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The aim of this study was to investigate whether the mitochondrial permeability transition pore (MPTP) opening was involved in the protective effects of CB2 receptor against ischemia-reperfusion (I-R) injury. For this, isolated perfused rat hearts were subjected to 30 min global ischemia followed by 120 min reperfusion, and left ventricle function was recorded. At the end of reperfusion, the infarct size in the hearts was measured by staining with triphenyltetrazolium chloride. MPTP opening and the mitochondrial membrane potential (ΔΨm) were measured by flow cytometry. Western blot analysis of cytochrome c in the mitochondrion and cytosol, as well as ERK1/2 and p-ERK1/2 were performed. Administration of CB2 receptor agonist JWH133 before ischemia significantly improved the recovery of cardiac ventricular function during reperfusion, increased coronary flow, reduced infarct size, prevented the loss of ΔΨm and MPTP opening, reduced the release of cytochrome c from mitochondria, and increased levels of p-ERK1/2. These effects of JWH133 were abolished by pretreatment with CB2 receptor antagonist AM630, or ERK1/2 inhibitor PD98059. Furthermore, JWH133 reversed the MPTP opening induced by atractyloside. The protective effect of JWH133 on the heart against I-R injury may be through increased ERK1/2 phosphorylation, inhibiting MPTP opening. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The aim of this study was to examine prospective memory (PM) and its socio-demographic, clinical, and neurocognitive correlates in first episode schizophrenia (FES). Methods: Fifty-one FES patients and 42 healthy controls formed the study sample. Time- and event-based PM (TBPM and EBPM) performance were measured with the Chinese version of the Cambridge Prospective Memory Test (C-CAMPROMPT). A battery of neuropsychological tests was also administered. Patients'' clinical symptoms were evaluated with the Positive and Negative Symptom Scale (PANSS). Results: Patients performed significantly worse in both TBPM (8.7±5.3 vs. 14.8±3.5) and EBPM (11.3±4.7 vs. 15.7±2.7) than the controls. After controlling for age, gender, education level and neurocognitive test score, the difference in performance on the two types of PM tasks between patients and controls was no longer present. In multiple linear regression analyses, longer duration of untreated psychosis (DUP), lower scores of the Hopkins Verbal Learning Test-Revised (HVLT-R) and the categories completed of the Wisconsin Card Sorting Test (WCST-CC) and higher score of the Color Trails Test-2 (CTT-2) contributed to poorer TBPM performance, while lower score of HVLT-R, higher score of the perseverative errors of the Wisconsin Card Sorting Test (WCST-PE) and longer DUP contributed to worse performance on EBPM. Conclusions: Both subtypes of PM are impaired in first-episode schizophrenia suggesting that PM deficits are an integral part of the cognitive dysfunction in the disease process. [Copyright &y& Elsevier]

Abstract: The integrated mechanisms of dynamic signaling of sodium channels involved in clinical pain are still not yet clear. In this study, a new rat inflammatory pain model was developed by using the unilateral intraplantar injection of BmK I, a receptor site 3-specific modulator of sodium channels from the venom of scorpion Buthus martensi Karsch (BmK). It was found that BmK I could induce several kinds of inflammatory pain-related behaviors including spontaneous pain companied with unique episodic paroxysms, primary thermal hypersensitivity, and mirror-image mechanical hypersensitivity with different time course of development, which could be suppressed by morphine, indomethacin, or bupivacaine to a different extent. The dramatic attenuation by pretreatment with resiniferatoxin (RTX), an ultrapotent analog of capsaicin, on BmK I-induced pain-related behaviors, paw edema, and spinal L4–L5 c-Fos expression demonstrated that capsaicin-sensitive primary afferent neurons played important roles in pain induced by BmK I. Furthermore, the electrophysiological recordings showed that BmK I persistently increased whole-cell and tetrodotoxin-resistant (TTX-R) peak sodium currents and significantly delayed the inactivation phase of whole-cell sodium currents but could not enhance capsaicin-evoked inward currents, in acute isolated small dorsal root ganglion neurons of rat. The results strongly suggested that the dynamic modulation of BmK I on sodium channels located in peripheral primary afferent neurons, especially in capsaicin-sensitive neurons, mediated pain sensation. Thus, BmK I may be a valuable pharmacological tool to understand the sodium channel-involved pain mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: The present study investigated whether spinal astrocyte and microglia were activated in Buthus martensi Karch (BmK) venom-induced rat pain-related behaviors. The results showed that glial fibrillary acidic protein (GFAP) immunoreactivity indicative astrocyte activation in bilateral spinal cord started to increase by day 3, peaked at day 7 and gradually reversed at day 14 following intraplantar injection of BmK venom. Western blotting analysis confirmed GFAP expression was up-regulated by BmK venom. In contrast, bilateral spinal increase of OX-42 immunoreactivity indicative of microglial activation began at 4h peaked at day 1 and gradually reversed by days 3 to 7 after the administration of BmK venom. Pretreatment with either intrathecal injection of fluorocitrate or intraperitonial injection of minocycline, and two glial activation inhibitors, suppressed the spontaneous nociceptive responses, and prevented the primary thermal and bilateral mechanical hyperalgesia induced by BmK venom. The post-treatment with fluorocitrate or minocycline could not affect the mechanical hyperalgesia. Moreover, minocycline partially inhibited BmK venom-induced spinal c-Fos expression but lack of effects on BmK venom-induced paw edema. Taken together, the current study demonstrated that spinal astrocyte and microglial activation may contribute to BmK venom-induced rat pain-related behaviors. Thus, spinal glia may represent novel targets for effective treatment of pain syndrome associated with scorpion envenomation. [Copyright &y& Elsevier]

Abstract: This paper proposed a self-learning, self-adapting algorithm (ANN-GA-Cascades) for extracting fuzzy rules, which is based on fusion of soft computing. We could use it to attain the fuzzy rules of oiliness in oil exploration: firstly, supervised learning of training sample is performed by using neural networks, with the inputs being the simplest well-logging attribute set which is relevant to the oiliness attributes, and the outputs being the corresponding oiliness partition C k (dry layer, water layer, inferiority layer and oil layer). When the neural network attained precision or the maximum iteration steps, the kth output node of neural network will be the corresponding partition of decision character, with the output function being ψ k = f(x i ,(WG1) ij ,(WG2) jk ), in which (WG1) ij are the connection weights between input layer and hidden layer, (WG2) jk are the connection weights between hidden layer and output layer. Then, the genetic algorithm (GA) was used to randomly assemble the input character and ψ k as the fitness function. In this way, the optimal chromosome will be the fuzzy rule of partition C k . Finally, the empirical study application of this algorithm on oil well oilsk81 and oilsk83 of Jianghan oilfield in China has proved to be satisfactory. [Copyright &y& Elsevier]

Abstract: The effects of α-cyano-4-hydroxycinnamic acid (HCCA) on the activity of mushroom tyrosinase have been studied. Results showed that HCCA could inhibit both the monophenolase activity and diphenolase activity of mushroom tyrosinase. For the monophenolase activity, the lag phase was obviously lengthened, and the steady-state activity of the enzyme decreased sharply. When the concentration of HCCA reached to 80μM, the lag time was lengthened from 20s to 150s and the steady-state activity was lost by about 75%. The IC50 value was estimated to be 48μM. For the diphenolase activity, the inhibitory effect of HCCA was also dose-dependent and the IC50 value was estimated to be 2.17mM. The kinetic analyses showed that the inhibition of HCCA on the diphenolase activity was reversible and competitive with the inhibition constants (K I) determined to be 1.24mM. [Copyright &y& Elsevier]

