HDAC9 in the Injury of Vascular Endothelial Cell Mediated by P38 MAPK Pathway.

Ischemic stroke caused by atherosclerosis (AS) poses a serious threat to human life expectancy and quality. With the development of genome-wide association studies, the association of histone deacetylase 9 (HDAC9) expression of atheromatous plaques with ischemic stroke in large arteries has been revealed, but the molecular mechanisms behind this phenomenon have not been elucidated. In this study, we explored the effect of HDAC9 on the P38 mitogen activated protein kinase (P38 MAPK), a classic cellular inflammation-related pathway, by knocking down HDAC9 in vascular endothelial cells with short hairpin RNA (shRNA) and found that HDAC9 may mediate oxidized low density lipoprotein (ox-LDL)-induced inflammatory injury in vascular endothelial cells by regulating the phosphorylation level of P38 MAPK to lead to AS. It can be seen that HDAC9 may be a target to control the formation of atherosclerotic plaques. In follow-up experiments, it was verified that sodium valproate (SVA), as a HDAC9 inhibitor, can indeed antagonize the inflammatory damage of vascular endothelial cells, as well as SB203580, which is a P38 MAPK inhibitor. It proves that SVA may be a potential drug for the prevention and treatment of ischemic stroke.

Microplastics increase susceptibility of amphibian larvae to the chytrid fungus Batrachochytrium dendrobatidis.

Microplastics (MPs), a new class of pollutants that pose a threat to aquatic biodiversity, are of increasing global concern. In tandem, the amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd) causing the disease chytridiomycosis is emerging worldwide as a major stressor to amphibians. We here assess whether synergies exist between this infectious disease and MP pollution by mimicking natural contact of a highly susceptible species (midwife toads, Alytes obstetricans) with a Bd-infected reservoir species (fire salamanders, Salamandra salamandra) in the presence and absence of MPs. We found that MP ingestion increases the burden of infection by Bd in a dose-dependent manner. However, MPs accumulated to a greater extent in amphibians that were not exposed to Bd, likely due to Bd-damaged tadpole mouthparts interfering with MP ingestion. Our experimental approach showed compelling interactions between two emergent processes, chytridiomycosis and MP pollution, necessitating further research into potential synergies between these biotic and abiotic threats to amphibians.

Regulatory T-Cell Therapy in Liver Transplantation and Chronic Liver Disease.

The constant exposure of the liver to gut derived foreign antigens has resulted in this organ attaining unique immunological characteristics, however it remains susceptible to immune mediated injury. Our understanding of this type of injury, in both the native and transplanted liver, has improved significantly in recent decades. This includes a greater awareness of the tolerance inducing CD4+ CD25+ CD127low T-cell lineage with the transcription factor FoxP3, known as regulatory T-Cells (Tregs). These cells comprise 5-10% of CD4+ T cells and are known to function as an immunological "braking" mechanism, thereby preventing immune mediated tissue damage. Therapies that aim to increase Treg frequency and function have proved beneficial in the setting of both autoimmune diseases and solid organ transplantations. The safety and efficacy of Treg therapy in liver disease is an area of intense research at present and has huge potential. Due to these cells possessing significant plasticity, and the potential for conversion towards a T-helper 1 (Th1) and 17 (Th17) subsets in the hepatic microenvironment, it is pre-requisite to modify the microenvironment to a Treg favourable atmosphere to maintain these cells' function. In addition, implementation of therapies that effectively increase Treg functional activity in the liver may result in the suppression of immune responses and will hinder those that destroy tumour cells. Thus, fine adjustment is crucial to achieve this immunological balance. This review will describe the hepatic microenvironment with relevance to Treg function, and the role these cells have in both native diseased and transplanted livers.

Per- and polyfluoroalkyl substances, epigenetic age and DNA methylation: a cross-sectional study of firefighters.

Background: Per- and polyfluoroalkyl substances (PFASs) are persistent chemicals that firefighters encounter. Epigenetic modifications, including DNA methylation, could serve as PFASs toxicity biomarkers. Methods: With a sample size of 197 firefighters, we quantified the serum concentrations of nine PFASs, blood leukocyte DNA methylation and epigenetic age indicators via the EPIC array. We examined the associations between PFASs with epigenetic age, site- and region-specific DNA methylation, adjusting for confounders. Results: Perfluorohexane sulfonate, perfluorooctanoate (PFOA) and the sum of branched isomers of perfluorooctane sulfonate (Sm-PFOS) were associated with accelerated epigenetic age. Branched PFOA, linear PFOS, perfluorononanoate, perfluorodecanoate and perfluoroundecanoate were associated with differentially methylated loci and regions. Conclusion: PFASs concentrations are associated with accelerated epigenetic age and locus-specific DNA methylation. The implications for PFASs toxicity merit further investigation.

