected host environment. Interestingly, a machine learning analysis to SARS-CoV-2 proteome reveals sequence motifs that mimic host antimicrobial peptides (xenoAMPs), especially highly cationic human cathelicidin LL-37 capable of augmenting inflammation. Such xenoAMPs are strongly enriched in SARS-CoV-2 relative to low-pathogenicity coronaviruses. Moreover, xenoAMPs from SARS-CoV-2 but not low-pathogenicity homologs assemble double-stranded RNA (dsRNA) into nanocrystalline complexes with lattice constants commensurate with the steric size of Toll-like receptor (TLR)-3 and therefore capable of multivalent binding. Such complexes amplify cytokine secretion in diverse uninfected cell types in culture (epithelial cells, endothelial cells, keratinocytes, monocytes, and macrophages), similar to cathelicidin's role in rheumatoid arthritis and lupus. The induced transcriptome matches well with the global gene expression pattern in COVID-19, despite using <0.3% of the viral proteome. Delivery of these complexes to uninfected mice boosts plasma interleukin-6 and CXCL1 levels as observed in COVID-19 patients.

Increased LL37 in psoriasis and other inflammatory disorders promotes LDL uptake and atherosclerosis.

Patients with chronic inflammatory disorders such as psoriasis have an increased risk of cardiovascular disease and elevated levels of LL37, a cathelicidin host defense peptide that has both antimicrobial and proinflammatory properties. To explore whether LL37 could contribute to the risk of heart disease, we examined its effects on lipoprotein metabolism and show that LL37 enhanced LDL uptake in macrophages through the LDL receptor (LDLR), scavenger receptor class B member 1 (SR-B1), and CD36. This interaction led to increased cytosolic cholesterol in macrophages and changes in expression of lipid metabolism genes consistent with increased cholesterol uptake. Structure-function analysis and synchrotron small-angle x-ray scattering showed structural determinants of the LL37-LDL complex that underlie its ability to bind its receptors and promote uptake. This function of LDL uptake is unique to cathelicidins from humans and some primates and was not observed with cathelicidins from mice or rabbits. Notably, Apoe-/- mice expressing LL37 developed larger atheroma plaques than did control mice, and a positive correlation between plasma LL37 and oxidized phospholipid on apolipoprotein B (OxPL-apoB) levels was observed in individuals with cardiovascular disease. These findings provide evidence that LDL uptake can be increased via interaction with LL37 and may explain the increased risk of cardiovascular disease associated with chronic inflammatory disorders.

3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity.

The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts. Integrating childhood obesity GWAS summary statistics with our existing 3D genomic datasets for 57 human cell types, consisting of high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, and RNA-seq, we applied stratified LD score regression and calculated the proportion of genome-wide SNP heritability attributable to cell type-specific features, revealing pancreatic alpha cell enrichment as the most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out for genome-wide significant childhood obesity loci and their linkage disequilibrium proxies to implicate effector genes, yielded the most abundant number of candidate variants and target genes at the BDNF, ADCY3, TMEM18 and FTO loci in skeletal muscle myotubes and the pancreatic beta-cell line, EndoC-BH1. One novel implicated effector gene, ALKAL2 - an inflammation-responsive gene in nerve nociceptors - was observed at the key TMEM18 locus across multiple immune cell types. Interestingly, this observation was also supported through colocalization analysis using expression quantitative trait loci (eQTL) derived from the Genotype-Tissue Expression (GTEx) dataset, supporting an inflammatory and neurologic component to the pathogenesis of childhood obesity. Our comprehensive appraisal of 3D genomic datasets generated in a myriad of different cell types provides genomic insights into pediatric obesity pathogenesis.

A survey of exposure to the use of Xiaflex for the treatment of Peyronie's disease among United States urology residency programs.

Xiaflex® (collagenase clostridium histolyticum) is a Food and Drug Administration-approved treatment for patients with Peyronie's disease. Despite its approval and implementation, there is concern that urologists in training are offered minimal exposure to its use. Thus, the purpose of this study was to evaluate the exposure of urology residents to Peyronie's disease and its management, particularly Xiaflex®. A Google Forms survey regarding the exposure of residents to Peyronie's disease and use of Xiaflex® was created and disseminated through email to urology programs. Overall, 47 institutional responses were received. At 45 institutions (95.7%), residents receive training in directly evaluating and caring for patients with Peyronie's disease. At 46 institutions (97.9%), residents receive training in observing and/or performing surgical procedures for Peyronie's disease. Residents at 31 institutions (66.0%) receive observational or procedural training for non-surgical management of Peyronie's disease, specifically Xiaflex®. Residents receive non-surgical training from an academic faculty who is fellowship trained in sexual medicine at 25 institutions and an academic faculty not trained in sexual medicine at six institutions. There exists a glaring disparity in residency exposure to Xiaflex®. Further research is warranted to elucidate how programs can provide residents with further exposure to the use of Xiaflex® in patients with Peyronie's disease.

