Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases

The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway,comprised of cyclic GMP-AMP synthase(cGAS),stimulator of interferon genes(STING), and downstream signaling adaptors, plays an essential role in protective immune defense against microbial DNA and internal damaged-associated DNA and is responsible for various immune-related diseases.After binding with DNA, cytosolic cGAS undergoes conformational change and DNA-linked liquid-liquid phase separation to produce 2’3’-c GAMP for the activation of endoplasmic reticulum(ER)-localized STING. However, further studies revealed that cGAS is predominantly expressed in the nucleus and strictly tethered to chromatin to prevent binding with nuclear DNA, and functions differently from cytosoliclocalized cGAS. Detailed delineation of this pathway,including its structure, signaling, and regulatory mechanisms, is of great significance to fully understand the diversity of cGAS-STING activation and signaling and will be of benefit for the treatment of inflammatory diseases and cancer. Here, we review recent progress on the above-mentioned perspectives of the cGAS-STING signaling pathway and discuss new avenues for further study.

高危型人乳头瘤病毒检测联合新柏液基细胞学筛查在宫颈癌前病变及宫颈癌早期诊断中的应用

目的:探讨高危型人乳头瘤病毒(HPV)检测联合新柏液基细胞学筛查(TCT)在宫颈癌前病变及宫颈早期诊断中的临床应用.方法:选取2019年1月至2022年12月本院收治的84例可疑宫颈癌患者为研究对象.对比高危型HPV检测联合TCT诊断宫颈癌病变阳性率,灵敏性、特异性、准确性,以宫颈癌及其癌前病变的组织病理学检查结果为金标准.结果:高危型HPV检查联合TCT检测不典型鳞状细胞病变(ASC)、低度鳞状上皮内病变(LSIL)、高度鳞状上皮细胞病变(HSIL)的阳性率,显著高于采取单一高危型HPV检测和TCT的检测阳性率.组织病理学检查证实宫颈癌前病变及宫颈癌为23例,高危型HPV检测阳性为15例,TCT阳性为15例,高危型HPV联合TCT为20例.高危型HPV联合TCT检测宫颈癌前病变的灵敏性为86.96%,特异性为91.80%,准确性为90.48%,均显著高于单一检测的灵敏性、特异性及准确性(P<0.05).结论:高危型HPV检测联合TCT在宫颈癌前病变及宫颈癌早期诊断中灵敏性以及准确性较高,能够提供有利依据,可广泛运用于临床.

Involvement of ayu NOD2 in NF-κB and MAPK signaling pathways: Insights into functional conservation of NOD2 in antibacterial innate immunity

Nucleotide oligomerization domain 2(NOD2) is a major cytoplasmic sensor for pathogens and is critical for the clearance of cytosolic bacteria in mammals.However, studies regarding NOD2, especially the initiated signaling pathways, are scarce in teleost species. In this study, we identified a NOD2 molecule(PaNOD2) from ayu(Plecoglossus altivelis).Bioinformatics analysis showed the structure of NOD2 to be highly conserved during vertebrate evolution. Dual-luciferase reporter assays examined the activation of NF-κB signaling and Western blotting analysis detected the phosphorylation of three MAP kinases(p-38, Erk1/2, and JNK1/2).Functional study revealed that, like its mammalian counterparts, PaNOD2 was the receptor of the bacterial cell wall component muramyl dipeptide(MDP), and the leucine-rich repeat motif was responsible for the recognition and binding of Pa NOD2 with the ligand. Overexpression of PaNOD2 activated the NF-κB signaling pathway, leading to the upregulation of inflammatory cytokines, including TNF-α and IL-1β in HEK293 T cells and ayu head kidney-derived monocytes/macrophages(MO/MΦ).Particularly, we found that PaNOD2 activated the MAPK signaling pathways, as indicated by the increased phosphorylation of p-38, Erk1/2, and JNK1/2, which have not been characterized in any teleost species previously. Our findings proved that the NOD2 molecule and initiated pathways are conserved between mammals and ayu. Therefore, ayu could be used as an animal model to investigate NOD2-based diseases and therapeutic applications.

