Role of Treg cell subsets in cardiovascular disease pathogenesis and potential therapeutic targets.

In the genesis and progression of cardiovascular diseases involving both innate and adaptive immune responses, inflammation plays a pivotal and dual role. Studies in experimental animals indicate that certain immune responses are protective, while others exacerbate the disease. T-helper (Th) 1 cell immune responses are recognized as key drivers of inflammatory progression in cardiovascular diseases. Consequently, the CD4+CD25+FOXP3+ regulatory T cells (Tregs) are gaining increasing attention for their roles in inflammation and immune regulation. Given the critical role of Tregs in maintaining immune-inflammatory balance and homeostasis, abnormalities in their generation or function might lead to aberrant immune responses, thereby initiating pathological changes. Numerous preclinical studies and clinical trials have unveiled the central role of Tregs in cardiovascular diseases, such as atherosclerosis. Here, we review the roles and mechanisms of Treg subsets in cardiovascular conditions like atherosclerosis, hypertension, myocardial infarction and remodeling, myocarditis, dilated cardiomyopathy, and heart failure. While the precise molecular mechanisms of Tregs in cardiac protection remain elusive, therapeutic strategies targeting Tregs present a promising new direction for the prevention and treatment of cardiovascular diseases.

Development and validation of a nomogram for predicting all-cause mortality in American adult hypertensive populations.

Backgrounds: Hypertension stands as the predominant global cause of mortality. A notable deficiency exists in terms of predictive models for mortality among individuals with hypertension. We aim to devise an effective nomogram model that possesses the capability to forecast all-cause mortality within hypertensive populations. Methods: The data for this study were drawn from nine successive cycles of the National Health and Nutrition Examination Survey (NHANES) spanning the years from 1999 to 2016. The dataset was partitioned into training and validation sets at a 7:3 ratio. We opted for clinical practice-relevant indicators, applied the least absolute shrinkage and selection operator (LASSO) regression to identify the most pertinent variables, and subsequently built a nomogram model. We also employed concordance index, receiver operating characteristic (ROC) curves, calibration curves and decision curve analysis (DCA) to assess the model's validity. Results: A total of 17,125 hypertensive participants were included in this study with a division into a training set (11,993 individuals) and a validation set (5,132 individuals). LASSO regression was applied for the training set to obtain nine variables including age, monocytes, neutrophils, serum albumin, serum potassium, cardiovascular disease, diabetes, serum creatinine and glycated hemoglobin (HbA1C), and constructed a nomogram prediction model. To validate this model, data from the training and validation sets were used for validation separately. The concordance index of the nomogram model was 0.800 (95% CI, 0.792-0.808, p < 0.001) based on the training set and 0.793 (95% CI, 0.781-0.805, p < 0.001) based on the validation set. The ROC curves, calibration curves, and DCA curves all showed good predictive performance. Conclusion: We have developed a nomogram that effectively forecasts the risk of all-cause mortality among American adults in hypertensive populations. Clinicians may use this nomogram to assess patient's prognosis and choose a proper intervention in a timely manner.

Predictive value of serum creatinine and total bilirubin for long-term death in patients with ischemic heart disease: A cohort study.

BACKGROUND: Ischemic heart disease (IHD) has a high mortality in the population. Although serum creatinine (Cr) and serum total bilirubin (TBil) are rapid and readily available biomarkers in routine blood tests, there is a lack of literature on the prognostic value of combined Cr and TBil tests for IHD. This study aimed to evaluate a combined equation based on Cr and TBil to predict the long-term risk of death in IHD and to find indicators sensitive to the prognosis of IHD patients. METHOD: In this study, 2625 patients with IHD were included, and the combined value and combined equations of Cr and TBil were obtained by logistic regression analysis based on Cr and TBil collected at the time of admission. Patients were divided into four groups according to the quartiles of the combined value. COX proportional hazard regression model was used to analyze the risk factors for long-term death in IHD patients. Receiver operating characteristic (ROC) curves were used to evaluate the prognostic effect of Cr, TBil and combined value on long-term death events. RESULTS: Logistic regression analysis was performed for long-term death events with Cr and TBil as independent variables, and the logit regression model was Logit(P) = 0.0129×TBil+0.007×Cr-0.417. Multifactorial Cox regression analysis showed that high values of the equation were independent risk factors for long-term death events (all-cause death: HR 1.457, 95% CI 1.256-1.689, P<0.001; cardiovascular death: HR 1.452, 95% CI 1.244-1.695, P<0.001). Combined Cr and TBil value are more valuable in predicting long-term death (AUC: 0.609, 95% CI 0.587-0.630, P<0.001). CONCLUSION: Combined Cr and TBil assay is superior to single biomarkers for predicting long-term death in patients with IHD. High values of the equation are independent predictors of long-term death and can be used to identify patients at high risk for IHD.

