Immunoglobulin repertoire sequencing and de novo sequencing - Powerful tools for identifying free light chains from patients with light chain cast nephropathy.

In patients with light chain cast nephropathy (LCCN), abundantly produced monoclonal immunoglobulin free light chains (FLCs) play a vital role in pathogenesis. Determining the precise sequences of patient-derived FLCs is therefore highly desirable. Although immunoglobulin repertoire sequencing (5' RACE-seq) has been proven to be sensitive enough to provide full-length V(D)J region (variable, diversity and joining genes) of FLCs using bone marrow samples, an invasive and bone marrow independent method is still in demand. Here a de novo sequencing workflow based on the bottom-up proteomics for patient-derived FLCs was established. PEAKS software was used for the de novo sequencing of peptides that were further assembled into full-length FLC sequences. This de novo protein sequencing method can obtain the full-length amino acid sequences of FLCs, and had been shown to be as reliable as 5' RACE-seq. The two LCCN sequences derived from above the two methods were identical, and they possessed more hydrophobic or nonpolar amino acids compared with the corresponding germline, which may be associated with the pathogenesis.

Comparative study of job burnout in Shanghai-based nurses against Maslach norm and Hangzhou norm.

AIM: This study aimed to analyze the trend in job burnout among nurses in Shanghai, China. BACKGROUND: The nursing profession globally faces a significant challenge due to aging populations, causing a human resources crisis. Job burnout notably impacts nurses' enthusiasm for work and their overall well-being. Understanding the trends in job burnout among nurses is crucial for addressing this issue. METHODS: A cross-sectional study involving 799 nurses from a tertiary-care hospital and 11 community health service centers in Pudong New Area South, Shanghai, was conducted using convenience sampling. Data were collected through a general information questionnaire and the Maslach Burnout Inventory scale, to assess job burnout levels. These data were compared with the established Maslach and Hangzhou norms in China. RESULTS: 74.6% of the participants experienced job burnout. The emotional exhaustion dimension had an average score of 27.27 ± 13.93, indicating high levels of burnout; the depersonalization dimension had an average score of 7.83 ± 6.68, showing moderate levels of fatigue; and the personal achievement dimension had an average score of 26.75 ± 10.26, also indicating moderate fatigue. Notably, nurses aged 32-33 years with 11-12 years of professional experience were the most affected. The findings suggest that job burnout is a significant issue in Pudong New Area South, Shanghai, with a notable increase in severe burnout cases over the past decade. CONCLUSION: Nurses, particularly during the COVID-19 pandemic, face high rates of burnout, with emotional exhaustion being particularly prevalent. To support and retain the nursing workforce, hospital administrators must implement external reward mechanisms and develop policies that encourage personal growth, career development, and a humanistic approach to care. IMPLICATIONS FOR NURSING AND HEALTH POLICY: From our review of the literature, we identified instances where burnout standards are either not assessed or lack uniformity in their application. Therefore, it is imperative to adopt a standardized occupational burnout scale for a nationwide survey, encompassing nurse populations across various levels, including province, region, city, and institution. This approach will facilitate the establishment of a practical norm for occupational burnout within China. This norm would enable conducting regular assessments and comparisons to understand the evolving trends of job burnout among nurses, which could pave the way for the creation of targeted support interventions for the nursing profession.

Clinicopathological characteristics and gene mutations in 11 patients with lipoprotein glomerulopathy.