Prior exposure to ciprofloxacin disrupts intestinal homeostasis and predisposes ayu(Plecoglossus altivelis)to subsequent Pseudomonas plecoglossicida-induced infection

With the rapid development of intensive farming,the aquaculture industry uses a great many antibiotics for the prevention and treatment of bacterial diseases.Despite their therapeutic functions,the overuse and accumulation of antibiotics also pose a threat to aquaculture organisms.In the present study,ayu(Plecoglossus altivelis)was used as a fish model to study the impacts of ciprofloxacin(CIP)overuse on intestinal homeostasis and immune response during subsequent Pseudomonas plecoglossicida infection.Based on 16S rRNA gene amplification and Illumina sequencing,we found that CIP pre-exposure caused significant variation in intestinal microbiota,including increased species richness,altered microbiota composition and interaction networks,and increased metabolic dysfunction.Furthermore,immunohistochemical analysis indicated that CIP pre-exposure resulted in severe mucosal layer damage,goblet cell reduction,and epithelial cell necrosis of the intestinal barrier in infected ayu.Quantitative real-time polymerase chain reaction(qRT-PCR)showed that disruption of intestinal homeostasis impaired systemic antiinfection immune responses in the intestine,gill,spleen,and head kidney,while inhibiting IL-1β,TNF-α,and IL-10 expression and promoting TGF-βexpression.Our findings indicated that CIP administration can directly affect intestinal microbiota composition and intestinal integrity in ayu fish.This perturbation of intestinal homeostasis is likely responsible for the lower survival rate of hosts following subsequent infection as the capacity to mount an effective immune response is compromised.This study also provides preliminary clues for understanding the effects of antibiotic overuse on higher vertebrates through trophic transfer.

Hyperosmolarity disrupts tight junction via TNF-α/MMP pathway in primary human corneal epithelial cells

AIM:To investigate the mechanism of the tight junction(TJ) disruption and the association between tumor necrosis factor(TNF)-α and matrix metalloproteinase(MMPs) under hyperosmotic condition in primary human corneal epithelial cells(HCECs).METHODS:The cultured HCECs were exposed to media which adding sodium chloride(Na Cl) for hyperosmolar stress or adding rh-TNF-α(10 ng/m L). NF-κB inhibitor(5 μmol/L) or GM-6001(potent and broad spectrum MMP inhibitor, 20 μmol/L)was added 1 h before that treatment. The integrity of TJ proteins was determined by immunofluorescent(IF) staining. The m RNA levels of TNF-α and MMPs were evaluated by quantitative reverse transcription polymerase chain reaction(RT-q PCR) and the protein expression by enzyme-linked immunosorbent assay(ELISA).RESULTS:TJ proteins ZO-1 and Occludin were disrupted in primary HCECs exposed to hyperosmotic medium. The m RNA expression and protein production of TNF-α increased significantly in hyperosmotic media at 500 m Os M. TNF-α mediated the expression and production of MMP-1, MMP-13, MMP-9, and MMP-3 stimulated by hyperosmotic stress. The production of MMPs in hyperosmolar media were increased through the increase of TNF-α. GM-6001 prevent the destruction of ZO-1 and Occludin in hyperosmolar stress and rh-TNF-α treated medium. TNF-α induced activation of MMPs was involved in the TJ disruption by hyperosmolarity.CONCLUSION:TJ proteins ZO-1 and Occludin are disrupted by hyperosmolar stress and TNF-α, but protected by MMP inhibitor(GM-6001). It suggests that TNF-α/MMP pathway mediates the TJ disruption in primary HCECs exposed to hyperosmotic stress.

