Protective Effect of Hydroxy safflor Yellow A against Chronic Mild Stress-induced Memory Impairments by Suppressing Tau Phosphorylation in Mice

Chronic stress plays a critical role in the etiology of sporadic Alzheimer's disease(AD).However,there are currently no effective drugs that can target chronic stress to prevent AD.In this study,we explored the neuroprotective effect of hydroxysafflor yellow A(HSYA)against chronic mild stress(CMS)-induced memory impairments in mice and the underlying mechanism.The Morris water maze test showed that HSYA significantly reduced CMS-induced learning and memory impairments in mice.HSYA increased the expression of brain-derived neurotrophic factor(BDNF)and activated downstream tropomyosin-related kinase B(TrkB)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)signaling.HSYA decreased the expression of regulator of calcineurin 1-1L(RCAN1-1L)that could promote the activity of glycogen synthase kinase-3β(GSK-3β).HSYA also attenuated tau phosphorylation by inhibiting the activity of GSK-3βand cyclin-dependent kinase-5(Cdk5).Our data indicated that HSYA has protective effects against CMS-induced BDNF downregulation,tau phosphorylation and memory impairments.HSYA may be a promising therapeutic candidate for AD by targeting chronic stress.

积极老龄化视角下老年数字健康的社会保障机制研究

近年来,我国老年人口数量持续上升,人口老龄化问题日益凸显,随着智慧医疗新时代的来临,数字化健康管理逐渐普及。在此背景下,如何应对人口老龄化的挑战成为社会普遍关心的问题。党的十九届五中全会正式提出积极老龄化,将积极老龄化上升到国家战略层面,为应对老龄化提供新的视角。本研究以促使老年人更好地养老为目的,从积极老龄化视角分析如何健全老年人数字健康的社会保障机制,并且对我国老年数字健康管理模式存在的问题以及社会保障制度提出对策和建议。

腹腔镜胆囊切除术3个切口疼痛程度及切口镇痛与恶心呕吐发生率的研究

目的探讨传统腹腔镜胆囊切除术(LC)后3个切口(剑突下、脐上、右侧腹部)的疼痛程度及切口镇痛与术后恶心呕吐发生率的关系。方法选择接受择期LC的患者100例,美国麻醉医师协会分级(ASA)Ⅰ级,手术方式均为传统三孔法,随机分为5个组:剑突下切口组(A组)、脐上切口组(B组)、右侧腹部切口组(C组)、全部切口组(D组)、对照组(E组),每组20例。手术结束缝合切口前,A组在剑突下切口给予0.5%罗哌卡因3 ml局部全层浸润;B组在脐上切口给予0.5%罗哌卡因3 ml局部全层浸润;C组在右侧腹部切口给予0.5%罗哌卡因3 ml局部全层浸润;D组分别在全部3个切口给予0.5%罗哌卡因各3 ml局部全层浸润;E组分别在全部3个切口给予生理盐水各3 ml局部全层浸润。采用视觉模拟评分法(VAS),于患者出手术室时、术后2 h、术后4 h、术后8 h、术后16 h和术后24 h对患者进行VAS疼痛评分,并且记录各组患者在术后24 h内发生恶心呕吐的情况。结果各组患者一般情况比较差异无统计学意义。由列的合计可以看出:随时间延长,患者VAS评分逐渐下降。由行的合计可以看出:5个组VAS评分从低到高依次为:A组<D组<C组<B组<E组。5个组在不同时间上的VAS评分变化趋势差异有统计学意义(F=7.16,P=0.000)。组间两两比较:A、D组的VAS评分与B、C组的VAS评分与E组的VAS评分互相之间的差异有统计学意义;A组与D组VAS评分差异无统计学意义;B组与C组VAS评分差异无统计学意义。各组患者术后恶心呕吐的发生率有差异(A组35%、B组5%、C组40%、D组20%、E组45%),B组患者术后恶心呕吐的发生率明显低于其他组,差异有统计学意义(χ2=10.39,P=0.034)。结论 LC后,剑突下切口的疼痛是患者术后疼痛的主要来源,在剑突下切口做局部浸润较其他两个切口能降低患者的VAS疼痛评分。在脐上切口做局部浸润较其他两个切口能降低患者术后恶心呕吐的发生率。

