The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity.

Obesity is associated with metabolic inflammation and endoplasmic reticulum (ER) stress, both of which promote metabolic disease progression. Adipose tissue macrophages (ATMs) are key players orchestrating metabolic inflammation, and ER stress enhances macrophage activation. However, whether ER stress pathways underlie ATM regulation of energy homeostasis remains unclear. Here, we identified inositol-requiring enzyme 1α (IRE1α) as a critical switch governing M1-M2 macrophage polarization and energy balance. Myeloid-specific IRE1α abrogation in Ern1f/f; Lyz2-Cre mice largely reversed high-fat diet (HFD)-induced M1-M2 imbalance in white adipose tissue (WAT) and blocked HFD-induced obesity, insulin resistance, hyperlipidemia and hepatic steatosis. Brown adipose tissue (BAT) activity, WAT browning and energy expenditure were significantly higher in Ern1f/f; Lyz2-Cre mice. Furthermore, IRE1α ablation augmented M2 polarization of macrophages in a cell-autonomous manner. Thus, IRE1α senses protein unfolding and metabolic and immunological states, and consequently guides ATM polarization. The macrophage IRE1α pathway drives obesity and metabolic syndrome through impairing BAT activity and WAT browning.

Optimal ICSI timing on immature oocytes for low prognosis patients under the POSEIDON classification.

BACKGROUND: The optimal timing of performing ICSI on immature oocytes for POSEIDON patients is still unknown to get better early embryonic development outcomes. The purpose of this study was to implore the most appropriate time to carry out ICSI on in vitro maturation GV and MI oocytes for POSEIDON patients. METHODS: Two hundred thirty-nine immature oocytes from 163 POSEIDON patients were prospectively performed ICSI at different timings: P-ICSI (ICSI was performed on in vitro matured oocytes 4-6 h after the first polar body extrusion, N = 81), R-ICSI (ICSI was performed on in vitro matured oocytes less than 4 h after the first polar body extrusion, N = 80), and E-ICSI (ICSI was performed on in vitro matured oocytes the next day after oocytes retrieval, N = 78). Fertilization and embryonic development outcomes were collected and statistically analyzed. Mitochondria distribution of cytoplasm of in vitro matured oocytes with different time cultures after the first polar body (PB1) extrusion was stained. RESULTS: Compared to the E-ICSI group, more day 3 embryos from P-ICSI became blastocysts after sequential culture though without statistical significance (OR = 3.71, 95% CI: 0.94-14.63, P = 0.061). Compared to the E-ICSI group, more embryos from both P-ICSI and R-ICSI groups were clinically used with statistical significance (OR = 5.67, 95% CI: 2.24-14.35, P = 0.000 for P-ICSI embryos; OR = 3.23, 95% CI: 1.23-8.45, P = 0.017 for R-ICSI embryos). Compared to the E-ICSI group, transferred embryos from P-ICSI and R-ICSI had a higher implantation rate though without statistical significance (35.3% for P-ICSI embryos; 9.1% or R-ICSI embryos and 0% for E-ICSI embryos, P = 0.050). Among the three group, there were most healthy babies delivered from the P-ICSI group (5, 1 and 0 for P-ICSI, R-ICSI and E-ICSI respectively). The mitochondria in the cytoplasm of in vitro matured oocytes with a less than 4 h and 4-6 h culture after PB1 extrusion presented semiperipheral and diffused distribution patterns, respectively. CONCLUSIONS: Our results revealed P-ICSI (ICSI was performed on in vitro matured oocytes 4-6 h after the first polar body extrusion) provided the most efficient method to utilize the immaturation oocytes basing on embryos utilization and live birth outcome for low prognosis patients under the POSEIDON classification. The mitochondria distribution of the in vitro matured oocytes' cytoplasm from P-ICSI varied that from R-ICSI.

Brown adipocyte mineralocorticoid receptor deficiency impairs metabolic regulation in diet-induced obese mice.

