Complement component(3b/4b)receptor 1(CR1)expression is positively related to the abundance of phosphorylated microtubule-associated protein tau(tau),and CR1 expression is associated with susceptibility to Alzheimer’...Complement component(3b/4b)receptor 1(CR1)expression is positively related to the abundance of phosphorylated microtubule-associated protein tau(tau),and CR1 expression is associated with susceptibility to Alzheimer’s disease.However,the exact role of CR1 in tau protein-associated neurodegenerative diseases is unknown.In this study,we show that the mouse Cr1-related protein Y(Crry)gene,Crry,is localized to microglia.We also found that Crry protein expression in the hippocampus and cortex was significantly elevated in P301S mice(a mouse model widely used for investigating tau pathology)compared with that in wild-type mice.Tau protein phosphorylation(at serine 202,threonine 205,threonine 231,and serine 262)and expression of the major tau kinases glycogen synthase kinase-3 beta and cyclin-dependent-like kinase 5 were greater in P301S mice than in wild-type mice.Crry silencing by lentivirus-transfected short hairpin RNA led to greatly reduced tau phosphorylation and glycogen synthase kinase-3 beta and cyclin-dependent-like kinase 5 activity.Crry silencing reduced neuronal apoptosis and rescued cognitive impairment of P301S mice.Crry silencing also reduced the levels of the neuroinflammatory factors interleukin-1 beta,tumor necrosis factor alpha,and interleukin-6 and the complement components complement 3 and complement component 3b.Our results suggest that Crry silencing in the P301S mouse model reduces tau protein phosphorylation by reducing the levels of neuroinflammation and complement components,thereby improving cognitive function.展开更多
Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD includes soft drusen and pigmentary changes in the retinal pigment epithelium (RPE). ...Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD includes soft drusen and pigmentary changes in the retinal pigment epithelium (RPE). As people age, such soft confluent drusen can progress into two forms of advanced AMD, geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD) and result in the loss of central vision. The exact mechanism for developing early AMD and progressing to advanced stage of disease is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as the cause of AMD progression. Together, complement factor H (CFH) and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress from activities such as smoking has also demonstrated a powerful contribution to AMD progression. To extend our previous finding that genetic polymorphisms in CFH results in OxPLs and the risk-form of CFH (CFH Y402H) has reduced affinity for oxidized phospholipids, and subsequent diminished capacity which subsequently diminishes the capability to attenuate the inflammatory effects of these molecules, we compared the binding properties of CFH and CFH related protein 1 (CFHR1), which is also associated with disease risk, to OxPLs and their effects on modulating inflammation and lipids uptake. As both CFH-402H and CFHR1 are associated with increased risk to AMD, we hypothesized that like CFH-402H, CFHR1 contribution to AMD risk may also be due to its diminished affinity for OxPLs. Interestingly, we found that association of CFHR1 with OxPLs was not statistically different than CFH. However, binding of CFHR1 did not elicit the same protective benefits as CFH in that both inflammation and lipid uptake are unaffected by CFHR1 association with OxPLs. These findings demonstrate a novel and interesting complexity to the potential interplay between the complement system and oxidative stress byproducts, such as OxPLs, in the mechanistic contribution to AMD. Future work will aim to identify the molecular distinctions between CFH and CFHR1 which confer protection by the former, but not latter molecules. Understanding the molecular domains necessary for protection could provide interventional insights in the generation of novel therapeutics for AMD and other diseases associated with oxidative stress.展开更多
1.Introduction.ecently,a study published in Nature Cancer by Shao et al.1 shows that intratumoral activation of the complement system promotes antitu-mor immunity and eliminates epidermal growth factor receptor(EGFR)-...1.Introduction.ecently,a study published in Nature Cancer by Shao et al.1 shows that intratumoral activation of the complement system promotes antitu-mor immunity and eliminates epidermal growth factor receptor(EGFR)-activated lung cancer resistance to immune-checkpoint inhibitor(ICI)treatment.This study unveiled the molecular and genetic mechanism underlying the EGFR-elicited intratumoral complement inhibition and provided a novel strategy to treat lung cancer with combination of ICIs and intratumoral complement system activation.展开更多
H7N9 subtype avian influenza virus poses a great challenge for poultry industry.Newcastle disease virus(NDV)-vectored H7N9 avian influenza vaccines(NDV_(vec)H7N9)are effective in disease control because they are prote...H7N9 subtype avian influenza virus poses a great challenge for poultry industry.Newcastle disease virus(NDV)-vectored H7N9 avian influenza vaccines(NDV_(vec)H7N9)are effective in disease control because they are protective and allow mass administration.Of note,these vaccines elicit undetectable H7N9-specific hemagglutination-inhibition(HI)but high IgG antibodies in chickens.However,the molecular basis and protective mechanism underlying this particular antibody immunity remain unclear.Herein,immunization with an NDV_(vec)H7N9 induced low anti-H7N9 HI and virus neutralization titers but high levels of hemagglutinin(HA)-binding IgG antibodies in chickens.Three residues(S150,G151 and S152)in HA of H7N9 virus were identified as the dominant epitopes recognized by the NDV_(vec)H7N9 immune serum.Passively transferred NDV_(vec)H7N9 immune serum conferred complete protection against H7N9 virus infection in chickens.The NDV_(vec)H7N9 immune serum can mediate a potent lysis of HA-expressing and H7N9 virus-infected cells and significantly suppress H7N9 virus infectivity.These activities of the serum were significantly impaired after heat-inactivation or treatment with complement inhibitor,suggesting the engagement of the complement system.Moreover,mutations in the 150-SGS-152 sites in HA resulted in significant reductions in cell lysis and virus neutralization mediated by the NDV_(vec)H7N9 immune serum,indicating the requirement of antibody-antigen binding for complement activity.Therefore,antibodies induced by the NDV_(vec)H7N9 can activate antibody-dependent complement-mediated lysis of H7N9 virus-infected cells and complement-mediated neutralization of H7N9 virus.Our findings unveiled a novel role of the complement in protection conferred by the NDV_(vec)H7N9,highlighting a potential benefit of engaging the complement system in H7N9 vaccine design.展开更多
