NUMB dysfunction defines a novel mechanism underlying hyperuricemia and gout.

Defective renal excretion and increased production of uric acid engender hyperuricemia that predisposes to gout. However, molecular mechanisms underlying defective uric acid excretion remain largely unknown. Here, we report a rare genetic variant of gout-unprecedented NUMB gene within a hereditary human gout family, which was identified by an unbiased genome-wide sequencing approach. This dysfunctional missense variant within the conserved region of the NUMB gene (NUMBR630H) underwent intracellular redistribution and degradation through an autophagy-dependent mechanism. Mechanistically, we identified the uric acid transporter, ATP Binding Cassette Subfamily G Member 2 (ABCG2), as a novel NUMB-binding protein through its intracellular YxNxxF motif. In polarized renal tubular epithelial cells (RTECs), NUMB promoted ABCG2 trafficking towards the apical plasma membrane. Genetic loss-of-function of NUMB resulted in redistribution of ABCG2 in the basolateral domain and ultimately defective excretion of uric acid. To recapitulate the clinical situation in human gout patients, we generated a NUMBR630H knock-in mouse strain, which showed marked increases of serum urate and decreased uric acid excretion. The NUMBR630H knock-in mice exhibited clinically relevant hyperuricemia. In summary, we have uncovered a novel NUMB-mediated mechanism of uric acid excretion and a functional missense variant of NUMB in humans, which causes hyperuricemia and gout.

Effect of low-purine diet on the serum uric acid of gout patients in different clinical subtypes: a prospective cohort study.

BACKGROUND: The pathogenic causes of primary gout include urate overproduction and/or renal or extra-renal urate underexcretion. The aim of this study was to evaluate the association of gout subtypes with the response to low-purine diet (LPD). METHODS: This is a single-center prospective clinical study. Gout patients visiting from 2019 to 2022, from Shandong Gout Clinic Center at the Affiliated Hospital of Qingdao University, China, assigned to three groups according to clinical subtypes, were enrolled and all treated with 2-week low-purine diet. General characteristics, serum uric acid (sUA) and other clinical biochemical variables before and after the diet were evaluated. RESULTS: A total of 626 gout patients (age 41.20 ± 13.41 years, male 98.0%) were included. Of these, 69 (11.0%) were overproduction type, 428 (68.37%) were underexcretion type, and 129 (20.61%) were combined type. Overall, there was a substantial decrease in sUA after a 2-week LPD (p < 0.001). In addition, systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), serum triglycerides (TG), serum total cholesterol (TC), blood urea nitrogen (BUN) and serum creatinine (Scr) levels were lower than those at baseline (p < 0.05). On the other hand, there were significant differences in the reduction of sUA among different types, the rank order being overproduction type (- 88.81 ± 63.01 µmol/L) > combined type (- 65.22 ± 44.13 µmol/L) > underexcretion type (- 57.32 ± 61.19 µmol/L). After adjusting for age, BMI and baseline sUA and eGFR, there were still significant differences in the decline of serum uric acid among different types. Higher baseline sUA (95%CI - 0.285, - 0.191; p < 0.001) and BUN (95%CI - 6.751, - 0.602; p < 0.001) were correlated with greater decrease of sUA. CONCLUSIONS: Our findings support the protective role of low-purine diet on sUA levels in gout patients, especially overproduction type. Furthermore, LPD could exert a beneficial effect on gout patients' blood pressure, BMI, blood lipid, BUN and Scr levels. Trial registration Registered with ChiCTR, No. ChiCTR1900022981 at 06/05/2019.

Hyperechoic Spots in the Renal Medulla as a Potential Indicator of Early Gouty Nephropathy.