Replication of hepatitis B virus in primary duck hepatocytes transfected with linear viral DNA

AIM: To explore the expression and replication of hepatitis B virus (HBV) DNA in primary duck hepatocytes (PDHs).METHODS: Complete HBV genome was transfected into PDHs by electroporation (transfected group, 1.19×1012copies of linear HBV DNA/1×107 PDHs). After 1-5 d of transfection, HBsAg and HBeAg in the supernatant and lysate of PDHs were measured with the IMX System.Meanwhile, replicative intermediates of HBV DNA were analyzed by Southern blotting and Dot blotting. PDHs electroporated were used as control group.RESULTS: HBsAg in the hepatocyte lysates of transfected group was 15.24 (1 d), 14.55 (3 d) and 5.13 (5 d; P/N values, positive≥2.1) respectively. HBeAg was negative (＜2.1). Both HBsAg and HBeAg were negative in the supernatant of transfected group. Dot blotting revealed that HBV DNA was strongly positive in the transfected group and negative in the control group. Southern blot analysis of intracellular total DNA indicated that there were relaxed circular (rc DNA), covalently closed circular (ccc DNA), and single-stranded (ss DNA) HBV DNA replicative intermediates in the transfected group, there was no integrated HBV DNA in the cellular genome. These parameters were negative in control group.CONCLUSION: Expression and replication of HBV genes can occur in hepatocytes from non-mammalian species.HBV replication has no critical species-specificity, and yet hepatic-specific regulating factors in hepatocytes may be essential for viral replication.

Prevalence and risk factors of prolonged grief disorder among bereaved survivors seven years after the Wenchuan earthquake in China: A cross-sectional study

Background:This study aimed to determine the prevalence and predictive factors of prolonged grief disorder(PGD)among those bereaved by the Wenchuan earthquake in Southwestern China seven years after the event.Methods:A cross-sectional survey based on census tracts was conducted on the bereaved earthquake survivors.Responses to the questionnaire regarding PGD and its potential associated factors were obtained either through face-to-face or telephone interview.PGD was screened by a validated Chinese version of the PGD questionnaire-13(PG-13).Bivariate and multivariate regression analyses were used to determine the prevalence and associated risk factors of PGD.Results:A total of 1464 bereaved earthquake survivors,with a response rate of 97.6%,were included in the study.Of the 1464 respondents studied,124(8.47%)were diagnosed with PGD.Multivariate regression analysis demonstrated that PGD in the bereaved earthquake individuals was significantly associated with several factors,including age,economic burden,close kinship with the deceased,and living with the deceased before the loss.Wenchuan earthquake bereaved aged 41e60 years were more likely to develop PGD compared to those aged younger than 40 or older than 60(OR=2.075,95%CI=1.297e3.319).Those who had a close kinship with the deceased had a higher tendency to develop PGD(OR=5.144,95%CI=2.716e9.740).The odds of PGD among the earthquake bereaved with economic burdens were higher relative to those who did not experience an economic burden(OR=8.123,95%CI=2.657e24.831).Those who living with the deceased before loss also had a higher tendency to develop PGD(OR=0.179,95%CI=0.053e0.602).Conclusions:This study revealed that a significantly high proportion(8.47%)of the Wenchuan earthquake-bereaved remain grieving seven years after the event.Those diagnosed with PGD should receive appropriate interventions from clinical psychologists.The risk factors identified in this study are crucial for the early screening and prevention of PGD in future nursing and psycho-clinical practices.