A parallel hybrid linear solver based on the Schur complement method has the potential to balance the robustness of direct solvers with the efficiency of preconditioned iterative solvers.However,when solving large-sca...A parallel hybrid linear solver based on the Schur complement method has the potential to balance the robustness of direct solvers with the efficiency of preconditioned iterative solvers.However,when solving large-scale highly-indefinite linear systems,this hybrid solver often suffers from either slow convergence or large memory requirements to solve the Schur complement systems.To overcome this challenge,we in this paper discuss techniques to preprocess the Schur complement systems in parallel. Numerical results of solving large-scale highly-indefinite linear systems from various applications demonstrate that these techniques improve the reliability and performance of the hybrid solver and enable efficient solutions of these linear systems on hundreds of processors,which was previously infeasible using existing state-of-the-art solvers.展开更多
BACKGROUND Complement-mediated thrombotic microangiopathy(TMA)is a rare endothelial injury syndrome caused by dysregulated activation of the alternative complement pathway,often linked to genetic abnormalities in comp...BACKGROUND Complement-mediated thrombotic microangiopathy(TMA)is a rare endothelial injury syndrome caused by dysregulated activation of the alternative complement pathway,often linked to genetic abnormalities in complement factor H(CFH),complement factor I,or complement factor H-related(CFHR)proteins.Both renal transplantation and pregnancy are independent triggers for recurrence.This case highlights a genetically high-risk patient who achieved a successful term pregnancy after renal transplantation without complement inhibition,emphasizing individualized risk stratification,close surveillance,and multidisciplinary management for favourable maternal and graft outcomes.CASE SUMMARY A 32-year-old woman with end-stage renal disease secondary to genetically confirmed complement-mediated TMA—homozygous CFH exon 17 deletion and CFHR3-CFHR1 duplication—was maintained on dialysis for 2.5 years before undergoing a successful live-donor kidney transplant from her mother.Post-transplant immunosuppression included tacrolimus,mycophenolate mofetil,and prednisolone,later modified to azathioprine during pregnancy planning.One-year post-transplant,she conceived spontaneously.Pregnancy was complicated by transient gestational hypertension,controlled with nifedipine,labetalol,and amlodipine.Proteinuria remained<150 mg/day;white blood cell counts 5.8-7.2×109/L without cytopenia.Serum creatinine ranged 0.9-1.1 mg/dL,and tacrolimus trough levels 5-7 ng/mL.At 36 weeks,she delivered a healthy 3 kg infant by elective caesarean section.Postpartum follow-up at three months confirmed stable maternal and graft function.CONCLUSION High-risk complement-mediated TMA patients can achieve successful pregnancy post-transplant through individualized care without mandatory complement blockade.展开更多
Sepsis is a life-threatening syndrome resulting from a dysregulated host response to infection.It is the primary cause of death in the intensive care unit,posing a substantial challenge to human health and medical res...Sepsis is a life-threatening syndrome resulting from a dysregulated host response to infection.It is the primary cause of death in the intensive care unit,posing a substantial challenge to human health and medical resource allocation.The pathogenesis and pathophysiology of sepsis are complex.During its onset,pro-inflammatory and anti-inflammatory mechanisms engage in intricate interactions,possibly leading to hyperinflammation,immuno-suppression,and long-term immune disease.Of all critical outcomes,hyperinflammation is the main cause of early death among patients with sepsis.Therefore,early suppression of hyperinflammation may improve the progno-sis of these patients.Nafamostat mesilate is a serine protease inhibitor,which can inhibit the activation of the complement system,coagulation system,and contact system.In this review,we discuss the pathophysiological changes occurring in these systems during sepsis,and describe the possible targets of the serine protease inhibitor nafamostat mesilate in the treatment of this condition.展开更多
Pancreatic cancer is ranked as the fourth leading cause of cancer-related mortality and is predicted to become the second leading cause of cancer-related death by 2030.The cause of this high mortality rate is due to p...Pancreatic cancer is ranked as the fourth leading cause of cancer-related mortality and is predicted to become the second leading cause of cancer-related death by 2030.The cause of this high mortality rate is due to pancreatic ductal adenocarcinoma’s rapid progression and metastasis,and development of drug resistance.Today,cancer immunotherapy is becoming a strong candidate to not only treat various cancers but also to combat against chemoresistance.Studies have suggested that complement system pathways play an important role in cancer progression and chemoresistance,especially in pancreatic cancer.A recent report also suggested that several signaling pathways play an important role in causing chemoresistance in pancreatic cancer,major ones including nuclear factor kappa B,signal transducer and activator of transcription 3,c-mesenchymal-epithelial transition factor,and phosphoinositide-3-kinase/protein kinase B.In addition,it has also been proven that the complement system has a very active role in establishing the tumor microenvironment,which would aid in promoting tumorigenesis,progression,metastasis,and recurrence.Interestingly,it has been shown that the downstream products of the complement system directly upregulate inflammatory mediators,which in turn activate these chemo-resistant pathways.Therefore,targeting complement pathways could be an innovative approach to combat against pancreatic cancer drugs resistance.In this review,we have discussed the role of complement system pathways in pancreatic cancer drug resistance and a special focus on the complement as a therapeutic target in pancreatic cancer.展开更多
The complement system plays an important role in mediating both acquired and innate responses to defend against microbial infection, and in disposing immunoglobins and apoptotic cells. The liver （mainly hepatocytes）...The complement system plays an important role in mediating both acquired and innate responses to defend against microbial infection, and in disposing immunoglobins and apoptotic cells. The liver （mainly hepatocytes） is responsible for biosynthesis of about 80-90% of plasma complement components and expresses a variety of complement receptors. Recent evidence from several studies suggests that the complement system is also involved in the pathogenesis of a variety of liver disorders including liver injury and repair, fibrosis, viral hepatitis, alcoholic liver disease, and liver ischemia/reperfusion injury. In this review, we will discuss the potential role of the complement system in the pathogenesis of liver diseases. Cellular ＆ Molecular Immunology.展开更多
