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.

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.

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.

Complement factor Ⅰ knockdown inhibits colon cancer development by affecting Wnt/β-catenin/c-Myc signaling pathway and glycolysis

BACKGROUND Colon cancer(CC)occurrence and progression are considerably influenced by the tumor microenvironment.However,the exact underlying regulatory mechanisms remain unclear.AIM To investigate immune infiltration-related differentially expressed genes(DEGs)in CC and specifically explored the role and potential molecular mechanisms of complement factor I(CFI).METHODS Immune infiltration-associated DEGs were screened for CC using bioinformatics.Quantitative reverse transcription polymerase chain reaction was used to examine hub DEGs expression in the CC cell lines.Stable CFI-knockdown HT29 and HCT116 cell lines were constructed,and the diverse roles of CFI in vitro were assessed using CCK-8,5-ethynyl-2’-deoxyuridine,wound healing,and transwell assays.Hematoxylin and eosin staining and immunohistochemistry staining were employed to evaluate the influence of CFI on the tumorigenesis of CC xenograft models constructed using BALB/c male nude mice.Key proteins associated with glycolysis and the Wnt pathway were measured using western blotting.RESULTS Six key immune infiltration-related DEGs were screened,among which the expression of CFI,complement factor B,lymphoid enhancer binding factor 1,and SRY-related high-mobility-group box 4 was upregulated,whereas that of fatty acid-binding protein 1,and bone morphogenic protein-2 was downregulated.Furthermore,CFI could be used as a diagnostic biomarker for CC.Functionally,CFI silencing inhibited CC cell proliferation,migration,invasion,and tumor growth.Mechanistically,CFI knockdown downregulated the expression of key glycolysis-related proteins(glucose transporter type 1,hexokinase 2,lactate dehydrogenase A,and pyruvate kinase M2)and the Wnt pathway-related proteins(β-catenin and c-Myc).Further investigation indicated that CFI knockdown inhibited glycolysis in CC by blocking the Wnt/β-catenin/c-Myc pathway.CONCLUSION The findings of the present study demonstrate that CFI plays a crucial role in CC development by influencing glycolysis and the Wnt/β-catenin/c-Myc pathway,indicating that it could serve as a promising target for therapeutic intervention in CC.

Different serum levels of IgG and complements and recurrence rates in IgG4-positive and negative lacrimal gland benign lymphoepithelial lesion

·AIM:To analyze the differences in immune indicators and prognosis between Ig G4-positive and negative lacrimal gland benign lymphoepithelial lesion(LGBLEL).·METHODS:This was a single-center retrospective clinical study including 105 cases of Ig G4-positive LGBLEL and 41 cases of Ig G4-negative LGBLEL.Basic information,related indicators of peripheral venous blood samples using immunoscattering turbidimetry,treatment(partial surgical excision and glucocorticoid therapy)and prognosis(recurrence and death)were collected.Survival curves for recurrence were created using the Kaplan-Meier analysis.Univariate analysis and multivariate regression analysis were used to analyze prognostic factors.·RESULTS:The mean age was 50.10±14.23y and 44.76±11.43y(P=0.033)in Ig G4-positive and negative group respectively.The serum C3 and C4 was lower in Ig G4-positive group(P=0.005,P=0.002),while the serum Ig G and Ig G2 was higher in Ig G4-positive group(P=0.000 and P=0.008).Twenty-one cases had recurrence in Ig G4-positive group and 3 cases recurrence in Ig G4-negative group.The 5-year recurrence-free cumulative percentages of Ig G4-positive group was 81.85%,and 83.46%in the Ig G-negative group(P=0.216).The history of preoperative glucocorticoid therapy,serum C4,Ig G1 and Ig G2 were the factors affecting recurrence in Ig G4-positive group,while serum C4,and Ig G1 were the factors affecting recurrence of LGBLEL.·CONCLUSION:Serum C4 and Ig G1 are the factors affecting recurrence of LGBLEL,while the Ig G4 does not affect recurrence of LGBLEL.