OBJECTIVE: Lipoprotein glomerulopathy (LPG) is a rare disorder characterized by the development of glomerular lipoprotein thrombosis. LPG exhibits familial aggregation, with mutations in the apolipoprotein E (APOE) gene identified as the leading cause of this disease. This study aimed to investigate APOE gene mutations and the clinicopathological features in eleven LPG patients. METHODS: Clinicopathological and follow-up data were obtained by extracting DNA, followed by APOE coding region sequencing analysis. This study analyzed clinical and pathological manifestations, gene mutations, treatment and prognosis. RESULTS: The mean age of the eleven patients was 33.82 years. Among them, five had a positive family history for LPG, ten presented with proteinuria, four exhibited nephrotic syndrome, and six presented with microscopic hematuria. Dyslipidemia was identified in ten patients. In all renal specimens, there was evident dilation of glomerular capillary lumens containing lipoprotein thrombi, and positive oil red O staining was observed in frozen sections of all samples. APOE gene testing revealed that one patient had no mutations, while the remaining ten patients exhibited mutations in the APOE gene, with three patients presenting with multiple mutations simultaneously. Following the confirmation of LPG diagnosis, treatment with angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) was initiated, and the disease progressed slowly. CONCLUSION: LPG is histologically characterized by lamellated lipoprotein thrombi in glomeruli, and kidney biopsy is essential for diagnosis. Mutations in the APOE gene are the leading cause of LPG. This study revealed clinicopathological characteristics and APOE gene mutations in patients with LPG, which helps us better understand the disease.

Facile Oxidation of Ce(III) to Ce(IV) Using Cu(I) Salts.

The synthesis, luminescence, and electrochemical properties of the Ce(III) compound, [(C5Me5)2(2,6-iPr2C6H3O)Ce(THF)], 1, were investigated. Based on the electrochemical data, treatment of 1 with CuX (X = Cl, Br, I) results in the formation of the corresponding Ce(IV) complexes, [(C5Me5)2(2,6-iPr2C6H3O)Ce(X)]. Each complex has been characterized using NMR, IR, and UV-vis spectroscopy as well as structurally determined using X-ray crystallography. Additionally, the treatment of [(C5Me5)2(2,6-iPr2C6H3O)Ce(Br)] with AgF results in the formation of the putative [(C5Me5)2(2,6-iPr2C6H3O)Ce(F)]. The electronic structure of these Ce(IV)-X complexes was investigated by bond analyses and the Ce(IV)-F moiety using quantum chemistry NMR calculations.

Exploring Spin-Orbit Effects in a [Cu6Tl]+ Nanocluster Featuring an Uncommon Tl-H Interaction.

Reaction of [CuH(PPh3)]6 with 1 equiv. of Tl(OTf) results in formation of [Cu6TlH6(PPh3)6][OTf] ([1]OTf]), which can be isolated in good yields. Variable-temperature 1H NMR spectroscopy, in combination with density functional theory (DFT) calculations, confirms the presence of a rare Tl-H orbital interaction. According to DFT, the 1H chemical shift of the Tl-adjacent hydride ligands of [1]+ includes 7.7 ppm of deshielding due to spin-orbit effects from the heavy Tl atom. This study provides valuable new insights into a rare class of metal hydrides, given that [1][OTf] is only the third isolable species reported to contain a Tl-H interaction.

Light-chain proximal tubulopathy: a retrospective study from a single Chinese nephrology referral center.

Background: Light-chain proximal tubulopathy (LCPT) is a rare disease characterized by the accumulation of monoclonal light chains within proximal tubular cells. This study aimed to investigate the clinical characteristics of LCPT from a single Chinese nephrology referral center.Methods: Patients with kidney biopsy-proven isolated LCPT between 2016 and 2022 at Peking University First Hospital were retrospectively included. Clinical data, kidney pathological type, treatment, and prognosis were analyzed.Results: Nineteen patients were enrolled, the mean age at diagnosis was 57 ± 11 and the sex ratio was 6/13 (female/male). Mean proteinuria was 2.44 ± 1.89 g/24 hr and the mean estimated glomerular filtration rate (eGFR) at the point of biopsy was 59.640 ± 27.449 ml/min/1.73 m2. κ-restriction (84%) was dominant among LCPTs. An abnormal free light chain ratio was observed in 86% of the patients. Proximal tubulopathy with cytoplasmic inclusions accounted for the majority (53%), followed by tubulopathy associated with interstitial inflammation reaction (26%), proximal tubulopathy without cytoplasmic inclusions (16%), and proximal tubulopathy with lysosomal indigestion/constipation (5%). One patient presented with acute kidney injury and 16 patients presented with chronic kidney disease. Regarding follow-up, patients received bortezomib-based or R-CHOP chemotherapy or supportive treatment only. The mean follow-up time was 22 ± 16 months, and the mean eGFR was 63.098 ± 27.439 ml/min/1.73 m2 at the end of follow-up. These patients showed improved or stable kidney function.Conclusions: This is the first case series report of LCPT in four different pathological types in northern China. Clone-targeted chemotherapy may help preserve the kidney function in these patients.

