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Chronic pain patients often have anxiety disorders, and some of them suffer from anxiety even after analgesic administration. In this study, we investigated the role of AMPAR-mediated synaptic transmission in the ventromedial prefrontal cortex (vmPFC) in chronic pain-induced persistent anxiety in mice and explored potential drug targets. Chronic inflammatory pain was induced in mice by bilateral injection of complete Freund's adjuvant (CFA) into the planta of the hind paws; anxiety-like behaviours were assessed with behavioural tests; S-nitrosylation and AMPAR-mediated synaptic transmission were examined using biochemical assays and electrophysiological recordings, respectively. We found that CFA induced persistent upregulation of AMPAR membrane expression and function in the vmPFC of anxious mice but not in the vmPFC of non-anxious mice. The anxious mice exhibited higher S-nitrosylation of stargazin (an AMPAR-interacting protein) in the vmPFC. Inhibition of S-nitrosylation by bilaterally infusing an exogenous stargazin (C302S) mutant into the vmPFC rescued the surface expression of GluA1 and AMPAR-mediated synaptic transmission as well as the anxiety-like behaviours in CFA-injected mice, even after ibuprofen treatment. Moreover, administration of ZL006, a small molecular inhibitor disrupting the interaction of nNOS and PSD-95 (20 mg·kg

This paper was aimed to clarify the effect of high-intensity interval training (HIIT) on depression. Animal running platforms were used to establish HIIT exercise models, depression models were prepared by chronic unpredictable mild stress (CUMS), and depression-related behaviors were detected by behavioral experiments. The results showed that HIIT exercise improved depression-related behavior in CUMS model mice. Western blot and ELISA results showed that in the hippocampus, medial prefrontal cortex (mPFC) and amygdala of the CUMS model mice, glucocorticoid receptor (GR) protein expression was down-regulated, and the content of tumor necrosis factor α (TNF-α) was increased, compared with those in the control group, whereas HIIT exercise could effectively reverse these changes in CUMS model mice. These results suggest that HIIT exercise can exert antidepressant effect, which brings new ideas and means for the clinical treatment of depressive diseases.

Anxiety is common in patients suffering from chronic pain. Here, we report anxiety-like behaviors in mouse models of chronic pain and reveal that nNOS-expressing neurons in ventromedial prefrontal cortex (vmPFC) are essential for pain-induced anxiety but not algesia, using optogenetic and chemogenetic strategies. Additionally, we determined that excitatory projections from the posterior subregion of paraventricular thalamic nucleus (pPVT) provide a neuronal input that drives the activation of vmPFC nNOS-expressing neurons in our chronic pain models. Our results suggest that the pain signal becomes an anxiety signal after activation of vmPFC nNOS-expressing neurons, which causes subsequent release of nitric oxide (NO). Finally, we show that the downstream molecular mechanisms of NO likely involve enhanced glutamate transmission in vmPFC CaMKIIα-expressing neurons through S-nitrosylation-induced AMPAR trafficking. Overall, our data suggest that pPVT excitatory neurons drive chronic pain-induced anxiety through activation of vmPFC nNOS-expressing neurons, resulting in NO-mediated AMPAR trafficking in vmPFC pyramidal neurons., Chronic pain usually induces anxiety. Here, the authors report that vmPFC nNOS-expressing neurons are activated by excitatory inputs from pPVT during chronic pain and subsequently induce anxiety-like behaviors in mice through promoting AMPAR trafficking.