INTRODUCTION: The aim of the study was to explore the causes and clinical significance of hyperechoic renal medulla observed by ultrasonography in patients with primary gout. METHODS: This study included 2,107 patients with primary gout treated in the Gout Clinic of our hospital from 2016 to 2022. The clinical data and biochemical data of these patients were collected and analyzed. According to the presence or absence of punctate hyperechogenicity in the renal medulla on ultrasound examination, the patients were divided into the hyperechoic medulla (HM) and the normal hypoechoic medulla (NM) groups, and the HM group was further divided into the partial HM (P-HM) and fulfilled HM (F-HM) subgroups according to the distribution range of hyperechogenicity. RESULTS: Among the 2,107 patients with primary gout, 380 had hyperechoic renal medulla on renal ultrasound, including 106 patients with F-HM and 274 with P-HM. There were significant differences in the gout duration, urate arthropathy number, serum urate (SU) level, clinical tophi number, blood urea nitrogen, serum creatinine (sCr), and estimated glomerular filtration rate between the HM and NM groups or between the F-HM and P-HM subgroups (p < 0.05). Multivariate regression analysis showed that the presence of HM was positively correlated with gout duration, urate arthropathy number, gout attack frequency, SU, and sCr. The number of clinical tophi and sCr were closely related to F-HM. CONCLUSION: Ultrasound examination showed that a high medulla echo in patients with gout was often related to renal function damage. P-HM may be a transitory condition between NM and F-HM in patients with gout.

Novel Genetic Loci in Early-Onset Gout Derived From Whole-Genome Sequencing of an Adolescent Gout Cohort.

OBJECTIVE: Mechanisms underlying the adolescent-onset and early-onset gout are unclear. This study aimed to discover variants associated with early-onset gout. METHODS: We conducted whole-genome sequencing in a discovery adolescent-onset gout cohort of 905 individuals (gout onset 12 to 19 years) to discover common and low-frequency single-nucleotide variants (SNVs) associated with gout. Candidate common SNVs were genotyped in an early-onset gout cohort of 2,834 individuals (gout onset ≤30 years old), and meta-analysis was performed with the discovery and replication cohorts to identify loci associated with early-onset gout. Transcriptome and epigenomic analyses, quantitative real-time polymerase chain reaction and RNA sequencing in human peripheral blood leukocytes, and knock-down experiments in human THP-1 macrophage cells investigated the regulation and function of candidate gene RCOR1. RESULTS: In addition to ABCG2, a urate transporter previously linked to pediatric-onset and early-onset gout, we identified two novel loci (Pmeta < 5.0 × 10-8): rs12887440 (RCOR1) and rs35213808 (FSTL5-MIR4454). Additionally, we found associations at ABCG2 and SLC22A12 that were driven by low-frequency SNVs. SNVs in RCOR1 were linked to elevated blood leukocyte messenger RNA levels. THP-1 macrophage culture studies revealed the potential of decreased RCOR1 to suppress gouty inflammation. CONCLUSION: This is the first comprehensive genetic characterization of adolescent-onset gout. The identified risk loci of early-onset gout mediate inflammatory responsiveness to crystals that could mediate gouty arthritis. This study will contribute to risk prediction and therapeutic interventions to prevent adolescent-onset gout.

Heterologous booster vaccination enhances antibody responses to SARS-CoV-2 by improving Tfh function and increasing B-cell clonotype SHM frequency.

Heterologous prime-boost has broken the protective immune response bottleneck of the COVID-19 vaccines. however, the underlying mechanisms have not been fully elucidated. Here, we investigated antibody responses and explored the response of germinal center (GC) to priming with inactivated vaccines and boosting with heterologous adenoviral-vectored vaccines or homologous inactivated vaccines in mice. Antibody responses were dramatically enhanced by both boosting regimens. Heterologous immunization induced more robust GC activation, characterized by increased Tfh cell populations and enhanced helper function. Additionally, increased B-cell activation and antibody production were observed in a heterologous regimen. Libra-seq was used to compare the differences of S1-, S2- and NTD-specific B cells between homologous and heterologous vaccination, respectively. S2-specific CD19+ B cells presented increased somatic hypermutations (SHMs), which were mainly enriched in plasma cells. Moreover, a heterologous booster dose promoted the clonal expansion of B cells specific to S2 and NTD regions. In conclusion, the functional role of Tfh and B cells following SARS-CoV-2 heterologous vaccination may be important for modulating antibody responses. These findings provide new insights for the development of SARS-CoV-2 vaccines that induce more robust antibody response.

Histidine Protonation Behaviors on Structural Properties and Aggregation Properties of Aß(1-42) Mature Fibril: Approaching by Edge Effects.