喹啉类化合物的合成及其结构对阴离子比色传感性能影响研究——介绍一个研究型综合实验项目

介绍了一个研究型综合实验项目——喹啉类化合物的合成及其结构对阴离子比色传感性能影响研究。在本实验中,学生将学习并掌握喹啉类杂环化合物及其衍生物的合成方法以及表征手段。学生在理解有机小分子传感识别原理的基础上,学会利用紫外-可见吸收光谱仪研究喹啉类化合物作为探针(P1、P2、P3)对阴离子传感识别性能。通过Origin软件处理的光谱数据以及可视化的比色图像,让学生更加直观地比较不同探针的阴离子传感识别性能,深入理解探针的分子结构影响和控制其传感性能的重要性。

Investigation and Analysis of Rural Medical Waste Management

Objective: The aim is to understand the status of rural medical waste management and problems and to make recommendations. Methods: The questionnaire survey, interviews and comparative analysis are used. Results: Compared with urban medical waste management, rural medical waste management is weaker in classification, unified recycle, disposals, protect measures of related personnel, regulations and policies of awareness. Conclusion: It is recommended to improve policies and regulations of rural medical waste management, strengthen rural infrastructures and facilities, improve supervision and innovates means of supervision.

Current understanding on the roles of gut microbiota in fish disease and immunity

Intensive aquaculture has increased the severity and frequency of fish diseases.Given the functional importance of gut microbiota in various facets of host physiology,modulation of this microbiota is a feasible strategy to mitigate emerging diseases in aquaculture.To achieve this,a fundamental understanding of the interplay among fish health,microbiota, and invading pathogens is required.This commentary focuses on current knowledge regarding the associations between fish diseases,dysbiosis of gut microbiota,and immune responses. Furthermore,updated research on fish disease from an ecological perspective is discussed,including colonization resistance imposed by commensals and strategies used by pathogens to overcome resistance.We also propose several directions for future research,such as exploration of the causal links between fish diseases and specific taxa,and identification of universal gut microbial biomarkers for rapid disease diagnosis.

Long Term Perinatal Deltamethrin Exposure Alters Electrophysiological Properties of Embryonic Ventricular Cardiomyocyte

Increased use of pyrethroids and the exposure to pyrethroids for pregnant women and children have raised the concerns over the potential effect of pyrethroids on developmental cardiotoxicity and other abnormalities.The purpose of this study was to investigate whether long tenn peri natal deltamethrin exposure altered embryonic cardiac electrophysiology in mice.Pregnant mice were administered with 0 or 3 mg/kg of deltamethrin by gavage daily from gestational day(gd)10.5 to gd 17.5.Whole cell patch-clamp technique was used in electrophysiological study,and real time RT-PCR was applied to analyze the molecular changes for the electrophysiological properties.Deltamethrin exposure resulted in increased mortality of pregnant mice and decreased viability of embryos.Moreover,deltamethrin slowed the maximum depolarization velocity(Vmax),prolonged the action potential duration(APD)and depolarized the maximuin diastolic potential(MDP)of embryonic cardiomyocytes.Additionally,perinatal deltamethrin exposure decreased the mRNA expression of Na^+channel regulatory subunit Navpl,inward rectifier K^+channel subunit Kir2.1,and delayed rectifier K^+channel subunit MERG while the L-type Ca^2+channel subunit,Cavl.2 expression was increased.On the contraiy,deltamethrin administration did not significantly alter the regulation ofβ-adrenergic or muscarinic receptor on embryonic cardiomyocytes.In conclusion,deltamethrin exposure at perinatal stage significantly alters mRNA expression of embryonic cardiac ion channels and therefore influences embryonic cardiac electrophysiological properties.This highlights the need to understand the persistent effects of pyrethroid exposure on cardiac function during embryonic development due to potential for cardiac arrhythmogenicity.