Dynamic reversibility of α-synuclein serine-129 phosphorylation is impaired in synucleinopathy models.

α-Synuclein phosphorylation at serine-129 (pS129) is a widely used surrogate marker of pathology in Parkinson's disease and other synucleinopathies. However, we recently demonstrated that phosphorylation of S129 is also a physiological activator of synaptic transmission. In a feed-forward fashion, neuronal activity triggers reversible pS129. Here, we show that Parkinson's disease-linked missense mutations in SNCA impact activity-dependent pS129. Under basal conditions, cytosol-enriched A30P, H50Q, and G51D mutant forms of α-synuclein exhibit reduced pS129 levels in rat primary cortical neurons. A53T pS129 levels are similar to wild-type, and E46K pS129 levels are higher. A30P and E46K mutants show impaired reversibility of pS129 after stimulation. For the engineered profoundly membrane-associated α-synuclein mutant "3K" (E35K + E46K + E61K), de-phosphorylation was virtually absent after blocking stimulation, implying that reversible pS129 is severely compromised. Importantly, pS129 excess resulting from proteasome inhibition is also associated with reduced reversibility by neuronal inhibition, kinase inhibition, or phosphatase activation. Our findings suggest that perturbed pS129 dynamics are probably a shared characteristic of pathology-associated α-synuclein, with possible implications for synucleinopathy treatment and diagnosis.

The role and mechanisms of microvascular damage in the ischemic myocardium.

Following myocardial ischemic injury, the most effective clinical intervention is timely restoration of blood perfusion to ischemic but viable myocardium to reduce irreversible myocardial necrosis, limit infarct size, and prevent cardiac insufficiency. However, reperfusion itself may exacerbate cell death and myocardial injury, a process commonly referred to as ischemia/reperfusion (I/R) injury, which primarily involves cardiomyocytes and cardiac microvascular endothelial cells (CMECs) and is characterized by myocardial stunning, microvascular damage (MVD), reperfusion arrhythmia, and lethal reperfusion injury. MVD caused by I/R has been a neglected problem compared to myocardial injury. Clinically, the incidence of microvascular angina and/or no-reflow due to ineffective coronary perfusion accounts for 5-50% in patients after acute revascularization. MVD limiting drug diffusion into injured myocardium, is strongly associated with the development of heart failure. CMECs account for > 60% of the cardiac cellular components, and their role in myocardial I/R injury cannot be ignored. There are many studies on microvascular obstruction, but few studies on microvascular leakage, which may be mainly due to the lack of corresponding detection methods. In this review, we summarize the clinical manifestations, related mechanisms of MVD during myocardial I/R, laboratory and clinical examination means, as well as the research progress on potential therapies for MVD in recent years. Better understanding the characteristics and risk factors of MVD in patients after hemodynamic reconstruction is of great significance for managing MVD, preventing heart failure and improving patient prognosis.

CHI3L1 promotes myocardial fibrosis via regulating lncRNA TUG1/miR-495-3p/ETS1 axis.