Mechanisms underlying functional recovery after stroke are little known, and effective drug intervention during the delayed stage is desirable. One potential drug target, the protein-protein interaction between neuronal nitric oxide synthase (nNOS) and postsynaptic density protein 95 (PSD-95), is critical to acute ischaemic damage and neurogenesis. We show that nNOS-PSD-95 dissociation induced by microinjection of a recombinant fusion protein, Tat-nNOS-N1-133 , or systemic administration of a small-molecule, ZL006, from day 4 to day 10 after photothrombotic ischaemia in mice reduced excessive tonic inhibition in the peri-infarct cortex and ameliorated motor functional outcome. We also demonstrated improved neuroplasticity including increased dendrite spine density and synaptogenesis after reducing excessive tonic inhibition by nNOS-PSD-95 dissociation. Levels of gamma-aminobutyric acid (GABA) and GABA transporter-3/4 (GAT-3/4) are increased in the reactive astrocytes in the peri-infarct cortex. The GAT-3/4-selective antagonist SNAP-5114 reduced tonic inhibition and promoted function recovery, suggesting that increased tonic inhibition in the peri-infarct cortex was due to GABA release from reversed GAT-3/4 in reactive astrocytes. Treatments with Tat-nNOS-N1-133 or ZL006 after ischaemia inhibited astrocyte activation and GABA production, prevented the reversal of GAT-3/4, and consequently decreased excessive tonic inhibition and ameliorated functional outcome. The underlying molecular mechanisms were associated with epigenetic inhibition of glutamic acid decarboxylase 67 and monoamine oxidase B expression through reduced NO production. The nNOS-PSD-95 interaction is thus a potential target for functional restoration after stroke and ZL006, a small molecule inhibitor of this interaction, is a promising pharmacological lead compound. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Background: Nasogastric decompression is routinely used for intestinal drainage or decompression after gastrectomy. However,nowadays its efficacy is under debate.Objectives: The purpose of this study was to investigate the efficacy and necessity of nasogastric decompression in radical gastrectomyfor gastric cancer.Methods: Two PubMed and EMBASE electronic databases were retrieved by November 2018. A prospective randomized controlledtrial (RCT) and comparison of nasogastric decompression with and without nasogastric decompression after gastrectomy are requiredfor eligible studies.Results: A total of 1,885 cases were included in 13 randomized controlled studies. There were 941 cases in nasogastric decompressiongroup and 944 cases in non-nasogastric decompression group after gastrectomy. The patients in non-nasogastric decompressiongroup had significantly shorter time of bowel sound return (WMD = -0.20, 95% CIs = -0.38 - 0.02, P = 0.03), shorter time of first oralintake (WMD = -0.58, 95% CIs = -0.92 - 0.24, P = 0.0007), faster tolerance to semi-solid diet (WMD = -0.65, 95% CIs = -0.96 - 0.34, P

Background and Purpose— Stroke is a major public health concern worldwide. Although clinical treatments have improved in the acute period after stroke, long-term therapeutics remain limited to physical rehabilitation in the delayed phase. This study is aimed to determine whether nNOS (neuronal NO synthase)-CAPON (carboxy-terminal postsynaptic density-95/discs large/zona occludens-1 ligand of nNOS) interaction may serve as a new therapeutic target in the delayed phase for stroke recovery. Methods— Photothrombotic stroke and transient middle cerebral artery occlusion were induced in mice. Adeno-associated virus (AAV)-cytomegalovirus (CMV)-CAPON-125C-GFP (green fluorescent protein)-3Flag and the other 2 drugs (Tat-CAPON-12C and ZLc-002) were microinjected into the peri-infarct cortex immediately and 4 to 10 days after photothrombotic stroke, respectively. ZLc-002 was also systemically injected 4 to 10 days after transient middle cerebral artery occlusion. Grid-walking task and cylinder task were conducted to assess motor function. Western blotting, immunohistochemistry, Golgi staining, and electrophysiology recordings were performed to uncover the mechanisms. Results— Stroke increased nNOS-CAPON association in the peri-infarct cortex in the delayed period. Inhibiting the ischemia-induced nNOS-CAPON association substantially decreased the number of foot faults in the grid-walking task and forelimb asymmetry in the cylinder task, suggesting the promotion of functional recovery from stroke. Moreover, dissociating nNOS-CAPON significantly facilitated dendritic remodeling and synaptic transmission, indicated by increased dendritic spine density, dendritic branching, and length and miniature excitatory postsynaptic current frequency but did not affect stroke-elicited neuronal loss, infarct size, or cerebral edema, suggesting that nNOS-CAPON interaction may function via regulating structural neuroplasticity, rather than neuroprotection. Furthermore, ZLc-002 reversed the transient middle cerebral artery occlusion–induced impairment of motor function. Conclusions— Our results reveal that nNOS-CAPON coupling can serve as a novel pharmacological target for functional restoration after stroke.