The histidine behavior plays a crucial role in the structural and aggregation properties of protein folding and misfolding. Understanding the histidine behavior at the edge of the protein structure is critical for finding ways to disrupt fibril elongation and growth, but this impact remains poorly understood. In the current study, we used molecular dynamics simulations to investigate the edge substitution effect of histidine protonation on the structural and aggregation properties. Our data showed that ΔG1 contributed the most to binding affinity compared to ΔG2 and ΔG3. The different protonation states at the edge chain significantly impacted the secondary structure properties of the edge chain. Specifically, we found that such protonation behavior significantly affected specific regions, particularly the N-terminus (G9-Q15) and C-terminus (K28-A30). Further analysis confirmed that H6, H13, and H14 were directly involved in H-bonding networks with the C1_H14//C2_H13 interchain interactions critical for maintaining the interchain stability. Furthermore, we confirmed that H6, H13, and H14 were directly involved in the loss of the carbon skeleton contact in the N-terminus. Our findings indicate that the edge condition is more susceptible to changes in structural properties than the middle condition. The current study is helpful for understanding the histidine behavior hypothesis in related misfolding diseases.

Immunogenicity of intranasal vaccine based on SARS-CoV-2 spike protein during primary and booster immunizations in mice.

Mucosal immunity plays a crucial role in combating and controlling the spread of highly mutated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recombinant subunit vaccines have shown safety and efficacy in clinical trials, but further investigation is necessary to evaluate their feasibility as mucosal vaccines. This study developed a SARS-CoV-2 mucosal vaccine using spike (S) proteins from a prototype strain and the omicron variant, along with a cationic chitosan adjuvant, and systematically evaluated its immunogenicity after both primary and booster immunization in mice. Primary immunization through intraperitoneal and intranasal administration of the S protein elicited cross-reactive antibodies against prototype strains, as well as delta and omicron variants, with particularly strong effects observed after mucosal vaccination. In the context of booster immunization following primary immunization with inactivated vaccines, the omicron-based S protein mucosal vaccine resulted in a broader and more robust neutralizing antibody response in both serum and respiratory mucosa compared to the prototype vaccine, enhancing protection against different variants. These findings indicate that mucosal vaccination with the S protein has the potential to trigger a broader and stronger antibody response during primary and booster immunization, making it a promising strategy against respiratory pathogens.

The Contribution of Mosaic Chromosomal Alterations to Schizophrenia.

BACKGROUND: Mosaic chromosomal alterations are implicated in neuropsychiatric disorders, but the contribution to schizophrenia (SCZ) risk for somatic copy number variations (sCNVs) emerging in early developmental stages has not been fully established. METHODS: We analyzed blood-derived genotype arrays from 9715 patients with SCZ and 28,822 control participants of Chinese descent using a computational tool (MoChA) based on long-range chromosomal information to detect mosaic chromosomal alterations. We focused on probable early developmental sCNVs through stringent filtering. We assessed the burden of sCNVs across varying cell fraction cutoffs, as well as the frequency with which genes were involved in sCNVs. We integrated this data with the PGC (Psychiatric Genomics Consortium) dataset, which comprises 12,834 SCZ cases and 11,648 controls of European descent, and complemented it with genotyping data from postmortem brain tissue of 936 participants (449 cases and 487 controls). RESULTS: Patients with SCZ had a significantly higher somatic losses detection rate than control participants (1.00% vs. 0.52%; odds ratio = 1.91; 95% CI, 1.47-2.49; two-sided Fisher's exact test, p = 1.49 × 10-6). Further analysis indicated that the odds ratios escalated proportionately (from 1.91 to 2.78) with the increment in cell fraction cutoffs. Recurrent sCNVs associated with SCZ (odds ratio > 8; Fisher's exact test, p < .05) were identified, including notable regions at 10q21.1 (ZWINT), 3q26.1 (SLITRK3), 1q31.1 (BRINP3) and 12q21.31-21.32 (MGAT4C and NTS) in the Chinese cohort, and some regions were validated with PGC data. Cross-tissue validation pinpointed somatic losses at loci like 1p35.3-35.2 and 19p13.3-13.2. CONCLUSIONS: The study highlights the significant impact of mosaic chromosomal alterations on SCZ, suggesting their pivotal role in the disorder's genetic etiology.

Predictors of Inadequate Serum Urate Response to Low-Dose Febuxostat in Male Patients with Gout.