Abnormal levels of CHI3L1 and lnc TUG1 are often associated with myocardial fibrosis, and their specific expressions may be closely related to the process of myocardial fibrosis. In addition, CHI3L1 was found to significantly up-regulate the expression of lncTUG1. Therefore, this study further explored the major role of CHI3L1 in regulating the progression of myocardial fibrosis. Myocardial fibrosis in mice was established using an angiotensin (Ang II) model, and the degree of myocardial fibrosis was assessed by qPCR, western blot and pathological techniques. HL-1 cells with overexpression and silencing of CHI3L1 were constructed, and the cell migration ability was detected using the Transwell method. Biological information was used to predict the potential target miRNA of lnc TUG1, and the interaction between them was verified by dual luciferase reporter assay. Using functional rescue assay and the rAAV9 technique, CHI3L1 was verified to affect the fibrotic process of myocardial cells by regulating the lnc TUG1/miR-495-3p/ETS1 axis in vitro and in vivo. The myocardial fibrosis index in the model group was significantly upregulated, and expression of both CHI3L1 and lnc TUG1 was upregulated. Pathological results revealed fibrosis and collagen deposition in the myocardium. Overexpression of lnc TUG1 reversed the inhibitory effect of CHI3L1 silencing on myocardial fibrosis. Mechanistically, CH3L1 upregulates the expression of lnc TUG1, and lnc TUG1 weakens the inhibition of ETS1 through sponge absorption of miR-495-3p, promoting the process of myocardial fibrosis.

Predictive Effect of Triglyceride-Glucose Index on Adverse Prognostic Events in Patients with Type 2 Diabetes Mellitus and Ischemic Cardiomyopathy.

Background: The triglyceride-glucose (TyG) index is regarded as an independent predictor of cardiovascular (CV) consequences and a reliable surrogate measure of insulin resistance (IR). However, the predictive significance of the TyG index in patients with type 2 diabetes mellitus (T2DM) and ischemic cardiomyopathy (ICM) remains unknown. Methods: This study included 1514 consecutive subjects with ICM and T2DM. The tertile of the TyG index values was used to categorize these patients into three groups. Major adverse cardiac and cerebral events (MACCEs) were also noted. The TyG index was calculated using the [fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2] equation. Results: After adjusting for age, BMI, and other potential confounders, the scores of multivariate Cox proportional hazards regression models for chest pain [9.056 (4.370 to 18.767), p<0.001], acute myocardial infarction [4.437 (1.420 to 13.869), p=0.010], heart failure [7.334 (3.424 to 15.708), p<0.001], cardiogenic shock [3.707 (1.207 to 11.384), p=0.022], malignant arrhythmia [5.309 (2.367 to 11.908), p<0.001], cerebral infarction [3.127 (1.596 to 6.128), p<0.001], gastrointestinal bleeding [4.326 (1.612 to 11.613), p=0.004], all-cause death [4.502 (3.478 to 5.827), p<0.001] and cumulative incidence of MACCEs [4.856 (3.842 to 6.136), p<0.001] increased significantly with an increase in TyG index levels (all p<0.05). Time-dependent ROC analysis revealed that the area under the TyG index curve (AUC) reached 0.653 in the 3rd year, 0.688 in the 5th year, and 0.764 in the 10th year. The predictive efficiency of this model on MACCEs improved [net reclassification improvement (NRI): 0.361 (0.253 to 0.454); C-index: 0.678 (0.658 to 0.698); integrated discrimination improvement (IDI): 0.138 (0.098 to 0.175), all p<0.05] following the incorporation of the TyG index into the base risk model. Conclusion: TyG index could be useful in predicting MACCEs and initiating preventive measures in subjects with ICM and T2DM.

Development and validation of a nomogram to predict mortality risk in patients with ischemic heart disease.