Ultrastrong Electron-Phonon Coupling in Uranium-Organic Frameworks Leading to Inverse Luminescence Temperature Dependence.

Electron-phonon interactions, crucial in condensed matter, are rarely seen in Metal-Organic Frameworks (MOFs). Detecting these interactions typically involves analyzing luminescence in lanthanide- or actinide-based compounds. Prior studies on Ln- and Ac-based MOFs at high temperatures revealed additional peaks, but these were too faint for thorough analysis. In our research, we fabricated a high-quality, crystalline uranium-based MOF (KIT-U-1) thin film using a layer-by-layer method. Under UV light, this film showed two distinct "hot bands," indicating a strong electron-phonon interaction. At 77 K, these bands were absent, but at 300 K, a new emission band appeared with half the intensity of the main luminescence. Surprisingly, a second hot band emerged above 320 K, deviating from previous findings in rare-earth compounds. We conducted a detailed ab-initio analysis employing time-dependent density functional theory to understand this unusual behaviour and to identify the lattice vibration responsible for the strong electron-phonon coupling. The KIT-U-1 film's hot-band emission was then utilized to create a highly sensitive, single-compound optical thermometer. This underscores the potential of high-quality MOF thin films in exploiting the unique luminescence of lanthanides and actinides for advanced applications.

Differential contributions of the C5b-9 and C5a/C5aR pathways to microvascular and macrovascular thrombosis in complement-mediated thrombotic microangiopathy patients.

To clarify the role of the C5a/C5aR (C5a receptor) and C5b-9 pathways in macrovascular thrombosis (MAT) and renal microthrombosis (MIT), 73 renal biopsy-proven complement-mediated thrombotic microangiopathy (C-TMA) patients were enrolled; 9 patients with pure MAT and 13 patients with pure MIT were selected for further study. Twenty-five external C-TMA patients were selected as the validation cohort. Plasma C5a and sC5b-9 (soluble C5b-9) levels were significantly higher in patients with MAT than in those with MIT (P = 0.008, P = 0.041, respectively). The mean optical density of C5aR1 in the kidney was significantly higher in MAT patients than in those with MIT (P < 0.001). Both urinary sC5b-9 levels (MIT: P < 0.001, MAT: P = 0.004) and renal deposition of C5b-9 (MIT: P < 0.001, MAT: P = 0.001) were significantly higher in C-TMA patients compared to normal control, but were similar between MAT and MIT groups. In the correlation analysis within 22C-TMA patients, urinary sC5b-9 levels and renal deposition of C5b-9 were positively correlated to renal MIT formation (P = 0.009 and P = 0.031, respectively). Furthermore, the renal citrullinated histone H3 (CitH3)- and neutrophil elastase (NE)-positive area ratios were both significantly higher in the MAT group than in the MIT group (P = 0.006 and P = 0.020, respectively). Therefore, the local C5b-9 and C5a/C5aR1 pathways might have differential contributions to MIT and MAT formation in the disease.

Assessing the Clinical Impact of Percutaneous Coronary Intervention in Patients with Acute Myocardial Infarction.

