Exendin-4 and linagliptin attenuate neuroinflammation in a mouse model of Parkinson's disease

Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson's disease in patients with diabetes mellitus.Therefore,using these two treatments may help treat Parkinson's disease.To further investigate the mechanisms of action of these two compounds,we established a model of Parkinson's disease by treating mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then subcutaneously injected them with the glucagon-like peptide-1 receptor agonist exendin-4 or the dipeptidyl peptidase 4 inhibitor linagliptin.We found that both exendin-4 and linagliptin reversed motor dysfunction,glial activation,and dopaminergic neuronal death in this model.In addition,both exendin-4 and linagliptin induced microglial polarization to the anti-inflammatory M2 phenotype and reduced pro-inflammatory cytokine secretion.Moreover,in vitro experiments showed that treatment with exendin-4 and linagliptin inhibited activation of the nucleotide-binding oligomerization domain-and leucine-rich-repeat-and pyrin-domaincontaining 3/caspase-1/interleukin-1βpathway and subsequent pyroptosis by decreasing the production of reactive oxygen species.These findings suggest that exendin-4 and linagliptin exert neuroprotective effects by attenuating neuroinflammation through regulation of microglial polarization and the nucleotidebinding oligomerization domain-and leucine-rich-repeat-and pyrin-domain-containing 3/caspase-1/interleukin-1βpathway in a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Therefore,these two drugs may serve as novel anti-inflammatory treatments for Parkinson's disease.

Huangqin flavonoid extraction for spinal cord injury in a rat model

Flavonoids from Huangqin（dried roots of Scutellaria baicalensis Georgi） have anti-inflammatory effects, and are considered useful for treatment of spinal cord injury. To verify this hypothesis, the T9-10 spinal cord segments of rats were damaged using Allen＇s method to establish a rat spinal cord injury model. Before model establishment, Huangqin flavonoid extraction（12.5 g/kg） was administered intragastrically for 1 week until 28 days after model establishment. Methylprednisolone（30 mg/kg） was injected into the tail vein at 30 minutes after model establishment as a positive control. Basso, Beattie, and Bresnahan locomotor scale scores were used to assess hind limb motor function. Hematoxylin-eosin staining was used to detect pathological changes in the injured spinal cord. Immunofluorescence and western blot assays were performed to measure immunoreactivity and expression levels of brain-derived neurotrophic factor, neuronal marker neurofilament protein, microglial marker CD11 b and astrocyte marker glial fibrillary acidic protein in the injured spinal cord. Huangqin flavonoid extraction markedly reduced spinal cord hematoma, inflammatory cell infiltration and cavities and scars, and increased the Basso, Beattie, and Bresnahan locomotor scale scores; these effects were identical to those of methylprednisolone. Huangqin flavonoid extraction also increased immunoreactivity and expression levels of brain-derived neurotrophic factor and neurofilament protein, and reduced immunoreactivity and expression levels of CD11 b and glial fibrillary acidic protein, in the injured spinal cord. Overall, these data suggest that Huangqin flavonoid extraction can promote recovery of spinal cord injury by inducing brain-derived neurotrophic factor and neurofilament protein expression, reducing microglia activation and regulating reactive astrocytes.

Long-term protection against dengue viruses in mice conferred by a tetravalent DNA vaccine candidate

DEAR EDITOR,The development of an effective tetravalent vaccine against dengue viruses(DENVs)has become a world priority.We previously showed that four monovalent dengue DNA vaccines expressing premembrane(prM)and envelope(E)proteins displayed effective protection against corresponding challenges in mice.Thus,to elucidate the overall immunity and persistence of the tetravalent formulation(TetraME),we evaluated the humoral and cellular immune responses as well as the long-term protection in the current study.TetraME-immunized mice displayed increased production of Th1/Th2-typed cytokines upon stimulation with heterologous DENV antigens.Moreover,high levels of tetravalent DENV antibodies and sterilized immunity were detected long-term(30 weeks after immunization).These findings provide feasible validation for the potential utility of this vaccine formulation.