Brain-Based Biotypes of Psychiatric Vulnerability in the Acute Aftermath of Trauma.

OBJECTIVE: Major negative life events, such as trauma exposure, can play a key role in igniting or exacerbating psychopathology. However, few disorders are diagnosed with respect to precipitating events, and the role of these events in the unfolding of new psychopathology is not well understood. The authors conducted a multisite transdiagnostic longitudinal study of trauma exposure and related mental health outcomes to identify neurobiological predictors of risk, resilience, and different symptom presentations. METHODS: A total of 146 participants (discovery cohort: N=69; internal replication cohort: N=77) were recruited from emergency departments within 72 hours of a trauma and followed for the next 6 months with a survey, MRI, and physiological assessments. RESULTS: Task-based functional MRI 2 weeks after a motor vehicle collision identified four clusters of individuals based on profiles of neural activity reflecting threat reactivity, reward reactivity, and inhibitory engagement. Three clusters were replicated in an independent sample with a variety of trauma types. The clusters showed different longitudinal patterns of posttrauma symptoms. CONCLUSIONS: These findings provide a novel characterization of heterogeneous stress responses shortly after trauma exposure, identifying potential neuroimaging-based biotypes of trauma resilience and psychopathology.

Pneumonia, Sinusitis, Influenza and Other Respiratory Illnesses in Acute Otitis Media-Prone Children.

BACKGROUND: Recurrent acute otitis media in the first years of life can be explained by immune dysfunction. Consequently, it would be expected that otitis-prone (OP) children would be more susceptible to other infectious diseases, especially respiratory infections, since a component of the immune problem involves nasopharyngeal innate immunity. DESIGN: Cohort study with prospective identification of all physician-diagnosed, medically attended respiratory illness visits in children 6 months to 5 years of age to determine the incidence of pneumonia, acute sinusitis, influenza and other bacterial and viral infections among OP compared with non-OP (NOP) children. Tympanocentesis to microbiologically confirm acute otitis media disease. RESULTS: Two hundred eighty-five children were studied. Thirty-nine met a standard definition of stringently defined OP (sOP) determined by tympanocentesis and 246 were NOP. sOP children had increased frequency of presumptive respiratory infections, pneumonia (6-fold higher, P < 0.001), sinusitis (2.1-fold higher, P = 0.026) and influenza (2.9-fold higher, P = 0.002), compared with NOP children. Demographic and risk factor covariate-adjusted fold difference between sOP and NOP children for all respiratory infection illness visits was 2.4-fold (P < 0.00001) at 6-18 months of age, 2.2-fold (P < 0.00001) at 18-30 months of age and at age and 2.4-fold (P = 0.035) higher at 30 to 42 months. For both sOP and NOP children, more frequent medically attended respiratory infection illness visits from 6-18 months of age predicted more frequent visits experienced from 18-60 months of age. CONCLUSIONS: Clinicians should be aware of a significant increased likelihood of bacterial and viral respiratory infection proneness among OP children.

Gastrin and the Moderate Hypergastrinemias.

The antral hormone gastrin potently regulates gastric acid secretion and fundic mucosal growth. Consequently, appropriate gastrin secretion and plasma concentrations are important for the early phases of digestion. This review describes as the first premise the normal biogenesis of gastrin in the antral mucosa, but also mentions the extraantral expression. Subsequently, the molecular nature and concentration levels of gastrin in serum or plasma are overviewed. Third, assays for accurate measurements of plasma or serum concentrations are commented. Finally, the problem of moderate hypergastrinemia due to Helicobacter pylori infections and/or treatment with proton-pump inhibitors (PPI) is discussed. The review concludes that accurate measurement of the true concentrations of bioactive gastrins in plasma is important. Moreover, it suggests that moderate hypergastrinemias are also essential health issues that require serious attention.

Glucagon Reduces Neutrophil Migration and Increases Susceptibility to Sepsis in Diabetic Mice.