Background: Ischemic Heart Disease (IHD) is the leading cause of death from cardiovascular disease. Currently, most studies have focused on factors influencing IDH or mortality risk, while few predictive models have been used for mortality risk in IHD patients. In this study, we constructed an effective nomogram prediction model to predict the risk of death in IHD patients by machine learning. Methods: We conducted a retrospective study of 1,663 patients with IHD. The data were divided into training and validation sets in a 3:1 ratio. The least absolute shrinkage and selection operator (LASSO) regression method was used to screen the variables to test the accuracy of the risk prediction model. Data from the training and validation sets were used to calculate receiver operating characteristic (ROC) curves, C-index, calibration plots, and dynamic component analysis (DCA), respectively. Results: Using LASSO regression, we selected six representative features, age, uric acid, serum total bilirubin, albumin, alkaline phosphatase, and left ventricular ejection fraction, from 31 variables to predict the risk of death at 1, 3, and 5 years in patients with IHD, and constructed the nomogram model. In the reliability of the validated model, the C-index at 1, 3, and 5 years was 0.705 (0.658-0.751), 0.705 (0.671-0.739), and 0.694 (0.656-0.733) for the training set, respectively; the C-index at 1, 3, and 5 years based on the validation set was 0.720 (0.654-0.786), 0.708 (0.650-0.765), and 0.683 (0.613-0.754), respectively. Both the calibration plot and the DCA curve are well-behaved. Conclusion: Age, uric acid, total serum bilirubin, serum albumin, alkaline phosphatase, and left ventricular ejection fraction were significantly associated with the risk of death in patients with IHD. We constructed a simple nomogram model to predict the risk of death at 1, 3, and 5 years for patients with IHD. Clinicians can use this simple model to assess the prognosis of patients at the time of admission to make better clinical decisions in tertiary prevention of the disease.

SLC27A5 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by downregulating glutathione reductase.

Sorafenib, a first-line drug for advanced hepatocellular carcinoma (HCC), shows a favorable anti-tumor effect while resistance is a barrier impeding patients from benefiting from it. Thus, more efforts are needed to lift this restriction. Herein, we first find that solute carrier family 27 member 5 (SLC27A5/FATP5), an enzyme involved in the metabolism of fatty acid and bile acid, is downregulated in sorafenib-resistant HCC. SLC27A5 deficiency facilitates the resistance towards sorafenib in HCC cells, which is mediated by suppressing ferroptosis. Further mechanism studies reveal that the loss of SLC27A5 enhances the glutathione reductase (GSR) expression in a nuclear factor erythroid 2-related factor 2 (NRF2)-dependent manner, which maintains glutathione (GSH) homeostasis and renders insensitive to sorafenib-induced ferroptosis. Notably, SLC27A5 negatively correlates with GSR, and genetic or pharmacological inhibition of GSR strengthens the efficacy of sorafenib through GSH depletion and the accumulation of lipid peroxide products in SLC27A5-knockout and sorafenib-resistant HCC cells. Based on our results, the combination of sorafenib and carmustine (BCNU), a selective inhibitor of GSR, remarkably hamper tumor growth by enhancing ferroptotic cell death in vivo. In conclusion, we describe that SLC27A5 serves as a suppressor in sorafenib resistance and promotes sorafenib-triggered ferroptosis via restraining the NRF2/GSR pathway in HCC, providing a potential therapeutic strategy for overcoming sorafenib resistance.

Dynamic physiological α-synuclein S129 phosphorylation is driven by neuronal activity.

In Parkinson's disease and other synucleinopathies, the elevation of α-synuclein phosphorylated at Serine129 (pS129) is a widely cited marker of pathology. However, the physiological role for pS129 has remained undefined. Here we use multiple approaches to show for the first time that pS129 functions as a physiological regulator of neuronal activity. Neuronal activity triggers a sustained increase of pS129 in cultured neurons (200% within 4 h). In accord, brain pS129 is elevated in environmentally enriched mice exhibiting enhanced long-term potentiation. Activity-dependent α-synuclein phosphorylation is S129-specific, reversible, confers no cytotoxicity, and accumulates at synapsin-containing presynaptic boutons. Mechanistically, our findings are consistent with a model in which neuronal stimulation enhances Plk2 kinase activity via a calcium/calcineurin pathway to counteract PP2A phosphatase activity for efficient phosphorylation of membrane-bound α-synuclein. Patch clamping of rat SNCA-/- neurons expressing exogenous wild-type or phospho-incompetent (S129A) α-synuclein suggests that pS129 fine-tunes the balance between excitatory and inhibitory neuronal currents. Consistently, our novel S129A knock-in (S129AKI) mice exhibit impaired hippocampal plasticity. The discovery of a key physiological function for pS129 has implications for understanding the role of α-synuclein in neurotransmission and adds nuance to the interpretation of pS129 as a synucleinopathy biomarker.

Somatic Mutation of PRKAR1A in Four Cases of Sporadic Cardiac Myxoma.