Association of C-reactive protein and complement factor H gene polymorphisms with risk of lupus nephritis in Chinese population

BACKGROUND Complement overactivation is a major driver of lupus nephritis(LN).Impaired interactions of C-reactive protein(CRP)with complement factor H(CFH)have been shown as a pathogenic mechanism that contributes to the overactivation of complement in LN.However,genetic variations of neither CRP nor CFH show consistent influences on the risk of LN.AIM To examine whether genetic variations of CRP and CFH in combination can improve the risk stratification in Chinese population.METHODS We genotyped six CRP single nucleotide polymorphisms(SNPs)(rs1205,rs3093062,rs2794521,rs1800947,rs3093077,and rs1130864)and three CFH SNPs(rs482934,rs1061170,and rs1061147)in 270 LN patients and 303 healthy subjects.RESULTS No linkage was found among CRP and CFH SNPs,indicating lack of genetic interactions between the two genes.Moreover,CRP and CFH SNPs,neither individually nor in combination,are associated with the risk or clinical manifestations of LN.Given the unambiguous pathogenic roles of the two genes.CONCLUSION These findings suggest that the biological effects of most genetic variations of CRP and CFH on their expressions or activities are not sufficient to influence the disease course of LN.

英藏“补语”比较及Complement一词藏译略考

在汉语基础薄弱的偏远藏族农牧区的英文教学中,进行英藏语法直接的比较,对该地区英语教学效果的提高具有积极意义。本文以英文语法教学为主体,旨在通过对英藏基础句法中"Complement"一词的直接对比和语法术语的藏译探讨,望能帮助解决农牧区藏族学生英文教学中对该语法盲点的理解困扰。

中外学习者使役结构使用对比研究——以“make+object+complement”结构为例

中国大学英语学习者在表达使役关系的时候多倾向于使用"make+object+complement"结构,但对中国学生在使用这一结构和本族语者使用这一结构存在哪些差异及其原因的研究却不多。利用WordNeighbors数据库对本族语者使用这一结构的情况进行了调查研究,结果显示:就使用频率而言,本族语者也比较频繁地使用这一结构,但在具体用法上与汉语存在两点不同之处。究其原因,主要是受母语负迁移的影响。研究表明,输入的匮乏是造成中国学习者过度依赖母语的一个原因。

Analysis of immunoglobulin, complements and CRP levels in serum of captive northern pig-tailed macaques （Macaca leonina）

The northem pig-tailed macaque （NPM, Macaca leonina） has become a widely used animal model in biomedical research. In this study, we measured serum immunoglobulin IgG, IgM, IgA, complement C3, C4 and CRP levels in 3-11 year old captive northem pig-tailed macaques using HITACHI 7600-20 automated chemistry analyzer in order to determine the influences of age and gender on these items. The results showed that serum IgA, IgM, C3 and C4 levels were not correlated with age （P〉0.05）, while serum IgG levels increased progressively with age （r=0.202; P=0.045）. Serum IgG, IgA, IgM and C3 levels were higher in females than in males （P〈0.05）. Moreover, serum C3 concentration was both positively and strongly correlated with that of C4 （r=0.700; P〈0.0001）. This study provides basic serum immunoglobulin and complement data of captive northem pig-tailed macaques, which may prove useful for future breeding efforts and biomedical research.

Complements are involved in alcoholic fatty liver disease, hepatitis and fibrosis

The complement system is a key component of the body's immune system. When abnormally activated, this system can induce inflammation and damage to normal tissues and participate in the development and progression of a variety of diseases. In the past, many scholars believed that alcoholic liver disease(ALD) is induced by the stress of ethanol on liver cells, including oxidative stress and dysfunction of mitochondria and protease bodies, causing hepatocyte injury and apoptosis. Recent studies have shown that complement activation is also involved in the genesis and development of ALD. This review focuses on the roles of complement activation in ALD and of therapeutic intervention in complement-activation pathways. We intend to provide new ideas on the diagnosis and treatment of ALD.

Characterization and Expression Analysis of a Complement Component Gene in Sea Cucumber(Apostichopus japonicus)

The complement system plays a crucial role in the innate immune system of animals. It can be activated by distinct yet overlapping classical, alternative and lectin pathways. In the alternative pathway, complement factor B(Bf) serves as the catalytic subunit of complement component 3(C3) convertase, which plays the central role among three activation pathways. In this study, the Bf gene in sea cucumber(Apostichopus japonicus), termed Aj Bf, was obtained by rapid amplification of c DNA ends(RACE). The full-length c DNA of Aj Bf was 3231 bp in length barring the poly(A) tail. It contained an open reading frame(ORF) of 2742 bp encoding 913 amino acids, a 105 bp 5'-UTR(5'-terminal untranslated region) and a 384 bp 3'-UTR. Aj Bf was a mosaic protein with six CCP(complement control protein) domains, a VWA(von Willebrand factor A) domain, and a serine protease domain. The deduced molecular weight of Aj Bf protein was 101 k Da. Quantitative real time PCR(q RT-PCR) analysis indicated that the expression level of Aj Bf in A. japonicus was obviously higher at larval stage than that at embryonic stage. Expression detection in different tissues showed that Aj Bf expressed higher in coelomocytes than in other four tissues. In addation, Aj Bf expression in different tissues was induced significantly after LPS or Poly I:C challenge. These results indicated that Aj Bf plays an important role in immune responses to pathogen infection.