Activation of brown adipose tissue (BAT) contributes to energy dissipation and metabolic health. Although mineralocorticoid receptor (MR) antagonists have been demonstrated to improve metabolism under obesity, the underlying mechanisms remain incompletely understood. We aimed to evaluate the role of BAT MR in metabolic regulation. After 8 weeks of high-fat diet (HFD) feeding, BAT MR KO (BMRKO) mice manifested significantly increased bodyweight, fat mass, serum fasting glucose, and impaired glucose homeostasis compared with littermate control (LC) mice, although insulin resistance and fasting serum insulin were not significantly changed. Metabolic cage experiments showed no change in O2 consumption, CO2 production, or energy expenditure in obese BMRKO mice. RNA sequencing analysis revealed downregulation of genes related to fatty acid metabolism in BAT of BMRKO-HFD mice compared with LC-HFD mice. Moreover, H&E and immunohistochemical staining demonstrated that BMRKO exacerbated HFD-induced macrophage infiltration and proinflammatory genes in epididymal white adipose tissue (eWAT). BMRKO-HFD mice also manifested significantly increased liver weights and hepatic lipid accumulation, an increasing trend of genes related to lipogenesis and lipid uptake, and significantly decreased genes related to lipolytic and fatty acid oxidation in the liver. Finally, the level of insulin-induced AKT phosphorylation was substantially blunted in eWAT but not liver or skeletal muscle of BMRKO-HFD mice compared with LC-HFD mice. These data suggest that BAT MR is required to maintain metabolic homeostasis, likely through its regulation of fatty acid metabolism in BAT and impacts on eWAT and liver.

Prediction model for day 3 embryo implantation potential based on metabolites in spent embryo culture medium.

BACKGROUND: Metabolites in spent embryo culture medium correlate with the embryo's viability. However, there is no widely accepted method using metabolite dada to predict successful implantation. We sought to combine metabolomic profiling of spent embryo culture medium and clinical variables to create an implantation prediction model as an adjunct to morphological screening of day 3 embryos. METHODS: This investigation was a prospective, nested case-control study. Forty-two day 3 embryos from 34 patients were transferred, and the spent embryo culture medium was collected. Twenty-two embryos implanted successfully, and the others failed. Metabolites in the medium relevant to implantation were detected and measured by Liquid Chromatography-Mass Spectrometry. Clinical signatures relevant to embryo implantation were subjected to univariate analysis to select candidates for a prediction model. Multivariate logistical regression of the clinical and metabolomic candidates was used to construct a prediction model for embryo implantation potential. RESULTS: The levels of 13 metabolites were significantly different between the successful and failed groups, among which five were most relevant and interpretable selected by Least Absolute Shrinkage and Selection Operator regression analysis. None of the clinical variables significantly affected day 3 embryo implantation. The most relevant and interpretable set of metabolites was used to construct a prediction model for day 3 embryo implantation potential with an accuracy of 0.88. CONCLUSIONS: Day 3 embryos'implantation potential could be noninvasively predicted by the spent embryo culture medium's metabolites measured by LC-MS. This approach may become a useful adjunct to morphological evaluation of day 3 embryos.

Chromosome-level genome assembly of the Muscovy duck provides insight into fatty liver susceptibility.

The Muscovy duck (Cairina moschata) is an economically important poultry species, which is susceptible to fatty liver. Thus, the Muscovy duck may serve as an excellent candidate animal model of non-alcoholic fatty liver disease. However, the mechanisms underlying fatty liver development in this species are poorly understood. In this study, we report a chromosome-level genome assembly of the Muscovy duck, with a contig N50 of 11.8 Mb and scaffold N50 of 83.16 Mb. The susceptibility of Muscovy duck to fatty liver was mainly attributed to weak lipid catabolism capabilities (fatty acid ß-oxidation and lipolysis). Furthermore, conserved noncoding elements (CNEs) showing accelerated evolution contributed to fatty liver formation by down-regulating the expression of genes involved in hepatic lipid catabolism. We propose that the susceptibility of Muscovy duck to fatty liver is an evolutionary by-product. In conclusion, this study revealed the potential mechanisms underlying the susceptibility of Muscovy duck to fatty liver.