Objective: This study aimed to understand predictors of inadequate response (IR) to low-dose febuxostat treatment based on clinical variables. Methods: We pooled data from 340 patients of an observational cohort and two clinical trials who received febuxostat 20 mg/day for at least 3 months. IR was defined as failure to reach the target serum urate level (sUA<6 mg/dL) at any time point during 3 months treatment. The potential predictors associated with short- or mid-term febuxostat IR after pooling the three cohorts were explored using mixed-effect logistic analysis. Machine learning models were performed to evaluate the predictors for IR using the pooled data as the discovery set and validated in an external test set. Results: Of the 340 patients, 68.9% and 51.8% were non-responders to low-dose febuxostat during short- and mid-term follow-up, respectively. Serum urate and triglyceride (TG) levels were significantly associated with febuxostat IR, but were also selected as significant features by LASSO analysis combined with age, BMI, and C-reactive protein (CRP). These five features in combination, using the best-performing stochastic gradient descent classifier, achieved an area under the receiver operating characteristic curve of 0.873 (95% CI [0.763, 0.942]) and 0.706 (95% CI [0.636, 0.727]) in the internal and external test sets, respectively, to predict febuxostat IR. Conclusion: Response to low-dose febuxostat is associated with early sUA improvement in individual patients, as well as patient age, BMI, and levels of TG and CRP.

Immunogenicity and safety of an ORF7-deficient skin-attenuated and neuro-attenuated live vaccine for varicella: a randomised, double-blind, controlled, phase 2a trial.

BACKGROUND: The Oka varicella vaccine strain remains neurovirulent and can establish lifelong latent infection, raising safety concerns about vaccine-related herpes zoster. In this study, we aimed to evaluate the immunogenicity and safety of a skin-attenuated and neuro-attenuated varicella vaccine candidate (v7D vaccine). METHODS: We did this randomised, double-blind, controlled, phase 2a clinical trial in Jiangsu, China. Healthy children aged 3-12 years with no history of varicella infection or vaccination were enrolled and randomly assigned (1:1:1:1) to receive a single subcutaneous injection of the v7D vaccine at 3·3 log10 plaque forming units (PFU; low-dose v7D group), 3·9 log10 PFU (medium-dose v7D group), and 4·2 log10 PFU (high-dose v7D group), or the positive control varicella vaccine (vOka vaccine group). All the participants, laboratory personnel, and investigators other than the vaccine preparation and management staff were masked to the vaccine allocation. The primary outcome was assessment of the geometric mean titres (GMTs) and seroconversion rates of anti-varicella zoster virus immunoglobulin G (IgG) induced by different dose groups of v7D vaccine at 0, 42, 60, and 90 days after vaccination in the per-protocol set for humoral immune response analysis. Safety was a secondary outcome, focusing on adverse events within 42 days post-vaccination, and serious adverse events within 6 months after vaccination. This study was registered on Chinese Clinical Trial Registry, ChiCTR2000034434. FINDINGS: On Aug 18-21, 2020, 842 eligible volunteers were enrolled and randomly assigned treatment. After three participants withdrew, 839 received a low dose (n=211), middle dose (n=210), or high dose (n=210) of v7D vaccine, or the vOka vaccine (n=208). In the per-protocol set for humoral immune response analysis, the anti-varicella zoster virus IgG antibody response was highest at day 90. At day 90, the seroconversion rates of the low-dose, medium-dose, and high-dose groups of v7D vaccine and the positive control vOka vaccine group were 100·0% (95% CI 95·8-100·0; 87 of 87 participants), 98·9% (93·8-100·0; 87 of 88 participants), 97·8% (92·4-99·7; 91 of 93 participants), and 96·4% (89·8-99·2; 80 of 83 participants), respectively; the GMTs corresponded to values of 30·8 (95% CI 26·2-36·0), 31·3 (26·7-36·6), 28·2 (23·9-33·2), and 38·5 (31·7-46·7). The v7D vaccine, at low dose and medium dose, elicited a humoral immune response similar to that of the vOka vaccine. However, the high-dose v7D vaccine induced a marginally lower GMT compared with the vOka vaccine at day 90 (p=0·027). In the per-protocol set, the three dose groups of the v7D vaccine induced a similar humoral immune response at each timepoint, with no statistically significant differences. The incidence of adverse reactions in the low-dose, medium-dose, and high-dose groups of v7D vaccine was significantly lower than that in the vOka vaccine group (17% [35 of 211 participants], 20% [41 of 210 participants], and 13% [27 of 210 participants] vs 24% [50 of 208 participants], respectively; p=0·025), especially local adverse reactions (10% [22 of 211 participants], 14% [30 of 210 participants] and 9% [18 of 210 participants] vs 18% [38 of 208 participants], respectively; p=0·016). None of the serious adverse events were vaccine related. INTERPRETATION: The three dose groups of the candidate v7D vaccine exhibit similar humoral immunogenicity to the vOka vaccine and are well tolerated. These findings encourage further investigations on two-dose vaccination schedules, efficacy, and the potential safety benefit of v7D vaccine in the future. FUNDING: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, the Fundamental Research Funds for the Central Universities, and Beijing Wantai. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