BACKGROUND: Inactivating mutations of the protein kinase A regulatory subunit 1 alpha (PRKAR1A) gene have been reported in familial cardiac myxoma. However, the role of PRKAR1A mutation in sporadic cardiac myxoma remains unknown. METHODS: Targeted next-generation sequencing (NGS) was performed to identify mutations with the PRKAR1A gene in seven cases of sporadic cardiac myxomas. Sanger sequencing of DNA from cardiac myxoma specimens and matched peripheral blood samples was performed to verify the identified mutations. RESULTS: Targeted NGS of myxoma DNA revealed 232 single nucleotide variants in 141 genes and 38 insertion-deletion mutations in 13 genes. Six PRKAR1A mutations were identified in four of the seven cardiac myxoma cases, and thus, the PRKAR1A inactivating mutation rate was 57.2% (4/7, 95% CI=0.44-0.58, P<0.05). The PRKAR1A variants identified by Sanger sequencing analysis were consistent with those from the NGS analysis for the four myxoma specimens. All of the pathogenic PRKAR1A mutations led to premature termination of PRKAR1A, except for one synonymous mutation. Moreover, none of the nonsense and missense mutations found in the myxoma specimens were found in the matched peripheral blood samples. CONCLUSION: Pathogenic mutations of the PRKAR1A gene were identified in tumor specimens from four cases of sporadic cardiac myxoma, and the absence of these mutations in peripheral blood samples demonstrated that they were somatic mutations.

Prediction for 2-year mortality of metastatic ovarian cancer patients based on surveillance, epidemiology, and end results database.

Aim: To establish prediction models for 2-year overall survival of ovarian cancer patients with metastasis. Methods: In total, 4,929 participants from Surveillance, Epidemiology, and End Results (SEER) database were randomly divided into the training set (n = 3,451) and the testing set (n = 1,478). Univariate and multivariable regression were conducted in the training set to identify predictors for 2-year overall survival of metastatic ovarian cancer patients. The C-index was calculated for assessing the performance of the models. The nomogram for the model was plotted. The prediction value of the model was validated in the testing set. Subgroup analysis were performed concerning surgery and chemotherapy status of patients and the metastatic site of ovarian cancer in the testing set. The calibration curves were plotted and the decision curve analysis (DCA) were conducted. Results: At the end of follow-up, 2,587 patients were survived and 2,342 patients were dead within 2 years. The 2-year survival rate was 52.5%. The prediction models were constructed based on predictors including age, radiation, surgery and chemotherapy, CA125, and bone, liver, and lung metastasis. The prediction model for 2-year overall survival of ovarian cancer patients with metastasis showed good predictive ability with the C-index of the model of 0.719 (95% CI: 0.706-0.731) in the training set and 0.718 (95% CI: 0.698-0.737) in the testing set. In terms of patients with bone metastasis, the C-index was 0.740 (95% CI: 0.652-0.828) for predicting the 2-year overall survival of ovarian cancer patients. The C-index was 0.836 (95% CI: 0.694-0.979) in patients with brain metastasis, 0.755 (95% CI: 0.721-0.788) in patients with liver metastasis and 0.725 (95% CI: 0.686-0.764) in those with lung metastasis for predicting the 2-year overall survival of ovarian cancer patients. Conclusion: The models showed good predictive performance for 2-year overall survival of metastatic ovarian cancer patients.

Aß oligomers from human brain impair mossy fiber LTP in CA3 of hippocampus, but activating cAMP-PKA and cGMP-PKG prevents this.

Early cognitive impairment in Alzheimer's disease may result in part from synaptic dysfunction caused by the accumulation oligomeric assemblies of amyloid ß-protein (Aß). Changes in hippocampal function seem critical for cognitive impairment in early Alzheimer's disease (AD). Diffusible oligomers of Aß (oAß) have been shown to block canonical long-term potentiation (LTP) in the CA1 area of hippocampus, but whether there is also a direct effect of oAß on synaptic transmission and plasticity at synapses between mossy fibers (axons) from the dentate gyrus granule cells and CA3 pyramidal neurons (mf-CA3 synapses) is unknown. Studies in APP transgenic mice have suggested an age-dependent impairment of mossy fiber LTP. Here we report that although endogenous AD brain-derived soluble oAß had no effect on mossy-fiber basal transmission, it strongly impaired paired-pulse facilitation in the mossy fiber pathway and presynaptic mossy fiber LTP (mf-LTP). Selective activation of both ß1 and ß2 adrenergic receptors and their downstream cAMP/PKA signaling pathway prevented oAß-mediated inhibition of mf-LTP. Unexpectedly, activation of the cGMP/PKG signaling pathway also prevented oAß-impaired mf-LTP. Our results reveal certain specific pharmacological targets to ameliorate human oAß-mediated impairment at the mf-CA3 synapse.