Serum complement C4a and its relation to liver fibrosis in children with chronic hepatitis C

AIM:To evaluate serum complement C4a and its relation to liver fibrosis in children with chronic hepatitis C virus(HCV)infection.METHODS:The study included 30 children with chronic HCV infection before receiving antiviral therapy.Chronic HCV infection was defined by positive anti-HCV,a positive polymerase chain reaction for HCV-RNA for more than 6 mo with absence of any associated liver disease.A second group of 30 age-and sex-matched healthy children served as controls.Serum C4a levels were measured by enzyme-linked immunosorbent assay.Liver fibrosis stage and inflammatory grade were assessed using Ishak scoring system.Serum C4a levels were compared according to different clinical,laboratory and histopathological parameters.Statistical significance for quantitative data was tested by MannWhitney U non-parametric tests.For qualitative data,significance between groups was tested by 2test.Correlation was tested by Spearman’s test.Results were considered significant if P value≤0.05.RESULTS:The age of the patients ranged from 3.5to 18 years and that of controls ranged from 4 to 17years.C4a mean levels were merely lower in patients(153.67±18.69 mg/L)than that in the controls(157.25±11.40 mg/L)with no statistical significance(P=0.378).It did not differ significantly in patients with elevated vs those with normal transaminases(152.25±16.62 vs 155.36±21.33;P=0.868)or with different HCV viremia(P=0.561).Furthermore,there was no statistical significant difference in serum levels between those with no/mild fibrosis and those with moderate fibrosis(154.65±20.59 vs 152.97±17.72;P=0.786)or minimal and mild activity(155.1±21.93 vs 152.99±17.43;P=0.809).Though statistically not significant,C4a was highest in fibrosis score 0(F0),decreasing in F1 and F2 to be the lowest in F3.When comparing significant fibrosis(Ishak score≥3)vs other stages,C4a was significantly lower in F3 compared to other fibrosis scores(143.55±2.33 mg/L vs 155.26±19.64 mg/L;P=0.047)and at a cutoff value of less than 144.01 mg/L,C4a could discriminate F3 with 76.9%sensitivity and75%specificity from other stages of fibrosis.CONCLUSION:Serum complement C4a did not correlate with any of transaminases,HCV viremia or with the histopathological scores.Although C4a decreased with higher stages of fibrosis,this change was not significant enough to predict individual stages of fibrosis.Yet,it could predict significant fibrosis with acceptable clinical performance.

Complement factors C1q, C3 and C5b-9 in the posterior sclera of guinea pigs with negative lens-defocused myopia

· AIM: To investigate the expression of complement factors in the posterior scleral fibroblasts of guinea pigs with negative lens-defocused myopia.· METHODS: Eighteen guinea pigs were assigned randomly to two groups: the negative lens-defocused group(NLD group, n =9) and the normal control without treatment group(NC group, n =9). The effect of myopic induction was compared in three subgroups: eyes treated with a-10.00 D negative lens in the NLD group(NL group), eyes treated with a plano(0 D) lens in the NLD group(PL group), and untreated right eyes in the NC group(NC group). The following analyses were conducted at four weeks: examination of the refractive error via retinoscopy, assessment of complement C5b-9expression in the posterior scleral fibroblasts using immunohistochemistry, and measurements of complement C1 q and C3 protein levels in the posterior sclera by Western blot.·RESULTS: After an induction period of four weeks, a significant myopic shift was detected in the eyes of the NL group, relative to that of the PL and NC groups(P 【0.05). Data analysis showed a significant increase in the percentage of C5b-9 immunopositive fibroblasts in the posterior sclera of the NL group eyes, compared to the PL group(q =11.50, P 【0.001). Significantly higher levels of C1q(q =4.94, P =0.01) and C3(q =4.07, P =0.03)protein were detected in the posterior sclera of NL group eyes, compared to the PL group. There were no significant difference between the PL and NC groups for C5b-9(q =2.44, P =0.10), C1q(q =1.55, P =0.53) and C3(q =0.98, P =0.77) in the posterior sclera.·CONCLUSION: The data from present study provide evidence of the up-regulation of C5b-9, C1 q and C3 in the posterior scleral fibroblasts in a NLD myopic animal model. The results suggest that the complement system may be involved in the development of myopia.

