Objective:This study aimed to evaluate the immunoprotective effect of anti-rabies virus cocktail monoclonal antibody Zamerovimab/Mazorelvimab after rabies exposure.Methods:The dynamic data of rabies virus neutralizing antibody (RVNA) were analyzed in the Zamerovimab/Mazorelvimab Chinese phase Ⅲ study (clinical trial registration number: CTR20201819).Results:The full analysis set showed that RVNA geometric mean titers (GMT) on the 4 th, 8 th, 15 th, 43 rd, and 99 th day in the Zamerovimab/Mazorelvimab group were 4.413 IU/ml, 5.178 IU/ml, 17.062 IU/ml, 14.672 IU/ml, and 2.836 IU/ml, respectively, while those in the human rabies immunoglobulin (HRIG) group were 0.299 IU/ml, 0.451 IU/ml, 11.374 IU/ml, 18.063 IU/ml, and 6.769 IU/ml, respectively. The positive rates of RVNA on the 4 th, 8 th, 15 th, 43 rd, and 99 th day in the Zamerovimab/Mazorelvimab group were 99.9%, 99.6%, 100%, 100%, and 97.4%, respectively, while those in the HRIG group were 23.3%, 34.1%, 97.6%, 99.6%, and 98.4%, respectively. Conclusions:Compared with HRIG, Zamerovimab/Mazorelvimab cocktail monoclonal antibody reached the required protection level of RVNA very soon, thus effectively provided an immediate neutralizing effect of passive immunization therapies against rabies virus.

RBM46 is a germ cell-specific RNA-binding protein required for gametogenesis, but the targets and molecular functions of RBM46 remain unknown. Here, we demonstrate that RBM46 binds at specific motifs in the 3'UTRs of mRNAs encoding multiple meiotic cohesin subunits and show that RBM46 is required for normal synaptonemal complex formation during meiosis initiation. Using a recently reported, high-resolution technique known as LACE-seq and working with low-input cells, we profiled the targets of RBM46 at single-nucleotide resolution in leptotene and zygotene stage gametes. We found that RBM46 preferentially binds target mRNAs containing GCCUAU/GUUCGA motifs in their 3'UTRs regions. In Rbm46 knockout mice, the RBM46-target cohesin subunits displayed unaltered mRNA levels but had reduced translation, resulting in the failed assembly of axial elements, synapsis disruption, and meiotic arrest. Our study thus provides mechanistic insights into the molecular functions of RBM46 in gametogenesis and illustrates the power of LACE-seq for investigations of RNA-binding protein functions when working with low-abundance input materials.
Animals ; Mice ; 3' Untranslated Regions/genetics* ; Cell Cycle Proteins/metabolism* ; Gametogenesis/genetics* ; Meiosis/genetics* ; Nuclear Proteins/genetics* ; RNA-Binding Proteins/genetics*

Objective To explore the relationship of Crohn's disease (CD) susceptibility to aryl hydrocarbon receptor (AhR) polymorphisms and haplotypes in Han population in Wenzhou city, China. Methods A total of 310 CD patients and 573 age-and sex-matched healthy controls were enrolled in our study. Three single nucleotide polymorphisms (SNPs) of AhR(rs10249788,rs2158041,rs2066853) were determined by the improved multiple ligase detection reaction technique. Unconditional logistic regression analyses was applied to analyze the allelic and genotypic differences of each SNP between CD patients and controls, as well as their influence on the clinicopathologic characteristics in CD patients. Analyses of linkage disequilibrium and haplotype were performed by Haploview 4.2 software in all study subjects. Results Compared with the controls, the variant allele (T) and genotype (CT+TT) of (rs2158041) were evidently decreased among CD patients (19.52% vs. 25.04%, P=0.009; 34.19% vs. 44.68%, P=0.003). According to"the Montreal Classification Standards", CD patients were divided into different subgroups. The variant allele(T)and genotype(CT+TT)of(rs2158041)were significantly lower in patients with terminal ileum CD than in controls (16.79% vs. 25.04%, P=0.005; 28.24% vs. 44.68%, P=0.001). Similar conclusions were also drawn in patients with constricting disease when compared with the controls(15.20%vs.25.04%,P=0.003;28.43% vs.44.68%,P=0.003).The three SNPs above were shown to be in a linkage disequilibrium.Compared with the controls respectively,the frequency of haplotype(CCG)was increased in CD patients (44.73% vs. 39.60%, P=0.039), whereas that of haplotype (CTG) was decreased (18.02% vs. 22.78%, P=0.047). Conclusions AhR (rs2158041) variation might influence the risk as well as the location and behavior of CD. The haplotype (CCG) possibly increase the risk of CD development, whereas haplotype(CTG)might decrease it.