Summary In neurons, increased protein–protein interactions between neuronal nitric oxide synthase (nNOS) and its carboxy‐terminal PDZ ligand (CAPON) contribute to excitotoxicity and abnormal dendritic spine development, both of which are involved in the development of Alzheimer's disease. In models of Alzheimer's disease, increased nNOS–CAPON interaction was detected after treatment with amyloid‐β in vitro, and a similar change was found in the hippocampus of APP/PS1 mice (a transgenic mouse model of Alzheimer's disease), compared with age‐matched background mice in vivo. After blocking the nNOS–CAPON interaction, memory was rescued in 4‐month‐old APP/PS1 mice, and dendritic impairments were ameliorated both in vivo and in vitro. Furthermore, we demonstrated that S‐nitrosylation of Dexras1 and inhibition of the ERK–CREB–BDNF pathway might be downstream of the nNOS–CAPON interaction.

Background Stroke is a leading cause of long‐term disability worldwide. However, current therapies that promote functional recovery from stroke are limited to physical rehabilitation. No pharmacological therapy is available. Thus, understanding the role of histone deacetylase 2 (HDAC2) in the pathophysiological process of stroke‐induced functional loss may provide a novel strategy for stroke recovery. Methods and Results Focal stroke was induced by photothrombosis. LV‐HDAC2‐shRNA‐GFP, LV‐GFP, Ad‐HDAC2‐Flag, or Ad‐inactive‐HDAC2‐Flag was microinjected into the peri‐infarct area immediately after stroke. HDAC inhibitors were microinjected into the peri‐infarct area 4 to 10 days after stroke. Grid‐walking task and cylinder task were conducted to assess motor function. Golgi‐Cox staining, chromatin immunoprecipitation, and electrophysiology were used to reveal the mechanisms underlying stroke recovery. Knockdown or knockout of HDAC2 promoted stroke recovery, whereas overexpression of HDAC2 worsened stroke‐induced functional impairment. More importantly, trichostatin A, a pan‐HDAC inhibitor, promoted functional recovery from stroke in WT mice when used in the delayed phase, but it was ineffective in Hdac2 conditional knockout ( Hdac2 CKO) mice. Treatment with suberoylanilide hydroxamic acid, a selective HDAC1 and HDAC2 inhibitor, in the delayed phase of stroke produced sustained functional recovery in mice via epigenetically enhancing neuroplasticity of surviving neurons in the peri‐infarct zone. Conclusions Our novel findings provide evidence that HDAC2 is a crucial target for functional recovery from stroke. As there are clinically available HDAC inhibitors, our findings could be directly translated into clinical research of stroke.

Mechanisms underlying functional recovery after stroke are little known, and effective drug intervention during the delayed stage is desirable. One potential drug target, the protein-protein interaction between neuronal nitric oxide synthase (nNOS) and postsynaptic density protein 95 (PSD-95), is critical to acute ischaemic damage and neurogenesis. We show that nNOS-PSD-95 dissociation induced by microinjection of a recombinant fusion protein, Tat-nNOS-N

Objective To analyze the variations of ER, PR and HER-2 in breast ductal carcinoma in situ (DCIS), DCIS with micro-invasive (DCIS-Mi), and invasive ductal carcinoma (IDC) to establish a basis for further study on DCIS-Mi. Methods The samples of 30 DCIS, 51 DCIS-Mi and 49 IDC diagnosed by pathology from patients hospitalized in 307 hospital of PLA from October 2002 to February 2013, were collected in the present study. The expressions of ER, PR and Her-2 in breast DCIS, DCISMi and IDC were determined by immunohistochemical staining method. Results When ≥10% tumor nuclei were colored, it was judged as positive, the expressions of ER in DCIS, DCIS-Mi and IDC were found to be 63.33%, 41.18% and 79.59% (P