Gabapentin and pregabalin are inhibitory ligands of both α2δ-1 and α2δ-2 proteins (also known as subunits of voltage-activated Ca2+ channels) and are commonly prescribed for the treatment of neuropathic pain and epilepsy. However, these drugs can cause gait disorders and ataxia through unknown mechanisms. α2δ-2 and GluK1, a glutamate-gated kainate receptor subtype, are coexpressed in cerebellar Purkinje cells. In this study, we used a heterologous expression system and Purkinje cells to investigate the potential role of α2δ-2 in regulating GluK1-containing kainate receptor activity. Whole-cell patch clamp recordings showed that α2δ-2 coexpression augmented GluK1, but not GluK2, currents in HEK293 cells, and pregabalin abolished this augmentation. Pregabalin lost its inhibitory effect on GluK1 currents in HEK293 cells expressing both GluK1 and the α2δ-2(R282A) mutant. Blocking GluK1-containing receptors with UBP310 substantially reduced the amplitude of excitatory postsynaptic currents at parallel fiber-Purkinje cell synapses in mice. Also, pregabalin markedly attenuated the amplitude of excitatory postsynaptic currents and currents elicited by ATPA, a selective GluK1 receptor agonist, in Purkinje cells in Cacna2d1 knockout mice. Coimmunoprecipitation assays indicated that α2δ-2, but not α2δ-1, formed a protein complex with GluK1 in cerebellar tissues and HEK293 cells through its C terminus. Furthermore, α2δ-2 coexpression potentiated surface expression of GluK1 proteins in HEK293 cells, whereas pregabalin reduced GluK1 proteins in cerebellar synaptosomes. Disrupting α2δ-2-GluK1 interactions using α2δ-2 C-terminus peptide abrogated the potentiating effect of α2δ-2 on GluK1 currents and attenuated the amplitude of GluK1-mediated excitatory postsynaptic currents in Purkinje cells. However, neither pregabalin nor α2δ-2 C-terminus peptide had significant effect on P/Q-type currents in HEK293 cells. Additionally, CRISPR/Cas9-induced conditional knockdown of Cacna2d2 or Grik1 in Purkinje cells, as well as microinjection of α2δ-2 C-terminus peptide or UBP310 into the cerebellum, substantially impaired beam walking and rotarod performance in mice. Our study reveals that α2δ-2 directly interacts with GluK1 independently of its conventional role as a voltage-activated Ca2+ channel subunit. α2δ-2 regulates motor coordination by promoting synaptic expression and activity in GluK1-containing kainate receptors in Purkinje cells., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Gastrointestinal symptoms are common in patients with uremia undergoing hemodialysis, and these symptoms seriously affect patients' prognosis., Aim: To assess the occurrence and factors influencing gastrointestinal symptoms in patients with uremia undergoing hemodialysis., Methods: We retrospectively selected 98 patients with uremia who underwent regular hemodialysis treatment in the blood purification center of our hospital from December 2022 to December 2023. The gastrointestinal symptoms and scores of each dimension were evaluated using the Gastrointestinal Symptom Grading Scale (GSRS). Patients were divided into gastrointestinal symptoms and no gastrointestinal symptom groups according to whether they had gastrointestinal symptoms. The factors that may affect gastrointestinal symptoms were identified by single-factor analysis. Multiple logistic regression analysis was performed to identify independent risk factors for gastrointestinal symptoms., Results: Gastrointestinal symptoms included indigestion, constipation, reflux, diarrhea, abdominal pain, and eating disorders, and the total average GSRS score was 1.35 ± 0.47. This study showed that age, number of tablets, dialysis time, glucocorticoid, parathyroid hormone (PTH), combined diabetes mellitus and C-reactive protein (CRP) were independent risk factors for gastrointestinal symptoms in patients with uremia undergoing hemodialysis, whereas body mass index (BMI), hemoglobin (Hb), and urea clearance index were independent protective factors ( P < 0.05)., Conclusion: Gastrointestinal symptoms are mostly mild in patients with uremia undergoing hemodialysis, most commonly including dyspepsia, eating disorders, and gastroesophageal reflux. The independent influencing factors mainly include the BMI, age, number of pills taken, dialysis time, urea clearance index, Hb, use of glucocorticoids, and thyroid hormone level. PTH, CRP, and diabetes are clinically related factors influencing the occurrence of gastrointestinal symptoms, and targeted prevention can be performed., Competing Interests: Conflict-of-interest statement: The authors declare having no conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Hypertension is a major adverse effect of calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, used clinically as immunosuppressants. Calcineurin inhibitor-induced hypertension (CIH) is linked to augmented sympathetic output from the hypothalamic paraventricular nucleus (PVN). GluA2-lacking, Ca 2+ -permeable AMPA receptors (CP-AMPARs) are a key feature of glutamatergic synaptic plasticity, yet their role in CIH remains elusive. Here, we found that systemic administration of FK506 in rats significantly increased serine phosphorylation of GluA1 and GluA2 in PVN synaptosomes. Strikingly, FK506 treatment reduced GluA1/GluA2 heteromers in both synaptosomes and endoplasmic reticulum-enriched fractions from the PVN. Blocking CP-AMPARs with IEM-1460 induced a larger reduction of AMPAR-mediated excitatory postsynaptic current (AMPAR-EPSC) amplitudes in retrogradely labelled, spinally projecting PVN neurons in FK506-treated rats than in vehicle-treated rats. Furthermore, FK506 treatment shifted the current-voltage relationship of AMPAR-EPSCs from linear to inward rectification in labelled PVN neurons. FK506 treatment profoundly enhanced physical interactions of α2δ-1 with GluA1 and GluA2 in the PVN. Inhibiting α2δ-1 with gabapentin, α2δ-1 genetic knockout, or disrupting α2δ-1-AMPAR interactions with an α2δ-1 C terminus peptide restored GluA1/GluA2 heteromers in the PVN and diminished inward rectification of AMPAR-EPSCs in labelled PVN neurons induced by FK506 treatment. Additionally, microinjection of IEM-1460 or α2δ-1 C terminus peptide into the PVN reduced renal sympathetic nerve discharges and arterial blood pressure elevated in FK506-treated rats but not in vehicle-treated rats. Thus, calcineurin in the hypothalamus constitutively regulates AMPAR subunit composition and phenotypes by controlling GluA1/GluA2 interactions with α2δ-1. Synaptic CP-AMPARs in PVN presympathetic neurons contribute to augmented sympathetic outflow in CIH. KEY POINTS: Systemic treatment with the calcineurin inhibitor increases serine phosphorylation of synaptic GluA1 and GluA2 in the PVN. Calcineurin inhibition enhances the prevalence of postsynaptic Ca 2+ -permeable AMPARs in PVN presympathetic neurons. Calcineurin inhibition potentiates α2δ-1 interactions with GluA1 and GluA2, disrupting intracellular assembly of GluA1/GluA2 heterotetramers in the PVN. Blocking Ca 2+ -permeable AMPARs or α2δ-1-AMPAR interactions in the PVN attenuates sympathetic outflow augmented by the calcineurin inhibitor., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Endoscopy is the primary modality for detecting asymptomatic esophageal squamous cell carcinoma (ESCC) and precancerous lesions. Improving detection rate remains challenging. We developed a system based on deep convolutional neural networks (CNNs) for detecting esophageal cancer and precancerous lesions [high-risk esophageal lesions (HrELs)] and validated its efficacy in improving HrEL detection rate in clinical practice (trial registration ChiCTR2100044126 at www.chictr.org.cn). Between April 2021 and March 2022, 3117 patients ≥50 years old were consecutively recruited from Taizhou Hospital, Zhejiang Province, and randomly assigned 1:1 to an experimental group (CNN-assisted endoscopy) or a control group (unassisted endoscopy) based on block randomization. The primary endpoint was the HrEL detection rate. In the intention-to-treat population, the HrEL detection rate [28 of 1556 (1.8%)] was significantly higher in the experimental group than in the control group [14 of 1561 (0.9%), P = 0.029], and the experimental group detection rate was twice that of the control group. Similar findings were observed between the experimental and control groups [28 of 1524 (1.9%) versus 13 of 1534 (0.9%), respectively; P = 0.021]. The system's sensitivity, specificity, and accuracy for detecting HrELs were 89.7, 98.5, and 98.2%, respectively. No adverse events occurred. The proposed system thus improved HrEL detection rate during endoscopy and was safe. Deep learning assistance may enhance early diagnosis and treatment of esophageal cancer and may become a useful tool for esophageal cancer screening.

Increased expression of angiotensin II AT 1A receptor (encoded by Agtr1a) and Na + -K + -Cl - cotransporter-1 (NKCC1, encoded by Slc12a2) in the hypothalamic paraventricular nucleus (PVN) contributes to hypertension development. However, little is known about their transcriptional control in the PVN in hypertension. DNA methylation is a critical epigenetic mechanism that regulates gene expression. Here, we determined whether transcriptional activation of Agtr1a and Slc12a2 results from altered DNA methylation in spontaneously hypertensive rats (SHR). Methylated DNA immunoprecipitation and bisulfite sequencing-PCR showed that CpG methylation at Agtr1a and Slc12a2 promoters in the PVN was progressively diminished in SHR compared with normotensive Wistar-Kyoto rats (WKY). Chromatin immunoprecipitation-quantitative PCR revealed that enrichment of DNA methyltransferases (DNMT1 and DNMT3A) and methyl-CpG binding protein 2, a DNA methylation reader protein, at Agtr1a and Slc12a2 promoters in the PVN was profoundly reduced in SHR compared with WKY. By contrast, the abundance of ten-eleven translocation enzymes (TET1-3) at Agtr1a and Slc12a2 promoters in the PVN was much greater in SHR than in WKY. Furthermore, microinjecting of RG108, a selective DNMT inhibitor, into the PVN of WKY increased arterial blood pressure and correspondingly potentiated Agtr1a and Slc12a2 mRNA levels in the PVN. Conversely, microinjection of C35, a specific TET inhibitor, into the PVN of SHR markedly reduced arterial blood pressure, accompanied by a decrease in Agtr1a and Slc12a2 mRNA levels in the PVN. Collectively, our findings suggest that DNA hypomethylation resulting from the DNMT/TET switch at gene promoters in the PVN promotes transcription of Agtr1a and Slc12a2 and hypertension development., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Calcineurin is highly enriched in immune T cells and the nervous system. Calcineurin inhibitors, including cyclosporine and tacrolimus (FK506), are the cornerstone of immunosuppressive regimens for preserving transplanted organs and tissues. However, these drugs often cause persistent hypertension owing to excess sympathetic outflow, which is maintained by N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory input to the hypothalamic paraventricular nucleus (PVN). It is unclear how calcineurin inhibitors increase NMDAR activity in the PVN to augment sympathetic vasomotor activity. α2δ-1 (encoded by the Cacna2d1 gene), known colloquially as a calcium channel subunit, is a newly discovered NMDAR-interacting protein. In this study, we determined whether α2δ-1 plays a role in calcineurin inhibitor-induced synaptic NMDAR hyperactivity in the PVN and hypertension development., Methods: Immunoblotting and coimmunoprecipitation assays were used to quantify synaptic protein levels and the physical interaction between GluN1 (the obligatory NMDAR subunit) and α2δ-1. Whole-cell patch-clamp recordings of retrogradely labeled, spinally projecting PVN were conducted in perfused brain slices to measure presynaptic and postsynaptic NMDAR activity. Radio-telemetry was implanted in rodents to continuously record arterial blood pressure in conscious states., Results: Prolonged treatment with FK506 in rats significantly increased protein levels of α2δ-1, GluN1, and the α2δ-1-GluN1 complex in PVN synaptosomes. These effects were blocked by inhibiting α2δ-1 with gabapentin or interrupting the α2δ-1-NMDAR interaction with an α2δ-1 C-terminus peptide. Treatment with FK506 potentiated the activity of presynaptic and postsynaptic NMDARs in spinally projecting PVN neurons; such effects were abolished by gabapentin, Cacna2d1 knockout, or α2δ-1 C-terminus peptide. Furthermore, microinjection of α2δ-1 C-terminus peptide into the PVN diminished renal sympathetic nerve discharges and arterial blood pressure that had been increased by FK506 treatment. Remarkably, concurrent administration of gabapentin prevented the development of FK506-induced hypertension in rats. Additionally, FK506 treatment induced sustained hypertension in wild-type mice but not in Cacna2d1 knockout mice., Conclusions: α2δ-1 is essential for calcineurin inhibitor-induced increases in synaptic NMDAR activity in PVN presympathetic neurons and sympathetic outflow. Thus, α2δ-1 and α2δ-1-bound NMDARs represent new targets for treating calcineurin inhibitor-induced hypertension. Gabapentinoids (gabapentin and pregabalin) could be repurposed for treating calcineurin inhibitor-induced neurogenic hypertension., Competing Interests: Disclosures None.