Accuracy of optimized Sirius ray-tracing method in intraocular lens power calculation

AIM:To evaluate the accuracy and predictability of ray tracing-assisted intraocular lens(IOL) calculation function in Sirius internal software and further improve the accuracy by optimizing the calculation of predicted lens position(PLP).METHODS:This retrospective study recruited 52 eyes of 49 patients.All of the cases with cataract had undergone phacoemulsification combined with IOL implantation.SRK-T,Haigis formula,and Sirius ray-tracing method were all used for each eye’s IOL calculation.The mean absolute value of prediction error(prediction error=predicted refraction-postoperative refraction) was defined as mean absolute prediction error(MAPE) and was determined for each method.Calculation of PLP was optimized by effective lens position(ELP).Optimized PLP was entered to Sirius internal software again to verify whether the method was improved.RESULTS:Compared with SRK-T and Haigis formulas,less accuracy was shown in Sirius ray-tracing method(P=0.001).The ELP of the IOL moved forward compared to PLP(P<0.001).The MAPE of the ELP-inputted Sirius ray-tracing method was reduced.ELP and PLP were well correlated.Taking ELP as y and PLP given by Sirius soft as x,a linear regression formula y=0.1637 x+3.1741 was concluded(R^(2)=0.1066,P=0.018).It was shown that the optimized Sirius ray-tracing method(optimized PLP entered),compared with SRK-T and Haigis formulas,worked with the same accuracy(P=0.038).CONCLUSION:The original Sirius ray tracing method is not satisfactory enough.However,in normal eyes,the optimized Sirius ray-tracing method in IOL calculation was as accurate as SRK-T and Haigis formulas.

MOSPD2 is a receptor mediating the LEAP-2 effect on monocytes/macrophages in a teleost,Boleophthalmus pectinirostris

Liver-expressed antimicrobial peptide 2(LEAP-2)is a cationic peptide that plays an important role in a host’s innate immune system.We previously demonstrated that mudskipper(Boleophthalmus pectinirostris)LEAP-2(BpLEAP-2)induces chemotaxis and activation of monocytes/macrophages(MO/MΦ).However,the molecular mechanism by which BpLEAP-2 regulates MO/MΦ remains unclear.In this study,we used yeast twohybrid cDNA library screening to identify mudskipper protein(s)that interacted with BpLEAP-2,and characterized a sequence encoding motile sperm domain-containing protein 2(BpMOSPD2).The interaction between BpLEAP-2 and BpMOSPD2 was subsequently confirmed by co-immunoprecipitation(Co-IP).Sequence analyses revealed that the predicted BpMOSPD2 contained an N-terminal extracellular portion composed of a CRAL-TRIO domain and a motile sperm domain,a C-terminal transmembrane domain,and a short cytoplasmic tail.Phylogenetic tree analysis indicated that BpMOSPD2 grouped tightly with fish MOSPD2 homologs and was most closely related to that of the Nile tilapia(Oreochromis niloticus).The recombinant BpMOSPD2 was produced by prokaryotic expression and the corresponding antibody was prepared for protein concentration determination.RNA interference was used to knockdown BpMOSPD2 expression in the mudskipper MO/MΦ,and the knockdown efficiency was confirmed by quantitative real-time polymerase chain reaction(qRT-PCR)and western blotting.Knockdown of BpMOSPD2 significantly inhibited BpLEAP-2-induced chemotaxis of mudskipper MO/MΦand BpLEAP-2-induced bacterial killing activity.Furthermore,knockdown of BpMOSPD2 inhibited the effect of BpLEAP-2 on mRNA expression levels of BpIL-10,BpTNFα,BpIL-1β,and BpTGFβ in MO/MΦ.In general,BpMOSPD2 directly interacted with BpLEAP-2,and mediated the effects of BpLEAP-2 on chemotaxis and activation of mudskipper MO/MΦ.This is the first identification of MOSPD2 as a receptor for LEAP-2.

Medical Waste Management in China: A Case Study of Xinxiang

Due to medical waste’s infection and hazard, it can cause potential environmental and public health risks, so medical waste management is of great importance especially in developing countries. The objective of the study was to analyze and assess current status of medical waste management in the light of semi-structured interview in medical institutions and the medical waste disposal centre. As a medium-sized city of China and its respective nature, Xinxiang was selected as the case study. In order to significantly improve eco-efficiency of medical waste management (MWM) and minimize the environmental risks, this paper identified key factors determining the implementation of MWM on the basis of the local realities and situations of medical waste, and then an integrated MWM system was developed. Such the regulations should be improved;MWM database platform should be strengthened;unified coordination ability of the MWM should be developed;and a suitable rural recycling network should be set up.