The complement system is crucial for maintaining immunological homeostasis in the liver,playing a significant role in both innate and adaptive immune responses.Dysregulation of this system is closely linked to the pat...The complement system is crucial for maintaining immunological homeostasis in the liver,playing a significant role in both innate and adaptive immune responses.Dysregulation of this system is closely linked to the pathogenesis of various liver diseases.Modulating the complement system can affect the progression of these conditions.To provide insights into treating liver injury by targeting the regu-lation of the complement system,we conducted a comprehensive search of major biomedical databases,including MEDLINE,PubMed,EMBASE,and Web of Science,to identify articles on complement and liver injury and reviewed the functions and mechanisms of the complement system in liver injury.展开更多
The complement system plays a key role in the pathogenesis of autoimmune diseases,which usually injures the kidney.More and more studies have shown the pathogenic role and indicated that abnormal activation of the com...The complement system plays a key role in the pathogenesis of autoimmune diseases,which usually injures the kidney.More and more studies have shown the pathogenic role and indicated that abnormal activation of the complement system was highly involved in the outbreak of autoimmune diseases.This review mainly introduced recent studies of complement system activation contributing to the pathogenesis of autoimmune diseases,including systemic lupus erythematosus,antiphospholipid syndrome,antineutrophil cytoplasmic antibody-associated vasculitides,and so on.Understanding the pathogenic roles of complement activation in various autoimmune diseases will identify potential novel therapeutic targets on complement systems.展开更多
AIM: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and complement factor H (CFH) polymorphism has been found to associate with the AMD. To investigate whether the Y402...AIM: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and complement factor H (CFH) polymorphism has been found to associate with the AMD. To investigate whether the Y402H variant in CFH is associated with AMD in Chinese populations, a systematic review and meta-analysis were performed to estimate the magnitude of the gene effect and the possible mode of action. METHODS: A meta-analysis was performed using data available from ten case-control studies assessing association between the CFH Y402H polymorphism and AMD in Chinese populations involving 1538 AMD. Data extraction and study quality assessment were performed in duplicate. Summary odds ratios (ORs) and 95% confidence intervals (CIs) an allele contrast and genotype contrast were estimated usingfixed- effects models. The Q-statistic test was used to assess heterogeneity, and Funnel plot was used to evaluate publication bias. RESULTS: Seven of ten case-control studies were neovascular AMD, and few studies came from west and north of China. There was strong evidence for association between CFH and AMD in Chinese population, with those having risk allele C 2.35 times more likely to have AMD than subjects with T allele. Evidence of publication bias was not observed in our meta-analysis. CONCLUSION: This meta-analysis summarizes the strong evidence for an association between CFH and AMD in Chinese and indicates each C allele increasing the odds of AMD by 2.33-fold. But more evidences about the relation between CFH polymorphism and different type of Chinese AMD from various district were needed.展开更多
Autism spectrum disorder(ASD)is one of the common neurodevelopmental disorders in children.Its etiology and pathogenesis are poorly understood.Previous studies have suggested potential changes in the complement and co...Autism spectrum disorder(ASD)is one of the common neurodevelopmental disorders in children.Its etiology and pathogenesis are poorly understood.Previous studies have suggested potential changes in the complement and coagulation pathways in individuals with ASD.In this study,using multiple reactions monitoring proteomic technology,16 of the 33 proteins involved in this pathway were identified as differentially-expressed proteins in plasma between children with ASD and controls.Among them,CFHR3,C4BPB,C4BPA,CFH,C9,SERPIND1,C8A,F9,and F11 were found to be altered in the plasma of children with ASD for the first time.SERPIND1 expression was positively correlated with the CARS score.Using the machine learning method,we obtained a panel composed of 12 differentially-expressed proteins with diagnostic potential for ASD.We also reviewed the proteins changed in this pathway in the brain and blood of patients with ASD.The complement and coagulation pathways may be activated in the peripheral blood of children with ASD and play a key role in the pathogenesis of ASD.展开更多
This paper presents a simultaneous H2/H∞ stabilization problem for the chemical reaction systems which can be modeled as a finite collection of subsystems. A single dynamic output feedback controller which simultaneo...This paper presents a simultaneous H2/H∞ stabilization problem for the chemical reaction systems which can be modeled as a finite collection of subsystems. A single dynamic output feedback controller which simultaneously stabilizes the multiple subsystems and captures the mixed H2/H∞ control performance is designed. To ensure that the stability condition, the H2 characterization and the H∞ characterization can be enforced within a unified matrix inequality framework, a novel technique based on orthogonal complement space is developed. Within such a framework, the controller gain is parameterized by the introduction of a common free positive definite matrix, which is independent of the multiple Lyapunov matrices. An iterative linear matrix inequality （ILMI） algorithm using Matlab Yalmip toolbox is established to deal with the proposed framework. Simulation results of a typical chemical reaction system are exploited to show the validity of the proposed methodology.展开更多
Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus,leading to long-term cognitive impairment.However,the mechanism underlying this neurogenesis impairment remains unknown.In ...Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus,leading to long-term cognitive impairment.However,the mechanism underlying this neurogenesis impairment remains unknown.In this study,we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain injury.Our results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development,delayed neuronal maturation,and reduced the complexity of neuronal dendrites and spines.Mice with repetitive traumatic brain injuryalso showed deficits in spatial memory retrieval.Moreover,following repetitive traumatic brain injury,neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased,C1q binding protein levels were decreased,and canonical Wnt/β-catenin signaling was downregulated.An inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological function.These findings suggest that repetitive traumatic brain injury–induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction.展开更多