Objective To investigate the relationship between forkhead/winged helix transcription factor (Foxp) 3 gene polymorphisms and susceptibility and phenotype of Crohn's disease (CD) in Han nationality in Zhejiang province.Methods From January 2007 to December 2015,268 diagnosed CD patients and 490 healthy controls were enrolled.The four single nucleotide polymorphism (SNP) of Foxp3 rs3761547,rs2232365,rs2294021 and rs3761548 were examined by a SNaPshot technique,and their relation with the efficacy of infliximab was evaluated.The linkage disequilibrium (LD) and haplotype were also analyzed.Unconditional Logistic regression analysis was performed for statistical analysis.Results There was no significant difference in the four mutant alleles and genotype frequencies between 31 patients with effective infliximab treatment and 19 patients with ineffective treatment (all P＞0.05).The results of LD analysis indicated that the above four SNP were in a tight linkage.The frequency of haplotype GCGC of male CD group was 29.20％ (40/137),which was higher than that of male healthy control group (19.37％,43/222),and the difference was statistically significant (odd ratio (OR)=1.717,95％ confidence interval (CI) 1.045 to 2.820,P=0.032).The frequency of haplotype ACGA of female CD group was 13.36％ (35/262),which was lower than that of female healthy control group (19.03％,102/536),and the difference was statistically significant (OR=0.656,95％CI 0.433 to 0.995,P=0.046).The frequency of haplotype ATAC of male colon (L2) type was 25.93％ (7/27),which was lower than that of ileocecal colon (L3) type (75.38％,49/65),and the difference was statistically significant (OR=0.114,95％CI 0.041 to 0.320,P＜0.01).The frequency of haplotype GCGC of male L2 type was 51.85％ (14/27),which was higher than that of L3 type (9.23％,6/65),and the difference was statistically significant (OR=10.590,95％CI 3.423 to 32.758,P＜0.01).The frequency of haplotype ATAC of male stenotic (B2) type was 73.21％ (41/56),which was higher than that of nonstenotic and nonpenetrated (B1) type (47.30％,35/74),and the difference was statistically significant (OR=0.328,95％CI 0.156 to 0.693,P=0.003).The frequency of haplotype GCGC of male B2 type was 17.86％ (10/56) which was lower than that of nonstenotic and nonpenetrated (B1) type (39.19％,29/74),and the difference was statistically significant (OR=2.946,95％CI 1.295 to 6.784,P=0.009).The frequency of haplotype ACGA of male penetrated (B3) type was 71.43％ (5/7),which was higher than that of nonstenotic and nonpenetrated (B1) type (12.16％,9/74),and the difference was statistically significant (OR =0.055,95％ CI 0.009 to 0.329,P ＜ 0.01).Conclusion Foxp3 (rs3761547,rs2232365,rs2294021,rs3761548) gene polymorphisms are associated with the susceptibility and phenotype of CD in Chinese Han patients,but not related with the efficacy of infliximab.

OBJECTIVETo assess the association of vascular endothelial growth factor (VEGF) gene polymorphisms with susceptibility to Crohn's disease (CD) in a Chinese population.