Background: Percutaneous coronary intervention (PCI) has emerged as a pivotal intervention in reducing mortality among ST-segment elevation myocardial infarction (STEMI) patients. Objective: This study aimed to evaluate the clinical effectiveness of PCI in the management of acute myocardial infarction (AMI). Design: A retrospective study design was adopted. Setting: The study was conducted at the Affiliated Taizhou People's Hospital of Nanjing Medical University. Participants: A total of 126 AMI patients were selected and categorized into two groups based on their treatment regimen: the study group (n=76) underwent PCI, while the control group (n=50) received standard drug therapy. Interventions: The control group was managed with conventional drug treatment, while the study group underwent PCI. Primary Outcome Measures: The primary outcome measures included (1) N-terminal pro-B-type natriuretic peptide levels, (2) cardiac function, (3) total clinical effectiveness, (4) incidence of adverse cardiovascular events, and (5) quality of life. Results: After treatment, both groups exhibited a reduction in N-terminal pro-B-type natriuretic peptide levels, with a more significant decrease observed in the study group compared to the control group (P < .05). Post-treatment left ventricular end-diastolic and end-systolic volumes decreased, while left ventricular ejection fraction increased in both groups. The study group exhibited more substantial improvements in these parameters compared to the control group (P < .05). The study group also demonstrated a higher total clinical effectiveness rate (χ2 = 9.95, P < 0.05) and a lower incidence of adverse cardiovascular events during follow-up (P < .05). Additionally, both groups reported an increase in quality-of-life scores, with the study group experiencing a more significant improvement (P < .05). Conclusions: This study suggests that PCI, when applied in the clinical management of AMI patients, can significantly reduce N-terminal pro-B-type natriuretic peptide levels, enhance cardiac function, lower the occurrence of cardiovascular adverse events, and improve patients' overall quality of life.

The Prevalence and Characteristics of Circulating IgA Anti-Glomerular Basement Membrane Autoantibodies in Anti-Glomerular Basement Membrane Disease.

Introduction: In some cases, immunoglobulin (IgA)-mediated antiglomerular basement membrane (anti-GBM) disease has been reported. Whether circulating IgA anti-GBM antibodies affect the clinico-pathologic characteristics and outcome of typical anti-GBM disease deserves further study. Methods: Circulating IgA anti-α3(IV)NC1 antibodies were examined by enzyme-linked immunosorbent assay (ELISA) using recombinant human α3(IV)NC1 as solid phase antigens in 107 patients with anti-GBM disease and 115 controls. Clinical, pathological, and follow-up data of patients were retrospectively analyzed. Results: Circulating IgA anti-α3(IV)NC1 antibodies were found in 18.7% (20/107) of patients with anti-GBM disease but were not detected in healthy controls or in patients with other glomerular diseases. The positivity of circulating IgA anti-α3(IV)NC1 antibodies was not associated with whether the patient was with combined IgA nephropathy or other glomerulonephritis. Kidney immunofluorescence showed no statistical difference in IgA deposition between patients with circulating IgA anti-α3(IV)NC1 antibodies and patients without (30.0% vs. 40.4%, P = 0.725). The titers of circulating immunoglobulin G (IgG) anti-α3(IV)NC1 antibodies in patients with circulating IgA anti-α3(IV)NC1 antibodies were significantly higher than those without (200 [183.3, 200] vs. 161 [85.5, 200] U/ml, P = 0.005). There were no significant differences in kidney outcome and mortality between the 2 groups. Conclusion: Circulating IgA anti-α3(IV)NC1 antibodies occurred in 18.7% (20/107) of patients with anti-GBM in our center and were specific to anti-GBM disease. Patients with circulating IgA anti-α3(IV)NC1 antibodies showed a higher levels of serum IgG anti-α3(IV)NC1 antibodies than those without.

Quantifying Actinide-Carbon Bond Covalency in a Uranyl-Aryl Complex Utilizing Solution 13C NMR Spectroscopy.

Reaction of [UO2Cl2(THF)2]2 with in situ generated LiFmes (FmesH = 1,3,5-(CF3)3C6H3) in Et2O resulted in the formation of the uranyl aryl complexes [Li(THF)3][UO2(Fmes)3] ([Li(THF)3][1]) and [Li(Et2O)3(THF)][UO2(Fmes)3] ([Li(Et2O)3(THF)][1]) in good to moderate yields after crystallization from hexanes and Et2O, respectively. Both complexes were characterized by X-ray crystallography and NMR spectroscopy. DFT calculations reveal that the Cispo resonance in [1]- exhibits a deshielding of 51 ppm from spin-orbit coupling effects originating at uranium, which indicates an appreciable covalency in the U-C bonding interaction.

Characteristics of Complement Protein Deposition in Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposition.