In arthropods,hematophagy has arisen several times throughout evolution.This specialized feeding behavior offered a highly nutritious diet obtained during blood feeds.On the other hand,blood-sucking arthropods must ov...In arthropods,hematophagy has arisen several times throughout evolution.This specialized feeding behavior offered a highly nutritious diet obtained during blood feeds.On the other hand,blood-sucking arthropods must overcome problems brought on by blood intake and digestion.Host blood complement acts on the bite site and is still ac-tive after ingestion,so complement activation is a potential threat to the host's skin feed-ing environment and to the arthropod gut enterocytes.During evolution,blood-sucking arthropods have selected,either in their saliva or gut,anticomplement molecules that inac-tivate host blood complement.This review presents an overview of the complement sys-tem and discusses the arthropod's salivary and gut anticomplement molecules studied to date,exploring their mechanism of action and other aspects related to the arthropod-host-pathogen interface.The possible therapeutic applications of arthropod's anticomplement molecules arealsodiscussed.展开更多
BACKGROUND Complement components could contribute to the tumor microenvironment and the systemic immune response.Nevertheless,their role in colorectal cancer(CRC)remains a contentious subject.AIM To elucidate the rela...BACKGROUND Complement components could contribute to the tumor microenvironment and the systemic immune response.Nevertheless,their role in colorectal cancer(CRC)remains a contentious subject.AIM To elucidate the relationship between complement components and CRC risk and clinical characteristics.METHODS Searches were conducted in PubMed,the Cochrane Library,and the China National Knowledge Infrastructure database until June 1,2023.We included cohort studies encompassing participants aged≥18 years,investigating the association between complement components and CRC.The studies were of moderate quality or above,as determined by the Agency for Healthcare Research and Quality.The meta-analysis employed fixed-effects or random-effects models based on the I^(2)test,utilizing risk ratio(RR)and their corresponding 95%confidence interval(CI)for outcomes.Sensitivity and subgroup analyses were performed to validate the robustness of the collective estimates and identify the source of heterogeneity.RESULTS Data from 15 studies,comprising 1631 participants that met the inclusion criteria,were included in the meta-analysis.Our findings indicated that protein levels of cluster of differentiation 46(CD46)(RR=3.66,95%CI:1.75-7.64,P<0.001),CD59(RR=2.86,95%CI:1.36-6.01,P=0.005),and component 1(C1)(RR=5.88,95%CI:1.75-19.73,P=0.004)and serum levels of C3(standardized mean difference=1.82,95%CI:0.06-3.58,P=0.040)were significantly elevated in patients with CRC compared to healthy controls.Strong expression of CD55 or CD59 was associated with a higher incidence of lymph node metastasis,whereas strong CD46 expression correlated with a higher incidence of tumor differentiation compared to low CD46 expression(P<0.05 for all).Although specific pooled results demonstrated notable heterogeneity,subgroup analyses pointed to regional differences as the primary source of inconsistency among the studies.CONCLUSION Our analysis underscores that increased levels of specific complement components are associated with a heightened risk of CRC,emphasizing the potential significance of monitoring elevated complement component levels.展开更多
In this editorial,we review the work of Razali et al published in World J Gas-troenterology,with a particular focus on the effect of rs10889677 variation in the phosphatidylinositol 3-kinase(PI3K)pathway and buparlisi...In this editorial,we review the work of Razali et al published in World J Gas-troenterology,with a particular focus on the effect of rs10889677 variation in the phosphatidylinositol 3-kinase(PI3K)pathway and buparlisib on colitis-associated cancer.The role of PI3K in promoting cancer progression has been widely recognized,as it is involved in regulating the survival,differentiation,and prolif-eration of cancer cells.The complement Clq/TNF-related protein 6(CTRP6)is a newer tumor-associated factor.Recent studies have revealed the pro-tumor effect of CTRP6 in gastric cancer,hepatocellular carcinoma,colorectal cancer,and other gastrointestinal tumors through the PI3K pathway.This article attempts to reveal the mechanism through which the CTRP6 affects the development of digestive system tumors through the PI3K pathway by summarizing recent research.展开更多
A lupus patient with a clinically quiescent disease stage will be described who had severely depressed C4 levels while levels of C3 en CH50 were normal. Additional testing revealed a homozygous C4Aisotype deficiency a...A lupus patient with a clinically quiescent disease stage will be described who had severely depressed C4 levels while levels of C3 en CH50 were normal. Additional testing revealed a homozygous C4Aisotype deficiency as the cause of the very low C4 levels. It should be emphasized that in SLE, a (very) low C4 level does not always means (subclinical) disease activity.展开更多
A new scheme termed as Complement Block Coding (CBC) technique is proposed to reduce the Peak-to-Average Power Ratio (PAPR) of OFDM signals. Utilizing the complement bits which are added to the original information bi...A new scheme termed as Complement Block Coding (CBC) technique is proposed to reduce the Peak-to-Average Power Ratio (PAPR) of OFDM signals. Utilizing the complement bits which are added to the original information bits,this method can effectively reduce the PAPR of OFDM systems with random frame size N and the coding rate R ≤ (N - k)/N, where kis a positive integer and k ≤ N/2. The performance results obtained with CBC are given and compared with that of some well known schemes, such as Simple Block Coding (SBC), Modified Simple Block Coding (MSBC) and Simple Odd Parity Code (SOPC) for the same purpose. The results show that, at the same coding rate 3/4, the CBC can achieve almost the same performance as SBC, MSBC, but with lower complexity, and that the same performance can be obtained with higher coding rate by using CBC. At the same coding rate (N - 1)/N, the PAPR reduction of CBC is almost the twice as that of SOPC when N ≥ 16. Further more, the PAPR reductions with coding rate (N - 1)/N are almost the same as that with coding rate less than (N - 1)/N,so the proposed scheme CBC is more suitable for the large frame size with high coding rate and can provide error detection.展开更多
基金supported by the National Natural Science Foundation of China(No.81801054)the Natural Science Foundation of Jiangsu Province of China(No.BK20180166)+2 种基金the Wuxi Municipal Health and Family Planning Commission Fund of China(No.Q201722)Wuxi Top Talent Support Program for Young and Middle-aged People of Wuxi Health Committee of China(No.HB2020023)China Postdoctoral Funding(all to XCZ).