Electrochemical study and application on rutin at chitosan/graphene films modified glassy carbon electrode

Graphene（G） was dispersed into 0.5% chitosan（Chit） solution,then the composite films were coated on glassy carbon electrode（GCE）,the electrochemical behavior of rutin on a Chit/G modified GCE was investigated and the electrochemical parameters of rutin were calculated.Rutin effectively accumulated on the Chit/G/GCE and caused a pair of redox peaks at around 408 mV and 482 mV（vs.SCE） in 0.1M phosphate buffer solution（pH 4.0）.Under optimized conditions,the anodic peak current was linear to the rutin concentration in the range of 5×107-1.04×105M.The regression equation was：y 9.9219x-0.0025,r=0.9958.The proposed method was successfully used for the determination of rutin content in tablet samples with satisfactory results.

Nonlocal nonreciprocal optomechanical circulator

A nonlocal circulator protocol is proposed in a hybrid optomechanical system.By analogy with quantum communication,using the input-output relationship,we establish the quantum channel between two optical modes with long-range.The three-body nonlocal interaction between the cavity and the two oscillators is obtained by eliminating the optomechanical cavity mode and verifying the Bell-CHSH inequality of continuous variables.By introducing the phase accumulation between cyclic interactions,the unidirectional transmission of quantum state between the optical mode and two mechanical modes is achieved.The results show that nonreciprocal transmissions are achieved as long as the accumulated phase reaches a certain value.In addition,the effective interaction parameters in our system are amplified,which reduces the difficulty of the implementation of our protocol.Our research can provide potential applications for nonlocal manipulation and transmission control of quantum platforms.

Study on the uterine artery and fetal umbilical artery hemodynamics in patients with HDP

Objective:To explore the uterine artery and fetal umbilical artery hemodynamic change in patients with HDP.Methods:A total of 80 patients with HDP who came to our hospital from July, 2015 to July, 2016 for pregnancy examination were included in the study and served as the observation group, while 80 healthy pregnant women who came for pregnancy examination in the same period were served as the control group. The pregnant women in the two groups were performed with sequential color Doppler ultrasound at gestation 30-40 weeks. The two-dimensional ultrasound apparatus was used to detect the uterine artery and umbilical artery. PI, RI, and S/D were recorded. The fetal BPD, head girth, femur length, and abdominal girth were measured. ELISA was used to detect 8-iso-PGF2α. The immunoturbidimetry was used to detect Cys-C and CRP.Results:The uterine artery PI, RI, and S/D in the observation group were significantly higher than those in the control group. The umbilical artery PI, RI, and S/D in the observation group were significantly higher than those in the control group. The fetal BPD, head girth, femur length, and abdominal girth in the observation group were significantly less than those in the control group. 8-iso-PGF2α, Cys C, and CRP levels in the observation group were significantly higher than those in the control group.Conclusions:The uterine artery and umbilical artery blood flow resistance in patients with HDP are significantly elevated, which can severely affect the placental blood perfusion and fetal growth and development, while the color Doppler ultrasound can provide a non-invasive diagnosis for fetal distress in uterus.

Development of the Life Gatekeeper suicide prevention training programme in China:a Delphi study

Background Youth suicide has been a pressing public mental health concern in China,yet there is a lack of gatekeeper intervention programmes developed locally to prevent suicide among Chinese adolescents.Aims The current Delphi study was the first step in the systematic development of the Life Gatekeeper programme,the first gatekeeper programme to be developed locally in China that aims to equip teachers and parents with the knowledge,skills and ability to identify and intervene with students at high risk of suicide.Methods The Delphi method was used to elicit a consensus of experts who were invited to evaluate the importance of training content,the feasibility of the training delivery method,the possibility of achieving the training goals and,finally,the appropriateness of the training materials.Two Delphi rounds were conducted among local experts with diversified professional backgrounds in suicide research and practice.Statements were accepted for inclusion in the adjusted training programme if they were endorsed by at least 80%of the panel.Results Consensus was achieved on 201 out of 207 statements for inclusion into the adapted guidelines for the gatekeeper programme,with 151 from the original questionnaire and 50 generated from comments of the panel members.These endorsed statements were synthesised to develop the content of the Life Gatekeeper training programme.Conclusions This Delphi study provided an evidence base for developing the first gatekeeper training programme systematically and locally in China.We hope that the current study can pave the way for more evidence-based suicide prevention programmes in China.Further study is warranted to evaluate the effectiveness of the Life Gatekeeper training programme.

Single-arm trials for domestic oncology drug approvals in China

The urgent need for effective cancer treatments,particularly for advanced and relapsed cases in which standard therapies are inadequate,has spurred the development of innovative therapeutic drugs1,2.Among the strategies to expedite drug development,the use of single-arm trials(SATs)is emerging as a promising avenue with substantial potential to shorten drug approval timelines and accelerate market entry.