A phase 3 randomized, open-label study evaluating the immunogenicity and safety of concomitant and staggered administration of a live, pentavalent rotavirus vaccine and an inactivated poliomyelitis vaccine in healthy infants in China.

This open-label, randomized, phase 3 study in China (V260-074; NCT04481191) evaluated the immunogenicity and safety of concomitant and staggered administration of three doses of an oral, live, pentavalent rotavirus vaccine (RV5) and three doses of an intramuscular, inactivated poliomyelitis vaccine (IPV) in 400 healthy infants. The primary objective was the non-inferiority of neutralizing antibody (nAb) responses in the concomitant- versus the staggered-use groups. Antibody responses were measured at baseline and 1-month post-dose 3 (PD3). Parents/legal guardians recorded adverse events for 30 or 15 d after study vaccinations in the concomitant-use or staggered-use groups, respectively. At PD3, >98% of participants seroconverted to all three poliovirus types, and the primary objective was met as lower bounds of the two-sided 95% CI for between-group difference in nAb seroconversion percentages ranged from - 4.3% to - 1.6%, for all poliovirus types, p < .001. At PD3, geometric mean titers (GMTs) of nAb responses to poliovirus types 1, 2, and 3 in the concomitant-use group and the staggered-use group were comparable; 100% of participants had nAb titers ≥1:8 and ≥1:64 for all poliovirus types. Anti-rotavirus serotype-specific IgA GMTs and participants with ≥3-fold rise in postvaccination titers from baseline were comparable between groups. Administration of RV5 and IPV was well tolerated with comparable safety profiles in both groups. The immunogenicity of IPV in the concomitant-use group was non-inferior to the staggered-use group and RV5 was immunogenic in both groups. No safety concerns were identified. These data support the concomitant use of RV5 and IPV in healthy Chinese infants.

Hyperuricemia Subtypes Classified According to Renal Uric Acid Handling Manifesting Distinct Phenotypic and Genetic Profiles in People With Gout.

OBJECTIVE: Hyperuricemia can be stratified into four subtypes according to renal uric acid handling. The aim of this study was to comprehensively describe the biologic characteristics (including genetic background) of clinically defined hyperuricemia subtypes in two large geographically independent gout cohorts. METHODS: Hyperuricemia subtype was defined as renal uric acid overload (ROL), renal uric acid underexcretion (RUE), combined, or renal normal. Twenty single nucleotide polymorphisms (SNPs) previously identified as gout risk loci or associated with serum urate (SU) concentration in the East Asian population were genotyped. Weighted polygenic risk scores were calculated to assess the cumulative effect of genetic risks on the subtypes. RESULTS: Of the 4,873 participants, 8.8% had an ROL subtype, 60.9% RUE subtype, 23.1% combined subtype, and 7.2% normal subtype. The ROL subtype was independently associated with older age at onset, lower SU, tophi, and diabetes mellitus; RUE was associated with lower body mass index (BMI) and non-diabetes mellitus; the combined subtype was associated with younger age at onset, higher BMI, SU, estimated glomerular filtration rate (eGFR), and smoking; and the normal subtype was independently associated with older age at onset, lower SU, and eGFR. Thirteen SNPs were associated with gout with 6 shared loci and subtype-dependent risk loci patterns. High polygenic risk scores were associated with ROL subtype (odds ratio [OR] = 9.63, 95% confidence interval [95% CI] 4.53-15.12), RUE subtype (OR = 2.18, 95% CI 1.57-3.03), and combined subtype (OR = 6.32, 95% CI 4.22-9.48) compared with low polygenic risk scores. CONCLUSION: Hyperuricemia subtypes classified according to renal uric acid handling have subtype-specific clinical and genetic features, suggesting subtype-unique pathophysiologic mechanisms.

The value of musculoskeletal ultrasound in predicting gout flares in index joints: A prospective cohort study of people with gout starting urate-lowering therapy.