文摘Complement component(3b/4b)receptor 1(CR1)expression is positively related to the abundance of phosphorylated microtubule-associated protein tau(tau),and CR1 expression is associated with susceptibility to Alzheimer’s disease.However,the exact role of CR1 in tau protein-associated neurodegenerative diseases is unknown.In this study,we show that the mouse Cr1-related protein Y(Crry)gene,Crry,is localized to microglia.We also found that Crry protein expression in the hippocampus and cortex was significantly elevated in P301S mice(a mouse model widely used for investigating tau pathology)compared with that in wild-type mice.Tau protein phosphorylation(at serine 202,threonine 205,threonine 231,and serine 262)and expression of the major tau kinases glycogen synthase kinase-3 beta and cyclin-dependent-like kinase 5 were greater in P301S mice than in wild-type mice.Crry silencing by lentivirus-transfected short hairpin RNA led to greatly reduced tau phosphorylation and glycogen synthase kinase-3 beta and cyclin-dependent-like kinase 5 activity.Crry silencing reduced neuronal apoptosis and rescued cognitive impairment of P301S mice.Crry silencing also reduced the levels of the neuroinflammatory factors interleukin-1 beta,tumor necrosis factor alpha,and interleukin-6 and the complement components complement 3 and complement component 3b.Our results suggest that Crry silencing in the P301S mouse model reduces tau protein phosphorylation by reducing the levels of neuroinflammation and complement components,thereby improving cognitive function.
文摘Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD includes soft drusen and pigmentary changes in the retinal pigment epithelium (RPE). As people age, such soft confluent drusen can progress into two forms of advanced AMD, geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD) and result in the loss of central vision. The exact mechanism for developing early AMD and progressing to advanced stage of disease is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as the cause of AMD progression. Together, complement factor H (CFH) and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress from activities such as smoking has also demonstrated a powerful contribution to AMD progression. To extend our previous finding that genetic polymorphisms in CFH results in OxPLs and the risk-form of CFH (CFH Y402H) has reduced affinity for oxidized phospholipids, and subsequent diminished capacity which subsequently diminishes the capability to attenuate the inflammatory effects of these molecules, we compared the binding properties of CFH and CFH related protein 1 (CFHR1), which is also associated with disease risk, to OxPLs and their effects on modulating inflammation and lipids uptake. As both CFH-402H and CFHR1 are associated with increased risk to AMD, we hypothesized that like CFH-402H, CFHR1 contribution to AMD risk may also be due to its diminished affinity for OxPLs. Interestingly, we found that association of CFHR1 with OxPLs was not statistically different than CFH. However, binding of CFHR1 did not elicit the same protective benefits as CFH in that both inflammation and lipid uptake are unaffected by CFHR1 association with OxPLs. These findings demonstrate a novel and interesting complexity to the potential interplay between the complement system and oxidative stress byproducts, such as OxPLs, in the mechanistic contribution to AMD. Future work will aim to identify the molecular distinctions between CFH and CFHR1 which confer protection by the former, but not latter molecules. Understanding the molecular domains necessary for protection could provide interventional insights in the generation of novel therapeutics for AMD and other diseases associated with oxidative stress.
基金supported by National Key R&D Program of China(grant numbers:2020YFA0803300,2020AAA0109500)National Natural Science Foundation of China(grant numbers:82188102,82030074,82122053,32100574)+1 种基金Zhejiang Natural Science Foundation-Key Project(grant number:LD21H160003)Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang(grant number:2019R01001).
文摘1.Introduction.ecently,a study published in Nature Cancer by Shao et al.1 shows that intratumoral activation of the complement system promotes antitu-mor immunity and eliminates epidermal growth factor receptor(EGFR)-activated lung cancer resistance to immune-checkpoint inhibitor(ICI)treatment.This study unveiled the molecular and genetic mechanism underlying the EGFR-elicited intratumoral complement inhibition and provided a novel strategy to treat lung cancer with combination of ICIs and intratumoral complement system activation.
基金supported by the earmarked fund for China Agriculture Research System(CARS-40)the Key Research and Development Project of Yangzhou(Modern Agriculture),China(YZ2022052)the‘‘High-end Talent Support Program’’of Yangzhou University,China。
文摘H7N9 subtype avian influenza virus poses a great challenge for poultry industry.Newcastle disease virus(NDV)-vectored H7N9 avian influenza vaccines(NDV_(vec)H7N9)are effective in disease control because they are protective and allow mass administration.Of note,these vaccines elicit undetectable H7N9-specific hemagglutination-inhibition(HI)but high IgG antibodies in chickens.However,the molecular basis and protective mechanism underlying this particular antibody immunity remain unclear.Herein,immunization with an NDV_(vec)H7N9 induced low anti-H7N9 HI and virus neutralization titers but high levels of hemagglutinin(HA)-binding IgG antibodies in chickens.Three residues(S150,G151 and S152)in HA of H7N9 virus were identified as the dominant epitopes recognized by the NDV_(vec)H7N9 immune serum.Passively transferred NDV_(vec)H7N9 immune serum conferred complete protection against H7N9 virus infection in chickens.The NDV_(vec)H7N9 immune serum can mediate a potent lysis of HA-expressing and H7N9 virus-infected cells and significantly suppress H7N9 virus infectivity.These activities of the serum were significantly impaired after heat-inactivation or treatment with complement inhibitor,suggesting the engagement of the complement system.Moreover,mutations in the 150-SGS-152 sites in HA resulted in significant reductions in cell lysis and virus neutralization mediated by the NDV_(vec)H7N9 immune serum,indicating the requirement of antibody-antigen binding for complement activity.Therefore,antibodies induced by the NDV_(vec)H7N9 can activate antibody-dependent complement-mediated lysis of H7N9 virus-infected cells and complement-mediated neutralization of H7N9 virus.Our findings unveiled a novel role of the complement in protection conferred by the NDV_(vec)H7N9,highlighting a potential benefit of engaging the complement system in H7N9 vaccine design.