Sepsis is one of the most common comorbidities observed in diabetic patients, associated with a deficient innate immune response. Recently, we have shown that glucagon possesses anti-inflammatory properties. In this study, we investigated if hyperglucagonemia triggered by diabetes might reduce the migration of neutrophils, increasing sepsis susceptibility. 21 days after diabetes induction by intravenous injection of alloxan, we induced moderate sepsis in Swiss-Webster mice through cecum ligation and puncture (CLP). The glucagon receptor (GcgR) antagonist des-his1-[Glu9]-glucagon amide was injected intraperitoneally 24h and 1h before CLP. We also tested the effect of glucagon on CXCL1/KC-induced neutrophil migration to the peritoneal cavity in mice. Neutrophil chemotaxis in vitro was tested using transwell plates, and the expression of total PKA and phospho-PKA was evaluated by western blot. GcgR antagonist restored neutrophil migration, reduced CFU numbers in the peritoneal cavity and improved survival rate of diabetic mice after CLP procedure, however, the treatment did no alter hyperglycemia, CXCL1/KC plasma levels and blood neutrophilia. In addition, glucagon inhibited CXCL1/KC-induced neutrophil migration to the peritoneal cavity of non-diabetic mice. Glucagon also decreased the chemotaxis of neutrophils triggered by CXCL1/KC, PAF, or fMLP in vitro. The inhibitory action of glucagon occurred in parallel with the reduction of CXCL1/KC-induced actin polymerization in neutrophils in vitro, but not CD11a and CD11b translocation to cell surface. The suppressor effect of glucagon on CXCL1/KC-induced neutrophil chemotaxis in vitro was reversed by pre-treatment with GcgR antagonist and adenylyl cyclase or PKA inhibitors. Glucagon also increased PKA phosphorylation directly in neutrophils in vitro. Furthermore, glucagon impaired zymosan-A-induced ROS production by neutrophils in vitro. Human neutrophil chemotaxis and adherence to endothelial cells in vitro were inhibited by glucagon treatment. According to our results, this inhibition was independent of CD11a and CD11b translocation to neutrophil surface or neutrophil release of CXCL8/IL-8. Altogether, our results suggest that glucagon may be involved in the reduction of neutrophil migration and increased susceptibility to sepsis in diabetic mice. This work collaborates with better understanding of the increased susceptibility and worsening of sepsis in diabetics, which can contribute to the development of new effective therapeutic strategies for diabetic septic patients.

Familial risk for endometriosis and its interaction with smoking, age at menarche and body mass index: a population-based cohort study among siblings.

OBJECTIVE: To quantify familial risk of endometriosis among full siblings and examine interactions between family history and smoking, age at menarche or body mass index (BMI). DESIGN, SETTING AND POPULATION: Population-based nationwide cohort study. METHODS: Using data from the Korean National Health Insurance and Screening Programme databases on kinship, healthcare utilisation, lifestyle and anthropometrics, we identified 2 109 288 women with full siblings and their environmental risk factors from 2002 to 2018. Familial risks were estimated using Cox proportional-hazards models, represented as incidence risk ratios (IRR) with 95% CI. Interaction between family history and smoking, age at menarche or BMI were assessed on an additive scale. MAIN OUTCOME MEASURES: IRR of endometriosis among women with and without affected siblings. RESULTS: From 19 195 women with affected siblings, 1126 developed endometriosis with an incidence of 35.45/10 000 person-years. Familial risk of endometriosis with versus without affected siblings was increased to IRR 2.75 (95% CI 2.25-3.36), and the highest risk was with affected twins (IRR 6.98; 95% CI 4.19-11.62). Women with both a family history and either smoking, early menarche or low BMI had a significantly higher risk of endometriosis compared with the general population and can be regarded as a high-risk group, the IRRs were 4.28 (95% CI 2.43-7.55), 3.47 (95% CI 2.82-4.26) and 3.09 (95% CI 2.68-3.56), respectively. Substantial effect modification of the associations was noted by smoking and early menarche, as their combined risk with family history exceeded the sum of their individual risks, which was also statistically significant. CONCLUSION: Genetic factors are the primary contributor to the familial aggregation of endometriosis. Significant gene-environment interaction exists between family history and smoking or early menarche. TWEETABLE ABSTRACT: Significant gene-environment interaction exists between family history of endometriosis and smoking or early menarche.