OBJECTIVES: To evaluate whether ultrasound findings of monosodium urate (MSU) crystal deposition predict frequent gout flares in index joints over 12 months. METHODS: This single-center study enrolled people with at least one gout flare involving the MTP1, ankle or knee joint. The most painful or most frequently joint was identified as index joint for analysis. All participants were started on urate-lowering therapy and had an ultrasound scan of the index joints at the baseline visit. OMERACT scores (for tophus, double contour sign and aggregates) were used to analyze whether ultrasound scores predicted frequent (≥2) gout flares in the index joint over 12 months. RESULTS: Frequent flares were significantly higher in those with ultrasound findings in all index joints (MTP1: tophus: 85.0% vs 46.0%, P < 0.001, aggregates: 78.8% vs 59.0%, P < 0.01; ankle: tophus: 54.6% vs 20.8%, P < 0.001; aggregates: 60.0% vs 35.9%, P < 0.05; knee: tophus: 68.4% vs 28.6%, P < 0.05). For the MTP1, for each 1-point increase in tophus score, the odds of frequent gout flares increased by 5.19 [(95%CI: 1.26-21.41), 7.91 [(95%CI: 2.23-28.14), and 13.79 [(95%CI: 3.79-50.20)] fold respectively. For the ankle, a tophus score of 3 markedly improved the prediction of the frequent flares [OR= 9.24 (95%CI=2.85-29.91)]. Semi-quantitative sum scores were associated with frequent flares with an OR (95%CI) of 13.66 (3.44-54.18), P < 0.001 at the MTP1, 7.05 (1.98-25.12), P < 0.001 at the ankle. CONCLUSION: Ultrasound features of MSU crystal deposition at the MTP1 and knee predict subsequent risk of frequent gout flares in the same joints following initiation of urate-lowering therapy, with the highest risk in those with high tophus scores.

Natural Changbai mineral water reduces obesity risk through regulating metabolism and gut microbiome in a hyperuricemia male mouse model.

Access to clean and safe drinking water is essential. This study aimed to evaluate the effect of a kind of small molecular natural mineral water, C-cell mineral water on hyperuricemia male mice metabolism condition. A 13-week drinking water intervention study was conducted in Uox-knockout mice (KO). The hepatic metabolite profiling and related genes expression were detected by UPLC-TOF-MS and transcriptomic, and the gut microbiota of KO mice was determined by metagenomics sequencing. Results showed that the body weight of mice fed with C-cell water was remarkably lower than that of control mice on D 77 and D 91. Hepatic metabolite profiling revealed a shift in the pathway of glycine, serine and threonine metabolism, pantothenate and CoA biosynthesis, and biosynthesis of cofactors in KO mice fed with C-cell mineral water. Increased energy metabolism levels were related to increased hepatic expression of genes responsible for coenzyme metabolism and lipid metabolism. Gut microbiota was characterized by increasing activity of beneficial bacteria Blautia, and reducing activity of pathobiont bacteria Parasutterella. These genera have been reported to be associated with obesity. Small molecular mineral-rich natural water ingestion regulates metabolism and gut microbiota, protecting against obesity induced by hyperuricemia through mediating a microbiota-liver axis.

Immune persistence after different polio sequential immunization schedules in Chinese infants.

Trivalent oral poliovirus vaccine (tOPV) has been withdrawn and instead an inactivated poliovirus vaccine (IPV) and bivalent type 1 and type 3 OPV (bOPV) sequential immunization schedule has been implemented since 2016, but no immune persistence data are available for this polio vaccination strategy. This study aimed to assess immune persistence following different polio sequential immunization schedules. Venous blood was collected at 24, 36, and 48 months of age from participants who had completed sequential schedules of combined IPV and OPV in phase III clinical trials. The serum neutralizing antibody titers against poliovirus were determined, and the poliovirus-specific antibody-positive rates were evaluated. A total of 1104 participants were enrolled in this study. The positive rates of poliovirus type 1- and type 3-specific antibodies among the sequential immunization groups showed no significant difference at 24, 36, or 48 months of age. The positive rates of poliovirus type 2-specific antibody in the IPV-IPV-tOPV group at all time points were nearly 100%, which was significantly higher than the corresponding rates in other immunization groups (IPV-bOPV-bOPV and IPV-IPV-bOPV). Immunization schedules involving one or two doses of IPV followed by bOPV failed to maintain a high positive rate for poliovirus type 2-specific antibody.