Sarcomatoid Carcinoma of the Lung With Gastrointestinal Metastasis Causing Small Intestinal Obstruction: A Rare Case of Acute Surgical Emergency.

Pulmonary sarcomatoid carcinomas (PSCA) are a rare subset of Non-Squamous-Cell Lung Carcinoma (NSCLC), the most common pathological subtype of lung cancers which are the most common malignancy in the world. These rarest of rare tumours may have gastrointestinal metastasis and present as an acute abdominal surgical emergency with bowel obstruction or bleeding, as in our patient, who did not have a diagnosis of lung cancer till then. Use of novel immunohistochemistry markers like thyroid transcription factor-1 (TTF-1) may help diagnose the site of the primary tumour with accuracy in this clinical setting. Further evaluation of these patients with positron emission tomography (PET) scans helps determine the tumour burden and degree of dissemination. The aim of this article is to emphasize this rare presentation which may be unsuspected as a cause of bowel obstruction by surgical teams on the acute surgical take due to its rarity. It is vital that nihilism is avoided in these patients as a subset of these patients can still be offered curative metastectomy and treatment of the primary tumour with reasonable outcomes.

Evaluation and management of male genital tract infections in the setting of male infertility: an updated review.

PURPOSE OF REVIEW: Male infertility may be secondary to male genital tract infection (MGTI) in an estimated 15% of cases. In the absence of overt clinical signs, evaluation for MGTI beyond semen analysis is not well established. Therefore, we review the literature on the evaluation and management of MGTI in the setting of male infertility. RECENT FINDINGS: A set of international guidelines recommends semen culture and PCR testing, but the significance of positive results remains unclear. Clinical trials evaluating anti-inflammatory or antibiotic treatment report improvements in sperm parameters and leukocytospermia, but data on the effect on conception rates are lacking. Human papillomavirus (HPV) and the novel coronavirus (SARS-CoV-2) have been associated with poor semen parameters and decreased conception rates. SUMMARY: The finding of leukocytospermia on semen analysis prompts further evaluation for MGTI, including focused physical examination. The role of routine semen culture is controversial. Treatment options include anti-inflammatories; frequent ejaculation; and antibiotics, which should not be used in the absence of symptoms or microbiological infection. SARS-CoV-2 represents a subacute threat to fertility that should be screened for in the reproductive history along with HPV and other viruses.

Exploring Mushroom Polysaccharides for the Development of Novel Prebiotics: A Review.

Prebiotics have gained much attention in recent years as functional food ingredients. This has encouraged researchers to look for sustainable alternative sources of prebiotics. Prebiotics help in the modulation of the human intestinal microbiota and thereby improve host health. Chicory, asparagus, and Jerusalem artichoke are some conventional prebiotics that have been extensively studied. Mushrooms are rich sources of medicinal foods as well as bioactive polysaccharides and essential amino acids. They contain large amounts of chitin, mannans, galactans, xylans, glucans, krestin, lentinan, and hemicellulose, thus making it a potential candidate for prebiotics. They are also rich sources of fibers, proteins, and antioxidants. Several mushroom species like Ganoderma lucidum, Pleurotus ostreatus, Hericium erinaceus, Agaricus bisporus, and Lentinula edodes are rich in medicinal properties that have an array of applications. These medicinal mushrooms can be repurposed to regulate gut microbiota. In this review, we discuss the prebiotic effects of different mushroom species on probiotic organisms. We also reviewed the potential of mushroom waste as novel, cheap, and alternative sources of prebiotics.

Majority of men with premature ejaculation do not receive pharmacotherapy.