[Covid-19 vaccination and renal patients: overcoming unwarranted fears and re-establishing priorities].

The SARS-CoV-2 (Covid-19) has infected about 124 million people worldwide and the total amount of casualties now sits at a staggering 2.7 million. One enigmatic aspect of this disease is the protean nature of the clinical manifestations, ranging from total absence of symptoms to extremely severe cases with multiorgan failure and death. Chronic Kidney Disease (CKD) has emerged as the primary risk factor in the most severe patients, apart from age. Kidney disease and acute kidney injury have been correlated with a higher risk of death. Notably the Italian Society of Nephrology have reported a 10-fold increase in mortality in patients undergoing dialysis compared to the rest of the population, especially during the second phase of the pandemic (26% vs 2.4). These dramatic numbers require an immediate response. At the moment of writing, three Covid-19 vaccines are being administered already , two of which, Pfizer-BioNTech and Moderna, share the same mRNA mechanism and Vaxzevria (AstraZeneca) based on a more traditional approach. All of them are completely safe and reliable. The AIFA scientific commission has suggested that the mRNA vaccines should be administered to older and more fragile patients, while the Vaxzevria (AstraZeneca) vaccine should be reserved for younger subjects above the age of 18. The near future looks bright: there are tens of other vaccines undergoing clinical and preclinical validation, whose preliminary results look promising. The high mortality of CKD and dialysis patients contracting Covid-19 should mandate top priority for their vaccination.

An Infection-Tolerant Mammalian Reservoir for Several Zoonotic Agents Broadly Counters the Inflammatory Effects of Endotoxin.

Animals that are competent reservoirs of zoonotic pathogens commonly suffer little morbidity from the infections. To investigate mechanisms of this tolerance of infection, we used single-dose lipopolysaccharide (LPS) as an experimental model of inflammation and compared the responses of two rodents: Peromyscus leucopus, the white-footed deermouse and reservoir for the agents of Lyme disease and other zoonoses, and the house mouse Mus musculus Four hours after injection with LPS or saline, blood, spleen, and liver samples were collected and subjected to transcriptome sequencing (RNA-seq), metabolomics, and specific reverse transcriptase quantitative PCR (RT-qPCR). Differential expression analysis was at the gene, pathway, and network levels. LPS-treated deermice showed signs of sickness similar to those of exposed mice and had similar increases in corticosterone levels and expression of interleukin 6 (IL-6), tumor necrosis factor, IL-1ß, and C-reactive protein. By network analysis, the M. musculus response to LPS was characterized as cytokine associated, while the P. leucopus response was dominated by neutrophil activity terms. In addition, dichotomies in the expression levels of arginase 1 and nitric oxide synthase 2 and of IL-10 and IL-12 were consistent with type M1 macrophage responses in mice and type M2 responses in deermice. Analysis of metabolites in plasma and RNA in organs revealed species differences in tryptophan metabolism. Two genes in particular signified the different phenotypes of deermice and mice: the Slpi and Ibsp genes. Key RNA-seq findings for P. leucopus were replicated in older animals, in a systemic bacterial infection, and with cultivated fibroblasts. The findings indicate that P. leucopus possesses several adaptive traits to moderate inflammation in its balancing of infection resistance and tolerance.IMPORTANCE Animals that are natural carriers of pathogens that cause human diseases commonly manifest little or no sickness as a consequence of infection. Examples include the deermouse, Peromyscus leucopus, which is a reservoir for Lyme disease and several other disease agents in North America, and some types of bats, which are carriers of viruses with pathogenicity for humans. Mechanisms of this phenomenon of infection tolerance and entailed trade-off costs are poorly understood. Using a single injection of lipopolysaccharide (LPS) endotoxin as a proxy for infection, we found that deermice differed from the mouse (Mus musculus) in responses to LPS in several diverse pathways, including innate immunity, oxidative stress, and metabolism. Features distinguishing the deermice cumulatively would moderate downstream ill effects of LPS. Insights gained from the P. leucopus model in the laboratory have implications for studying infection tolerance in other important reservoir species, including bats and other types of wildlife.

Major dietary patterns and predicted cardiovascular disease risk in an Iranian adult population.