PCK1 dysregulation in cancer: Metabolic reprogramming, oncogenic activation, and therapeutic opportunities

The last few decades have witnessed an advancement in our understanding of multiple cancer cell pathways related to metabolic reprogramming.One of the most important cancer hallmarks,including aerobic glycolysis(the Warburg effect),the central carbon pathway,and multiple-branch metabolic pathway remodeling,enables tumor growth,progression,and metastasis.Phosphoenolpyruvate carboxykinase1(PCK1),a key rate-limiting enzyme in gluconeogenesis,catalyzes the conversion of oxaloacetate to phosphoenolpyruvate.PCK1 expression in gluconeogenic tissues is tightly regulated during fasting.In tumor cells,PCK1 is regulated in a cell-autonomous manner rather than by hormones or nutrients in the extracellular environment.Interestingly,PCK1has ananti-oncogenic role in gluconeogenic organs(the liver and kidneys),but a tumor-promoting role in cancers arising from non-gluconeogenic organs.Recent studies have revealed that PCK1 has metabolic and non-metabolic roles in multiple signaling networks linking metabolic and oncogenic pathways.Aberrant PCK1 expression results in the activation of oncogenic pathways,accompanied by metabolic reprogramming,to maintain tumorigenesis.In this review,we summarize the mechanisms underlying PCK1 expression and regulation,and clarify the crosstalk between aberrant PCK1 expression,metabolic rewiring,and signaling pathway activation.In addition,we highlight the clinical relevance of PCK1 and its value as a putative cancer therapeutic target.

Relationship between serum levels of IL-4,IL-8,TNF-alpha,T cell subsets and prognosis in patients with psoriasis vulgaris

Objective:To study the relationship between serum levels of IL-4,IL-8,TNF-alpha,T cell subsets and prognosis in patients with psoriasis vulgaris.Methods:A total of 120 patients with psoriasis vulgaris who were treated in our hospital from January 2018 to January 2019 were selected as the study group,and 50 normal subjects who underwent health examination in our hospital during the same period were selected as the control group.The levels of serum IL-4,IL-8,TNF-alpha and T cell subsets in the observation group and the control group were detected and compared.The levels of IL-4,IL-8,TNF-alpha and T cell subsets in the observation group at different time after treatment were compared after standardized western medicine treatment.Pearson test was used to analyze the correlation between IL-4,IL-8,TNF-alpha and T cell subsets.Results:The levels of IL-4,IL-8 and TNF-a in the observation group were higher than those in the control group,while the levels of CD3+,CD4+,CD4+/CD8+in the observation group were lower than those in the control group,and the levels of CD8+in the observation group were higher than those in the control group.There was a significant difference between the two groups.In the observation group,after 8 weeks of treatment,the levels of IL-4,IL-8 and TNF-alpha continued to decrease,CD3+,CD4+,CD4+/CD8+increased and CD8+decreased with the prolongation of treatment time.There was significant difference among the groups.Pearson correlation test was used.IL-4,IL-8,TNF-a had negative correlation with CD3+,CD4+,CD4+/CD8+,and positive correlation with CD8+.Conclusion:The incidence of psoriasis vulgaris is related to the elevation of IL-4,IL-8,TNF-alpha levels and immunodeficiency.The prognosis of psoriasis vulgaris can be judged by monitoring the levels of IL-4,IL-8,TNF-alpha and T cell subsets.

Changes in the humoral immunity response in SARS-CoV-2 convalescent patients over 8 months

Many countries around the world have seen a sharp rise in COVID-19 cases since the beginning of October due to the second wave of the pandemic.A decline in the antibody response to severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which was reported exclusively in the early month,increases the risk of reinfection for convalescent individuals.There is a current need to follow the maintenance of specific antibodies against SARS-CoV-2.

Depletion of VPS35 attenuates metastasis of hepatocellular carcinoma by restraining the Wnt/PCP signaling pathway

Vesicle Protein Sorting 35(VPS35)is a novel oncogene that promotes tumor growth through the PI3K/AKT signaling in hepatocellular carcinoma(HCC).However,the role of VPS35 in HCC metastasis and the underlying mechanisms remain largely unclear.In this study,we observed that overexpression of VPS35 enhanced hepatoma cell invasion and metastasis by inducing epithelialemesenchymal transition(EMT)-related gene expression.Conversely,knockout of VPS35 significantly inhibited hepatoma cell migration and invasion.Furthermore,depletion of VPS35 decreased the lung metastasis of HCC in nude mice.By transcriptome analysis,we determined that VPS35 promoted HCC metastasis by activating the Wnt/non-canonical planar cell polarity(PCP)pathway.Mechanistically,VPS35 activated the PCP pathway by regulating membrane sorting and trafficking of Frizzled-2(FZD2)and ROR1 in hepatoma cells.Collectively,our results indicate that VPS35 promotes HCC metastasis via enhancing the Wnt/PCP signaling,thus providing a potential prognostic marker and therapeutic target for HCC.