METHODSFor 275 CD patients and 495 controls, the genotypes of VEGF gene rs699947 and rs3025039 loci were determined with a SNaPshot method.

RESULTSThe allelic and genotypic frequencies of the rs699947 and rs3025039 loci did not differ between the two groups (all P>0.05). By stratification analysis, allele A and genotype CA+AA of rs699947 were more frequent in patients with colonic CD compared with the controls (P=0.006, 95%CI:1.143-2.234; P=0.005, 95%CI:1.203-2.900, respectively). Compared with the controls, the allele A and genotype CA+AA of rs699947 were less frequent in patients with ileal lesions including ileal CD and ileocolonic CD (P=0.033, 95%CI:0.524-0.974;P=0.043, 95%CI:0.481-0.989, respectively). The frequency of TT homozygote of rs3025039 was lower in patients with non-stricturing and non-penetrating CD compared with the controls (P=0.036, 95%CI:0.016-0.870).

CONCLUSIONPolymorphisms of the VEGF gene rs699947 locus may contribute to an increased risk for colonic CD, but may play a protective role in patients with ileal lesion. Individuals carrying the TT genotype for VEGF rs3025039 locus may be less susceptible to non-stricturing and non-penetrating CD.

OBJECTIVETo assess the association of transcobalamine II (TCN2) gene polymorphisms and serum levels of homocysteine (Hcy), vitamin Band folate with ulcerative colitis (UC) among Chinese patients.

METHODSFor 397 UC patients and 574 controls, two single nucleotide polymorphisms of the TCN2 gene (rs1801198, rs9606756) were tested with an improved multiple ligase detection reaction method. Serum Hcy, vitamin Band folate were measured with an enzymatic cycling assay and an chemiluminescence immunoassay, respectively.

RESULTSThe allelic and genotypic frequencies of rs1801198 and rs9606756 did not differ significantly between the two groups (all P> 0.05). Compared with those of the control group, the frequencies of G allele and CG+GG genotype of rs1801198 were greater in patients with moderate and severe UC (both P< 0.05). The same conclusion may also be drawn for the G allele and AG genotype of rs9606756 (both P< 0.05). Compared with the controls, average Hcy level was enhanced in UC patients (P< 0.01), whereas average vitamin Band folate levels were decreased in UC patients (both P< 0.01). In both groups, the average level of Hcy was lower in individuals carrying CC of (rs1801198) than in those with CG+GG (both P< 0.05). A similar conclusion was also drawn for individuals with AA of rs9606756 when compared with those carrying AG(both P< 0.05). Compared with patients with mild UC, average Hcy level was increased in those with moderate and severe UC (P< 0.01), while average vitamin Band folate levels were decreased in those with moderate and severe UC (both P< 0.01). The prevalence of hyperhomocysteinemia(HHcy), vitamin Bdeficiency and folate deficiency was greater in UC patients than in controls (all P< 0.01). In UC patients, the level of Hcy was negatively correlated with those of vitamin B(P< 0.01), albumin(P< 0.01), red blood cells(P< 0.01) and platelet (P< 0.05), but positively correlated with white blood cells(P< 0.01) and Mayo score (P< 0.01). Both HHcy and folate deficiency were independent risk factors for UC (OR=4.173, OR=5.206, both P< 0.01).

CONCLUSIONTCN2 (rs1801198, rs9606756) variations, as well as serum levels of Hcy, vitamin Band folate, are correlated with UC. Both HHcy and folate deficiency are independent risk factors for UC.

Adult ; Colitis, Ulcerative ; blood ; etiology ; genetics ; Female ; Folic Acid ; blood ; Genotype ; Homocysteine ; blood ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Transcobalamins ; genetics ; Vitamin B 12 ; blood

OBJECTIVETo assess the association of single nucleotide polymorphisms (SNPs) and haplotypes of solute-linked carrier family 26 member A3 (SLC26A3) gene with ulcerative colitis (UC) among Chinese patients.