BACKGROUND: Hypocomplementemia and complement co-deposition with monoclonal immunoglobulins in glomeruli are not rare in proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID). Deposition of monoclonal immunoglobulins in glomeruli has been suggested to activate complement and cause kidney injury. However, the profiles of complement activation in PGNMID and their clinical and pathologic significance need to be clarified. METHODS: Forty-six patients with PGNMID were enrolled. Proteomic analysis of glomeruli using laser microdissection and mass spectrometry was performed for ten patients with PGNMID to determine the composition of glomerular deposits. Kidney deposition of complement components was detected by immunohistochemistry and immunofluorescence. Urinary and plasma levels of complement components were measured by an enzyme-linked immunosorbent assay. Group differences were assessed using t tests or Mann-Whitney U tests depending on the distribution. Correlation analysis was performed using Spearman rank correlation or Pearson correlation. RESULTS: Laser microdissection and mass spectrometry-based proteomic analysis showed that complement components were the most enriched proteins deposited in the glomeruli of patients with PGNMID. Glomerular deposition of C3c, C4d, and C5b-9 was detected in most patients. Levels of urinary and plasma C3a, C5a, soluble C5b-9, C4d, Bb, and C1q as well as urinary mannose-binding lectin were significantly higher in patients with PGNMID compared with healthy controls. The intensity of C3c and C4d deposition in glomeruli correlated with serum creatinine and the percentage of crescents, respectively. Furthermore, levels of urinary complement components correlated positively with serum creatinine, urinary protein excretion, percentage of crescents, and global glomerulosclerosis in kidney biopsies, whereas plasma levels of most complement components did not show a significant correlation with clinicopathologic parameters. In multivariable analysis, a higher level of urinary C4d was identified as an independent risk factor of kidney failure. CONCLUSIONS: The complement system was found to be overactivated in PGNMID, and levels of urinary complements correlated with disease severity. A higher level of urinary C4d was identified as an independent risk factor of kidney failure.

Clinical and immunological characteristics of patients with combined anti-glomerular basement membrane disease and IgA nephropathy.

Background: The combination of anti-glomerular basement membrane (GBM) disease and immunoglobulin A nephropathy (IgAN) has been well documented in sporadic cases, but lacks overall assessment in large collections. Herein, we investigated the clinical and immunological characteristics and outcome of this entity. Methods: Seventy-five consecutive patients with biopsy-proven anti-GBM disease from March 2012 to March 2020 were screened. Among them, patients with concurrent IgAN were identified and enrolled. The control group included biopsied classical anti-GBM patients during the same period, excluding patients with IgAN, other glomerular diseases or tumors, or patients with unavailable blood samples and missing data. Serum IgG and IgA autoantibodies against GBM were detected by enzyme-linked immunosorbent assay, as were circulating IgG subclasses against GBM. Results: Fifteen patients with combined anti-GBM disease and IgAN were identified, accounting for 20% (15/75) of all patients. Among them, nine were male and six were female, with an average (± standard deviation) age of 46.7 ± 17.3 years. Thirty patients with classical anti-GBM disease were enrolled as controls, with 10 males and 20 females at an average age of 45.4 ± 15.3 years. Patients with combined anti-GBM disease and IgAN had restricted kidney involvement without pulmonary hemorrhage. Compared with classical patients, anti-GBM patients with IgAN presented with significantly lower levels of serum creatinine on diagnosis (6.2 ± 2.9 vs 9.5 ± 5.4 mg/dL, P = .03) and less occurrence of oliguria/anuria (20%, 3/15 vs 57%, 17/30, P = .02), but more urine protein excretion [2.37 (1.48, 5.63) vs 1.11 (0.63, 3.90) g/24 h, P = .01]. They showed better kidney outcome during follow-up (ESKD: 47%, 7/15 vs 80%, 24/30, P = .03). The autoantigen and epitope spectrum were comparable between the two groups, but the prevalence of circulating anti-α3(IV)NC1 IgG1 (67% vs 97%, P = .01) and IgG3 (67% vs 97%, P = .01) were lower in patients with IgAN. Conclusions: Concurrent IgAN was not rare in anti-GBM disease. Patients showed milder kidney lesions and better recovery after immunosuppressive therapies. This might be partly explained by lower prevalence of anti-GBM IgG1 and IgG3 in these patients.