Edge Substitution Effects of Histidine Tautomerization Behaviors on the Structural Properties and Aggregation Properties of Aß(1-42) Mature Fibril.

Histidine behaviors play critical roles in folding and misfolding processes due to the changes in net charge and the various N/N-H orientations on imidazole rings. However, the effect of histidine tautomerization (HIE (Nε-H, ε) and HID (Nδ-H, δ) states) behaviors on the edge chain of Aß mature fibrils remains inadequately understood, which is critical for finding a strategy to disturb fibril elongation and growth. In the current study, eight independent molecular dynamics simulations were conducted to investigate such impacts on the structural and aggregation properties. Our results from three different binding models revealed that the binding contributions of edge substitution effects are primarily located between chains 1 and 2. Histidine states significantly influence the secondary structure of each domain. Further analysis confirmed that the C1_H6//C1_E11 intrachain interaction is essential in maintaining the internal stability of chain 1, while the C1_H13//C2_H13 and C1_H14//C2_H13 interchain interactions are critical in maintaining the interchain stability of the fibril structure. Our subsequent analysis revealed that the current edge substitution leads to the loss of the C1_H13//C1_E11 intrachain and C1_H13//C2_H14 interchain interactions. The N-terminal regularity was significantly directly influenced by histidine states, particularly by the residue of C1_H13. Our study provides valuable insights into the effect of histidine behaviors on the edge chain of Aß mature fibril, advancing our understanding of the histidine behavior hypothesis in misfolding diseases.

Clinical characteristics of adolescent-onset gout in Chinese: A hospital-based cross-sectional study.

OBJECTIVE: Adolescent-onset gout has a greater impact on the lives and health of patients than adult-onset gout. However, there is a relative lack of clinical information on adolescent-onset gout. Hence, we analyzed a Chinese cohort. METHODS: We studied clinical features of 9,003 Chinese patients. Gout onset age of 12 - 19 years is defined as adolescent-onset group (AG), 20 - 40 years as early-onset group (EG), and 41 - 64 years as late-onset group (LG). Multivariable regression analysis evaluated factors associated with recurrent flares, serum urate (SU) levels, and underexcretion type in AG. RESULTS: Compared with EG and LG, the AG had higher SU levels [AG: 9.5 (2.2) mg/dL, EG: 8.6 (2.1) mg/dL, LG: 7.73 (2.0) mg/dL, P < 0.001], higher percentage of positive family history of gout (AG: 41.8 %, EG: 29.6 %, LG: 24.6 %, P < 0.001), underexcretion type (AG: 62.4 %, EG: 62.5 %, LG: 58.8 %, P = 0.04), recurrent flares (AG: 78.1 %, EG: 70.3 %, LG: 68.9 %, P = 0.01). Urate-lowering therapy (ULT) initiated [OR 6.58 (95 % CI 1.35 - 32.00)] and hypercholesterolemia [OR 4.16 (95 % CI 1.28 - 13.53)] were associated with recurrent flares. eGFR was identified to be a significant variable of increasing SU levels [beta -0.24 (95 % CI -0.04 to -0.01)]. Hypertriglyceridemia [OR 0.35 (95 % CI 0.17 - 0.71)] was related to underexcretion type. CONCLUSION: Adolescent-onset gout patients had clinically distinctive features with higher SU levels, BMI, positive gout family history, underexcretion type and recurrent flares. These specific populations were less likely to achieve ULT target, requiring more clinical attention.

An updated systematic review and meta-analysis of randomised controlled trials on the effects of urate-lowering therapy initiation during a gout flare.