基金supported in part by the Director,Office of Science,Office of Advanced Scientific Computing Research,of the U.S.Department of Energy under Contract No.DE-AC02-05CH11231.
文摘A parallel hybrid linear solver based on the Schur complement method has the potential to balance the robustness of direct solvers with the efficiency of preconditioned iterative solvers.However,when solving large-scale highly-indefinite linear systems,this hybrid solver often suffers from either slow convergence or large memory requirements to solve the Schur complement systems.To overcome this challenge,we in this paper discuss techniques to preprocess the Schur complement systems in parallel. Numerical results of solving large-scale highly-indefinite linear systems from various applications demonstrate that these techniques improve the reliability and performance of the hybrid solver and enable efficient solutions of these linear systems on hundreds of processors,which was previously infeasible using existing state-of-the-art solvers.
文摘BACKGROUND Complement-mediated thrombotic microangiopathy(TMA)is a rare endothelial injury syndrome caused by dysregulated activation of the alternative complement pathway,often linked to genetic abnormalities in complement factor H(CFH),complement factor I,or complement factor H-related(CFHR)proteins.Both renal transplantation and pregnancy are independent triggers for recurrence.This case highlights a genetically high-risk patient who achieved a successful term pregnancy after renal transplantation without complement inhibition,emphasizing individualized risk stratification,close surveillance,and multidisciplinary management for favourable maternal and graft outcomes.CASE SUMMARY A 32-year-old woman with end-stage renal disease secondary to genetically confirmed complement-mediated TMA—homozygous CFH exon 17 deletion and CFHR3-CFHR1 duplication—was maintained on dialysis for 2.5 years before undergoing a successful live-donor kidney transplant from her mother.Post-transplant immunosuppression included tacrolimus,mycophenolate mofetil,and prednisolone,later modified to azathioprine during pregnancy planning.One-year post-transplant,she conceived spontaneously.Pregnancy was complicated by transient gestational hypertension,controlled with nifedipine,labetalol,and amlodipine.Proteinuria remained<150 mg/day;white blood cell counts 5.8-7.2×109/L without cytopenia.Serum creatinine ranged 0.9-1.1 mg/dL,and tacrolimus trough levels 5-7 ng/mL.At 36 weeks,she delivered a healthy 3 kg infant by elective caesarean section.Postpartum follow-up at three months confirmed stable maternal and graft function.CONCLUSION High-risk complement-mediated TMA patients can achieve successful pregnancy post-transplant through individualized care without mandatory complement blockade.
基金supported by the National Natural Science Foundation of China(grant numbers 82102287)Key dis-cipline of Shanghai’s Three-year Action Plan to Strengthen the construction of public health system(2023-2025)(grant num-bers GWVI-11.1-14).
文摘Sepsis is a life-threatening syndrome resulting from a dysregulated host response to infection.It is the primary cause of death in the intensive care unit,posing a substantial challenge to human health and medical resource allocation.The pathogenesis and pathophysiology of sepsis are complex.During its onset,pro-inflammatory and anti-inflammatory mechanisms engage in intricate interactions,possibly leading to hyperinflammation,immuno-suppression,and long-term immune disease.Of all critical outcomes,hyperinflammation is the main cause of early death among patients with sepsis.Therefore,early suppression of hyperinflammation may improve the progno-sis of these patients.Nafamostat mesilate is a serine protease inhibitor,which can inhibit the activation of the complement system,coagulation system,and contact system.In this review,we discuss the pathophysiological changes occurring in these systems during sepsis,and describe the possible targets of the serine protease inhibitor nafamostat mesilate in the treatment of this condition.
文摘Pancreatic cancer is ranked as the fourth leading cause of cancer-related mortality and is predicted to become the second leading cause of cancer-related death by 2030.The cause of this high mortality rate is due to pancreatic ductal adenocarcinoma’s rapid progression and metastasis,and development of drug resistance.Today,cancer immunotherapy is becoming a strong candidate to not only treat various cancers but also to combat against chemoresistance.Studies have suggested that complement system pathways play an important role in cancer progression and chemoresistance,especially in pancreatic cancer.A recent report also suggested that several signaling pathways play an important role in causing chemoresistance in pancreatic cancer,major ones including nuclear factor kappa B,signal transducer and activator of transcription 3,c-mesenchymal-epithelial transition factor,and phosphoinositide-3-kinase/protein kinase B.In addition,it has also been proven that the complement system has a very active role in establishing the tumor microenvironment,which would aid in promoting tumorigenesis,progression,metastasis,and recurrence.Interestingly,it has been shown that the downstream products of the complement system directly upregulate inflammatory mediators,which in turn activate these chemo-resistant pathways.Therefore,targeting complement pathways could be an innovative approach to combat against pancreatic cancer drugs resistance.In this review,we have discussed the role of complement system pathways in pancreatic cancer drug resistance and a special focus on the complement as a therapeutic target in pancreatic cancer.