Transcriptomic, Physiological, and Metabolomic Response of an Alpine Plant, Rhododendron delavayi, to Waterlogging Stress and Post-Waterlogging Recovery.

Climate change has resulted in frequent heavy and prolonged rainfall events that exacerbate waterlogging stress, leading to the death of certain alpine Rhododendron trees. To shed light on the physiological and molecular mechanisms behind waterlogging stress in woody Rhododendron trees, we conducted a study of Rhododendron delavayi, a well-known alpine flower species. Specifically, we investigated the physiological and molecular changes that occurred in leaves of R. delavayi subjected to 30 days of waterlogging stress (WS30d), as well as subsequent post-waterlogging recovery period of 10 days (WS30d-R10d). Our findings reveal that waterlogging stress causes a significant reduction in CO2 assimilation rate, stomatal conductance, transpiration rate, and maximum photochemical efficiency of PSII (Fv/Fm) in the WS30d leaves, by 91.2%, 95.3%, 93.3%, and 8.4%, respectively, when compared to the control leaves. Furthermore, the chlorophyll a and total chlorophyll content in the WS30d leaves decreased by 13.5% and 16.6%, respectively. Both WS30d and WS30d-R10d leaves exhibited excessive H2O2 accumulation, with a corresponding decrease in lignin content in the WS30d-R10d leaves. At the molecular level, purine metabolism, glutathione metabolism, photosynthesis, and photosynthesis-antenna protein pathways were found to be primarily involved in WS30d leaves, whereas phenylpropanoid biosynthesis, fatty acid metabolism, fatty acid biosynthesis, fatty acid elongation, and cutin, suberin, and wax biosynthesis pathways were significantly enriched in WS30d-R10d leaves. Additionally, both WS30d and WS30d-R10d leaves displayed a build-up of sugars. Overall, our integrated transcriptomic, physiological, and metabolomic analysis demonstrated that R. delavayi is susceptible to waterlogging stress, which causes irreversible detrimental effects on both its physiological and molecular aspects, hence compromising the tree's ability to fully recover, even under normal growth conditions.

[Oral Microbiome and Systemic Diseases].

As one of the most diverse microbial communities within the human body, the oral microbiome is an important component that contributes to the maintenance of human health. The microbial composition of different sites in the oral cavity varies significantly and a dynamic equilibrium is maintained through communications with the environment and oral and distal organs of the host. It has been reported that there is significant correlation between dysbiotic oral microbiome and the occurrence or progression of a variety of systemic diseases. In this review, we summarized recent advances in research on the relationship between oral microbiome and systemic health, focusing on the interaction and pathological mechanisms between oral microbiome and systemic health and hoping to provide new avenues for the early prevention and clinical diagnosis and treatment of systemic diseases.

Osteoblast MR deficiency protects against adverse ventricular remodeling after myocardial infarction.

RATIONALE: Mineralocorticoid receptor (MR) antagonists have been clinically used to treat heart failure. However, the underlying cellular and molecular mechanisms remain incompletely understood. METHODS AND RESULTS: Using osteoblast MR knockout (MRobko) mouse in combination with myocardial infarction (MI) model, we demonstrated that MR deficiency in osteoblasts significantly improved cardiac function, promoted myocardial healing, as well as attenuated cardiac hypertrophy, fibrosis and inflammatory response after MI. Gene expression profiling using RNA sequencing revealed suppressed expression of osteocalcin (OCN) in calvaria from MRobko mice compared to littermate control (MRfl/fl) mice with or without MI. Plasma levels of undercarboxylated OCN (ucOCN) were also markedly decreased in MRobko mice compared to MRfl/fl mice. Administration of ucOCN abolished the protective effects of osteoblast MR deficiency on infarcted hearts. Mechanistically, ucOCN treatment promoted proliferation and inflammatory cytokine secretion in macrophages. Spironolactone, an MR antagonist, significantly inhibited the expression and secretion of OCN in post-MI mice. More importantly, spironolactone decreased plasma levels of ucOCN and inflammatory cytokines in heart failure patients. CONCLUSIONS: MR deficiency in osteoblasts alleviates pathological ventricular remodeling after MI, likely through its regulation on OCN. Spironolactone may work through osteoblast MR/OCN axis to exert its therapeutic effects on pathological ventricular remodeling and heart failure in mice and human patients.