Premature ejaculation is the most common male sexual dysfunction, with therapies including selective serotonin reuptake inhibitors, clomipramine, topical anesthetics, dapoxetine and tramadol. However, it is currently unknown how many men are receiving pharmacotherapy for premature ejaculation. Using the TriNetX Research network, a large multicenter database containing over 75 million patient records from hospitals across the United States, we evaluated prescribing patterns for treatment of premature ejaculation and assessed variations in prescription patterns among patients from 2015-2021. In addition, we examined if the prescription patterns for tramadol changed with the establishment of Prescription Drug Monitoring Programs. We found that most men (51.7%) were not receiving any pharmacotherapy for premature ejaculation. However, men with mental health disorders, were more likely (56.0%), to have been treated than those without (44.4%). On further analysis, men with mental health diagnoses were significantly more likely to be treated with Selective Serotonin Reuptake Inhibitors (45.0 vs 32.2%) and Tramadol (5.1% vs 3.5%). While the pharmacotherapy for premature ejaculation has been well researched, our findings revealed that most patients diagnosed with premature ejaculation do not receive pharmacotherapy and that patients are more likely to be prescribed premature ejaculation medications if they have a pre-existing mental health diagnosis.

Skeletal muscle metastasis from colorectal adenocarcinoma: A literature review.

BACKGROUND: Colorectal adenocarcinoma is the third most common cancer worldwide. It accounts for almost 10% of all cancer-related deaths. Skeletal muscle is a very unusual site for metastasis from colorectal cancers and is associated with a poor prognosis and high mortality. AIM: To review the literature for cases of skeletal muscle metastasis (SMM) from colorectal adenocarcinoma. METHODS: A systematic literature search using a validated search strategy was carried out to identify the incidence of SMM associated with colorectal adenocarcinoma. The studies identified were tabulated in a PRISMA, and data was extracted in a tabulated form. RESULTS: Twenty-nine studies were included in this literature review. SMM was most commonly detected in the thigh muscles. Most of the tumours had originated from the rectum or the right colon. The histopathology of the primary tumour was generally advanced. The mean time interval between the primary tumour and onset of SMM was 22 mo. In 3 cases, asymptomatic SMM had been picked up by advanced imaging systems, like fluorodeoxyglucose-positron emission tomography scan. CONCLUSION: SMM from colorectal adenocarcinomas is a rare complication. However, it is possible that the low incidence could be due to under-reporting. Early use of advanced imaging techniques and a high index of clinical suspicion might increase the reporting of SMM from colorectal adenocarcinoma.

Impact of Low-Dose Melatonin Supplementation on Testosterone Levels in U.S. Adult Males.

OBJECTIVE: Amidst the rapid rise in melatonin supplementation, decreased testosterone levels amongst males in recent decades, and the unclear association between melatonin and the hypogonadal-pituitary-gland (HPG) axis, this study aimed to further examine the association between melatonin use and testosterone levels among men in a nationally representative sample. METHODS: U.S. men over the age of 18 surveyed from 2011-2016 via the National Health and Nutrition Examination Survey (NHANES) without missing demographic or pertinent health information were included in the analysis. A total testosterone (TT) level of less than 300 ng/dL was considered low. An average daily dose (ADD) was calculated to quantify participants' exposure to melatonin supplementation in the past 30 days. RESULTS: Analysis included 7,656 participants after selection criteria. The median age of participants was 47 [31-63] years old; the median TT level was 389.9 [289 - 513.9] ng/dL. Melatonin intake was reported in 51 (0.7%) individuals with an ADD of 1 [0.4 - 3] mg/day. We found no association between melatonin intake in the past 30 days and low TT levels (OR = 0.958, 95% CI: 0.496 -1.850; P=0.898). As expected, increasing BMI (OR = 1.133, 95% CI: 1.122 - 1.144; P < 0.001) and older age (OR = 1.019, 95% CI: 1.016 - 1.022; P < 0.001) were associated with low TT levels. CONCLUSION: Predominantly low-dose melatonin supplementation was not associated with low TT levels. Future studies are needed to better quantify the relationship between melatonin intake and low TT levels, especially in the setting of supratherapeutic doses and prolonged periods of exposure.

Acute appendicitis in the context of De Garengeot hernia: a case report.

De Garengeot hernia is a rare type of hernia so called when the vermiform appendix is found within the hernia sac of a femoral hernia. For the appendix to be inflamed is yet more uncommon. We present the case of a 61-year-old man who presented with a painful right groin lump. Computed tomography imaging reported an inguinal hernia containing a non-inflamed appendix however, intraoperative findings confirmed a femoral hernia containing an appendix with a necrotic tip. As such, these cases prove a diagnostic challenge as not only are the clinical findings illusive, but the radiological findings are often misleading. Diagnosis is often intraoperative and case reports such as this are useful in highlighting this challenging pathology.