Objectives: We aimed to compare the effectiveness of interventions in cognitive function and frailty status and rank these interventions., Methods: Data Sources-We searched PubMed, Embase, CINAHL, PsycINFO, Web of Science, Cochrane Library, Central Register of Controlled Trials (CENTRAL), CNKI, Wanfang, VIP and Google scholar. Data synthesis-The risk of bias was assessed using the Cochrane risk bias assessment tool. Statistical heterogeneity was assessed using the Chi-square test and quantified by I 2 . The results were pooled using the standardized mean difference (SMD). The rank probability for each intervention was calculated using the surface under the cumulative ranking curve (SUCRA). Additionally, the quality of the evidence was evaluated using the GRADE approach., Results: A total of 10 randomized controlled trials (RCTs) involving 1110 patients were included in our analysis. The network map of cognitive function comprised 9 RCTs with 1347 participants, examining eight different interventions. Nutritional support (SUCRA = 99.9%, SMD = 3.02, 95% CI: 2.53, 3.51) may be the most effective intervention to improve cognitive function. The network map of frailty (including 9 RCTs with 1017 participants and 9 interventions) suggested that multicomponent exercises (SUCRA = 96.4%, SMD = -5.10, 95% CI: -5.96, -4.23) tended to have a greater effect., Conclusions: Community-based multicomponent exercises have shown significant benefits for improving cognitive function and frailty status in older adults, with moderate certainty. For hospitalized older patients with Cognitive frailty (CF), current evidence suggests that nutritional support yields the most improvement. Additionally, aerobic exercise and dual-task training have proven effective in managing CF. Further studies are needed to validate these preliminary findings and exploring more accessible and effective physical and cognitive interventions to prevent CF in aging., (© 2023 John Wiley & Sons Ltd.)

Corticotropin-releasing hormone (CRH) is a neuropeptide regulating neuroendocrine and autonomic function. CRH mRNA and protein levels in the hypothalamic paraventricular nucleus (PVN) are increased in primary hypertension. However, the role of CRH in elevated sympathetic outflow in primary hypertension remains unclear. CRHR1 proteins were distributed in retrogradely labeled PVN presympathetic neurons with an increased level in the PVN tissue in adult spontaneously hypertensive rats (SHRs) compared with age-matched male Wistar-Kyoto (WKY) rats. CRH induced a more significant increase in the firing rate of PVN-rostral ventrolateral medulla (RVLM) neurons and sympathoexcitatory response in SHRs than in WKY rats, an effect that was blocked by preapplication of NMDA receptors (NMDARs) antagonist AP5 and PSD-95 inhibitor, Tat-N-dimer. Blocking CRHRs with astressin or CRHR1 with NBI35965 significantly decreased the firing rate of PVN-RVLM output neurons and reduced arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) in SHRs but not in WKY, whereas blocking CRHR2 with antisauvagine-30 did not. Furthermore, Immunocytochemistry staining revealed that CRHR1 colocalized with NMDARs in PVN presympathetic neurons. Blocking CRHRs significantly decreased the NMDA currents in labeled PVN neurons. PSD-95-bound CRHR1 and PSD-95-bound GluN2A in the PVN were increased in SHRs. These data suggested that the upregulation of CRHR1 in the PVN is critically involved in the hyperactivity of PVN presympathetic neurons and elevated sympathetic outflow in primary hypertension. SIGNIFICANCE STATEMENT Our study found that corticotropin-releasing hormone receptor (CRHR)1 protein levels were increased in the paraventricular nucleus (PVN), and CRHR1 interacts with NMDA receptors (NMDARs) through postsynaptic density protein (PSD)-95 in the PVN neurons in primary hypertension. The increased CRHR1 and CRHR1-NMDAR-PSD-95 complex in the PVN contribute to the hyperactivity of the PVN presympathetic neurons and elevated sympathetic vasomotor tone in hypertension in SHRs. Thus, the antagonism of CRHR1 decreases sympathetic outflow and blood pressure in hypertension. These findings determine a novel role of CRHR1 in elevated sympathetic vasomotor tone in hypertension, which is useful for developing novel therapeutics targeting CRHR1 to treat elevated sympathetic outflow in primary hypertension. The CRHR1 receptor antagonists, which are used to treat health consequences resulting from chronic stress, are candidates to treat primary hypertension., (Copyright © 2023 the authors.)

Background: The study explored sources of meaning in older adults and the action path among family care, meaning in life, quality of life, and depression., Materials and Methods: We investigated 627 older adults using the Sources of Meaning in Life Scale for the Elderly (SMSE), the Family Care Index (APGAR), the Center for Epidemiological Studies Depression Scale-10 (CES-D-10), and the EuroqOL-5 Dimensions (EQ-5D)., Results: Scores categorized 454 older adults with good family function, 99 with moderate, and 47 with severe family dysfunction; 110 older adults had depression. The structural equation model showed that family care affected the quality of life and depression by influencing meaning, and depression had a significant negative effect on the quality of life ( P  < 0.05). The model was a good fit for the data (χ 2 /df = 3.300, SRMR = 0.0291, GFI = 0.975, IFI = 0.971, TLI = 0.952, CFI = 0.971, RMSEA = 0.062)., Conclusion: Meaning in life is an intermediary factor that affects depression and quality of life in older adults. Family care had a significant positive impact on SMSE and a negative influence on depression. The SMSE effectively clarifies the sources of meaning in life and can be used to improve meaning and promote mental health in older adults., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhou, Zhang, Ren, Li, Lin, Liao, Chen, Tong and Gao.)

Aims: Orchestrating the transition from reversible medial hypertrophy to irreversible plexiform lesions is crucial for pulmonary arterial hypertension related to congenital heart disease (CHD-PAH). Transgelin is an actin-binding protein that modulates pulmonary arterial smooth muscle cell (PASMC) dysfunction. In this study, we aimed to probe the molecular mechanism and biological function of transgelin in the pathogenesis of CHD-PAH., Methods and Results: Transgelin expression was detected in lung tissues from both CHD-PAH patients and monocrotaline (MCT)-plus aortocaval (AV)-induced PAH rats by immunohistochemistry. In vitro, the effects of transgelin on the proliferation, migration, and apoptosis of human PASMCs (HPASMCs) were evaluated by the cell count and EdU assays, transwell migration assay, and TUNEL assay, respectively. And the effect of transgelin on the expression of HPASMC phenotype markers was assessed by the immunoblotting assay. (i) Compared with the normal control group (n = 12), transgelin expression was significantly overexpressed in the pulmonary arterioles of the reversible (n = 15) and irreversible CHD-PAH group (n = 4) (reversible group vs. control group: 18.2 ± 5.1 vs. 13.6 ± 2.6%, P < 0.05; irreversible group vs. control group: 29.9 ± 4.7 vs. 13.6 ± 2.6%, P < 0.001; irreversible group vs. reversible group: 29.9 ± 4.7 vs. 18.2 ± 5.1, P < 0.001). This result was further confirmed in MCT-AV-induced PAH rats. Besides, the transgelin expression level was positively correlated with the pathological grading of pulmonary arteries in CHD-PAH patients (r = 0.48, P = 0.03, n = 19). (ii) Compared with the normal control group (n = 12), TGF-β1 expression was notably overexpressed in the pulmonary arterioles of the reversible (n = 15) and irreversible CHD-PAH group (n = 4) (reversible group vs. control group: 14.8 ± 4.4 vs. 6.0 ± 2.5%, P < 0.001; irreversible group vs. control group: 20.1 ± 4.4 vs. 6.0 ± 2.5%, P < 0.001; irreversible group vs. reversible group: 20.1 ± 4.4 vs. 14.8 ± 4.4, P < 0.01). The progression-dependent correlation between TGF-β1 and transgelin was demonstrated in CHD-PAH patients (r = 0.48, P = 0.04, n = 19) and MCT-AV-induced PAH rats, which was further confirmed at sub-cellular levels. (iii) Knockdown of transgelin diminished proliferation, migration, apoptosis resistance, and phenotypic transformation of HPASMCs through repressing the TGF-β1 signalling pathway. On the contrary, transgelin overexpression resulted in the opposite effects., Conclusions: These results indicate that transgelin may be an indicator of CHD-PAH development via boosting HPASMC dysfunction through positive regulation of the TGF-β1 signalling pathway, as well as a potential therapeutic target for the treatment of CHD-PAH., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Small intestinal lymphangioma is a very rare benign lesion. Thus far, the literature on small intestinal lymphangioma has mainly involved case reports. The present study retrospectively examined the clinical features of patients with a pathological diagnosis of small intestinal lymphangioma., Materials and Methods: From January 2010 to January 2021, 15 patients were pathologically diagnosed with small intestinal lymphangioma. The age, gender, clinical manifestation, computed tomography (CT) findings, endoscopic findings, localization of the lesion, treatment method, complications, and follow-up were retrospectively analyzed., Results: Most of the patients had no symptoms, and those with symptoms had melena or abdominal pain. Lymphangioma was located in the duodenum in nine cases (60.0%), jejunum in two (13.3%), jejunal-ileal junction with mesentery involvement in one (6.7%) and ileum in three (20.0%). Three cases (20.0%) had multiple lesions, and the other 12 (80.0%) had single lesions. The median size of the lesions was 0.8 cm. Thirteen cases were found by endoscopy, and nine cases of them had white-colored spots on the surface. Ten cases (66.7%) underwent endoscopic treatment, three (20.0%) underwent surgical treatment, and two (13.3%) were followed up. Postoperative acute pancreatitis developed in one patient after endoscopic resection of duodenal papillary lymphangioma; postoperative abdominal bleeding occurred in one patient with jejunal lymphangioma who underwent partial small bowel resection., Conclusion: Small intestinal lymphangioma is extremely rare, and its clinical manifestations are non-specific. Endoscopy is of great value in the diagnosis of small intestinal lymphangioma. Depending on the clinical manifestations, the size, location and scope of the lesions, follow-up, endoscopic treatment and surgery can be selected., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Shen, Zhou, Tang, Ye, Shen, Li and Zhou.)