Single-cell RNA sequencing to understand host-virus interactions

Single-cell RNA sequencing(scRNA-seq)has allowed for the profiling of host and virus transcripts and host-virus interactions at single-cell resolution.This review summarizes the existing scRNA-seq technologies together with their strengths and weaknesses.The applications of scRNA-seq in various virological studies are discussed in depth,which broaden the understanding of the immune atlas,host-virus interactions,and immune repertoire.scRNA-seq can be widely used for virology in the near future to better understand the pathogenic mechanisms and discover more effective therapeutic strategies.

地铁区间隧道竖井送风有效风量研究

为得到地铁区间隧道竖井送风有效风量的无量纲计算模型,通过推导地铁区间隧道竖井送风有效风量的无量纲公式,并采用数值模拟方法明确竖井送风有效风量与火源功率、火源距离、阻塞比和竖井送风量之间的量化关系。结果表明:火源功率、火源距离与竖井送风有效风量之间不存在函数关系;阻塞比对竖井送风有效风量影响显著,随着阻塞比的增大,有效风量逐渐减小,单侧列车停靠时,无量纲有效风量Qe*与阻塞比β呈-1.08次方减小关系,两侧列车停靠时,无量纲有效风量Qe*与阻塞比β呈-0.22次方减小关系;有效风量随竖井送风风量的增大逐渐增大,且有效风量增大比例高于送风风量,单侧列车停靠时,无量纲有效风量与无量纲送风风量呈1.11次方增大关系,两侧列车停靠时,无量纲有效风量与无量纲送风风量呈1.07次方增大关系。

大鼠眼内组织对内毒素特异敏感的原因

内毒素诱导的葡萄膜炎(endotoxin-induced uveitis,EIU)是革兰氏阴性菌感染相关的人类内源性葡萄膜炎的常用模型。然而在全身注射内毒素诱导的大鼠EIU中,尽管眼内组织表现出明显炎症,但在其它器官组织观察不到明显的病理组织学变化。大鼠眼内组织选择性被内毒素感染的现象提示,其眼内组织对内毒素可能具有某种未知的特殊敏感性。本文就大鼠眼内组织对内毒素特异敏感的可能原因进行综述分析,以期能为临床治疗葡萄膜炎提供新思路。

Recent progress in dengue vaccine development

Dengue virus(DENV) has four distinct serotypes. DENV infection can result in classic dengue fever and life-threatening dengue hemorrhagic fever/dengue shock syndrome. In recent decades, DENV infection has become an important public health concern in epidemic-prone areas. Vaccination is the most effective measure to prevent and control viral infections. However, several challenges impede the development of effective DENV vaccines, such as the lack of suitable animal models and the antibody-dependent enhancement phenomenon. Although no licensed DENV vaccine is available, significant progress has been made. This review summarizes candidate DENV vaccines from recent investigations.

光化学法建立视网膜分支静脉阻塞大鼠模型及相关研究

目的:观察光化学法构建视网膜分支静脉阻塞(branch retinal vein occlusion,BRVO)大鼠模型的自然病程和不良事件。方法:选取30只SD(Sprague Dawley)大鼠尾静脉注射孟加拉红1min后,532nm激光(80mW,100μm,100ms)于视盘颞侧视网膜静脉二级分叉处进行单光点光凝50点建立BRVO模型。分别于1、3、5、7、10、14和21d检测全视野视网膜电图(electroretinogram,ERG)、荧光素眼底血管造影(fundus fluorescein angiography,FFA)和相干光断层扫描(optical coherence tomography,OCT)。于1、5和21d各时间点随机处死2只大鼠行HE病理和血管内皮生长因子-α(vascular endothelial growth factor-α,VEGF-α)免疫组化染色。结果:光凝后,3只大鼠死亡,3只严重出血导致视网膜大部分脱离,1只出现视网膜凹陷,1只白内障。FFA和眼底(荧光)彩照发现BRVO大鼠模型造模成功率为73%(22/30),1d时近端变粗,远端变细,3～7d光凝血管完全再通。ERG示光凝1d后暗适应3.0反应b波降低至正常眼的0.694±0.042倍,5～7d下降至最低点约为正常眼0.487±0.064倍,之后开始上升,21d上升至初始值0.708±0.0465倍。OCT和HE病理切片分别于在体和离体水平发现第1d视网膜节细胞层和外核层水肿,3～5d水肿消失且激光光凝点视网膜附近250μm外核层开始凋亡变薄,到21d外核层变薄只剩3～4层细胞。免疫组化发现激光光凝部位VEGF-α第1d表达水平大于光凝前,第5d光凝处VEGF-α表达量无明显差异,21d光凝处VEGF-α表达略低于光凝前。结论:激光光凝制作BRVO模型是一种切实可行的方法,其疾病的演变和发展可以部分模拟人体BRVO的进程。同时由于造模成功率较低以及激光光凝相关并发症较多,在实际使用中有待进一步改进方法。