Case Report: Giant Pelvic Cystic Appearance-An Unusual Feature of Uterine Cervical Adenocarcinoma.

Cervical adenocarcinoma can present as a solid, mixed solid, cystic, or multiple cystic cervical mass in the endocervical canal. In this report, we present an extremely rare case of cervical adenocarcinoma with giant cystic lesions. A 37-year-old Chinese woman with a regular menstrual cycle presented to her local doctor complaining of mild abdominal distension. Abdominal ultrasonography suggested an ovarian cyst, whose mean diameter increased from 3 to 8 cm in 3 months. Thereafter, she was referred to our hospital. She had no abnormal vaginal bleeding or discharge. Transvaginal ultrasonography revealed a 95 × 80 mm cyst below the back of the uterus. Computed tomography revealed a 9.8 × 8.5 cm multilocular cyst between the cervix and right ovary. Human papillomavirus (HPV)-E6 and -E7 mRNA tests revealed HPV-16 positivity. The thin-layer, liquid-based cytological test of the cervix showed negative results. No tumor lesions were observed on the cervical biopsy histopathology. The lesion was misdiagnosed as an ovarian cyst prior to the surgery. Intraoperatively, a cyst of the size of a child's head was observed extending from the low posterior wall of the uterus to the posterior lip of the cervix, and the cervical cysts were resected. Histological examination revealed cervical adenocarcinoma. Subsequently, she underwent extensive hysterectomy, bilateral salpingectomy, and pelvic lymphadenectomy. The final diagnosis was stage IB3 cervical adenocarcinoma. After 21 months of follow-up, no clinical or radiological evidence of recurrence has been found.

An ultra-sensitive immunoassay detects and quantifies soluble Aß oligomers in human plasma.

INTRODUCTION: Evidence strongly suggests that soluble oligomers of amyloid beta protein (oAß) help initiate the pathogenic cascade of Alzheimer's disease (AD). To date, there have been no validated assays specific for detecting and quantifying oAß in human blood. METHODS: We developed an ultrasensitive oAß immunoassay using a novel capture antibody (71A1) with N-terminal antibody 3D6 for detection that specifically quantifies soluble oAß in the human brain, cerebrospinal fluid (CSF), and plasma. RESULTS: Two new antibodies (71A1; 1G5) are oAß-selective, label Aß plaques in non-fixed AD brain sections, and potently neutralize the synaptotoxicity of AD brain-derived oAß. The 71A1/3D6 assay showed excellent dilution linearity in CSF and plasma without matrix effects, good spike recovery, and specific immunodepletion. DISCUSSION: We have created a sensitive, high throughput, and inexpensive method to quantify synaptotoxic oAß in human plasma for analyzing large cohorts of aged and AD subjects to assess the dynamics of this key pathogenic species and response to therapy.

The role of CD74 in cardiovascular disease.

Leukocyte differentiation antigen 74 (CD74), also known as invariant chain, is a molecular chaperone of major histocompatibility complex class II (MHC II) molecules involved in antigen presentation. CD74 has recently been shown to be a receptor for the macrophage migration inhibitory factor family proteins (MIF/MIF2). Many studies have revealed that CD74 plays an important role in cardiovascular disease. In this review, we summarize the structure and main functions of CD74 and then focus on the recent research progress on the role of CD74 in cardiovascular diseases. In addition, we also discuss potential treatment strategies that target CD74. Our systematic review of the role of CD74 in cardiovascular disease will fill some knowledge gaps in the field.

Astroglial FMRP modulates synaptic signaling and behavior phenotypes in FXS mouse model.