Rationale: Hypertension is a common and serious adverse effect of calcineurin inhibitors, including cyclosporine and tacrolimus (FK506). Although increased sympathetic nerve discharges are associated with calcineurin inhibitor-induced hypertension, the sources of excess sympathetic outflow and underlying mechanisms remain elusive. Calcineurin (protein phosphatase-2B) is broadly expressed in the brain, including the paraventricular nuclear (PVN) of the hypothalamus, which is critically involved in regulating sympathetic vasomotor tone., Objective: We determined whether prolonged treatment with the calcineurin inhibitor causes elevated sympathetic output and persistent hypertension by potentiating synaptic N-methyl-D-aspartate (NMDA) receptor activity in the PVN., Methods and Results: Telemetry recordings showed that systemic administration of FK506 (3 mg/kg per day) for 14 days caused a gradual and profound increase in arterial blood pressure in rats, which lasted at least 7 days after discontinuing FK506 treatment. Correspondingly, systemic treatment with FK506 markedly reduced calcineurin activity in the PVN and circumventricular organs, but not rostral ventrolateral medulla, and increased the phosphorylation level and synaptic trafficking of NMDA receptors in the PVN. Immunocytochemistry labeling showed that calcineurin was expressed in presympathetic neurons in the PVN. Whole-cell patch-clamp recordings in brain slices revealed that treatment with FK506 increased baseline firing activity of PVN presympathetic neurons; this increase was blocked by the NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist. Also, treatment with FK506 markedly increased presynaptic and postsynaptic NMDA receptor activity of PVN presympathetic neurons. Furthermore, microinjection of the NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist into the PVN of anesthetized rats preferentially attenuated renal sympathetic nerve discharges and blood pressure elevated by FK506 treatment. In addition, systemic administration of memantine, a clinically used NMDA receptor antagonist, effectively attenuated FK506 treatment-induced hypertension in conscious rats., Conclusions: Our findings reveal that normal calcineurin activity in the PVN constitutively restricts sympathetic vasomotor tone via suppressing NMDA receptor activity, which may be targeted for treating calcineurin inhibitor-induced hypertension.

(+)- and (-)-Chlorahupetenes A ( 1a and 1b ), B ( 2a and 2b ), C ( 3a and 3b ), and D ( 4a and 4b ), four unique enantiomeric pairs of eudesmane-type sesquiterpenoid dimers with two new carbon skeletons, were isolated from the aerial parts of Chloranthus henryi var. hupehensis . Compounds 1 and 2 possess an unprecedented 6/6/5/6/6 pentacyclic carbon skeleton with a new dimerization pattern of two eudesmane-type sesquiterpenoids. Compounds 3 and 4 , which are fused with two eudesmane-type sesquiterpenoids via an unprecedented five-membered O -heterocyclic ring, represent a new 6/6/5/5/6/6/5 heptacyclic ring system. The structures of the compounds were determined through spectroscopic data and X-ray crystallography. Compounds 1a - 3b significantly inhibited NO production with IC 50 values ranging from 9.62 to 12.91 μM. Moreover, compounds 1b and 3a suppressed the production of a proinflammatory mediator (TNF-α) and enzyme expression (iNOS) at the mRNA level.

Hydrogen sulfide (H 2 S) is one of the three known gas signal transducers, and since its potential physiological role was reported, the literature on H 2 S has been increasing. H 2 S is involved in processes such as vasodilation, neurotransmission, angiogenesis, inflammation, and the prevention of ischemia-reperfusion injury, and its mechanism remains to be further studied. At present, the role of post-translational processing of proteins has been considered as a possible mechanism for the involvement of H 2 S in a variety of physiological processes. Current studies have shown that H 2 S is involved in S-sulfhydration, phosphorylation, and S-nitrosylation of proteins, etc. This paper focuses on the effects of protein modification involving H 2 S on physiological and pathological processes, looking forward to providing guidance for subsequent research., (© 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

Glutamate AMPA receptors (AMPARs) lacking GluA2 subunit are calcium permeable (CP-AMPARs), which are increased in the hypothalamic paraventricular nucleus (PVN) and maintain sympathetic outflow in hypertension. Here, we determined the role of α2δ-1, an NMDA receptor-interacting protein, in regulating synaptic CP-AMPARs in the hypothalamus in spontaneously hypertensive rats (SHR). Co-immunoprecipitation showed that levels of GluA1/GluA2, but not GluA2/GluA3, protein complexes in hypothalamic synaptosomes were reduced in SHR compared with Wistar-Kyoto rats (WKY). The level of GluA1/GluA2 heteromers in endoplasmic reticulum-enriched fractions of the hypothalamus was significantly lower in SHR than in WKY, which was restored by inhibiting α2δ-1 with gabapentin. Gabapentin also switched AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs) from inward rectifying to linear and attenuated the inhibitory effect of IEM-1460, a selective CP-AMPAR blocker, on AMPAR-EPSCs in spinally projecting PVN neurons in SHR. Furthermore, co-immunoprecipitation revealed that α2δ-1 directly interacted with GluA1 and GluA2 in the hypothalamus of rats and humans. Levels of α2δ-1/GluA1 and α2δ-1/GluA2 protein complexes in the hypothalamus were significantly greater in SHR than in WKY. Disrupting the α2δ-1-AMPAR interaction with an α2δ-1 C terminus peptide normalized GluA1/GluA2 heteromers in the endoplasmic reticulum of the hypothalamus diminished in SHR. In addition, α2δ-1 C terminus peptide diminished inward rectification of AMPAR-EPSCs and the inhibitory effect of IEM-1460 on AMPAR-EPSCs of PVN neurons in SHR. Thus, α2δ-1 augments synaptic CP-AMPARs by inhibiting GluA1/GluA2 heteromeric assembly in the hypothalamus in hypertension. These findings extend our understanding of the molecular basis of sustained sympathetic outflow in neurogenic hypertension., (© 2022 International Society for Neurochemistry.)

The long juvenile period of perennial woody plants is a major constraint in breeding programs. FLOWERING LOCUS T (FT) protein is an important mobile florigen signal that induces plant flowering. However, whether FT can be transported in woody plants to shorten the juvenile period is unknown, and its transport mechanism remains unclear. In this study, trifoliate orange FT ( ToFT ) and Arabidopsis FT ( AtFT , which has been confirmed to be transportable in Arabidopsis ) as a control were transformed into tomato and trifoliate orange, and early flowering was induced in the transgenic plants. Long-distance and two-way (upward and downward) transmission of ToFT and AtFT proteins was confirmed in both tomato and trifoliate orange using grafting and western blot analysis. However, rootstocks of transgenic trifoliate orange could not induce flowering in grafted wild-type juvenile scions because of the low accumulation of total FT protein in the grafted scions. It was further confirmed that endogenous ToFT protein was reduced in trifoliate orange, and the accumulation of the transported ToFT and AtFT proteins was lower than that in grafted juvenile tomato scions. Furthermore, the trifoliate orange FT-INTERACTING PROTEIN1 homolog ( ToFTIP1 ) was isolated by yeast two-hybrid analysis. The FTIP1 homolog may regulate FT transport by interacting with FT in tomato and trifoliate orange. Our findings suggest that FT transport may be conserved between the tomato model and woody plants. However, in woody plants, the transported FT protein did not accumulate in significant amounts in the grafted wild-type juvenile scions and induce the scions to flower., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nanjing Agricultural University.)