Mineralocorticoid receptor deficiency in Treg cells ameliorates DSS-induced colitis in a gut microbiota-dependent manner.

Mineralocorticoid receptor (MR) is a classic nuclear receptor and an effective drug target in the cardiovascular system. The function of MR in immune cells such as macrophages and T cells has been increasingly appreciated. The aim of this study was to investigate the function of Treg MR in the process of inflammatory bowel disease (IBD). We treated Treg MR-deficient (MRflox/flox Foxp3YFP-Cre , KO) mice and control (Foxp3YFP-Cre , WT) mice with dextran sodium sulphate (DSS) to induce colitis and found that the severity of DSS-induced colitis was markedly alleviated in Treg MR-deficient mice, accompanied by reduced production of inflammatory cytokines, and relieved infiltration of monocytes, neutrophils and interferon γ+ T cells in colon lamina propria. Faecal microbiota of mice with colitis was analysed by 16S rRNA gene sequencing and the composition of gut microbiota was vastly changed in Treg MR-deficient mice. Furthermore, depletion of gut microbiota by antibiotics abolished the protective effects of Treg MR deficiency and resulted in similar severity of DSS-induced colitis in WT and KO mice. Faecal microbiota transplantation from KO mice attenuated DSS-induced colitis characterized by alleviated inflammatory infiltration compared to that from WT mice. Hence, our study demonstrates that Treg MR deficiency protects against DSS-induced colitis by attenuation of colonic inflammatory infiltration. Gut microbiota is both sufficient and necessary for Treg MR deficiency to exert the beneficial effects.

The combination of experimental periodontitis and oral microbiota from periodontitis patients aggravates liver fibrosis in mice.

AIM: Periodontitis (PD) is the sixth most prevalent disease around the world and is involved in the development and progression of multiple systemic diseases. Previous studies have reported that PD may aggravate liver injuries. The objective of this study was to investigate whether and how PD affects liver fibrosis. MATERIALS AND METHODS: Ligature-induced PD (LIP) was induced in male C57/B6J mice, and sub-gingival plaques (PL) from patients with PD were applied to mouse teeth. Liver fibrosis was induced by carbon tetrachloride (CCl4 ) injection. The mice were randomly divided into six groups: Oil, Oil+LIP, Oil+LIP+PL, CCl4 , CCl4 +LIP, and CCl4 +LIP+PL. Alveolar bone resorption was evaluated by methylene blue staining. Hepatic function was analysed by serum alanine aminotransferase and hepatic hydroxyproline. Picrosirius red and α-smooth muscle actin (SMA) staining were used to evaluate the fibrotic area. RNA sequencing and quantitative RT-PCR were used to measure gene expression. Western blotting was used to measure protein levels. Flow cytometry was used to analyse the accumulation of immune cells. Mouse microbiota were analysed using 16S rRNA gene sequencing. RESULTS: Mice in the CCl4 +LIP+PL group displayed higher serum alanine aminotransferase and hepatic hydroxyproline as well as more Picrosirius red-positive and α-SMA-positive areas in liver samples than those of the CCl4 group, suggesting that PD (LIP+PL) aggravated CCl4 -induced hepatic dysfunction and liver fibrosis. Consistently, the expression of fibro-genic genes and the protein levels of transforming growth factor ß were much higher in the CCl4 +LIP+PL group than in the CCl4 group. Flow cytometry revealed that PD increased the accumulation of immune cells, including Kupffer cells, B cells, and Th17 cells, in the liver of mice with CCl4 treatment. PD also increased the expression of inflammatory genes and activated pro-inflammatory nuclear factor-kappa B pathway in the livers of CCl4 -injected mice. Moreover, PD altered both oral and liver microbiota in CCl4 -injected mice. CONCLUSIONS: PD aggravates CCl4 -induced hepatic dysfunction and fibrosis in mice, likely through the increase of inflammation and alteration of microbiota in the liver.