基于网络药理学和分子对接技术探讨沉香治疗胃溃疡的作用机制

目的 基于网络药理学方法结合动物体内实验探讨沉香治疗胃溃疡的作用机制。方法 (1)通过TCMSP数据库检索并筛选沉香的活性成分及其潜在作用靶点;通过OMIM数据库、GeneCard数据库检索胃溃疡的疾病相关靶点;通过Venny平台对沉香的活性成分作用靶点与胃溃疡的重要疾病靶点取交集,获得沉香治疗胃溃疡的关键靶点(共同靶点);采用Cytoscape 3.7.1软件构建沉香治疗胃溃疡的“药物-活性成分-关键靶点”网络,分析关键活性成分;将共同靶点导入STRING数据库,构建蛋白互作(PPI)网络,筛选核心靶点;将共同靶点导入DAVID数据库进行GO功能及KEGG通路富集分析;通过AutoDock软件对关键活性成分与核心靶点进行分子对接。(2)将SD大鼠随机分为正常组、模型组、阳性药组(奥美拉唑,0.2 g·kg^(-1))及沉香提取物低、中、高剂量组(0.1、0.3、0.9 g·kg^(-1)),每组7只;灌胃给药(10 mL·kg^(-1)),每天1次,连续7 d;末次给药1 h后,大鼠灌胃给予无水乙醇(5 mL·kg^(-1))复制急性胃黏膜损伤模型。计算大鼠溃疡指数及溃疡抑制率;采用HE染色法观察大鼠胃组织病理学变化;Western Blot法检测胃组织相关蛋白的表达;免疫组化法检测胃组织中Bcl-2、Bax、Caspase3蛋白表达。结果 (1)筛选出沉香活性成分9个,预测得到活性成分作用靶点173个,胃溃疡疾病相关靶点1 297个;得到交集靶点(共同靶点)110个,即沉香治疗胃溃疡的关键靶点。关键活性成分包括槲皮素、β谷甾醇、6,7-二甲氧基-2-(2-苯乙基)色酮、6,7-二甲氧基-2-[2-(4-甲氧基苯基)乙基]色原酮、波尔定碱等;AKT1、TP53、IL6、VEGFA、JUN、TNF、CASP3、MYC、PTGS2、MAPK1等可能是沉香治疗胃溃疡的核心靶点;GO功能富集分析得到580个生物学过程条目、51个细胞组分条目、101个分子功能条目;KEGG富集共得到110条信号通路,主要涉及癌症通路、TNF信号通路、乙型肝炎通路。6,7-二甲氧基-2-(2-苯乙基)色酮与AKT1、TP53、IL6有较强的结合性,β谷甾醇与AKT1、VEGFA有较强的结合性。(2)与模型组比较,沉香提取物各剂量组大鼠胃黏膜组织的出血点明显减少,溃疡和糜烂程度降低,溃疡指数均显著降低(P<0.01);沉香提取物低、中、高剂量组的溃疡抑制率分别为19.12%、40.43%、64.48%;沉香提取物各剂量组大鼠胃组织的p-PI3K/PI3K、p-Akt/Akt、p-IκBα/IκBα、p-P65/P65蛋白表达均显著下调(P<0.01),抗凋亡蛋白Bcl-2表达显著上调(P<0.01),Bax、Caspase3等凋亡蛋白表达显著下调(P<0.01)。结论 沉香可能通过多成分、多靶点、多通路发挥抗炎、抗凋亡作用来治疗胃溃疡。

Development of a supercritical and an ultra-supercritical circulating fluidized bed boiler