Cell cycle and complement inhibitors may be specific for treatment of spinal cord injury in aged and young mice: transcriptomic analyses

Previous studies have reported age-specific pathological and functional outcomes in young and aged patients suffering spinal cord injury,but the mechanisms remain poorly understood. In this study, we examined mice with spinal cord injury. Gene expression profiles from the Gene Expression Omnibus database （accession number GSE93561） were used, including spinal cord samples from 3 young injured mice （2–3-months old, induced by Impactor at Th9 level） and 3 control mice （2–3-months old, no treatment）, as well as 2 aged injured mice （15–18-months old, induced by Impactor at Th9 level） and 2 control mice （15–18-months old, no treatment）. Differentially expressed genes （DEGs） in spinal cord tissue from injured and control mice were identified using the Linear Models for Microarray data method,with a threshold of adjusted P 〈 0.05 and ｜logFC（fold change）｜ 〉 1.5. Protein–protein interaction networks were constructed using data from the STRING database, followed by module analysis by Cytoscape software to screen crucial genes. Kyoto encyclopedia of genes and genomes pathway and Gene Ontology enrichment analyses were performed to investigate the underlying functions of DEGs using Database for Annotation, Visualization and Integrated Discovery. Consequently, 1,604 and 1,153 DEGs were identified between injured and normal control mice in spinal cord tissue of aged and young mice, respectively. Furthermore, a Venn diagram showed that 960 DEGs were shared among aged and young mice, while 644 and 193 DEGs were specific to aged and young mice, respectively. Functional enrichment indicates that shared DEGs are involved in osteoclast differentiation, extracellular matrix–receptor interaction, nuclear factor-kappa B signaling pathway, and focal adhesion. Unique genes for aged and young injured groups were involved in the cell cycle （upregulation of PLK1） and complement （upregulation of C3） activation, respectively. These findings were confirmed by functional analysis of genes in modules （common, 4; aged, 2; young, 1） screened from protein–protein interaction networks. Accordingly, cell cycle and complement inhibitors may be specific treatments for spinal cord injury in aged and young mice, respectively.

New insight into the role of the complement in the most common types of retinopathy-current literature review

Pathological neovascularisation, which is a critical component of diseases such as age-related macular degeneration（AMD）, diabetic retinopathy（DR） and retinopathy of prematurity（ROP）, is a frequent cause of compromised vision or blindness. Researchers continuously investigate the role of the complement system in the pathogenesis of retinopathy. Studies have confirmed the role of factors H and I in the development of AMD, and factors H and B in the development of DR. Other components, such as C2, C3, and C5, have also been considered. However, findings on the involvement of the complement system in the pathogenesis of ROP are still inconclusive. This paper presents a review of the current literature data, pointing to the novel results and achievements from research into the role of complement components in the development of retinopathy. There is still a need to continue research in new directions, and to gather more detailed information about this problem which will be useful in the treatment of these diseases.

Complement activation in the context of stem cells and tissue repair

The complement pathway is best known for its role in immune surveillance and inflammation. However,its ability of opsonizing and removing not only pathogens,but also necrotic and apoptotic cells,is a phylogenetically ancient means of initiating tissue repair. The means and mechanisms of complement-mediated tissue repair are discussed in this review. There is increasing evidence that complement activation contributes to tissue repair at several levels. These range from the chemo-attraction of stem and progenitor cells to areas of complement activation,to increased survival of various cell types in the presence of split products of complement,and to the production of trophic factors by cells activated by the anaphylatoxins C3 a and C5 a. This repair aspect of complement biology has not found sufficient appreciation until recently. The following will examine this aspect of complement biology with an emphasis on the anaphylatoxins C3 a and C5 a.

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.

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.