BACKGROUND: Limited data are available on the association of major dietary patterns and predicted risk of cardiovascular disease (CVD) using the Framingham Risk Score (FRS). AIM: To investigate the association between major dietary patterns and the predicted 10-year CVD risk in an Iranian population. METHODS: This cross-sectional study was conducted on 522 apparently healthy adults referred to health centers in Tehran. Usual dietary intake was assessed using a validated semi-quantitative food frequency questionnaire. The association between dietary patterns and the predicted risk of development of CVD was evaluated using linear multiple regression. Principal component analysis was used to identify major dietary patterns. RESULTS: In total, 41% of the men (n = 95) and 46% of women (n = 134) were in the low risk (<10%) and 6% of men (n = 14) and 1% of women (n = 3) were in the high risk (> 20%) category of the FRS. A significant decrease was found for body mass index (p < 0.001), systolic blood pressure (SBP) (p = 0.003), diastolic blood pressure (p = 0.005), and triglyceride (p = 0.02) in the higher tertile of healthy dietary pattern. Adherence to an unhealthy dietary pattern was associated with a significant increase in body weight (p = 0.03) and a significant decrease in high-density lipoprotein cholesterol (p < 0.001). The healthy dietary pattern score was negatively associated with SBP (p = 0.04) and FRS (p < 0.001). CONCLUSION: Although we observed improvements in CVD risk factors with greater adherence to healthy dietary patterns, there was no association between identified dietary patterns and the predicted risk of 10-year CVD.

Alterations of neurotransmitters and related metabolites in the habenula from CUMS-susceptible and -resilient rats.

Although major depressive disorder (MDD) has caused severe mental harm to overwhelming amounts of patients, the pathogenesis of MDD remains to be studied. Due to the in-depth discussion of the mechanism of new antidepressants like ketamine, the habenula (Hb) was reported to be significant in the onset of MDD and the antidepressant mechanism. In the Hb of depressive-like rodents, various molecular mechanisms and neuronal electrical activities have been reported, but neurotransmitters disorder in response to stress are still unclear. Thus, we divided stress-susceptible and stress-resilient rats after exposure to chronic unpredictable mild stress (CUMS). Multiple metabolites in the Hb were determined by liquid chromatography-tandem mass spectrometry. Based on this approach, we found that glutamate was significantly increased in susceptible group and resilient group, while dopamine was significant decreased in two groups. Gamma-aminobutyric acid was significantly upregulated in susceptible group but downregulated in resilient group. Our study firstly provides quantitative evidence regarding alterations of main neurotransmitters in the Hb of CUMS rats, showing the different role of neurotransmitters in stress susceptibility and stress resilience.

Increased susceptibility to SARS-CoV-2 infection in patients with reduced left ventricular ejection fraction.

AIMS: Cardiovascular disease has been recognized as a major determinant of coronavirus disease 2019 (COVID-19) vulnerability and severity. Angiotensin-converting enzyme (ACE) 2 is a functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is up-regulated in patients with heart failure. We sought to examine the potential association between reduced left ventricular ejection fraction (LVEF) and the susceptibility to SARS-CoV-2 infection. METHODS AND RESULTS: Of the 1162 patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention between February 2014 and October 2018, we enrolled 889 patients with available clinical follow-up data. Follow-up was conducted by telephone interviews 1 month after the start of the French lockdown which began on 17 March 2020. Patients were divided into two groups according to LVEF <40% (reduced LVEF) (n = 91) or ≥40% (moderately reduced + preserved LVEF) (n = 798). The incidence of COVID-19-related hospitalization or death was significantly higher in the reduced LVEF group as compared with the moderately reduced + preserved LVEF group (9% vs. 1%, P < 0.001). No association was found between discontinuation of ACE-inhibitor or angiotensin-receptor blockers and COVID-19 test positivity. By multivariate logistic regression analysis, reduced LVEF was an independent predictor of COVID-19 hospitalization or death (odds ratio: 6.91, 95% confidence interval: 2.60 to 18.35, P < 0.001). CONCLUSIONS: In a large cohort of patients with previous ACS, reduced LVEF was associated with increased susceptibility to COVID-19. Aggressive COVID-19 testing and therapeutic strategies may be considered for patient with impaired heart function.

Biometric, nutritional, biochemical, and cardiovascular outcomes in male rats submitted to an experimental model of early weaning that mimics mother abandoning.