Seroepidemiologic study on convalescent sera from dengue fever patients in Jinghong,Yunnan

After dengue virus(DENV)infection,antibody-dependent enhancement(ADE)is easy to occur when the neutralizing antibody(NAb)gradually decreases to a sub-neutralizing concentration.In this cohort surveillance,we utilized sera samples collected from dengue fever patients at different convalescent phases in Jinghong City,to investigate the dynamic change rule of DENV-specific antibodies,and to analyze the risk of ADE caused by secondary infection with heterologous serotypes DENVs.For baseline serosurvey,191 four-year and 99 six-year sera samples during convalescence were collected in 2017 and 2019,respectively.The positive rate of DENVspecific immunoglobulin G was 98.4%in 2017,which significantly decreased to 82.8%in 2019.The geometric mean titer(GMT)of NAb decreased from 1:155.35 to 1:46.66.Among 290 overall samples,73 paired consecutive samples were used for follow-up serosurvey.In four-year sera,the GMTs of NAb against DENV-3 and cross-reactive antibodies against DENV-1,DENV-2 and DENV-4 were 1:167.70,1:13.80,1:18.54 and 1:45.26,respectively,which decreased to 1:53.18,1:10.30,1:14.60 and 1:8.17 in six-year sera.In age-stratified analysis,due to the increasing number of ADE positive samples from 2017 to 2019 in 31–40 and 51–60 years groups,the risk of ADE in DENV-4 infection was positively associated with the extension of convalescent phase,and the odd ratio was higher than other groups.With the recovery period lengthened,the risk of secondary infection with DENV-1 and DENV-2 was reduced.Our results offer essential experimental data for risk prediction of severe dengue in hyper-endemic dengue areas,and provide crucial scientific insight for the development of effective dengue vaccines.

Mice 3D testicular organoid system as a novel tool to study Zika virus pathogenesis

Zika virus(ZIKV)poses a serious threat to global public health due to its close relationship with neurological and male reproductive damage.However,deficiency of human testicular samples hinders the in-depth research on ZIKV-induced male reproductive system injury.Organoids are relatively simple in vitro models,which could mimic the pathological changes of corresponding organs.In this study,we constructed a 3D testicular organoid model using primary testicular cells from adult BALB/c mice.Similar to the testis,this organoid system has a blood-testis barrier(BTB)-like structure and could synthesize testosterone.ZIKV tropism of testicular cells and ZIKV-induced pathological changes in testicular organoid was also similar to that in mammalian testis.Therefore,our results provide a simple and reproducible in vitro testicular model for the investigations of ZIKV-induced testicular injury.

1972年马思聪在台湾的音乐活动安婧

马思聪晚期曾7次赴台湾进行音乐活动,文章以《中央日报》《联合报》《中国时报》三大报刊中的报纸信息为基础,并结合当时台湾的社会背景、台湾音乐的发展状况,以及1968年前马思聪在中国大陆的演出活动,以期较为清晰地呈现1972年马思聪在台湾的各项音乐活动状况。

Atmospheric gaseous aromatic hydrocarbons in eastern China based on mobile measurements:Spatial distribution,secondary formation potential and source apportionment