Periodontitis aggravates renal inflammatory response in a mouse model of renal fibrosis.

OBJECTIVES: To assess the effects of periodontitis on renal interstitial fibrosis in a mouse model. MATERIALS AND METHODS: Thirty C57BL/6 male mice were divided into control, periodontitis (PD), unilateral ureteral ligation (UUO) and PD+UUO groups. Unilateral ureteral ligation was performed 6 days after periodontitis. After 2 weeks, all mice were sacrificed, and samples were collected for the assessment of gene expression, immune cells, biochemical indicators and renal pathology. RESULTS: Expression of tumour necrosis factor-α, interleukin-1ß, and Ly6G in the kidneys in the PD+UUO group was significantly greater than in the UUO group. The percentage of CD11b+ Ly6G+ cells was significantly higher in the PD+UUO than in the UUO group. Fibrotic areas in the kidneys in the PD+UUO group were slightly, but not significantly, greater than those in the UUO group. Kidneys from the PD+UUO group showed markedly higher gene expression of matrix metalloproteinase-9, but not α-smooth muscle actin or collagen I, than those in the UUO group. There were no significant differences in blood urea nitrogen, serum creatinine and uric acid between the PD+UUO and UUO groups. CONCLUSIONS: Periodontitis increases the renal inflammatory response without showing a significant influence on renal interstitial fibrosis or renal function in the UUO mouse model.

Acetazolamide Alleviate Cerebral Edema Induced by Ischemic Stroke Through Inhibiting the Expression of AQP4 mRNA.

OBJECTIVE: We want to investigate the effect of aquaporin-4 (AQP4) on cerebral edema induced by ischemic stroke in rats and explore whether inhibiting the expression of AQP4 through acetazolamide (AZA) could attenuate brain edema and protect cerebral function. METHODS: The Sprague Dawley (SD) rats were randomly divided into four groups: sham + saline group, sham + AZA group, AZA intervention group, and nonintervention group. Each group was divided into five subgroups according to the time of cerebral ischemia (6 h, 1 day, 3 days, 5 days, and 7 days). The model of cerebral infarction in rats was adopted by means of the bilateral carotid arteries ligation (2-VO) method. The rats in intervention group were given intraperitoneal injection of AZA (35 mg/kg/day). Hematoxylin-eosin staining was performed for pathological analysis of the infarcted area. The brain water content was calculated to evaluate the degree of brain edema. The messenger RNA (mRNA) and protein expressions of AQP4 in the brain were measured by quantitative real-time polymerase chain reaction and immunohistochemistry, respectively. RESULTS: Significant cerebral pathological damages were found in ischemic stroke rats. The brain water content, protein, and mRNA expression of AQP4 of the intervention and nonintervention groups were markedly higher than those of the sham groups. By contrast, AZA administration reduced the brain water content, whereas improved cerebral dysfunction was induced by ischemic stroke. Moreover, AZA obviously reduced the protein and mRNA expression of AQP4 after ischemic stroke in rats' brains. CONCLUSIONS: The expression of AQP4 was closely related to cerebral edema induced by ischemic stroke. Decreasing the expression of AQP4 mRNA by AZA administration can effectively relieve cerebral edema and decrease cerebral pathological damage.

Effects of embryo density on cell number of day 3 embryos cultured in a 30-µl drop: a retrospective cohort study.