The clinical and immunological features of pediatric COVID-19 patients in China

In December 2019,the corona virus disease 2019(COVID-19)caused by novel coronavirus(SARS-CoV-2)emerged in Wuhan,China and rapidly spread worldwide.Few information on clinical features and immunological profile of COVID-19 in paediatrics.The clinical features and treatment outcomes of twelve paediatric patients confirmed as COVID-19 were analyzed.The immunological features of children patients was investigated and compared with twenty adult patients.The median age was 14.5-years(range from 0.64 to 17),and six of the patients were male.The average incubation period was 8 days.Clinically,cough(9/12,75%)and fever(7/12,58.3%)were the most common symptoms.Four patients(33.3%)had diarrhea during the disease.As to the immune profile,children had higher amount of total T cell,CD8t T cell and B cell but lower CRP levels than adults(P<0.05).Ground-glass opacity(GGO)and local patchy shadowing were the typical radiological findings on chest CT scan.All patients received antiviral and symptomatic treatment and the symptom relieved in 3e4 days after admitted to hospital.The paediatric patients showed mild symptom but with longer incubation period.Children infected with SARS-CoV-2 had different immune profile with higher T cell amount and low inflammatory factors level,which might ascribed to the mild clinical symptom.We advise that nucleic acid test or examination of serum IgM/IgG antibodies against SARS-CoV-2 should be taken for children with exposure history regardless of clinical symptom.

‘Plug-and-play’ plasmonic metafibers for ultrafast fibre lasers

Metafibers expand the functionalities of conventional optical fibres to unprecedented nanoscale light manipulations by integrating metasurfaces on the fibre tips,becoming an emerging light-coupling platform for both the nanoscience and fibre optics communities.Current metafibers remain proof-of-concept demonstrations that mostly explore isolated bare fibres owing to the lack of standard interfaces with universal fibre networks.Here,we develop methodologies for fabricating well-defined plasmonic metasurfaces directly on the end facets of commercial single-mode fibre jumpers using standard planar technologies and provide the first demonstration of their practical applications in the nonlinear plasmonic regime.Featuring plug-and-play connections with fibre circuitry and arbitrary metasurface landscapes,the metafibers with tunable plasmonic resonances are implemented into fibre laser cavities,yielding all-fibre sub-picosecond(minimum 513 fs)soliton mode locked lasers at optical wavelengths of 1.5μm and 2μm,demonstrating their unusual polarimetric nonlinear transfer functions and superior saturation absorption responses.The nanofabrication process flow is compatible with existing cleanroom technologies,offering metafibers an avenue to become a regular member of functionalised fibre components.This work paves the way toward the next generation of ultrafast lasers,optical frequency combs,and ultracompact‘all-in-fibre’optical systems.

Correction: Changes in the humoral immunity response in SARS-CoV-2 convalescent patients over 8 months

Correction to:Cellular&Molecular Immunology https:/doi.org/10.1038/s41423-020-00605-4,published online 08 January 2021 The licence information was missing from this article and should havebeen CC-BY.The original article has been corrected.

O-GlcNAcylation of YTHDF2 promotes HBV-related hepatocellular carcinoma progression in an N^(6)-methyladenosine-dependent manner

Hepatitis B virus(HBV)infection is a major risk factor for hepatocellular carcinoma(HCC),but its pathogenic mechanism remains to be explored.The RNA N^(6)-methyladenosine(m^(6)A)reader,YTH(YT521-B homology)domain 2(YTHDF2),plays a critical role in the HCC progression.However,the function and regulatory mechanisms of YTHDF2 in HBV-related HCC remain largely elusive.Here,we discovered that YTHDF2 O-GlcNAcylation was markedly increased upon HBV infection.O-GlcNAc transferase(OGT)-mediated O-GlcNAcylation of YTHDF2 on serine 263 enhanced its protein stability and oncogenic activity by inhibiting its ubiquitination.Mechanistically,YTHDF2 stabilized minichromosome maintenance protein 2(MCM2)and MCM5 transcripts in an m^(6)A-dependent manner,thus promoting cell cycle progression and HBV-related HCC tumorigenesis.Moreover,targeting YTHDF2 O-GlcNAcylation by the OGT inhibitor OSMI-1 significantly suppressed HCC progression.Taken together,our findings reveal a new regulatory mechanism for YTHDF2 and highlight an essential role of YTHDF2 O-GlcNAcylation in RNA m^(6)A methylation and HCC progression.Further description of the molecular pathway has the potential to yield therapeutic targets for suppression of HCC progression due to HBV infection.