文摘The complement system plays an important role in mediating both acquired and innate responses to defend against microbial infection, and in disposing immunoglobins and apoptotic cells. The liver （mainly hepatocytes） is responsible for biosynthesis of about 80-90% of plasma complement components and expresses a variety of complement receptors. Recent evidence from several studies suggests that the complement system is also involved in the pathogenesis of a variety of liver disorders including liver injury and repair, fibrosis, viral hepatitis, alcoholic liver disease, and liver ischemia/reperfusion injury. In this review, we will discuss the potential role of the complement system in the pathogenesis of liver diseases. Cellular ＆ Molecular Immunology.
基金Supported by the Science and Technology Planning Projects of Guizhou Province,No.QKHJC-ZK[2022]YB642the Science and Technology Planning Projects of Zunyi City,No.ZSKHHZ(2022)344+4 种基金the WBE Liver Fibrosis Foundation,No.CFHPC2025028the Chinese Foundation for Hepatitis Prevention and Control Muxin Research Fund of CHB,No.MX202404Beijing Liver and Gallbladder Mutual Aid Public Welfare Foundation Artificial Liver Special Fund,No.iGandanF-1082024-Rgg018the Graduate Research Fund Project of Zunyi Medical University,No.ZYK246the Student Innovation and Entrepreneurship Training Program of Zunyi Medical University,No.2024106610923 and No.S202310661028.
文摘The complement system is crucial for maintaining immunological homeostasis in the liver,playing a significant role in both innate and adaptive immune responses.Dysregulation of this system is closely linked to the pathogenesis of various liver diseases.Modulating the complement system can affect the progression of these conditions.To provide insights into treating liver injury by targeting the regu-lation of the complement system,we conducted a comprehensive search of major biomedical databases,including MEDLINE,PubMed,EMBASE,and Web of Science,to identify articles on complement and liver injury and reviewed the functions and mechanisms of the complement system in liver injury.
基金National Natural Science Foundation of China(Grant/Award Number:81870479)Beijing Natural Science Foundation(Grant/Award Number:7192207)Chinese Academy of Medical Sciences Research(Grant/Award Number:2019RU023)。
文摘The complement system plays a key role in the pathogenesis of autoimmune diseases,which usually injures the kidney.More and more studies have shown the pathogenic role and indicated that abnormal activation of the complement system was highly involved in the outbreak of autoimmune diseases.This review mainly introduced recent studies of complement system activation contributing to the pathogenesis of autoimmune diseases,including systemic lupus erythematosus,antiphospholipid syndrome,antineutrophil cytoplasmic antibody-associated vasculitides,and so on.Understanding the pathogenic roles of complement activation in various autoimmune diseases will identify potential novel therapeutic targets on complement systems.
文摘AIM: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and complement factor H (CFH) polymorphism has been found to associate with the AMD. To investigate whether the Y402H variant in CFH is associated with AMD in Chinese populations, a systematic review and meta-analysis were performed to estimate the magnitude of the gene effect and the possible mode of action. METHODS: A meta-analysis was performed using data available from ten case-control studies assessing association between the CFH Y402H polymorphism and AMD in Chinese populations involving 1538 AMD. Data extraction and study quality assessment were performed in duplicate. Summary odds ratios (ORs) and 95% confidence intervals (CIs) an allele contrast and genotype contrast were estimated usingfixed- effects models. The Q-statistic test was used to assess heterogeneity, and Funnel plot was used to evaluate publication bias. RESULTS: Seven of ten case-control studies were neovascular AMD, and few studies came from west and north of China. There was strong evidence for association between CFH and AMD in Chinese population, with those having risk allele C 2.35 times more likely to have AMD than subjects with T allele. Evidence of publication bias was not observed in our meta-analysis. CONCLUSION: This meta-analysis summarizes the strong evidence for an association between CFH and AMD in Chinese and indicates each C allele increasing the odds of AMD by 2.33-fold. But more evidences about the relation between CFH polymorphism and different type of Chinese AMD from various district were needed.
基金supported by the National Natural Science Foundation of China(31870825)the Shenzhen Bureau of Science,Technology,and Information(JCYJ20170412110026229)+1 种基金the Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions(2022SHIBS0003)2019 Guiyang Science and Technology Bureau,and the Guiyang First People’s Hospital,Great Health Science and Technology Cooperation Project.
文摘Autism spectrum disorder(ASD)is one of the common neurodevelopmental disorders in children.Its etiology and pathogenesis are poorly understood.Previous studies have suggested potential changes in the complement and coagulation pathways in individuals with ASD.In this study,using multiple reactions monitoring proteomic technology,16 of the 33 proteins involved in this pathway were identified as differentially-expressed proteins in plasma between children with ASD and controls.Among them,CFHR3,C4BPB,C4BPA,CFH,C9,SERPIND1,C8A,F9,and F11 were found to be altered in the plasma of children with ASD for the first time.SERPIND1 expression was positively correlated with the CARS score.Using the machine learning method,we obtained a panel composed of 12 differentially-expressed proteins with diagnostic potential for ASD.We also reviewed the proteins changed in this pathway in the brain and blood of patients with ASD.The complement and coagulation pathways may be activated in the peripheral blood of children with ASD and play a key role in the pathogenesis of ASD.
基金supported by National Natural Science Foundation of China(No.61174064)National Basic Research Program of China(973 Program)(No.2012CB720502)
文摘This paper presents a simultaneous H2/H∞ stabilization problem for the chemical reaction systems which can be modeled as a finite collection of subsystems. A single dynamic output feedback controller which simultaneously stabilizes the multiple subsystems and captures the mixed H2/H∞ control performance is designed. To ensure that the stability condition, the H2 characterization and the H∞ characterization can be enforced within a unified matrix inequality framework, a novel technique based on orthogonal complement space is developed. Within such a framework, the controller gain is parameterized by the introduction of a common free positive definite matrix, which is independent of the multiple Lyapunov matrices. An iterative linear matrix inequality （ILMI） algorithm using Matlab Yalmip toolbox is established to deal with the proposed framework. Simulation results of a typical chemical reaction system are exploited to show the validity of the proposed methodology.