Magnetic Properties of Tetravalent Pu in the Perovskites BaPuO3 and SrPuO3.

BaPuO3 and SrPuO3 were synthesized, and their structures were refined in the orthorhombic space group Pbnm, a common distortion from the classic Pm3̅m cubic perovskite. Magnetic-susceptibility measurements, obtained as a function of temperature over the range of 1.8-320 K, exhibit temperature-dependent behavior, with evidence of long-range magnetic order at temperatures higher than their lanthanide and actinide analogues: BaPuO3 below 164(1) K and SrPuO3 below 76(1) K. Effective moments of 1.66(10)µB for BaPuO3 and 1.84(8)µB for SrPuO3 were obtained by fitting their paramagnetic susceptibilities using the Curie-Weiss law. Both are below the free-ion value of 2.68 µB expected for a Pu4+ 5I4 ground level. Ab initio wave function calculations, performed at the relativistic complete active space level including spin-orbit coupling and with an embedded cluster approach that neglects interactions between Pu centers, were used to generate embedded-cluster Pu4+ magnetic susceptibilities. The calculations agree well with experimental data at higher temperatures, providing evidence that a single-ion representation is sufficient to account for the observed paramagnetic behavior without the need to invoke charge transfer, disproportionation, strong covalent bonding, or other more complex electronic behavior.

An Investigation of the Correlation between miRNA-21-5p and the Classification and Short-term Prognosis of Acute Ischemic Cerebrovascular Disease.

Objective: This study aimed to investigate the potential of miRNA-21-5p as a diagnostic and prognostic marker for acute ischemic stroke (AIS), specifically examining its relevance in distinguishing between AIS and transient ischemic attack (TIA) and its predictive ability for short-term prognosis. Methods: A total of 84 AIS patients (AIS group), 39 TIA cases (TIA group), and 30 healthy volunteers (Control group) were enrolled in this study. The relative expressions of miRNA-21-5p in serum upon admission were recorded and compared. The statistical analysis involved employing Student's t-test or analysis of variance (ANOVA) to compare means. Additionally, linear correlations were evaluated to determine the associations between different variables. Results: The expression of miRNA-21-5p was significantly upregulated in the AIS group compared to the TIA and Control groups (P < .001), with no statistical difference observed between the TIA and Control groups. Furthermore, within the AIS group, the expression of miRNA-21-5p was found to be significantly increased in the poor prognosis subgroup (mRS 3-6 points) compared to the good prognosis subgroup (mRS 0-2 points) (P < .05). The area under the curve (AUC) of miRNA-21-5p for predicting AIS from TIA and 30-day poor prognosis of AIS were 0.710 and 0.641, respectively. Additionally, miRNA-21-5p showed positive correlations with the National Institutes of Health Stroke Scale (NIHSS) score and modified Rankin Scale (mRS) score of AIS patients, respectively. Conclusions: Serum miRNA-21-5p levels exhibit considerable potential as a promising biomarker. They play a crucial role in distinguishing between AIS and TIA. Additionally, these levels offer valuable predictive insights into the severity and short-term prognosis of AIS.

Establishing a novel and sensitive assay for bioactivity determination of anti-CD25 antibodies.

Anti-CD25 antibodies have been approved for renal transplantation and has been used prior to and during transplantation by the Food and Drug Administration (FDA). However, no reported bioassays have been reflected the mechanism of action (MOA) of anti-CD25 antibodies. Here, we describe the development and validation of a reporter gene assay (RGA) based on the engineered C8166-STAT5RE-Luc cells expressing endogenous IL-2 receptors and a STAT5-inducible element-driven firefly luciferase in C8166 cell lines. The RGA was fully validated according to the International Conference on the Harmonization of Technical Requirements for the Registration of Pharmaceuticals for the Human Use-Q2 (ICH-Q2). After optimization, the assay showed excellent specificity, linearity, accuracy, precision, and robustness. Due to the MOA relatedness and the excellent assay performance, the RGA is suitable for exploring the critical quality attributes (CQAs), release inspection, comparability and stability of anti-CD25 mAbs.