METHODSFor 416 UC patients and 584 controls, 5 SNPs of the SLC26A3 gene (rs17154444, rs7810937, rs7785539, rs2108225 and rs6951457) were determined with a SNaPshot method. Linkage disequilibrium (LD) and haplotype were analyzed for all subjects.

RESULTSThe G allele and AG+GG genotype of rs2108225 were more prevalent in UC patients compared with the controls (65.14% vs. 58.65%, P=0.030; 87.02% vs. 81.85%, P=0.012, respectively). The C allele and TC+CC genotype of rs17154444 were more prevalent in patients with severe UC than in other patients (14.00% vs. 6.01%, P<0.01; 28.00% vs. 11.48%, all P<0.01). Similar conclusion may also be drawn for C allele and GC+CC genotype of rs7785539 (8.00% vs. 7.38%, P=0.011; 16.00% vs. 13.93%, P=0.017, respectively). The SNPs rs17154444, rs7810937, rs7785539 and rs2108225 were found to be in strong LD. Compared with the controls, the T-A-G-G haplotype was more prevalent in UC patients (62.60% vs. 58.20%, P=0.017), whereas the T-G-G-A haplotype was less common in UC patients (27.40% vs. 31.60%, P=0.041).

CONCLUSIONVariations of the SLC26A3 rs2108225 may enhance the risk of UC. The rs17154444 and rs7785539 polymorphisms of the SLC26A3 gene are correlated with the severity of UC. The T-A-G-G haplotype formed by rs17154444, rs781093, rs7785539 and rs2108225 of the SLC26A3 gene may increase the risk for UC, whereas the T-G-G-A haplotype may decrease this risk.

Adult ; Asian Continental Ancestry Group ; genetics ; China ; Chloride-Bicarbonate Antiporters ; genetics ; Colitis, Ulcerative ; genetics ; Female ; Genotype ; Haplotypes ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide

Objective To explore the association of Crohn's disease (CD) with T cell immunoglobulin and mucin domain 3 (Tim-3) gene polymorphisms in patients of Zhejiang Han population in China.Methods A total of 308 CD patients and 573 age-and sex-matched healthy controls were enrolled in our study.Two single nucleotide polymorphisms (SNPs) of Tim-3 (rs1036199 and rs10515746) were examined by the improved multiple ligase detection reaction technique (iMLDR).Analyses of linkage disequilibrium and haplotype were also performed by Haploview 4.2 software in all study subjects.Results In general,the allele and genotype frequencies of Tim-3 (rs1036199 and rs10515746) were not statistically different between CD patients and the controls (all P ＞0.05).According to the Montreal Classification,CD patients were divided into different subgroups.The variant allele (C) and genotype (AC + CC) of rs1036199 were more frequent in CD patients with penetrating diseases than in the controls (10.4％ vs 1.7％,P =0.002;20.8％ vs 3.5％,P =0.023).Similar conclusions were also drawn for the variant allele (A) and genotype (CA + AA) of rs10515746 in patients with penetrating diseases when compared with the controls (10.4％ vs 2.2％,P =0.000;20.8％ vs 4.2％,P =0.033,respectively).The two SNPs of Tim-3 were in strong linkage disequilibrium (D'=1.0,r2 =0.928).The haplotype (AC) formed by their wild-type alleles (A) and (C) was decreased in patients with penetrating CD compared with the controls (89.6％ vs 98.3％,P =0.000).However,the haplotype (CA) formed by their variant alleles was more frequent in patients with penetrating CD than in the controls (10.4％ vs 1.6％,P =0.000).Conclusions Tim-3 (rs1036199 and rs10515746) variations might be correlated with the enhanced risk of penetrating diseases in CD patients.Furthermore,the haplotype (AC) and (CA) formed by the two SNPs might be a protective and a risky factor for penetrating CD respectively.