New strategies must be developed to resolve the problems of stroke treatment. In recent years, stem cell-based therapy after stroke has come into the public and academic lens. Previously we have shown that uncoupling neuronal nitric oxide synthase (nNOS) from the postsynaptic density protein-95 (PSD-95) by ZL006, a small molecular compound, can ameliorate ischemic damage and promote neuronal differentiation of endogenous neural stem cells (NSCs) in focal cerebral ischemic male rats. In this study, we transplanted exogenous NSCs into the ipsilateral hemisphere of male rats in combination with ZL006 treatment after ischemic stroke. We show that ZL006 treatment facilitates the migration of transplanted NSCs into the ischemia-injured area and promotes neuronal differentiation of these cells, which is not due to a direct effect of ZL006 on exogenous NSCs but is associated with increased phosphorylation of cAMP response element-binding protein (CREB) in neurons and favorable microenvironment. Moreover, improved functional outcome in the ZL006-treated group was also found. Taken together, our data indicate that ZL006, uncoupling nNOS-PSD-95 in neurons, positively regulates the fate of transplanted NSCs and benefits the functional outcome after stroke in male rats.

The data for neutron-induced reactions are indispensable in a lot of applications of nuclear science and technologies. All reaction cross sections, angular distributions, energy spectra, and double-differential cross sections of neutron, proton, deuteron, triton, and alpha-particle emissions are consistently calculated and analyzed for n+ $$^{23}$$ Na reactions at incident neutron energies below 200 MeV, based on nuclear theoretical models. The calculated results are compared with the experimental data and the evaluated data in the ENDF/B-VII, JENDL-4.0, and JEFF-3.2 libraries. In most cases, the calculated results describe the corresponding experimental data well. At the resonance energy region, evaluated experimental data are adopted to fit to the resonance structures.

To investigate the prevalence and major risk factors of peripartum thromboembolic disease in different regions of Guangdong province.Data from 169 218 pregnant women in different regions of Guangdong province from January 2005 to June 2010 were analyzed retrospectively. The prevalence and epidemiological characteristics of thromboembolic disease during pregnancy or puerperium were investigated.Of the studied population, (1) 201 cases (1.3‰) suffered from thromboembolic disease during pregnancy or puerperium including 128 cases of deep vein thrombosis (DVT), 68 cases of cerebral venous thrombosis (CVT) and 5 pulmonary embolism, the prevalence rates were 0.8‰, 0.4‰, and 0.02‰ respectively. (2) Risk factors in different regions showed that, in the Pearl River Delta area, the major risk factors for DVT would include previous or family history of thrombosis, pregnancy complications, with medically involved diseases, prolonged bed rest and pregnancy weight gain15 kg etc. While in eastern, western, northern parts of Guangdong, the major risk factors for DVT would include pregnancy weight gain15 kg, prolonged bed rest, preeclampsia, cesarean section and complications during pregnancy. In Pearl River Delta region, the major risk factors for CVT would include eclampsia, preeclampsia, pregnancy complications, prolonged bed rest3 days, past history or family history of thrombosis. While eclampsia, preeclampsia, advanced age or younger age, pregnancy weight gain15 kg, complications during pregnancy were the major risk factors for CVT in the eastern, western or northern parts of Guangdong.Prevalence and major risk factors of peripartum thromboembolic disease in different regions of Guangdong were different. It was crucial to take effective measures in pregnant women with different epidemiological characteristics and risk factors to prevent and reduce the incidence of peripartum thromboembolic disease.

This paper puts forward a model of path fault recovery of MPLS VPN, which is DR-PFR (Double Recovery-Path Fault Recovery), for the failure on the path of MPLS VPN. DR-PFR can solve the failures in both the working path and the backup path. Experiments show that under the condition of using the resources effectively, when the network fails, DR-PFR can enable the network recover timely and effectively reduce the impacts on users.

To evaluate the antioxidant activity of astragalus and its therapeutic effect on gestational diabetes.Eighty-four pregnant women with gestational diabetes were divided into insulin and insulin plus astragalus groups after regular dietary control and insulin treatment to maintain stable blood glucose level. The 43 patients in insulin group received insulin injection, whereas the 41 patients in the other group received treatment with both insulin and astragalus. The SOD activity, MDA level, blood lipids and renal function were determined in both groups after the treatments.The patients with both insulin and astragalus treatments showed significantly increased serum SOD activity and decreased MDA level, renal function and blood lipids in comparison with those with exclusive insulin treatment.Astragalus can effectively control blood glucose, reduce the free radicals, and promote the antioxidative activity, and may play a role in the prevention and treatment of gestational diabetes.