Long-term potentiation (LTP) and long-term depression (LTD) in the spinal dorsal horn reflect activity-dependent synaptic plasticity and central sensitization in chronic pain. Tetanic high-frequency stimulation is commonly used to induce LTP in the spinal cord. However, primary afferent nerves often display low-frequency, rhythmic bursting discharges in painful conditions. Here, we determined how theta-burst stimulation (TBS) of primary afferents impacts spinal cord synaptic plasticity and nociception in male and female mice. We found that TBS induced more LTP, whereas tetanic stimulation induced more LTD, in mouse spinal lamina II neurons. TBS triggered LTP, but not LTD, in 50% of excitatory neurons expressing vesicular glutamate transporter-2 (VGluT2). By contrast, TBS induced LTD and LTP in 12-16% of vesicular GABA transporter (VGAT)-expressing inhibitory neurons. Nerve injury significantly increased the prevalence of TBS-induced LTP in VGluT2-expressing, but not VGAT-expressing, lamina II neurons. Blocking NMDARs, inhibiting α2δ-1 with gabapentin, or α2δ-1 knockout abolished TBS-induced LTP in lamina II neurons. Also, disrupting the α2δ-1-NMDAR interaction with α2δ-1Tat peptide prevented TBS-induced LTP in VGluT2-expressing neurons. Furthermore, TBS of the sciatic nerve induced long-lasting allodynia and hyperalgesia in wild-type, but not α2δ-1 knockout, mice. TBS significantly increased the α2δ-1-NMDAR interaction and synaptic trafficking in the spinal cord. In addition, treatment with NMDAR antagonists, gabapentin, or α2δ-1Tat peptide reversed TBS-induced pain hypersensitivity. Therefore, TBS-induced primary afferent input causes a neuropathic pain-like phenotype and LTP predominantly in excitatory dorsal horn neurons via α2δ-1-dependent NMDAR activation. α2δ-1-bound NMDARs may be targeted for reducing chronic pain development at the onset of tissue/nerve injury. SIGNIFICANCE STATEMENT Spinal dorsal horn synaptic plasticity is a hallmark of chronic pain. Although sensory nerves display rhythmic bursting discharges at theta frequencies during painful conditions, the significance of this naturally occurring firing activity in the induction of spinal synaptic plasticity is largely unknown. In this study, we found that theta-burst stimulation (TBS) of sensory nerves induced LTP mainly in excitatory dorsal horn neurons and that the prevalence of TBS-induced LTP was potentiated by nerve injury. This TBS-driven synaptic plasticity required α2δ-1 and its interaction with NMDARs. Furthermore, TBS of sensory nerves induced persistent pain, which was maintained by α2δ-1-bound NMDARs. Thus, TBS-induced LTP at primary afferent-dorsal horn neuron synapses is an appropriate cellular model for studying mechanisms of chronic pain., (Copyright © 2022 the authors.)

Background: To investigate the prevalence of burnout syndrome among Chinese female nurses during the controlled coronavirus disease 2019 (COVID-19) period and explore its associated socio-demographic factors and job characteristics. Methods: With the multistage, stratified sampling method, a cross-sectional online survey was conducted from September to October 2020 in China. The survey tool included revised Maslach Burnout Inventory (MBI) with 15 items, socio-demographic and job characteristics. Univariate logistic regression analysis and multivariate factor logistic regression analysis were used to identify the risk factors for burnout of female nurses. Results: During controlled COVID-19 period in China, the overall prevalence of burnout symptoms among Chinese female nurses was 60.2% with a breakdown in severity as follows: 451 (39.8 %) mild, 163 (14.4%) moderate, and 68 (6.0%) severe burnout. Little variance was reported for burnout symptoms according to job tenure ( Waldχ 2 = 14.828, P < 0.05,odds ratio [OR] <1), monthly salary income ( Waldχ 2 = 12.460, P < 0.05, OR <1), and night shift ( Waldχ 2 = 3.821, P < 0.05, OR > 1). Conclusion: Burnout symptoms among Chinese female nurses were prevalent and associated with job tenure, monthly salary income, and night shift. Female nurses who were with shorter job tenure, worked at night shifts, and had lower monthly salaries tended to exhibit increasing high-level burnout than their counterparts. This study serves as an implication for administrators and policy-makers to improve the work conditions of nurses for promoting overall healthcare service quality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Zhang, Liu, Wang, Liu, Zhou, Bu, Gao, Sun and Liu.)

Stress-related growth (SRG) can be understood as stressful experiences that act as catalysts for positive life changes. Although less severe than typical 'trauma,' some daily obstacles may nevertheless derail faith and intentions, produce distress, result in a demand for reflection, and provide a possibility for SRG. This study examined the direct and indirect effects of event severity, social support, and optimism on SRG among emerging adults attending college in China. A convenience sample of 365 college students, ranging from 18 to 24 years old, completed surveys on event severity, social support, optimism, and SRG. We applied structural equation modeling and bootstrapping to explore optimism in the mediation model. Results demonstrated that event severity and social support have direct and indirect effects on SRG through a partial mediation effect of optimism. The results indicate that interventions targeting optimism might be an effective approach to improving SRG among college students in China.

Objectives: People who find meaning in life can endure 'any' pain. However, there were no tools to investigate elderly individuals' sources of meaning in life in China. This study aimed to develop the Sources of Meaning in Life Scale for the Elderly (SMSE), and examine the validation and reliability in Chinese elderly., Methods: A 43-item pool of SMSE was formed by combining the preliminary interview and literature review. A cross-sectional survey of 627 elderly people was then conducted in two community health service centers, two hospitals, and two nursing homes in Guangzhou by the convenience sampling method. Test-retest reliability was assessed with 24 elderly persons., Results: Six dimensions, containing family (four items), social support (four items), value (seven items), life security (four items), personal development (four items), and leisure activity (five items) explained 62.16% of the variance in total. Confirmatory factor analysis model fitting indices were χ 2 = 694.652, df  = 330, χ 2 / df  = 2.105, SRMR = 0.0695, GFI = 0.853, IFI = 0.905, TLI = 0.889, CFI = 0.903, and RMSEA = 0.062. The Cronbach's alpha value of the scale was 0.924, while that of each dimension was between 0.727 and 0.870. The inter-class correlation (ICC) of the scale was 0.856., Conclusion: The SMSE has good reliability and validity that can be used to evaluate the sources of meaning and meaning in life for the elderly.

The novel coronavirus pneumonia (COVID-19) pandemic is a great threat to human society and now is still spreading. Although several vaccines have been authorized for emergency use, only one recombinant subunit vaccine has been permitted for widespread use. More subunit vaccines for COVID-19 should be developed in the future. The receptor binding domain (RBD), located at the S protein of SARS-CoV-2, contains most of the neutralizing epitopes. However, the immunogenicity of RBD monomers is not strong enough. In this study, we fused the RBD-monomer with a modified Fc fragment of human IgG1 to form an RBD-Fc fusion protein. The recombinant vaccine candidate based on the RBD-Fc protein could induce high levels of IgG and neutralizing antibody in mice, and these could last for at least three months. The secretion of IFN-γ, IL-2 and IL-10 in the RBD-stimulated splenocytes of immunized mice also increased significantly. Our results first showed that the RBD-Fc vaccine could induce both humoral and cellular immune responses and might be an optional strategy to control COVID-19.

Pulmonary arterial hypertension (PAH) is a common complication of congenital heart disease (CHD). Deubiquitinase cylindromatosis (CYLD) has been reported to significantly aggravate vascular smooth muscle cell (VSMC) phenotypic transformation, proliferation, and migration. Here, we aimed to further investigate its roles and underlying mechanisms in the CHD-PAH development. The expression of CYLD in the lung tissues from CHD-PAH patients and monocrotaline (MCT) plus aortocaval (AV)-induced PAH rats, pulmonary artery smooth muscle cells (PASMCs) from MCT-AV-induced PAH rats, and human PASMCs (HPASMCs) was evaluated. After infection with CYLD siRNA or pcNDA3.1-CYLD, the proliferation, migration, and apoptosis of HPASMCs were measured using an EdU assay, transwell and scratch wound healing assays, and flow cytometric assay, respectively. An adeno-associated virus (AAV) vector encoding CYLD was used to suppress CYLD expression by being intratracheally instilled in rats 7 days before MCT-AV treatment. The results showed that CYLD was increased in the lung tissues from CHD-PAH patients and MCT-AV-induced PAH rats, and in PASMCs from MCT-AV-induced PAH rats. The contractile-type HPASMCs expressed low levels of CYLD, while the proliferative synthetic-type HPASMCs expressed high levels of CYLD. In addition, CYLD could mediate HPASMC dysfunction, which regulated HPASMC phenotypic transformation and proliferation via the modulation of p38 and ERK activation, while CYLD regulated HPASMC migration via the modulation of p38 activation. In vivo results demonstrated that the local suppression of CYLD expression could attenuate the increased levels of PAH and its associated pulmonary vascular remodeling in MCT-AV-induced PAH rats. Collectively, these results indicated that CYLD might be a potential novel therapeutic target for the prevention of PAH and pulmonary vascular remodeling in CHD-PAH through the modulation of HPASMC dysfunction., (© 2021 Wiley Periodicals LLC.)

The interplay between genetic and environmental factors is critically involved in hypertension development. The paraventricular nucleus (PVN) of the hypothalamus regulates sympathetic output during stress responses and chronic hypertension. In this study, we determined mechanisms of synaptic plasticity in the PVN in chronic stress-induced persistent hypertension in male borderline hypertensive rats (BHR), the first offspring of spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. In Wistar-Kyoto rats, chronic unpredictable mild stress (CUMS) increased arterial blood pressure (ABP) and heart rate, which quickly returned to baseline after CUMS ended. In contrast, in BHR, CUMS caused persistent elevation in ABP, which lasted at least 2 weeks after CUMS ended. CUMS also increased the mRNA level of α2δ-1 and synaptic protein levels of GluN1, α2δ-1, and α2δ-1-GluN1 complexes in the PVN in BHR. Furthermore, CUMS significantly increased the frequency of miniature EPSCs and the amplitude of NMDAR currents in spinally projecting PVN neurons in BHR; these increases were normalized by blocking NMDARs with AP5, inhibiting α2δ-1 with gabapentin, or disrupting the α2δ-1-NMDAR interaction with α2δ-1Tat peptide. Microinjection of AP5 or α2δ-1Tat peptide into the PVN normalized elevated ABP and renal sympathetic nerve activity in stressed BHR. In addition, systemically administered gabapentin or memantine attenuated higher ABP induced by CUMS in BHR. Our findings indicate that chronic stress-induced persistent hypertension is mediated by augmented sympathetic outflow via α2δ-1-bound NMDARs in the PVN. This new information provides a cellular and molecular basis for how the genetic-environment interactions cause persistent hypertension. SIGNIFICANCE STATEMENT Chronic stress is a major risk factor for hypertension development, especially for individuals with a genetic predisposition to hypertension. Using a rat model of borderline hypertension, we showed that chronic stress induced long-lasting hypertension and sympathetic nerve hyperactivity, which were maintained by NMDAR activation in the hypothalamus. Chronic stress also increased the expression of α2δ-1, previously regarded as a Ca 2+ channel subunit, promoting physical interaction with and synaptic trafficking of NMDARs in the hypothalamus. Inhibiting α2δ-1, blocking NMDARs, or disrupting α2δ-1-bound NMDARs reversed chronic stress-induced sympathetic outflow and persistent hypertension. Thus, α2δ-1-dependent NMDAR activity in the hypothalamus is an effector of genetic-environment interactions and may be targeted for treating stress-induced neurogenic hypertension., (Copyright © 2021 the authors.)