For individual cultures, findings on regulating embryo density by changing the microdrop volume are contradictory. The aim of this study was to investigate the relationship between embryo density and the developmental outcome of day 3 embryos after adjusting covariates. In total, 1196 embryos from 206 couples who had undergone in vitro fertilization treatment were analyzed retrospectively. Three embryo densities were used routinely, i.e. one embryo in a drop (30 µl/embryo), two embryos in a drop (15 µl/embryo) and three embryos in a drop (10 µl/embryo). Embryo quality on day 3 was evaluated, both the cell number of day 3 embryos and the proportion of successful implantations served as endpoints. Maternal age, paternal age, antral follicles and level of anti-Müllerian hormone, type of infertility, controlled ovarian stimulation protocol, length of stimulation, number of retrieved oocytes, number of zygotes (two pronuclei) and insemination type were covariates and adjusted. After adjusting fully for all covariates, the cell number of day 3 embryos was significantly increased by 0.40 (95% CI 0.00, 0.79; P = 0.048) and 0.78 (95% CI 0.02, 1.54; P = 0.044) in the 15 µl/embryo and 10 µl/embryo group separately, compared with the 30 µl/embryo group. The proportions of implanted embryos were 42.1%, 48.7% and 0.0% in the 30 µl/embryo, 15 µl/embryo and 10 µl/embryo groups respectively. There was no statistical significance (P = 0.22) between the 30 µl/embryo group and the 15 µl/embryo group. After adjusting for confounders that were significant in univariate analysis, embryo density was still not associated with day 3 embryo implantation potential (P > 0.05). In a 30-µl microdrop, culturing embryos with an embryo density of both 15 and 10 µl/embryo increased the cell number of day 3 embryos, which did not benefit embryo implanting potential, compared with individual culture of 30 µl/embryo.

DP1 Activation Reverses Age-Related Hypertension Via NEDD4L-Mediated T-Bet Degradation in T Cells.

BACKGROUND: Blood pressure often rises with aging, but exact mechanisms are still not completely understood. With aging, the level of proinflammatory cytokines increases in T lymphocytes. Prostaglandin D2, a proresolution mediator, suppresses Type 1 T helper (Th1) cytokines through D-prostanoid receptor 1 (DP1). In this study, we aimed to investigate the role of the prostaglandin D2/DP1 axis in T cells on age-related hypertension. METHODS: To clarify the physiological and pathophysiological roles of DP1 in T cells with aging, peripheral blood samples were collected from young and older male participants, and CD4+ T cells were sorted for gene expression, prostaglandin production, and Western blot assays. Mice blood pressure was quantified by invasive telemetric monitor. RESULTS: The prostaglandin D2/DP1 axis was downregulated in CD4+ T cells from older humans and aged mice. DP1 deletion in CD4+ T cells augmented age-related hypertension in aged male mice by enhancing Th1 cytokine secretion, vascular remodeling, CD4+ T cells infiltration, and superoxide production in vasculature and kidneys. Conversely, forced expression of exogenous DP1 in T cells retarded age-associated hypertension in mice by reducing Th1 cytokine secretion. Tumor necrosis factor α neutralization or interferon γ deletion ameliorated the age-related hypertension in DP1 deletion in CD4+ T cells mice. Mechanistically, DP1 inhibited Th1 activity via the PKA (protein kinase A)/p-Sp1 (phosphorylated specificity protein 1)/neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) pathway-mediated T-box-expressed-in-T-cells (T-bet) ubiquitination. T-bet deletion or forced NEDD4L expression in CD4+ T cells attenuated age-related hypertension in CD4+ T cell-specific DP1-deficient mice. DP1 receptor activation by BW245C prevented age-associated blood pressure elevation and reduced vascular/renal superoxide production in male mice. CONCLUSIONS: The prostaglandin D2/DP1 axis suppresses age-related Th1 activation and subsequent hypertensive response in male mice through increase of NEDD4L-mediated T-bet degradation by ubiquitination. Therefore, the T cell DP1 receptor may be an attractive therapeutic target for age-related hypertension.

Insights on bio-degumming of kenaf bast based on metagenomic and proteomics.