Fragile X syndrome (FXS) is one of the most common inherited intellectual disability (ID) disorders, in which the loss of FMRP protein induces a range of cellular signaling changes primarily through excess protein synthesis. Although neuron-centered molecular and cellular events underlying FXS have been characterized, how different CNS cell types are involved in typical FXS synaptic signaling changes and behavioral phenotypes is largely unknown. Recent evidence suggests that selective loss of astroglial FMRP is able to dysregulate glutamate uptake, increase spine density, and impair motor-skill learning. Here we investigated the effect of astroglial FMRP on synaptic signaling and FXS-related behavioral and learning phenotypes in astroglial Fmr1 cKO and cON mice in which FMRP expression is selectively diminished or restored in astroglia. We found that selective loss of astroglial FMRP contributes to cortical hyperexcitability by enhancing NMDAR-mediated evoked but not spontaneous miniEPSCs and elongating cortical UP state duration. Selective loss of astroglial FMRP is also sufficient to increase locomotor hyperactivity, significantly diminish social novelty preference, and induce memory acquisition and extinction deficits in astroglial Fmr1 cKO mice. Importantly, re-expression of astroglial FMRP is able to significantly rescue the hyperactivity (evoked NMDAR response, UP state duration, and open field test) and social novelty preference in astroglial Fmr1 cON mice. These results demonstrate a profound role of astroglial FMRP in the evoked synaptic signaling, spontaneously occurring cortical UP states, and FXS-related behavioral and learning phenotypes and provide important new insights in the cell type consideration for the FMRP reactivation strategy.

RASGRF1 in CRF cells controls the early adolescent female response to repeated stress.

RASGRF1 (GRF1) is a calcium-stimulated guanine-nucleotide exchange factor that activates RAS and RAC GTPases. In hippocampus neurons, it mediates the action of NMDA and calcium-permeable AMPA glutamate receptors on specific forms of synaptic plasticity, learning, and memory in both male and female mice. Recently, we showed GRF1 also regulates the HPA axis response to restraint stress, but only in female mice before puberty. In particular, we found that after 7 days of restraint stress (7DRS) (30 min/day) both elevated serum CORT levels and induction of an anxiolytic phenotype normally observed in early adolescent (EA) female mice are blocked in GRF1-knockout mice. In contrast, no effects were observed in EA male or adult females. Here, we show this phenotype is due, at least in part, to GRF1 loss in CRF cells of the paraventricular nucleus of the hypothalamus, as GRF1 knockout specifically in these cells suppressed 7DRS-induced elevation of serum CORT levels specifically in EA females, but only down to levels found in comparably stressed EA males. Nevertheless, it still completely blocked the 7DRS-induced anxiolytic phenotype observed in EA females. Interestingly, loss of GRF1 in CRF cells had no effect after only three restraint stress exposures, implying a role for GRF1 in 7DRS stress-induced plasticity of CRF cells that appears to be specific to EA female mice. Overall, these findings indicate that GRF1 in CRF cells makes a key contribution to the distinct response EA females display to repeated stress.

[Epidemiology, Treatment, and Epidemic Prevention and Control of the Coronavirus Disease 2019: a Review].

This review summarizes the ongoing researches regarding etiology, epidemiology, transmission dynamics, treatment, and prevention and control strategies of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with comparison to severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and pandemic H1N1 virus. SARS-CoV-2 may be originated from bats, and the patients and asymptomatic carriers are the source of epidemic infection. The virus can be transmitted human-to-human through droplets and close contact, and people at all ages are susceptible to this virus. The main clinical symptoms of the patients are fever and cough, accompanied with leukocytopenia and lymphocytopenia. Effective drugs have been not yet available thus far. In terms of the prevention and control strategies, vaccine development as the primary prevention should be accelerated. Regarding the secondary prevention, ongoing efforts of the infected patients and close contacts quarantine, mask wearing promotion, regular disinfection in public places should be continued. Meanwhile, rapid detection kit for serological monitoring of the virus in general population is expected so as to achieve early detection, early diagnosis, early isolation and early treatment. In addition, public health education on this disease and prevention should be enhanced so as to mitigate panic and mobilize the public to jointly combat the epidemic.