Hydrogen sulfide (H 2 S), as one of the three known gaseous signal transduction molecules in organisms, has attracted a surging amount of attention. H 2 S is involved in a variety of physiological and pathological processes in the body, such as dilating blood vessels (regulating blood pressure), protecting tissue from ischemia-reperfusion injury, anti-inflammation, carcinogenesis, or inhibition of cancer, as well as acting on the hypothalamus and pancreas to regulate hormonal metabolism. The change of H 2 S concentration is related to a variety of endocrine disorders, and the change of hormone concentration also affects the synthesis of H 2 S. Understanding the effect of biosynthesis and the concentration of H 2 S on the endocrine system is useful to develop drugs for the treatment of hypertension, diabetes, and other diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, Ngowi, Qian, Li, Qin, Zhou, Li, Ji and Wu.)

Objective: Exposure to microgravity results in postflight cardiovascular deconditioning in astronauts. Vascular oxidative stress injury and mitochondrial dysfunction have been reported during this process. To elucidate the mechanism for this condition, we investigated whether mitochondrial oxidative stress regulates calcium homeostasis and vasoconstriction in hindlimb unweighted (HU) rat cerebral arteries., Methods: Three-week HU was used to simulate microgravity in rats. The contractile responses to vasoconstrictors, mitochondrial fission/fusion, Ca 2+ distribution, inositol 1,4,5-trisphosphate receptor (IP 3 R) abundance, and the activities of voltage-gated K + channels (K V ) and Ca 2+ -activated K + channels (BK Ca ) were examined in rat cerebral vascular smooth muscle cells (VSMCs)., Results: An increase of cytoplasmic Ca 2+ and a decrease of mitochondrial/sarcoplasmic reticulum (SR) Ca 2+ were observed in HU rat cerebral VSMCs. The abundance of fusion proteins (mitofusin 1/2 [MFN1/2]) and fission proteins (dynamin-related protein 1 [DRP1] and fission-mitochondrial 1 [FIS1]) was significantly downregulated and upregulated, respectively in HU rat cerebral VSMCs. The cerebrovascular contractile responses to vasoconstrictors were enhanced in HU rats compared to control rats, and IP 3 R protein/mRNA levels were significantly upregulated. The current densities and open probabilities of K V and BK Ca decreased and increased, respectively. Treatment with the mitochondrial-targeted antioxidant mitoTEMPO attenuated mitochondrial fission by upregulating MFN1/2 and downregulating DRP1/FIS1. It also decreased IP 3 R expression levels and restored the activities of the K V and BK Ca channels. MitoTEMPO restored the Ca 2+ distribution in VSMCs and attenuated the enhanced vasoconstriction in HU rat cerebral arteries., Conclusion: The present results suggest that mitochondrial oxidative stress enhances cerebral vasoconstriction by regulating calcium homeostasis during simulated microgravity., (Copyright © 2020 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Objective: Reportedly, nestin was re-expressed in proliferative synthetic-type pulmonary artery smooth muscle cells (PASMCs) and obligatory for PASMC proliferation in pulmonary arterial hypertension (PAH). Accordingly, nestin is increased in pulmonary vascular lesions of congenital heart disease (CHD)-associated PAH patients. We tested the hypothesis whether nestin was re-expressed in proliferative synthetic-type PASMCs and associated with pulmonary vascular remodeling in CHD-PAH., Materials and Methods: Nestin expression was tested using lung tissues from CHD-PAH patients and monocrotaline (MCT) plus aortocaval (AV) shunt-induced PAH rats, human PASMCs (HPASMCs), and pulmonary artery endothelial cells (PAECs) and PASMCs from MCT-AV-induced PAH rats. The role and possible mechanism of nestin on HPASMC proliferation, apoptosis, cell cycle and migration were investigated by assays of CCK-8, EdU, TUNEL, flow cytometry, transwell chamber and immunoblotting assays., Results: Nestin was solely expressed in proliferative synthetic-type PASMCs, but rarely detected in PAECs. Nestin was barely detected in normal pulmonary arterioles and occlusive pulmonary vascular lesions. Its expression was robustly increased in developing pulmonary vasculature, but returned to normal levels at the late stage of pulmonary vascular remodeling in lung tissues from CHD-PAH patients and MCT-AV-induced PAH rats. Besides, nestin peaks were consistent with the histological features in lung tissues of MCT-AV-induced PAH rats. Moreover, nestin overexpression effectively promoted HPASMC phenotypic transformation, proliferation, apoptosis resistance and migration via enhancing Wnt/β-catenin activation., Conclusions: These data indicated that nestin was re-expressed in proliferative synthetic-type PASMCs and might represent a potential marker of pulmonary vascular remodeling in CHD-PAH., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: This study aims to evaluate the efficacy and safety of three bismuth-based quadruple regimens for eradication of Helicobacter pylori (H pylori) infection in a large number of H pylori-positive patients with or without previous eradication therapy., Methods: Consecutive adult patients with H pylori infection, regardless of previous eradication therapy, were eligible for the present study. Three bismuth-based quadruple regimens were selected according to the past history of antibiotics use: (A) esomeprazole, amoxicillin, clarithromycin, and colloidal bismuth tartrate; (B) esomeprazole, amoxicillin, furazolidone, and colloidal bismuth tartrate; and (C) esomeprazole, doxycycline, furazolidone, and colloidal bismuth tartrate. All patients received a 14-day course of treatment, and 13 C/ 14 C urea breath test was utilized at four weeks after the completion of treatment to determine the H pylori eradication. Then, the eradication rates were calculated in terms of intention-to-treat (ITT) and per-protocol (PP) analyses. Adverse events (AEs) were recorded during the treatment., Results: Overall, 1,226 patients were recruited, and 331, 57, and 838 patients were allocated to receive regimens A, B, and C, respectively. The H pylori eradication rates were 84.0%, 82.5%, and 82.9% (ITT) and 94.6%, 92.2%, and 93.7% (PP), respectively, in regimens A, B, and C. However, there was no significant difference among these three regimens. The incidence of AEs was 4.6% for all patients during the study, that is, 3.3%, 10.5%, and 4.7% for regimens A, B, and C, respectively. All AEs were mild and recovered at the follow-up visit., Conclusion: All three bismuth-based quadruple regimens based on the previous antibiotic use can achieve satisfactory eradication rates for H pylori infection and are safe., (© 2020 John Wiley & Sons Ltd.)