BACKGROUND: There is uncertainty about the optimal time to start urate-lowering therapy (ULT) in the setting of a gout flare. The aim was to perform a systematic review and meta-analysis of randomised controlled trials (RCTs) assessing the effects of ULT initiation during a gout flare. METHODS: This systematic review was conducted in accordance with PRISMA methodology. MEDLINE, EMBASE and The Cochrane Library were searched for studies published between database inception to 1 March 2023. RCTs published in English that examined ULT initiation during a gout flare in adults ≥18 years were included. The quality of included studies was assessed using the revised Cochrane Risk of Bias tool 2.0. Data were extracted for the following outcomes: patient-rated pain score, duration of gout flare, recurrent gout flares, time to achieve target serum urate, adherence to ULT, patient satisfaction with treatment and adverse events. Meta-analyses were performed using Review Manager v5.4. This study is registered on PROSPERO, number CRD42023404680. RESULTS: A total of 972 studies were identified and of these, six RCTs met the criteria for inclusion in the analysis. Three studies were assessed as having high risk of bias, one study as having some concerns, and two studies as having low risk of bias. In total, there were 445 pooled participants; 226 participants randomised to early initiation of ULT and 219 to placebo or delayed initiation of ULT. Allopurinol was used in three studies, febuxostat in two studies and probenecid in one study. Few participants (n = 62, 13.9 %) had tophaceous gout. Participants with renal impairment were excluded from most studies. There were no differences in patient-rated pain scores at baseline, days 3-4, days 7-8, day 10 or days 14-15 (p ≥ 0.42). Additionally, there was no significant difference in time to resolution of gout flare (standardised mean difference 0.77 days; 95 % CI -0.26 to 1.79; p = 0.14) or the risk of recurrent gout flare in the subsequent 28 to 30 days (RR 1.06; 95 % CI 0.59 to 1.92; p = 0.84). Adverse events were similar between groups. The included studies did not report time to achieve target serum urate, long-term adherence to ULT, or patient satisfaction with treatment. CONCLUSION: There appears to be no evidence for harm or for benefit to initiating ULT during a gout flare. These findings have limited applicability to patients with tophaceous gout, or those with renal impairment.

The Immunogenicity of CpG, MF59-like, and Alum Adjuvant Delta Strain Inactivated SARS-CoV-2 Vaccines in Mice.

The continuous evolution and mutation of SARS-CoV-2 have highlighted the need for more effective vaccines. In this study, CpG, MF59-like, and Alum adjuvant Delta strain inactivated SARS-CoV-2 vaccines were prepared, and the immunogenicity of these vaccines in mice was evaluated. The Delta + MF59-like vaccine group produced the highest levels of S- and RBD-binding antibodies and live Delta virus neutralization levels after one shot of immunization, while mice in the Delta + Alum vaccine group had the highest levels of these antibodies after two doses, and the Delta + MF59-like and Delta + Alum vaccine groups produced high levels of cross-neutralization antibodies against prototype, Beta, and Gamma strain SARS-CoV-2 viruses. There was no significant decrease in neutralizing antibody levels in any vaccine group during the observation period. CpG, MF59-like, and Alum adjuvant Delta strain inactivated SARS-CoV-2 vaccines excited different antibody subtypes compared with unadjuvanted vaccines; the Delta + CpG vaccine group had a higher proportion of IgG2b antibodies, indicating bias towards Th1 immunity. The proportions of IgG1 and IgG2b in the Delta + MF59-like vaccine group were similar to those of the unadjuvanted vaccine. However, the Delta + Alum vaccine group had a higher proportion of IgG1 antibodies, indicating bias towards Th2 immunity. Antigen-specific cytokine secretion CD4/8+ T cells were analyzed. In conclusion, the results of this study show differences in the immune efficacy of CpG, MF59-like, and Alum adjuvant Delta strain inactivated SARS-CoV-2 vaccines in mice, which have significant implications for the selection strategy for vaccine adjuvants.

A stable liver-specific urate oxidase gene knockout hyperuricemia mouse model finds activated hepatic de novo purine biosynthesis and urate nephropathy.

Urate oxidase (Uox)-deficient mice could be an optimal animal model to study hyperuricemia and associated disorders. We develop a liver-specific conditional knockout Uox-deficient (UoxCKO) mouse using the Cre/loxP gene targeting system. These UoxCKO mice spontaneously developed hyperuricemia with accumulated serum urate metabolites. Blocking urate degradation, the UoxCKO mice showed significant de novo purine biosynthesis (DNPB) in the liver along with amidophosphoribosyltransferase (Ppat). Pegloticase and allopurinol reversed the elevated serum urate (SU) levels in UoxCKO mice and suppressed the Ppat up-regulation. Although urate nephropathy occurred in 30-week-old UoxCKO mice, 90 % of Uox-deficient mice had a normal lifespan without pronounced urate transport abnormality. Thus, UoxCKO mice are a stable model of human hyperuricemia. Activated DNPB in the UoxCKO mice provides new insights into hyperuricemia, suggesting increased SU influences purine synthesis.