Literature describes breast milk as the best food for the newborn, recommending exclusive breastfeeding for up to 6 months of age. However, it is not available for more than 40% of children worldwide. Pharmacological and non-pharmacological models of 3-day early weaning were developed in rodents to investigate later outcomes related solely to this nutritional insult. Thus, the present work aimed to describe biometric, nutritional, biochemical, and cardiovascular outcomes in adult male rats submitted to 3-day early weaning achieved by maternal deprivation. This experimental model comprises not only nutritional insult but also emotional stress, simulating mother abandoning. Male offspring were physically separated from their mothers at 21st (control) or 18th (early weaning) postnatal day, receiving water/food ad libitum. Analysis performed at postnatal days 30, 90, 150, and 365 encompassed body mass and food intake monitoring and serum biochemistry determination. Further assessments included hemodynamic, echocardiographic, and cardiorespiratory evaluation. Early-weaned males presented higher body weight when compared to control as well as dyslipidemia, higher blood pressure, diastolic dysfunction, and cardiac hypertrophy in adult life. Animals early deprived of their mothers have also presented a worse performance on the maximal effort ergometer test. This work shows that 3-day early maternal deprivation favors the development of cardiovascular disease in male rats.

Atherosclerotic plaque vulnerability is increased in mouse model of lupus.

Anti-apolipoprotein A-1 (anti-apoA-1 IgG) and anti-double stranded DNA (anti-dsDNA IgG) autoantibodies have been described as mediators of atherogenesis in mice and humans. In the present study, we aim to investigate the association between atherosclerotic parameters, autoantibodies and plaque vulnerability in the context of systemic lupus erythematosus (SLE). We therefore bred a lupus prone-mouse model (Nba2.Yaa mice) with Apoe-/- mice resulting in Apoe-/-Nba2.Yaa mice spontaneously producing anti-apoA-1 IgG antibodies. Although Apoe-/-Nba2.Yaa and Apoe-/- mice subject to a high cholesterol diet displayed similar atherosclerosis lesions size in aortic roots and abdominal aorta, the levels of macrophage and neutrophil infiltration, collagen, MMP-8 and MMP-9 and pro-MMP-9 expression in Apoe-/-Nba2.Yaa mice indicated features of atherosclerotic plaque vulnerability. Even though Apoe-/-Nba2.Yaa mice and Apoe-/- mice had similar lipid levels, Apoe-/-Nba2.Yaa mice showed higher anti-apoA-1 and anti-dsDNA IgG levels. Apoe-/-Nba2.Yaa mice displayed a reduction of the size of the kidney, splenomegaly and lymph nodes (LN) hypertrophy. In addition, anti-apoA-1 and anti-dsDNA IgG increased also in relation with mRNA levels of GATA3, IL-4, Bcl-6 and CD20 in the spleen and aortic arch of Apoe-/-Nba2.Yaa mice. Our data show that although atherosclerosis-lupus-prone Apoe-/-Nba2.Yaa mice did not exhibit exacerbated atherosclerotic lesion size, they did show features of atherosclerotic plaque destabilization in correlation with the increase of pro-atherogenic autoantibodies.

Prenatal Exposure to Perfluoroalkyl Substances Associated With Increased Susceptibility to Liver Injury in Children.

BACKGROUND AND AIMS: Per- and polyfluoroalkyl substances (PFAS) are widespread and persistent pollutants that have been shown to have hepatotoxic effects in animal models. However, human evidence is scarce. We evaluated how prenatal exposure to PFAS associates with established serum biomarkers of liver injury and alterations in serum metabolome in children. APPROACH AND RESULTS: We used data from 1,105 mothers and their children (median age, 8.2 years; interquartile range, 6.6-9.1) from the European Human Early-Life Exposome cohort (consisting of six existing population-based birth cohorts in France, Greece, Lithuania, Norway, Spain, and the United Kingdom). We measured concentrations of perfluorooctane sulfonate, perfluorooctanoate, perfluorononanoate, perfluorohexane sulfonate, and perfluoroundecanoate in maternal blood. We assessed concentrations of alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase in child serum. Using Bayesian kernel machine regression, we found that higher exposure to PFAS during pregnancy was associated with higher liver enzyme levels in children. We also measured child serum metabolomics through a targeted assay and found significant perturbations in amino acid and glycerophospholipid metabolism associated with prenatal PFAS. A latent variable analysis identified a profile of children at high risk of liver injury (odds ratio, 1.56; 95% confidence interval, 1.21-1.92) that was characterized by high prenatal exposure to PFAS and increased serum levels of branched-chain amino acids (valine, leucine, and isoleucine), aromatic amino acids (tryptophan and phenylalanine), and glycerophospholipids (phosphatidylcholine [PC] aa C36:1 and Lyso-PC a C18:1). CONCLUSIONS: Developmental exposure to PFAS can contribute to pediatric liver injury.

