Antibodies elicited by Newcastle disease virus-vectored H7N9 avian influenza vaccine are functional in activating the complement system

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.

Crry silencing alleviates Alzheimer’s disease injury by regulating neuroinflammatory cytokines and the complement system

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.

Novel Mechanistic Interplay between Products of Oxidative Stress and Components of the Complement System in AMD Pathogenesis

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.

Preconditioning Schur Complement Systems of Highly-Indefinite Linear Systems for a Parallel Hybrid Solver

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.

Activation of the complement system sensitizes immune checkpoint blockade

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.

Pathophysiological dynamics in the contact,coagulation,and complement systems during sepsis:Potential targets for nafamostat mesilate

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.

Inhibition of vertebrate complement system by hematophagous arthropods: inhibitory molecules, mechanisms, physiological roles, and applications

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.

Association of complement components with risk of colorectal cancer:A systematic review and meta-analysis

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.

Tumor-related factor complement Clq/TNF-related protein 6 affects the development of digestive system tumors through the phosphatidylinositol 3-kinase pathway

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.

Complement-dependent neuroinflammation in spinal cord injury:from pathology to therapeutic implications

Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this population.Following the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing research.In this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the pathology.We study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular patterns.Several effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord injury.Following this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human subjects.This review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.

Repetitive traumatic brain injury–induced complement C1–related inflammation impairs long-term hippocampal neurogenesis

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.

Targeting the complement system in pancreatic cancer drug resistance:a novel therapeutic approach

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.

The Complement System in Liver Diseases

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.

Association between complementary factor H Y402H polymorphisms and age-related macular degeneration in Chinese: Systematic review and meta-analysis

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.

The complement system and autoimmune diseases

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.

Low Levels of Complement Factor C4 Not Always Implicate Disease Activity in Systemic Lupus Erythematosus

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.

COMPLEMENT BLOCK CODING SCHEME FOR REDUCING PEAK-TO-AVERAGE POWER RATIO OF OFDM SYSTEMS

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.

The Case-agreement System in Subjunctive Complements

Unlike matrix verbs, the verb in subjunctive complements in Standard Arabic lacks tense; nonetheless, it inflects for agreement and mood. The subject of subjunctive verbs is Case-marked accusative if it surfaces in a preverbal position; and nominative if it appears in a postverbal position. In addition, the subjunctive verb shows agreement asymmetry with its subject, depending on the position of the subject. Subjunctive complements appear in tenseless contexts in this language, i.e. control structures, ECM-like structures, and obviative structures. In this paper, I provide a new analysis for subject-verb agreement asymmetry in these complements and account for the different Case markers that appear on their subject. In particular, I argue that feature-specification on the inflectional head T triggers the verbal agreement asymmetry in subjunctive complements. I also argue that formal features and nominative Case in these complements can be valued by a defective probe. Crucially, I argue that the defective probe can establish agreement and assign nominative Case in-situ, without resorting to A-movement, and the subsequent movement of the embedded subject to a preverbal position is triggered by the EPP feature on the O-complete T. The corollary of this investigation lends support to the assumption that the Case-agreement system in this language is not contingent on tense.

Interleukin-1 receptor associated kinase 2 is a functional downstream regulator of complement factor D that controls mitochondrial fitness in diabetic cardiomyopathy

Diabetic cardiomyopathy is a disorder of the cardiac muscle that affects patients with diabetes.The exact mechanisms underlying diabetic cardiomyopathy are mostly unknown,but several factors have been implicated in the pathogenesis of the disease and its progression towards heart failure,including endothelial dysfunction,autonomic neuropathy,metabolic alterations,oxidative stress,and alterations in ion homeostasis,especially calcium transients[1].In Military Medical Research,Jiang et al.[2]sought to determine the functional role of complement factor D(Adipsin)in the pathophysiology of diabetic cardiomyopathy.

Complement activation targeted inhibitor C2-FH ameliorates acetaminophen-induced liver injury in mice

BACKGROUND Complement activation is recognized as an important factor in the progression of liver damage caused by acetaminophen(APAP).However,the role of the complement inhibitor C2-FH in APAP-induced liver injury remains unclear.AIM To explore C2-FH in protecting against APAP-induced liver injury by inhibiting complement activation.METHODS A model of APAP-induced liver injury was used to study the protective effect of C2-FH on liver injury.C2-FH was administered through intraperitoneal injection 30 minutes after APAP treatment.We detected the effects of C2-FH on liver function,inflammatory response and complement activation.Additionally,RNA-sequencing(RNA-Seq)analysis was conducted to understand the mechanism through which C2-FH provides protection against APAP-induced liver injury.RESULTS C2-FH inhibited the increase in serum alanine aminotransferase activity,aspartate aminotransferase activity and lactate dehydrogenase,and reduced liver tissue necrosis caused by APAP.Moreover,it attenuated the inflammatory response and inhibited complement activation in APAP-induced liver injury.RNA-Seq analysis provided additional explanations for the protective role of C2-FH against APAP-induced liver injury.CONCLUSION C2-FH attenuates APAP-induced liver injury by inhibiting complement activation.