Monocyclic aromatic hydrocarbons(MAHs)and polycyclic aromatic hydrocarbons(PAHs)are both well known as hazardous air pollutants and also important anthropogenic precursors of tropospheric ozone(O3)and secondary organic aerosols(SOA).In recent years,there have been intensive studies covering MAHs emission from various sources and their behavior under stimulated photochemical conditions.Yet in-situ measurements of PAHs presence and variations in ambient air are sparse.Herein we conducted large geometrical scale mobile measurements for 16 aromatic hydrocarbons(AHs,including 7 MAHs and 9 PAHs)in eastern China between October 27 and November 8,2019.This unique dataset has allowed for some insights in terms of AHs concentration variations,accompanying chemical composition,source contributions and spatial distributions in eastern China.In general,AHs showed a clear concentration variability between the south and the north of the Yangtze River Delta(YRD).The concentrations of PAHs were approximately 9%of AHs,but contributed 23%of SOA formation potential.Source apportionment via positive matrix factorization(PMF)model revealed that industrial processes as the largest source(44%)of observed AHs,followed by solvent usage(21%),vehicle exhaust(19%),coal combustion(11%)and coking processes(6%).In the perspective of PAHs sources,coal combustion emissions were identified as the dominating factor of a share of 41%–52%in eastern China.Our findings complemented the simultaneously monitoring information of PAHs and MAHs in eastern China,revealed the importance of PAHs to SOA formation and highlighted the necessity of formulating strategies to reduce emissions from anthropogenic sources and reduce risks to human health.

Mice with type I interferon signaling deficiency are prone to epilepsy upon HSV-1 infection

Viral encephalitis continues to be a significant public health concern.In our previous study,we discovered a lower expression of antiviral factors,such as IFN-β,STING and IFI16,in the brain tissues of patients with Rasmussen's encephalitis(RE),a rare chronic neurological disorder often occurred in children,characterized by unihemispheric brain atrophy.Furthermore,a higher cumulative viral score of human herpes viruses(HHVs)was also found to have a significant positive correlation with the unihemispheric atrophy in RE.Type I IFNs(IFN-I)signaling is essential for innate anti-infection response by binding to IFN-α/βreceptor(IFNAR).In this study,we infected WT mice and IFNAR-deficient A6 mice with herpes simplex virus 1(HSV-1)via periocular injection to investigate the relationship between IFN-I signaling and HHVs-induced brain lesions.While all mice exhibited typical viral encephalitis lesions in their brains,HSV-induced epilepsy was only observed in A6 mice.The gene expression matrix,functional enrichment analysis and protein-protein interaction network revealed four gene models that were positively related with HSV-induced epilepsy.Additionally,ten key genes with the highest scores were identified.Taken together,these findings indicate that intact IFN-I signaling can effectively limit HHVs induced neural symptoms and brain lesions,thereby confirming the positive correlation between IFN-I signaling repression and brain atrophy in RE and other HHVs encephalitis.

Expression of human cytomegalovirus components in the brain tissues of patients with Rasmussen＇s encephalitis

Rasmussen's encephalitis(RE) is a rare and severe progressive epileptic syndrome with unknown etiology. Infection by viruses, including human cytomegalovirus(HCMV), has been speculated to be a potential trigger for RE. However, no viral antigens have been detected in the brains of patients with RE; thus, a possible clinical linkage between viral infections and RE has not been firmly established. In this study, we evaluated the expression of HCMV pp65 antigen in brain sections from 26 patients with RE and 20 non-RE patients by immunohistochemistry and in situ hybridization, and assessed the associations between HCMV infection and clinical parameters.Elevated expression of HCMV pp65 protein and DNA was observed in 88.5%(23/26) and 69.2%(18/26) of RE cases, respectively. In the non-RE group, HCMV pp65 antigen was detected only in two cases(10%), both of which were negative for DNA staining. Additionally, the intensity of HCMV pp65 staining was correlated with a shorter duration of the prodromal stage, younger age of seizure onset, and more severe unilateral cortical atrophy. Elevated expression of HCMV pp65 was observed in RE brain tissue and was correlated with the clinical features of RE disease. In summary, our results suggested that HCMV infection may be involved in the occurrence and progression of RE disease. Thus, further studies are needed to determine whether early treatment with anti-HCMV antibodies could modulate the course of RE.

Zika virus and Zika fever

An emerging mosquito-borne arbovirus named Zika virus(ZIKV), of the family Flaviviridae and genus Flavivirus, is becoming a global health threat. ZIKV infection was long neglected due to its sporadic nature and mild symptoms. However, recently, with its rapid spread from Asia to the Americas, affecting more than 30 countries, accumulating evidences have demonstrated a close association between infant microcephaly and Zika infection in pregnant women. Here, we reviewed the virological, epidemiological, and clinical essentials of ZIKV infection.