Association between complement factor I gene polymorphisms and the risk of age-related macular degeneration:a Meta-analysis of literature

AIM： To systematically review the association between complement factors I （CFI） polymorphisms and age- related macular degeneration （AMD） and to explore whether CFI polymorphisms are associated with AMD, METHODS： Meta-analysis of articles published from 1995 to January 2015 of articles involved with AMD and polymorphisms of the CFI gene. Eligible data were pooled in a Meta-analysis, analyzing using STATA software （version 12.0）, Review Manager （version 5.2） and different models based on the heterogeneity of effect sizes. Egger＇s test, Begg＇s rank correlation methods were used to evaluate for publication bias.~ RESULTS： Thirteen articles were eligible, describing two loci polymorphisms of the CFI gene （of which 12 articles focus on rs10033900T〉C and 3 articles focus on rs2285714C〉T）. For rs10033900T〉C, the results of our study revealed that having a mutant allele C, TC, CC and TC＋CC was associated with a decreased risk of AMD in all population groups studied （C versus T models, OR=0.84, 95%Ch 0.72-0.99, P=0.04; TC versus TT models OR= 0.89, 95%Ch 0.88-0.99, P=0.04;CC versus ＂1-1＂ models, OR=0.76, 95%Ch 0.60-0.98, P=-0.03; TC＋CC versus TT models, OR=0.81, 95%Ch0.65-0.99, P=0.04）. We found that C allele were related to lower AMD risk in the Caucasian population by subgroup analysis, but there was no association with AMD under the allele and genotypes comparison in Asian studies. For rs2285714 C〉T, the TC, TT genotypes contributed to a higher risk of AMD, compared with the CC carriers and CT＋CC （OR=1.34, 95%Ch 1.09-1.63, P=0.004; OR=1.50, 95%Ch 1.25-1.80, P〈0.0001）. CONCLUSION： This Meta-analysis suggests that CFI rs10033900T〉C and rs2285714C〉T polymorphisms may contribute to AMD.

Complement C3a activates osteoclasts by regulating the PI3K/PDK1/SGK3 pathway in patients with multiple myeloma

Objective:Myeloma bone disease(MBD)is the most common complication of multiple myeloma(MM).Our previous study showed that the serum levels of C3/C4 in MM patients were significantly positively correlated with the severity of bone disease.However,the mechanism of C3 a/C4 a in osteoclasts MM patients remains unclear.Methods:The formation and function of osteoclasts were analyzed after adding C3 a/C4 a in vitro.RNA-seq analysis was used to screen the potential pathways affecting osteoclasts,and the results were verified by Western blot,q RT-PCR,and pathway inhibitors.Results:The osteoclast area per view induced by 1μg/m L(mean±SD:50.828±12.984%)and 10μg/m L(53.663±12.685%)of C3 a was significantly increased compared to the control group(0μg/m L)(34.635±8.916%)(P<0.001 and P<0.001,respectively).The relative m RNA expressions of genes,OSCAR/TRAP/RANKL/cathepsin K,induced by 1μg/m L(median:5.041,3.726,1.638,and 4.752,respectively)and 10μg/m L(median:5.140,3.702,2.250,and 5.172,respectively)of C3 a was significantly increased compared to the control group(median:3.137,2.004,0.573,and 2.257,respectively)(1μg/m L P=0.001,P=0.003,P<0.001,and P=0.008,respectively;10μg/m L:P<0.001,P=0.019,P<0.001,and P=0.002,respectively).The absorption areas of the osteoclast resorption pits per view induced by 1μg/m L(mean±SD:51.464±11.983%)and 10μg/m L(50.219±12.067%)of C3 a was also significantly increased(33.845±8.331%)(P<0.001 and P<0.001,respectively)compared to the control.There was no difference between the C4 a and control groups.RNA-seq analysis showed that C3 a promoted the proliferation of osteoclasts using the phosphoinositide 3-kinase(PI3 K)signaling pathway.The relative expressions of PIK3 CA/phosphoinositide dependent kinase-1(PDK1)/serum and glucocorticoid inducible protein kinases(SGK3)genes and PI3 K/PDK1/p-SGK3 protein in the C3 a group were significantly higher than in the control group.The activation role of C3 a in osteoclasts of MM patients was reduced by the SGK inhibitor(EMD638683).Conclusions:C3 a activated osteoclasts by regulating the PI3 K/PDK1/SGK3 pathways in MM patients,which was reduced using a SGK inhibitor.Overall,our results identified potential therapeutic targets and strategies for MBD patients。