Volume-regulated anion channels (VRACs) are critically involved in regulating cell volume, and leucine-rich repeat-containing protein 8A (LRRC8A, SWELL1) is an obligatory subunit of VRACs. Cell swelling occurs early after brain ischemia, but it is unclear whether neuronal LRRC8a contributes to ischemia-induced glutamate release and brain injury. We found that Lrrc8a conditional knockout (Lrrc8a-cKO) mice produced by crossing Nestin Cre+/- with Lrrc8a flox+/+ mice died 7-8 weeks of age, indicating an essential role of neuronal LRRC8A for survival. Middle cerebral artery occlusion (MCAO) caused an early increase in LRRC8A protein levels in the hippocampus in wild-type (WT) mice. Whole-cell patch-clamp recording in brain slices revealed that oxygen-glucose deprivation significantly increased the amplitude of VRAC currents in hippocampal CA1 neurons in WT but not in Lrrc8a-cKO mice. Hypotonicity increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in hippocampal CA1 neurons in WT mice, and this was abolished by DCPIB, a VRAC blocker. But in Lrrc8a-cKO mice, hypotonic solution had no effect on the frequency of sEPSCs in these neurons. Furthermore, the brain infarct volume and neurological severity score induced by MCAO were significantly lower in Lrrc8a-cKO mice than in WT mice. In addition, MCAO-induced increases in cleaved caspase-3 and calpain activity, two biochemical markers of neuronal apoptosis and death, in brain tissues were significantly attenuated in Lrrc8a-cKO mice compared with WT mice. These new findings indicate that cerebral ischemia increases neuronal LRRC8A-dependent VRAC activity and that VRACs contribute to increased glutamatergic input to hippocampal neurons and brain injury caused by ischemic stroke., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest with the contents of this article., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The hypothalamic paraventricular nucleus (PVN) plays a major role in generating increased sympathetic output in hypertension. Although group III metabotropic glutamate receptors (mGluRs) are expressed in the hypothalamus, little is known about their contribution to regulating PVN presympathetic neurons in hypertension. Here we show that activating group III mGluRs with L-2-amino-4-phosphonobutyric acid (L-AP4) consistently inhibited the firing activity of spinally projecting PVN neurons in normotensive rats. However, in spontaneously hypertensive rats (SHRs), L-AP4 inhibited 45% of PVN neurons but excited 37%. L-AP4 significantly reduced glutamatergic and GABAergic input to PVN neurons in both groups. Blocking postsynaptic G protein signaling eliminated the excitatory but not the inhibitory effect of L-AP4 on PVN neurons in SHRs. Remarkably, prior activation of group I mGluRs converted the L-AP4 effect from inhibitory to excitatory in PVN neurons, and L-AP4 consistently inhibited PVN neurons when mGluR5 was blocked in SHRs. Furthermore, the expression level of mGluR4 and mGluR6 in the PVN was significantly higher in SHRs than in normotensive rats. Microinjection of L-AP4 into the PVN decreased blood pressure and lumbar sympathetic nerve discharges in normotensive rats and SHRs. Additionally, blocking group I mGluRs in the PVN potentiated L-AP4's sympathoinhibitory effect in SHRs. Therefore, activation of presynaptic group III mGluRs inhibits the excitability of PVN presympathetic neurons to attenuate sympathetic vasomotor activity. Through crosstalk with mGluR5, postsynaptic group III mGluR stimulation paradoxically excites PVN presympathetic neurons in SHRs. Concurrently blocking mGluR5 and activating group III mGluRs in the PVN can effectively reduce sympathetic outflow in hypertension., Competing Interests: Declaration of competing interest The authors declare no conflict of interest with the contents of this article., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The objective of the present study was to investigate the molecular mechanism underlying the role of metformin (Met) in reducing the risk of endometrial hyperplasia (EH). Reverse transcription‑quantitative polymerase chain reaction, western blot and immunohistochemistry (IHC) assays were used to study the effects of Met and tamoxifen on the expression levels of urothelial cancer associated 1 (UCA1), microRNA‑144 (miR‑144) and other factors along the transforming growth factor‑β1 (TGF‑β1)/protein kinase B (AKT) signaling pathway. In addition, MTT and flow cytometry assays were performed to detect the effect of Met on cell proliferation and apoptosis. Tamoxifen treatment increased the weight of the uterus and the level of UCA1, while decreasing the expression of miR‑144. In addition, treatment with tamoxifen (2.0 and 3.5 µg) upregulated the protein expression levels of TGF‑β and p‑AKT, while downregulating the protein expression of active Caspase‑3 in a dose‑dependent manner. By contrast, Met reduced cell viability, promoted cell apoptosis, and reduced the expression levels of UCA1, TGF‑β and p‑AKT, while upregulating the expression of miR‑144 and active Caspase‑3 in a dose‑dependent manner. Furthermore, Met also reduced the weight of uterus. However, tamoxifen and Met did not exert any effect on the protein levels of total AKT and total Caspase‑3. The levels of TGF‑β and p‑AKT proteins in the EH group were much higher when compared with those in the sham group, while Met treatment reduced these protein levels to a certain extent. In addition, the expression of active Caspase‑3 in the EH group was much lower than that in the sham group, while Met treatment increased its level to a certain extent. In conclusion, the current study suggested that Met reduces the risk of EH by reducing the expression levels of UCA1, TGF‑β and p‑AKT, while increasing the levels of miR‑144 and active Caspase‑3 in a dose‑dependent manner.

Aims & Objectives: Age differences exist in many aspects in patients with major depressive disorder (MDD). The present study aims to examine the effect of age on treatment outcomes in first-episode MDD., Methodology: A total of 982 first-episode major depressive patients, who were above 18 years old and admitted in both psychiatric hospitals and units of general hospitals were recruited for the present study. These patients were newly treated and responded to 8-12 weeks of antidepressant treatment. Depressive symptoms, psychosocial functioning and quality of life were measured using standardized instruments. The study population was divided into three age groups: early adult (18-44 years old), middle adult (45-59 years old), and late adult (60-85 years old)., Results: Earlier age was associated with greater symptom severity, severer depressive symptoms in hypersomnia, concentration/decision making, negative view of the self, suicide ideation and restlessness, more impaired function, poorer satisfaction in social relationship and economic status, when compared to late adults with MDD (all P < 0.05). In the multivariable analyses, among the other variables, early age remained as an independent correlation of residual depressive severity (middle age vs. early age: OR = 0.631, 95%CI[0.462, 0.862]; old age vs. early age: OR = 0.521, 95%CI[0.348, 0.780]) and functional impairment. Comorbidity of physical illness had a negative contribution to all treatment outcomes., Conclusion: In first major depressive episode, early age was strongly associated with depressive severity and functional impairment after responding to antidepressant treatment. Early-life depression may be an indicator of MDD for poor clinical outcomes and high clinical burden., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Rheumatoid arthritis (RA) is characterized by chronic inflammatory synovitis resulting in progressive joint destruction. Persistent synovial inflammation is induced by activation of various inflammatory cells. G‑protein‑coupled bile acid receptor 1 (TGR5) is a G‑protein‑coupled receptor activated by various bile acids, which has been reported to act as a key adaptor in regulating various signaling pathways involved in inflammatory responses and a diverse array of physiological processes, including bile acid synthesis, lipid and carbohydrate metabolism, carcinogenesis, immunity and inflammation. In the present study, TGR5 expression was detected in RA peripheral blood mononuclear cells (PBMCs), and its association with clinical disease activity, histological synovitis severity and radiological joint destruction was analyzed. Subsequently, the role and potential underlying mechanisms of TGR5 in the PBMCs of patients with RA and mice with collagen II‑induced arthritis (CIA) were investigated. PBMCs were obtained from 50 patients with RA and 40 healthy controls (HCs). The mRNA and protein expression levels of TGR5 were detected in PBMCs via reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and immunofluorescence staining, respectively. Additionally, the levels of proinflammatory cytokines were analyzed by RT‑qPCR and enzyme‑linked immunosorbent assay (ELISA). The activation of nuclear factor‑κB (NF‑κB) and IκB kinase a was determined via western blot analysis. The anti‑arthritic and anti‑inflammatory effects of LCA on mice with CIA were then investigated. The arthritis score was assessed, and the protein levels of proinflammatory cytokines in the plasma of mice were detected via ELISA. TGR5 mRNA expression was significantly downregulated in the PBMCs of patients with RA compared with in those of the HCs (0.53±0.58 for patients vs. 1.49±0.83 for HCs; P<0.001); similar findings were observed at the protein level. The mRNA expression levels of TGR5 in the PBMCs of patients with RA with a high 28‑Joint Disease Activity Score (DAS28) were significantly decreased compared with in patients with a low DAS28 (0.81±0.65 for low score vs. 0.35±0.46 for high score; P=0.002). Furthermore, TGR5 expression was significantly correlated with the levels of C‑reactive protein (r=‑0.429; P=0.002) and the DAS28 (r=‑0.383; P=0.006). RT‑qPCR and ELISA analyses indicated that lithocholic acid (LCA, 10 mg/kg/day) attenuated lipopolysaccharide‑induced proinflammatory cytokine production via inhibition of NF‑κB activity in the PBMCs of patients with RA. In addition, the arthritis score was significantly decreased in LCA‑treated CIA mice compared with in non‑treated CIA mice. The increased production of tumor necrosis factor‑α, interleukin (IL)‑1β, IL‑6 and IL‑8 was significantly reduced in the plasma of LCA‑treated CIA mice compared with the control. In conclusion, TGR5 may contribute to the inflammation of PBMCs in patients with RA and mice with CIA.

Featuring the simultaneous generation of a library of compounds from a certain intermediate, divergent synthesis has found increasing applications in the construction of natural products and potential medicines. Inspired by this approach, presented herein is a general strategy to introduce functionality, in a divergent manner, into covalent organic frameworks (COFs). This modular protocol includes two stages of covalent assembly, through which functional COFs can be constructed by a three-step transformation of a key platform molecule, such as 4,7-dibromo-2-chloro-1H-benzo[d]imidazole (DBCBI). Constructed herein are four types of chiral COFs (CCOFs) from DBCBI by nucleophilic substitution, Suzuki coupling, and imine formation. The unique array of eight isoframework CCOFs allowed investigation of their catalytic performance and structure-activity relationship in an asymmetric amination reaction., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background Orexin and its receptors are critical regulating sympathetic vasomotor tone under physiological and pathophysiological conditions. Orexin receptor 1 ( OXR 1) is upregulated in the paraventricular nucleus ( PVN ) in the hypothalamus and contributes to increased sympathetic outflow in obese Zucker rats ( OZR s). We hypothesized that silencing OXR 1 expression in the PVN decreases heightened blood pressure and elevated sympathetic outflow in OZR s. Methods and Results An adeno-associated virus ( AAV ) vector containing a short hairpin RNA (sh RNA ) targeting rat OXR 1 was designed to silence OXR 1 expression in the PVN . The AAV - OXR 1-sh RNA or scrambled sh RNA was injected into the PVN in OZR s. The arterial blood pressure in free-moving OZR s was continuously monitored by using a telemetry approach. The firing activity of spinally projecting PVN neurons in rat brain slices was recorded 3 to 4 weeks after injection of viral vectors. The free-moving OZR s treated with AAV - OXR 1-sh RNA had markedly lower OXR 1 expression and lower mean arterial blood pressure, heart rate, and ratio of low- to high-frequency components of heart rate variability compared with OZR s treated with scrambled sh RNA . Furthermore, AAV - OXR 1-sh RNA treatment markedly reduced renal sympathetic nerve activity and attenuated sympathoexcitatory response induced by microinjection of orexin A into the PVN . In addition, treatment with AAV - OXR 1-sh RNA substantially decreased the basal firing activity of spinally projecting PVN neurons in OZR s and attenuated the excitatory effect of orexin A on the firing activity of these neurons. Conclusions These data suggest that chronic downregulation of OXR 1 expression in the PVN reduces sympathetic vasomotor tone in obesity-related hypertension.