Objective To explore the association of genetic polymorphism of fucosyltransferase (FUT) 2 and FUT3 and expression of Lewis antigen with ulcerative colitis (UC) in Chinese Zhejiang Han population.Methods We genotyped FUT2 (rs281377, rs1047781 and rs601338) and FUT3 (rs28362459, rs3745635 and rs3894326) in 485 UC patients and 580 healthy controls using SNaPshot. By immunohistochemistry method, we also evaluated expression of Lewis a and b antigens in the sigmoid colon of 10 UC patients and 10 patients with benign colonic polyps.Results The frequencies of mutant allele (A) and genotype (GA+AA) in FUT3 rs3745635 were higher in UC patients than in controls (P=0.016, 95%CI 1.339-1.699;P=0.038, 95%CI 1.330-1.742, respectively). Stratified analyses revealed that the frequencies of mutant allele (G) and genotype (TG+GG) of FUT3 rs28362459 were significantly lower in patients with extensive colitis than in those with distal colitis (P=0.001, 95%CI 0.567-0.786;P<0.001, 95%CI 0.503-0.742, respectively). Similar conclusions were drawn for the mutant allele (A) and genotype (GA+AA) of FUT3 rs3745635 in patients with extensive colitis compared to those with distal colitis (P=0.011, 95%CI 0.621-0.900;P=0.006, 95%CI 0.553-0.845, respectively). Although expression of Lewis b antigen in the sigmoid colon did not differ between UC patients and controls, Lewis a antigen expression was higher in the crypt epithelium of both inflammatory and non-inflammatory sigmoid colon of UC patients than in controls (P=0.028).Conclusion Polymorphisms of FUT3 and expression level of Lewis a antigen might be associated with UC.

Objective To investigate the relationship between gene polymorphisms of T cell immunoglobulin domain and mucin domain protein-3 (Tim-3) and ulcerative colitis (UC) in Han nationality of Zhejiang.Methods A total of 391 UC patients and 573 healthy controls were recruited.Two single nucleotide polymorphisms (SPNs) of Tim-3 (rs1036199 and rs10515746) were examined by the improved multiple ligase detection reaction technique.Chi-square test or Fisher's exact test was performed to analyze the differences in the distribution of Tim-3 gene polymorphisms and its influence on the location and severity.Haploview 4.2 software was used to analyze linkage disequilibrium (LD) and haplotype.Results The frequencies of genotype CA+AA and mutant allele A of rs10515746 in UC were lower than those in healthy controls (1.79％,7/391 vs 4.19％,24/573;0.90％,7/782 vs 2.18％,25/1 146;x2=4.295 and 4.712,P=0.038 and 0.030).However,there was no significant differences in frequencies of genotype CA+ CC and mutant allele C of gene rs1036199 between UC patients and the healthy controls (1.79％,7/891 vs 8.49％,20/578;0.90％,7/782 vs 1.74％,20/1 146;both P＞0.05).The frequencies of genotype CA+AA and mutant allele A of rs10515746 in mild and moderate UC patients were both higher than those in severe UC patients (2.87 ％,7/244 vs 0;1.43 ％,7/488 vs 0),and the differences were statistically significant (Fisher's exact test,P=0.049 and 0.048).The analysis for LD indicated that rs1036199andrs10515746 were closeLD (D'=0.92,r2=0.72).Furthermore,the frequency of haplotype CA formed by the mutant alleles C and A of these two SNPs was lower in UC patients than that in healthy controls (0.64％,5/782 vs 1.74％,20/1 146),and the difference was statistically significant (x2 =4.441,P=0.035).Conclusions Tim-3 (rs10515746) gene mutation may not only decrease the incidence,but also reduce the severity of UC.Moreover,the haplotype CA formed by the mutant alleles of rs1036199 and rs10515746 may also reduce the incidence of UC.