BACKGROUND: Microbes play important roles in kanef-degumming. This study aims at identifying the key candidate microbes and proteins responsible for the degumming of kenaf bast (Hibiscus cannabinus). Kenaf bast was cut into pieces and immersed into microbia fermentation liquid collected from different sites. Fermentation liquid samples were collected at 0, 40, 110 and 150 h and then subjected to the 16S/18S rRNA sequencing analysis and isobaric tag for relative and absolute quantitation (iTRAQ) analysis. The microbial (bacterial and fungal) diversity and the differentially expressed proteins/peptides (DEPs) were identified. RESULTS: With the prolonged degumming time, the weight loss rate increased, the bacterial diversity was decreased. [Weeksellaceae], Enterobacteriaceae and Moraxellaceae were rapidly increased at 0~40 h, and then decreased and were gradually replaced by Bacteroidaceae from 40 h to 150 h. Similarly, Chryseobacterium and Dysgonomonas were gradually increased at 0~110 h and then decreased; Acinetobacter and Lactococcus were increased at 0~40 h, followed by decrease. Bacteroides was the dominant genus at 150 h. Sequencing 18S rRNA-seq showed the gradually decreased Wallemia hederae and increased Codosiga hollandica during degumming. iTRAQ data analysis showed Rds1, and pyruvate kinase I was decreased and increased in the kanef-degumming, respectively. Other DEPs of ferredoxin I, superoxide dismutase and aconitatehydratase were identified to be related to the Glyoxylate and dicarboxylate metabolism (ko00630). CONCLUSIONS: Bacteria including Chryseobacterium, Dysgonomonas, Acinetobacter, Lactococcus and Bacteroidesand fungi like Wallemia hederae and Codosiga hollandica are key candidate microbes for kanef degumming.

Mineralocorticoid receptor negatively regulates angiogenesis through repression of STAT3 activity in endothelial cells.

The mineralocorticoid receptor (MR) plays important roles in cardiovascular pathogenesis. The function of MR in angiogenesis is still controversial. This study aimed to explore the role of endothelial MR in angiogenesis and to delineate the underlying mechanism. Endothelial-hematopoietic MR knockout (EMRKO) mice were generated and subjected to hindlimb ischemia and injection of melanoma cells. Laser Doppler measurements showed that EMRKO mice had improved blood flow recovery and increased vessel density in ischemic limbs. In addition, EMRKO accelerated growth and increased the vessel density of tumors. Matrigel implantation, aortic ring assays, and tube formation assays demonstrated that MRKO endothelial cells (ECs) manifested increased angiogenic potential. MRKO ECs also displayed increased migration ability and proliferation. MRKO and MR knockdown both upregulated gene expression, protein level, and phosphorylation of signal transducer and activator of transcription 3 (STAT3). Stattic, a selective STAT3 inhibitor, attenuated the effects of MRKO on tube formation, migration, and proliferation of ECs. At the molecular level, MR interacted with CCAAT enhancer-binding protein beta (C/EBPß) to suppress the transcription of STAT3. Furthermore, interactions between MR and STAT3 blocked the phosphorylation of STAT3. Finally, stattic abolished the pro-angiogenic phenotype of EMRKO mice. Taken together, endothelial MR is a negative regulator of angiogenesis, likely in a ligand-independent manner. Mechanistically, MR downregulates STAT3 that mediates the impacts of MR deficiency on the angiogenic activity of ECs and angiogenesis. Targeting endothelial MR may be a potential pro-angiogenic strategy for ischemic diseases. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Elevated sodium chloride drives type I interferon signaling in macrophages and increases antiviral resistance.