基金supported by the Fundamental Research Program of Shanxi Province of China,No.20210302124277the Science Foundation of Shanxi Bethune Hospital,No.2021YJ13(both to JW)。
文摘Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus,leading to long-term cognitive impairment.However,the mechanism underlying this neurogenesis impairment remains unknown.In this study,we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain injury.Our results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development,delayed neuronal maturation,and reduced the complexity of neuronal dendrites and spines.Mice with repetitive traumatic brain injuryalso showed deficits in spatial memory retrieval.Moreover,following repetitive traumatic brain injury,neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased,C1q binding protein levels were decreased,and canonical Wnt/β-catenin signaling was downregulated.An inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological function.These findings suggest that repetitive traumatic brain injury–induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction.
文摘In arthropods,hematophagy has arisen several times throughout evolution.This specialized feeding behavior offered a highly nutritious diet obtained during blood feeds.On the other hand,blood-sucking arthropods must overcome problems brought on by blood intake and digestion.Host blood complement acts on the bite site and is still ac-tive after ingestion,so complement activation is a potential threat to the host's skin feed-ing environment and to the arthropod gut enterocytes.During evolution,blood-sucking arthropods have selected,either in their saliva or gut,anticomplement molecules that inac-tivate host blood complement.This review presents an overview of the complement sys-tem and discusses the arthropod's salivary and gut anticomplement molecules studied to date,exploring their mechanism of action and other aspects related to the arthropod-host-pathogen interface.The possible therapeutic applications of arthropod's anticomplement molecules arealsodiscussed.
文摘BACKGROUND Complement components could contribute to the tumor microenvironment and the systemic immune response.Nevertheless,their role in colorectal cancer(CRC)remains a contentious subject.AIM To elucidate the relationship between complement components and CRC risk and clinical characteristics.METHODS Searches were conducted in PubMed,the Cochrane Library,and the China National Knowledge Infrastructure database until June 1,2023.We included cohort studies encompassing participants aged≥18 years,investigating the association between complement components and CRC.The studies were of moderate quality or above,as determined by the Agency for Healthcare Research and Quality.The meta-analysis employed fixed-effects or random-effects models based on the I^(2)test,utilizing risk ratio(RR)and their corresponding 95%confidence interval(CI)for outcomes.Sensitivity and subgroup analyses were performed to validate the robustness of the collective estimates and identify the source of heterogeneity.RESULTS Data from 15 studies,comprising 1631 participants that met the inclusion criteria,were included in the meta-analysis.Our findings indicated that protein levels of cluster of differentiation 46(CD46)(RR=3.66,95%CI:1.75-7.64,P<0.001),CD59(RR=2.86,95%CI:1.36-6.01,P=0.005),and component 1(C1)(RR=5.88,95%CI:1.75-19.73,P=0.004)and serum levels of C3(standardized mean difference=1.82,95%CI:0.06-3.58,P=0.040)were significantly elevated in patients with CRC compared to healthy controls.Strong expression of CD55 or CD59 was associated with a higher incidence of lymph node metastasis,whereas strong CD46 expression correlated with a higher incidence of tumor differentiation compared to low CD46 expression(P<0.05 for all).Although specific pooled results demonstrated notable heterogeneity,subgroup analyses pointed to regional differences as the primary source of inconsistency among the studies.CONCLUSION Our analysis underscores that increased levels of specific complement components are associated with a heightened risk of CRC,emphasizing the potential significance of monitoring elevated complement component levels.
文摘In this editorial,we review the work of Razali et al published in World J Gas-troenterology,with a particular focus on the effect of rs10889677 variation in the phosphatidylinositol 3-kinase(PI3K)pathway and buparlisib on colitis-associated cancer.The role of PI3K in promoting cancer progression has been widely recognized,as it is involved in regulating the survival,differentiation,and prolif-eration of cancer cells.The complement Clq/TNF-related protein 6(CTRP6)is a newer tumor-associated factor.Recent studies have revealed the pro-tumor effect of CTRP6 in gastric cancer,hepatocellular carcinoma,colorectal cancer,and other gastrointestinal tumors through the PI3K pathway.This article attempts to reveal the mechanism through which the CTRP6 affects the development of digestive system tumors through the PI3K pathway by summarizing recent research.
文摘A lupus patient with a clinically quiescent disease stage will be described who had severely depressed C4 levels while levels of C3 en CH50 were normal. Additional testing revealed a homozygous C4Aisotype deficiency as the cause of the very low C4 levels. It should be emphasized that in SLE, a (very) low C4 level does not always means (subclinical) disease activity.
基金Supported in part by the National High Technology Research Development Program of China (863 Program) (No.2001AA123014)
文摘A new scheme termed as Complement Block Coding (CBC) technique is proposed to reduce the Peak-to-Average Power Ratio (PAPR) of OFDM signals. Utilizing the complement bits which are added to the original information bits,this method can effectively reduce the PAPR of OFDM systems with random frame size N and the coding rate R ≤ (N - k)/N, where kis a positive integer and k ≤ N/2. The performance results obtained with CBC are given and compared with that of some well known schemes, such as Simple Block Coding (SBC), Modified Simple Block Coding (MSBC) and Simple Odd Parity Code (SOPC) for the same purpose. The results show that, at the same coding rate 3/4, the CBC can achieve almost the same performance as SBC, MSBC, but with lower complexity, and that the same performance can be obtained with higher coding rate by using CBC. At the same coding rate (N - 1)/N, the PAPR reduction of CBC is almost the twice as that of SOPC when N ≥ 16. Further more, the PAPR reductions with coding rate (N - 1)/N are almost the same as that with coding rate less than (N - 1)/N,so the proposed scheme CBC is more suitable for the large frame size with high coding rate and can provide error detection.