Real-world effectiveness of an intranasal spray A8G6 antibody cocktail in the post-exposure prophylaxis of COVID-19

Previously,we identified an antibody combination A8G6 that showed promising efficacy in COVID-19 animal models and favorable safety profile in preclinical models as well as in a first-in-human trial.To evaluate the real-word efficacy of A8G6 neutralizing antibody nasal spray in post-exposure prophylaxis of COVID-19,an open-label,non-randomized,two-arm,blank-controlled,investigator-initiated trial was conducted in Chongqing,China(the register number:ChiCTR2200066416).High-risk healthy participants(18–65 years)within 72 h after close contact to COVID-19 patients were recruited and received a three-dose(1.4 mg/dose)A8G6 treatment daily or no treatment(blank control)for 7 consecutive days.SARS-CoV-2 infection occurred in 151/340(44.4%)subjects in the blank control group and 12/173(6.9%)subjects in the A8G6 treatment group.The prevention efficacy of the A8G6 treatment within 72 h exposure was calculated to be 84.4%(95%CI:74.4–90.4%).Moreover,compared to the blank-control group,the time from the SARS-CoV-2 negative to the positive COVID-19 conversion was significantly longer in the AG86 treatment group(mean time:3.4 days vs 2.6 days,p=0.019).In the secondary end-point analysis,the A8G6 nasal treatment had no effects on the viral load at baseline SARS-CoV-2 RT-PCR positivity and the time of the negative COVID-19 conversion.Finally,except for 5 participants(3.1%)with general adverse effects,we did not observe any severe adverse effects related to the A8G6 treatment.In this study,the intranasal spray AG86 antibody cocktail showed potent efficacy for prevention of SARS-CoV-2 infection in close contacts of COVID-19 patients.

Development of cell-based pseudovirus entry assay to identify potential viral entry inhibitors and neutralizing antibodies against SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is the causative virus of the coronavirus disease 2019(COVID-19)pandemic.To establish a safe and convenient assay system for studying entry inhibitors and neutralizing antibodies against SARS-CoV-2,we constructed a codon-optimized,full-length C-terminal mutant spike(S)gene of SARS-CoV-2.We generated a luciferase(Luc)-expressing pseudovirus containing the wild-type or mutant S protein of SARS-CoV-2 in the envelope-defective HIV-1 backbone.The key parameters for this pseudovirus-based assay,including the S mutants and virus incubation time,were optimized.This pseudovirus contains a Luc reporter gene that enabled us to easily quantify virus entry into angiotensin-converting enzyme 2(ACE2)-expressing 293T cells.Cathepsin(Cat)B/L inhibitor E64d could significantly block SARS-CoV-2 pseudovirus infection in 293T-ACE2 cells.Furthermore,the SARS-CoV-2 spike pseudotyped virus could be neutralized by sera from convalescent COVID-19 patients or recombinant ACE2 with the fused Fc region of human IgG1.Thus,we developed a pseudovirus-based assay for SARS-CoV-2,which will be valuable for evaluating viral entry inhibitors and neutralizing antibodies against this highly pathogenic virus.

Emerging SARS-CoV-2 variants reduce neutralization sensitivity to convalescent sera and monoclonal antibodies

Coronaviruses are enveloped,positive-stranded RNA viruses that contain the largest known RNA genomes to date.As severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continues to circulate in the human population,multiple mutations have accumulated over time,which may affect its transmission,virulence and antigenicity.