Inflammasomes and Cell Death: Common Pathways in Microparticle Diseases.

The accumulation of cellular and environmental microparticles has been linked to many diseases associated with tissue inflammation. These particulate-driven diseases include joint, lung, kidney, cardiovascular, and neurodegenerative disorders. Recently a conserved proinflammatory inflammasome signaling pathway elicited by such microparticles has become apparent. Here, we review disease-promoting microparticles and the mechanisms by which they trigger activation of the inflammasome complexes responsible for generating bioactive interleukin-1ß (IL-1ß) and inducing cell death. We highlight how microparticle-induced inflammasome and cell death responses diverge from canonical inflammasome activators, and discuss the preclinical and clinical targeting of inflammasomes to treat microparticle-driven diseases.

Nest Carbon Dioxide Masks GABA-Dependent Seizure Susceptibility in the Naked Mole-Rat.

African naked mole-rats were likely the first mammals to evolve eusociality, and thus required adaptations to conserve energy and tolerate the low oxygen (O2) and high carbon dioxide (CO2) of a densely populated fossorial nest. As hypercapnia is known to suppress neuronal activity, we studied whether naked mole-rats might demonstrate energy savings in GABAergic inhibition. Using whole-colony behavioral monitoring of captive naked mole-rats, we found a durable nest, characterized by high CO2 levels, where all colony members spent the majority of their time. Analysis of the naked mole-rat genome revealed, uniquely among mammals, a histidine point variation in the neuronal potassium-chloride cotransporter 2 (KCC2). A histidine missense substitution mutation at this locus in the human ortholog of KCC2, found previously in patients with febrile seizures and epilepsy, has been demonstrated to diminish neuronal Cl- extrusion capacity, and thus impairs GABAergic inhibition. Seizures were observed, without pharmacological intervention, in adult naked mole-rats exposed to a simulated hyperthermic surface environment, causing systemic hypocapnic alkalosis. Consistent with the diminished function of KCC2, adult naked mole-rats demonstrate a reduced efficacy of inhibition that manifests as triggering of seizures at room temperature by the GABAA receptor (GABAAR) positive allosteric modulator diazepam. These seizures are blocked in the presence of nest-like levels of CO2 and likely to be mediated through GABAAR activity, based on in vitro recordings. Thus, altered GABAergic inhibition adds to a growing list of adaptations in the naked mole-rat and provides a plausible proximate mechanism for nesting behavior, where a return to the colony nest restores GABA-mediated inhibition.

Early life stress increases vulnerability to the sequelae of pediatric mild traumatic brain injury.

Early life stress (ELS) is a risk factor for many psychopathologies that happen later in life. Although stress can occur in cases of child abuse, studies on non-accidental brain injuries in pediatric populations do not consider the possible increase in vulnerability caused by ELS. Hence, we sought to determine whether ELS increases the effects of pediatric mild traumatic brain injury (mTBI) on cognition, hippocampal inflammation, and plasticity. Male rats were subjected to maternal separation for 180 min per day (MS180) or used as controls (CONT) during the first 21 post-natal (P) days. At P21 the rats were anesthetized with isoflurane and subjected to a mild controlled cortical impact or sham injury. At P32 the rats were injected with the cell proliferation marker bromodeoxyuridine (BrdU, 500 mg/kg), then evaluated for spatial learning and memory in a water maze (P35-40) and sacrificed for quantification of Ki67+, BrdU+ and Iba1+ (P42). Neither MS180 nor mTBI impacted cognitive outcome when provided alone but their combination (MS180 + mTBI) decreased spatial learning and memory relative to Sham controls (p < .01). mTBI increased microglial activation and affected BrdU+ cell survival in the ipsilateral hippocampus without affecting proliferation rates. However, only MS180 + mTBI increased microglial activation in the area adjacent to the injury and the contralateral CA1 hippocampal subfield, and decreased cell proliferation in the ipsilateral neurogenic niche. Overall, the data show that ELS increases the vulnerability to the sequelae of pediatric mTBI and may be mediated by increased neuroinflammation.