Management of Acute Lower Gastrointestinal Bleeding: A Survey to Assess Adherence to Guidelines Across the United Kingdom and Ireland.

INTRODUCTION: Acute gastrointestinal bleeding (GIB) is a common surgical problem requiring hospitalization in the United Kingdom (UK) and Ireland. The first UK lower gastrointestinal bleeding (LGIB) management guidelines were published in 2019 by the British Society of Gastroenterology (BSG). We aimed to evaluate self-reported adherence to BSG clinical guidance (CG) within the UK and Ireland. METHODS AND MATERIALS: A Questionnaire was designed based on LGIB BSG CG 2019 using Google Forms (Google LLC, Mountain View, CA). This was distributed to surgical consultants and senior surgical practitioners (specialists, Trust grade registrars, and specialist registrars) across different centers in the UK and Ireland over four weeks (13th March to 5th April 2021). Data were analyzed using Statistical Package for Social Sciences (SPSS) version 27 (IBM Corp., Armonk, NY, USA). RESULTS: A total of 64 responses were recorded from 18 different centers in the UK and Ireland. The ratio of consultants and registrars was almost the same (34:30, 53.1%:46.9%). The majority of respondents were from colorectal surgery (65.6%, n=42) followed by general surgeons (23.4%, n=15). A total of 41 respondents (64.1%) admitted that BSG CG 2019 were practically applicable at their center. Approximately 75% of respondents did not use or were unaware of the Shock index or Oakland score to stratify patients. That translated into 59% opting to admit patients with a minor bleed. Around 36% wanted to perform a CT angiogram for a stable major bleed, while 37% were unaware of the interventional radiology (IR) referral pathway. CONCLUSION: There is patchy adherence to the guidelines leading to significant variations in LGIB management practice and avoidable admissions.

Antimicrobials from a feline commensal bacterium inhibit skin infection by drug-resistant S. pseudintermedius.

Methicillin-resistant Staphylococcus pseudintermedius (MRSP) is an important emerging zoonotic pathogen that causes severe skin infections. To combat infections from drug-resistant bacteria, the transplantation of commensal antimicrobial bacteria as a therapeutic has shown clinical promise. We screened a collection of diverse staphylococcus species from domestic dogs and cats for antimicrobial activity against MRSP. A unique strain (S. felis C4) was isolated from feline skin that inhibited MRSP and multiple gram-positive pathogens. Whole genome sequencing and mass spectrometry revealed several secreted antimicrobials including a thiopeptide bacteriocin micrococcin P1 and phenol-soluble modulin beta (PSMß) peptides that exhibited antimicrobial and anti-inflammatory activity. Fluorescence and electron microscopy revealed that S. felis antimicrobials inhibited translation and disrupted bacterial but not eukaryotic cell membranes. Competition experiments in mice showed that S. felis significantly reduced MRSP skin colonization and an antimicrobial extract from S. felis significantly reduced necrotic skin injury from MRSP infection. These findings indicate a feline commensal bacterium that could be utilized in bacteriotherapy against difficult-to-treat animal and human skin infections.

Cutaneous innate immune tolerance is mediated by epigenetic control of MAP2K3 by HDAC8/9.

The skin typically tolerates exposure to various microbes and chemicals in the environment. Here, we investigated how the epidermis maintains this innate immune tolerance to stimuli that are recognized by Toll-like receptors (TLRs). Loss of tolerance to TLR ligands occurred after silencing of the histone deacetylases (HDACs) HDAC8 and HDAC9 in keratinocytes. Transcriptional analysis identified MAP2K3 as suppressed by HDAC8/9 activity and a potential key intermediary for establishing this tolerance. HDAC8/9 influenced acetylation at H3K9 and H3K27 marks in the MAP2K3 promoter. Proteomic analysis further identified SSRP1 and SUPT16H as associated with HDAC8/9 and responsible for transcriptional elongation of MAP2K3. Silencing of MAP2K3 blocked the capacity of HDAC8/9 to influence cytokine responses. Relevance in vivo was supported by observations of increased MAP2K3 in human inflammatory skin conditions and the capacity of keratinocyte HDAC8/9 to influence dendritic cell maturation and T cell proliferation. Keratinocyte-specific deletion of HDAC8/9 also increased inflammation in mice after exposure to ultraviolet radiation, imiquimod, or Staphylococcus aureus These findings define a mechanism for the epidermis to regulate inflammation in the presence of ubiquitous TLR ligands.