The supercritical circulating fluidized bed(CFB)boiler,which combines the advantages of CFB combustion with low cost emission control and supercritical steam cycle with high efficiency of coal energy,is believed to be the future of CFB combustion technology.It is also of greatest importance for low rank coal utilization in China.Different from the supercritical pulverized coal boiler that has been developed more than 50 years,the supercritical CFB boiler is still a new one which requires further investigation.Without any precedentor engineering reference,Chinese researchers have con ducted fundamental research,development,design of the supercritical CFB boilers independently.The design theory and key technology for supercritical CFB boiler were proposed.Key components and novel structures were invented.The first 600 MWe supercritical CFB boiler and its auxiliaries were successfully developed and demonstrated in Baima Power Plant,Shenhua Group as well as the simulator,control technology,installation technology,commissioning technology,system integration and operation technology.Compared with the 460 MWe supercritical CFB in Poland,developed in the same period and the only other supercritical one of commercial running in the word beside Baima,the 600 MWe one in Baima has a better performance.Besides,supercritical CFB boilers of 350 MWe have been developed and widely commercialized in China.In this paper,the updated progress of 660 MWe ultra-supercritical CFB boilers under development is introduced.

RIG-I： a multifunctional protein beyond a pattern recognition receptor

It was widely known that retinoic acid inducible gene I （RIG-I） functions as a cytosolic pattern recognition receptor that initiates innate antiviral immunity by detecting exogenous viral RNAs. However, recent stud- ies showed that RIG-I participates in other various cellular activities by sensing endogenous RNAs under different circumstances. For example, RIG-I facilitates the therapy resistance and expansion of breast cancer cells and promotes T cell-independent B cell activation through interferon signaling activation by recognizing non-coding RNAs and endogenous retroviruses in certain situations. While in hepatocellular carcinoma and acute myeloid leukemia, RIG-I acts as a tumor suppressor through either augmenting STAT1 activation by competitively binding STAT1 against its negative regulator SliP1 or inhibiting AKT-mTOR signaling pathway by directly interacting with Src respectively. These new findings suggest that RIG-I plays more diverse roles in various cellular life activities, such as cell proliferation and differentiation, than previously known. Taken together, the function of RIG-I exceeds far beyond that of a pattern recognition receptor.

Comparison of the anterior and posterior approach in treating four-level cervical spondylotic myelopathy

Background:The optimal surgical approach for four-level cervical spondylotic myelopathy remains controversial.The purpose of this study was to compare clinical and radiological outcomes and complications between the anterior and posterior approaches for four-level cervical spondylotic myelopathy.Methods:A total of 19 patients underwent anterior decompression and fusion and 25 patients underwent posterior laminoplasty and instrumentation in this study.Perioperative information,intraoperative blood loss,clinical and radiological outcomes,and complications were recorded.Japanese Orthopedic Association(JOA)score,36-item short form survey(SF-36)score and cervical alignment were assessed.Results:There were no significant differences in JOA scores between the anterior and posterior group preoperatively(11.6±1.6 vs.12.1±1.5),immediately postoperatively(14.4±1.1 vs.13.8±1.3),or at the last follow-up(14.6±1.0 vs.14.2±1.1)(P>0.05).The JOA scores significantly improved immediately postoperatively and at the last follow-up in both groups compared with their preoperative values.The recovery rate was significantly higher in the anterior group both immediately postoperatively and at the last follow-up.The SF-36 score was significantly higher in the anterior group at the last follow-up compared with the preoperative value(69.4 vs.61.7).Imaging revealed that there was no significant difference in the Cobb angle at C2-C7 between the two groups preoperatively(-2.0°±7.3°vs.-1.4°±7.5°).The Cobb angle significantly improved immediately postoperatively(12.3°±4.2°vs.9.2°±3.6°)and at the last follow-up(12.4°±3.5°vs.9.0°±2.6°)in both groups compared with their preoperative values(P=0.00).Three patients had temporary dysphagia in the anterior group and four patients had persistent axial symptoms in the posterior group.Conclusions:Both the anterior and posterior approaches were effective in treating four-level cervical spondylotic myelopathy in terms of neurological clinical outcomes and radiological features.However,the JOA score recovery rate and SF-36 score in the anterior group were significantly higher.Persistent axial pain could be a major concern when undertaking the posterior approach.