Type I IFN production and signaling in macrophages play critical roles in innate immune responses. High salt (i.e. high concentrations of NaCl) has been proposed to be an important environmental factor that influences immune responses in multiple ways. However, it remains unknown whether high salt regulates type I IFN production and signaling in macrophages. Here, we demonstrated that high salt promoted IFNß production and its signaling in both human and mouse macrophages, and consequentially primed macrophages for strengthened immune sensing and signaling when challenged with viruses or viral nucleic acid analogues. Using both pharmacological inhibitors and RNA interference we showed that these effects of high salt on IFNß signaling were mediated by the p38 MAPK/ATF2/AP1 signaling pathway. Consistently, high salt increased resistance to vesicle stomatitis virus (VSV) infection in vitro. In vivo data indicated that a high-salt diet protected mice from lethal VSV infection. Taken together, these results identify high salt as a crucial regulator of type I IFN production and signaling, shedding important new light on the regulation of innate immune responses.

T-Cell Mineralocorticoid Receptor Controls Blood Pressure by Regulating Interferon-Gamma.

RATIONALE: Hypertension remains to be a global public health burden and demands novel intervention strategies such as targeting T cells and T-cell-derived cytokines. Mineralocorticoid receptor (MR) antagonists have been clinically used to treat hypertension. However, the function of T-cell MR in blood pressure (BP) regulation has not been elucidated. OBJECTIVE: We aim to determine the role of T-cell MR in BP regulation and to explore the mechanism. METHODS AND RESULTS: Using T-cell MR knockout mouse in combination with angiotensin II-induced hypertensive mouse model, we demonstrated that MR deficiency in T cells strikingly decreased both systolic and diastolic BP and attenuated renal and vascular damage. Flow cytometric analysis showed that T-cell MR knockout mitigated angiotensin II-induced accumulation of interferon-gamma (IFN-γ)-producing T cells, particularly CD8+ population, in both kidneys and aortas. Similarly, eplerenone attenuated angiotensin II-induced elevation of BP and accumulation of IFN-γ-producing T cells in wild-type mice. In cultured CD8+ T cells, T-cell MR knockout suppressed IFN-γ expression whereas T-cell MR overexpression and aldosterone both enhanced IFN-γ expression. At the molecular level, MR interacted with NFAT1 (nuclear factor of activated T-cells 1) and activator protein-1 in T cells. Finally, T-cell MR overexpressing mice manifested more elevated BP compared with control mice after angiotensin II infusion and such difference was abolished by IFN-γ-neutralizing antibodies. CONCLUSIONS: MR may interact with NFAT1 and activator protein-1 to control IFN-γ in T cells and to regulate target organ damage and ultimately BP. Targeting MR in T cells specifically may be an effective novel approach for hypertension treatment.

A Survey of Vision-Based Human Action Evaluation Methods.

The fields of human activity analysis have recently begun to diversify. Many researchers have taken much interest in developing action recognition or action prediction methods. The research on human action evaluation differs by aiming to design computation models and evaluation approaches for automatically assessing the quality of human actions. This line of study has become popular because of its explosively emerging real-world applications, such as physical rehabilitation, assistive living for elderly people, skill training on self-learning platforms, and sports activity scoring. This paper presents a comprehensive survey of approaches and techniques in action evaluation research, including motion detection and preprocessing using skeleton data, handcrafted feature representation methods, and deep learning-based feature representation methods. The benchmark datasets from this research field and some evaluation criteria employed to validate the algorithms' performance are introduced. Finally, the authors present several promising future directions for further studies.

A Comprehensive Survey of Vision-Based Human Action Recognition Methods.

Although widely used in many applications, accurate and efficient human action recognition remains a challenging area of research in the field of computer vision. Most recent surveys have focused on narrow problems such as human action recognition methods using depth data, 3D-skeleton data, still image data, spatiotemporal interest point-based methods, and human walking motion recognition. However, there has been no systematic survey of human action recognition. To this end, we present a thorough review of human action recognition methods and provide a comprehensive overview of recent approaches in human action recognition research, including progress in hand-designed action features in RGB and depth data, current deep learning-based action feature representation methods, advances in human⁻object interaction recognition methods, and the current prominent research topic of action detection methods. Finally, we present several analysis recommendations for researchers. This survey paper provides an essential reference for those interested in further research on human action recognition.