The hypothalamic paraventricular nucleus (PVN) is a crucial region involved in maintaining homeostasis through the regulation of cardiovascular, neuroendocrine, and other functions. The PVN provides a dominant source of excitatory drive to the sympathetic outflow through innervation of the brainstem and spinal cord in hypertension. We discuss current findings on the role of the PVN in the regulation of sympathetic output in both normotensive and hypertensive conditions. The PVN seems to play a major role in generating the elevated sympathetic vasomotor activity that is characteristic of multiple forms of hypertension, including primary hypertension in humans. Recent studies in the spontaneously hypertensive rat model have revealed an imbalance of inhibitory and excitatory synaptic inputs to PVN pre-sympathetic neurons as indicated by impaired inhibitory and enhanced excitatory synaptic inputs in hypertension. This imbalance of inhibitory and excitatory synaptic inputs in the PVN forms the basis for elevated sympathetic outflow in hypertension. In this review, we discuss the disruption of balance between glutamatergic and GABAergic inputs and the associated cellular and molecular alterations as mechanisms underlying the hyperactivity of PVN pre-sympathetic neurons in hypertension.

The striatum receives extensive cortical input and plays a prominent role in motor learning and habit formation. Glutamate N -methyl-d-aspartate (NMDA) receptor (NMDAR)-mediated long-term potentiation (LTP) is a major synaptic plasticity involved in learning and memory. However, the molecular mechanism underlying NMDAR plasticity in corticostriatal LTP is unclear. Here, we show that theta-burst stimulation (TBS) consistently induced corticostriatal LTP and increased the coincident presynaptic and postsynaptic NMDAR activity of medium spiny neurons. We also found that α2δ-1 (previously known as a subunit of voltage-gated calcium channels; encoded by the Cacna2d1 gene) physically interacted with NMDARs in the striatum of mice and humans, indicating that this cross-talk is conserved across species. Strikingly, inhibiting α2δ-1 trafficking with gabapentin or disrupting the α2δ-1-NMDAR interaction with an α2δ-1 C terminus-interfering peptide abolished TBS-induced LTP. In Cacna2d1 -knockout mice, TBS failed to induce corticostriatal LTP and the associated increases in presynaptic and postsynaptic NMDAR activities. Moreover, systemic gabapentin treatment, microinjection of α2δ-1 C terminus-interfering peptide into the dorsomedial striatum, or Cacna2d1 ablation impaired the alternation T-maze task and rotarod performance in mice. Our findings indicate that the interaction between α2δ-1 and NMDARs is of high physiological relevance and that a TBS-induced switch from α2δ-1-free to α2δ-1-bound NMDARs is critically involved in corticostriatal LTP and LTP-associated learning and memory. Gabapentinoids at high doses may adversely affect cognitive function by targeting α2δ-1-NMDAR complexes., (© 2018 Zhou et al.)

Background and Purpose- Glutamate NMDARs (N-methyl-D-aspartate receptors) play a major role in the initiation of ischemic brain damage. However, NMDAR antagonists have no protective effects in stroke patients, possibly because they impair physiological functions of NMDARs. α2δ-1 (encoded by Cacna2d1) is strongly expressed in many brain regions. We determined the contribution of α2δ-1 to NMDAR hyperactivity and brain injury induced by ischemia and reperfusion. Methods- Mice were subjected to 90 minutes of middle cerebral artery occlusion followed by 24 hours of reperfusion. Neurological deficits, brain infarct volumes, and calpain/caspase-3 activity in brain tissues were measured. NMDAR activity of hippocampal CA1 neurons was measured in an in vitro ischemic model. Results- Middle cerebral artery occlusion increased α2δ-1 protein glycosylation in the cerebral cortex, hippocampus, and striatum. Coimmunoprecipitation showed that ischemia rapidly enhanced the α2δ-1-NMDAR physical interaction in the mouse brain tissue. Inhibiting α2δ-1 with gabapentin, uncoupling the α2δ-1-NMDAR interaction with an α2δ-1 C terminus-interfering peptide, or genetically ablating Cacna2d1 had no effect on basal NMDAR currents but strikingly abolished oxygen-glucose deprivation-induced NMDAR hyperactivity in hippocampal CA1 neurons. Systemic treatment with gabapentin or α2δ-1 C-terminus-interfering peptide or Cacna2d1 genetic knock-out reduced middle cerebral artery occlusion-induced infarct volumes, neurological deficit scores, and calpain/caspase-3 activation in brain tissues. Conclusions- α2δ-1 is essential for brain ischemia-induced neuronal NMDAR hyperactivity, and α2δ-1-bound NMDARs mediate brain damage caused by cerebral ischemia. Targeting α2δ-1-bound NMDARs, without impairing physiological α2δ-1-free NMDARs, may be a promising strategy for treating ischemic stroke.

Both the sympathetic nervous system and the renin-angiotensin system are critically involved in hypertension development. Although angiotensin II (Ang II) stimulates hypothalamic paraventricular nucleus (PVN) neurons to increase sympathetic vasomotor tone, the molecular mechanism mediating this action remains unclear. The glutamate NMDAR in the PVN controls sympathetic outflow in hypertension. In this study, we determined the interaction between α2δ-1 (encoded by Cacna2d1 ), commonly known as a Ca 2+ channel subunit, and NMDARs in the hypothalamus and its role in Ang II-induced synaptic NMDAR activity in PVN presympathetic neurons. Coimmunoprecipitation assays showed that α2δ-1 interacted with the NMDAR in the hypothalamus of male rats and humans (both sexes). Ang II increased the prevalence of synaptic α2δ-1-NMDAR complexes in the hypothalamus. Also, Ang II increased presynaptic and postsynaptic NMDAR activity via AT1 receptors, and such effects were abolished either by treatment with pregabalin, an inhibitory α2δ-1 ligand, or by interrupting the α2δ-1-NMDAR interaction with an α2δ-1 C terminus-interfering peptide. In Cacna2d1 knock-out mice (both sexes), Ang II failed to affect the presynaptic and postsynaptic NMDAR activity of PVN neurons. In addition, the α2δ-1 C terminus-interfering peptide blocked the sympathoexcitatory response to microinjection of Ang II into the PVN. Our findings indicate that Ang II augments sympathetic vasomotor tone and excitatory glutamatergic input to PVN presympathetic neurons by stimulating α2δ-1-bound NMDARs at synapses. This information extends our understanding of the molecular basis for the interaction between the sympathetic nervous and renin-angiotensin systems and suggests new strategies for treating neurogenic hypertension. SIGNIFICANCE STATEMENT Although both the sympathetic nervous system and renin-angiotensin system are closely involved in hypertension development, the molecular mechanisms mediating this involvement remain unclear. We showed that α2δ-1, previously known as a calcium channel subunit, interacts with NMDARs in the hypothalamus of rodents and humans. Angiotensin II (Ang II) increases the synaptic expression level of α2δ-1-NMDAR complexes. Furthermore, inhibiting α2δ-1, interrupting the α2δ-1-NMDAR interaction, or deleting α2δ-1 abolishes the potentiating effects of Ang II on presynaptic and postsynaptic NMDAR activity in the hypothalamus. In addition, the sympathoexcitatory response to Ang II depends on α2δ-1-bound NMDARs. Thus, α2δ-1-NMDAR complexes in the hypothalamus serve as an important molecular substrate for the interaction between the sympathetic nervous system and the renin-angiotensin system. This evidence suggests that α2δ-1 may be a useful target for the treatment neurogenic hypertension., (Copyright © 2018 the authors 0270-6474/18/386388-11$15.00/0.)

Targeting star-like water surface clutter, a clutter suppression method based on infrared polarization information is proposed. First, the clutter is suppressed from a global perspective using infrared polarization imaging technology, and a basic clutter-suppressed image is obtained. Then, using the Reed-Xiaoli anomaly detection algorithm, the remaining clutter positions in the basic image are determined from the polarization intensity image and basic image. Finally, an image filtering algorithm is utilized to further suppress the remaining clutter in the basic image. In experiments, the proposed method can not only improve the signal-to-clutter ratio as much as 152%, but also preserve the target information and background texture features effectively, indicating clear superiority of our method over existing clutter suppression algorithms. Clutter suppression and target detail preservation can enhance observer understanding of a scene significantly, so this method is applied to the detection and recognition of targets on the water surface.

Main Conclusion: A total of 558 potential circular RNAs (circRNAs) were identified in citrus, and these were analyzed and compared. One hundred seventy-six differentially expressed circRNAs were identified in two genotypes of trifoliate orange. Circular RNAs (circRNAs) play diverse roles in transcriptional control and microRNA (miRNA) function. However, little information is known about circRNAs in citrus. To identify citrus circRNAs and investigate their functional roles, high-throughput sequencing of precocious trifoliate orange (an early-flowering trifoliate orange mutant, Poncirus trifoliata L. Raf.) and its wild type was performed. A total of 558 potential circRNAs were identified by bioinformatic analysis, and 86.02% of these were sense-overlapping circRNAs. Their sequence features, alternative circularization, and other characteristics were investigated in this study. Compared with the wild type, 176 circRNAs were identified as differentially expressed circRNAs, 61 were significantly up-regulated and 115 were down-regulated in precocious trifoliate orange, indicating that they may play an important role in the early flowering process. Alternative circularization and differential expression of some circRNAs were verified by Sanger sequencing and real-time polymerase chain reaction. The functions of differentially expressed circRNAs and their host genes were predicted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. We found that many differentially expressed circRNAs had abundant miRNA binding sites: 29 circRNAs were found to act as the 16 miRNA targets. Overall, these results will help to reveal the biological functions of circRNAs in growth and development of citrus.