Anti-complement factor H (CFH) autoantibodies could delay pristane-induced lupus nephritis.

PURPOSE: Anti-complement factor H (CFH) autoantibodies could be detected in lupus and its significance remained to be elucidated. Herein, we aimed to explore the roles of anti-CFH autoantibodies based on pristane-induced lupus mice. METHODS: Twenty-four female Balb/c mice were randomly divided into four groups, with one group injected with pristane (pristane group), one group with pristane and then human CFH (hCFH) (pristane-CFH group) 3 times, and the other two as vertical controls, PBS group and PBS-CFH group. Histopathological analysis was performed six months after pristane administration. Levels of hCFH, anti-CFH autoantibodies and anti-dsDNA antibody were detected. Murine IgG (mIgG) were purified and cross-reactivity, epitopes, subclasses and functional analysis were further evaluated in vitro. RESULTS: Immunization with hCFH and subsequent development of anti-CFH autoantibodies significantly attenuated nephritis of pristane-induced lupus, including lower levels of urinary protein and serum creatinine, decreased levels of serum anti-dsDNA antibody, greatly ameliorated renal histopathologic damage, decreased IgG, complements (C1q, C3) deposits and lower inflammatory factor (IL-6) expression in glomerulus. Furthermore, the purified mIgG (contained anti-CFH autoantibodies) could recognize both hCFH and murine CFH, and the epitopes were predominantly located in hCFH short consensus repeats (SCRs) 1-4, 7 and 11-14. The IgG subclasses were predominant IgG1. The autoantibodies could enhance the binding between hCFH and C3b, and increase factor I mediated-C3b lysis in vitro. CONCLUSION: Our results suggested that anti-CFH autoantibodies could attenuate pristane-induced lupus nephritis by increasing bio-functions of CFH on regulating complement activation and controlling inflammation.

Safety and immunogenicity of a skin- and neuro-attenuated live vaccine for varicella: a randomized, double-blind, controlled, dose-escalation and age de-escalation phase 1 clinical trial.

Background: Despite the success in decreasing varicella-related disease burden, live-attenuated Oka vaccine strain of varicella-zoster virus (vOka) remains neuro-virulence and may establish latency and reactivate, raising safety concerns. Here we aimed to evaluate the safety and immunogenicity of a skin- and neuro-attenuated varicella vaccine candidate (v7D). Methods: This is a randomized, double-blind, placebo-controlled, dose-escalation and age de-escalation phase 1 clinical trial conducted in Liuzhou, China (ChiCTR1900022284). Eligible healthy participants aged 1-49 years, with no history of varicella vaccination and had no history of varicella or herpes zoster were sequentially enrolled and allocated to subcutaneously receive one of the three doses (3.3, 3.9, and 4.2 lg PFU) of v7D, vOka or placebo in a dose-escalation and age de-escalation manner. The primary outcome was safety, assessed by adverse events/reactions within 42 days after vaccination and serious adverse events (SAEs) throughout six months after vaccination. The secondary outcome was immunogenicity, assessed by the VZV IgG antibodies measured with fluorescent antibody to membrane antigen (FAMA) assay. Findings: Between April 2019 and March 2020, totally 224 participants were enrolled. Within 42 days post-vaccination, the incidences of adverse reactions were 37.5%-38.7% in the three doses of v7D groups which were similar to that of the vOka (37.5%) and placebo (34.4%) groups. No SAE has been judged as causally related to vaccination. At 42 days post-vaccination, 100% of children aged 1-12 years in the per-protocol set of immunogenicity cohort of the v7D groups became seropositive. Meanwhile, in the intent-to-treat set of immunogenicity cohort of subjects aged 1-49 years, the geometric mean increases of the three groups of v7D vaccine were 3.8, 5.8 and 3.2, respectively, which were similar to that of the vOka vaccine group (4.4) and significantly higher than that of the placebo group (1.3). Interpretation: The candidate v7D vaccine has been preliminarily shown to be well-tolerated and immunogenic in humans. The data warrant further evaluation of the safety advantage and efficacy of v7D as a varicella vaccine. Funding: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, and Beijing Wantai CO., LTD.