Increased immune escape of the new SARS-CoV-2 variant of concern Omicron

On 24 November,a new detected variant B.1.1.529 of SARS-CoV-2 by South Africa was reported to WHO.After only 2 days,this variant was designated as“variant of concern”(VOC)and named as Omicron.In the past few weeks,Omicron had reported from more than 80 countries.It has been reported as the dominant SARS-CoV-2 in U.S.due to the rapid spread of Omicron.A new wave of infection driven by Omicron is in progress.

Stay Active to Cope with Fear: A Cortico-Intrathalamic Pathway for Conditioned Flight Behavior

When facing fear-provoking situations,animals and humans alternate between active and passive coping responses[1].Active coping such as flight or escape is thought to occur when animals perceive the situation to be controllable.In contrast,passive coping such as immobility or freezing is evoked if the situation is perceived to be inescapable.

All-trans retinoic acid reverses malignant biological behavior of hepatocarcinoma cells by regulating miR-200 family members

As a potential chemo-therapeutic agent,all-trans retinoic acid(ATRA)can signif-icantly reverse epithelial-mesenchymal transition(EMT)of hepal-6 hepatocarcinoma cell line in vitro,but the mechanism is unclear.The expression profile of microRNA-200(miR-200)families is different in hepatocellular carcinoma.In this study,we found that ATRA trea tment could up-regulate the expression of miR-200a-3p,200c-3p,and 141-3p,which were involved in ATRA regulated proliferation and apoptosis of hepal-6 cell,but not colony formation.Meanwhile,miR-200a-3p,200c-3p,and 141-3p could recovery ATRA inhibited migration and invasion abilities of hepal-6 cells at various levels.miR-200a-3p and 200c-3p prevented ATRA from inducing the differentia tion and hepatic functions of hepal-6 cells.An-tagomir specific for miR-200a-3p and 200c-3p down-regulated the expression of CK18,but only miR-200a-3p anta gomir played prominent role in regula ting the expression of these mesenchymal markers,N-Cadherin,Snail and Twist.The transcriptional activities of 8 tran-scription factors were up-regulated and 35 transcription factors were down-regulated by ATRA.Compared with ATRA group,inhibition of miR-200a-3p,200c-3p,and 141-3p significantly strengthened the expression of Fra1/Jun(AP1),Ets1/PEA3,Brn3,and Zeb1/AREB6 at varying degrees.Therefore,this result suggested that ATRA may suppress EMT through down-regulating miR-200a-3p,200c-3p and 141-3p related transcription factors.miR-200 and their downstream genes might be the potentially specific targets for the treat-ment of hepatocarcinoma.

Histone Deacetylase Inhibitors Romidepsin and Vorinostat Promote Hepatitis B Virus Replication by Inducing Cell Cycle Arrest

Background and Aims:Chronic hepatitis B virus(HBV)infection is a global public health challenge.HBV reactivation usually occurs in cancer patients after receiving cytotoxic chemotherapy or immunosuppressive therapies.Romidepsin(FK228)and vorinostat(SAHA)are histone deacetylase inhibitors(HDACi)approved by the Food and Drug Administration as novel antitumor agents.The aim of this study was to explore the effects and mechanisms of HDACi treatment on HBV replication.Methods:To assess these effects,human hepatoma cell lines were cultured and cell viability after FK228 or SAHA treatment was measured by the CCK-8 cell counting kit-8 assay.Then,HBV DNA and RNA were quantified by real-time PCR and Southern blotting.Furthermore,analysis by western blotting,enzyme-linked immunosorbent assay(ELISA),immunohistochemistry,and flow cytometry was performed.Results:FK228/SAHA treatment significantly promoted HBV replication and biosynthesis in both HBV-replicating cells and HBV-transgenic mouse model.Flow cytometry assay indicated that FK228/SAHA enhanced HBV replication by inducing cell cycle arrest through modulating the expression of cell cycle regulatory proteins.In addition,simultaneous inhibition of HDAC1/2 by FK228 promoted HBV replication more effectively than the broad spectrum HDAC inhibitor SAHA.Conclusions:Overall,our results demonstrate that cell cycle blockage plays an important role in FK228/SAHAenhanced HBV replication,thus providing a potential avenue for rational use of HDACi in patients with chronic hepatitis B.