Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening.

Mitochondria are key regulators of hematopoietic stem cell (HSC) homeostasis. Our research identifies the transcription factor Nynrin as a crucial regulator of HSC maintenance by modulating mitochondrial function. Nynrin is highly expressed in HSCs under both steady-state and stress conditions. The knockout Nynrin diminishes HSC frequency, dormancy, and self-renewal, with increased mitochondrial dysfunction indicated by abnormal mPTP opening, mitochondrial swelling, and elevated ROS levels. These changes reduce HSC radiation tolerance and promote necrosis-like phenotypes. By contrast, Nynrin overexpression in HSCs diminishes irradiation (IR)-induced lethality. The deletion of Nynrin activates Ppif, leading to overexpression of cyclophilin D (CypD) and further mitochondrial dysfunction. Strategies such as Ppif haploinsufficiency or pharmacological inhibition of CypD significantly mitigate these effects, restoring HSC function in Nynrin-deficient mice. This study identifies Nynrin as a critical regulator of mitochondrial function in HSCs, highlighting potential therapeutic targets for preserving stem cell viability during cancer treatment.

[The Efficacy and Influencing Factors of Cyclosporine Alone in the Treatment of Children with Acquired Aplastic Anemia].

OBJECTIVE: To analyze the efficacy and influencing factors of cyclosporine (CsA) alone in the treatment of children with acquired aplastic anemia (AA). METHODS: The clinical data of children diagnosed with AA and treated with CsA alone from January 1, 2016 to December 31, 2020 in the Children's Hospital of Chongqing Medical University were collected, and the efficacy and influencing factors of CsA treatment were evaluated. RESULTS: Among the 119 patients, there were 62 male and 57 female, with a median age of 7 years and 1 month. There were 45 cases of very severe AA (VSAA), 47 cases of severe AA (SAA), and 27 cases of non-severe AA (NSAA). At 6 months after treatment, the efficacy of VSAA was lower than that of SAA and NSAA, and there was a statistical difference (P < 0.01). 6 cases died early, 16 cases relapsed, 2 cases progressed to AML and ALL. The results of univariate analysis showed that the high proportion of lymphocyte in the bone marrow at 6 months was an adverse factor for the efficacy of CsA, while high PLT count was a protective factor (P =0.008, P =0.002). The ROC curve showed that the cut-off values of PLT count and the proportion of bone marrow lymphocyte at 6 months were 16.5×109 /L, 68.5%, respectively. Multivariate analysis showed that the high proportion of lymphocyte in bone marrow at 6 months was an independent adverse factor for IST (P =0.020, OR =0.062), and high PLT count was a protective factor (P =0.044, OR =1.038). At 3 months of treatment, CsA response and NSAA were the risk factor for recurrence (P =0.001, 0.031). CONCLUSION: The efficacy of NSAA was higher than that of SAA and VSAA after 6 months of treatment with CsA alone. A high PLT count at the initial diagnosis was a good factor for the effectiveness of CsA, and a high proportion of bone marrow lymphocyte was an unfavorable factor. CsA response at 3 months and NSAA were risk factors for recurrence.

Successful Immune Reconstitution in a Patient with a TYK2 Deficiency after Allogeneic Stem Cell Transplantation from Unrelated Donors.

A boy with primary immunodeficiency, caused by a tyrosine kinase 2 (TYK2) mutation, presented with immune defects and a lifelong history of severe infections. Our aim was to determine whether allogeneic hematopoietic stem cell transplantation (HSCT) could restore the patient's immune defenses and reduce susceptibility to infection. In the absence of a suitable HLA-matched blood relative to act as a donor, the patient received an allogeneic HSCT from unrelated donors. The patient's clinical data were analyzed in the Children's Hospital of Chongqing Medical University (Chongqing, China) before transplantation and during the 4-year follow-up period using a combination of western blotting (e.g., TYK2 and STAT levels), qRT-PCR (e.g., T cell receptor rearrangement excision circles, kappa deletion element recombination circles, and TYK2 transcript levels), and flow cytometry (e.g., lymphocyte subpopulations and CD107α secretion). We found that HSCT significantly reduced the incidence of severe infections, restored normal TKY2 levels, and reversed defects such as impaired JAK/STAT signaling in response to interferon-α or interleukin-10 treatment. Although the patient did not develop acute graft-versus-host disease (GVHD) after transplantation, he did experience chronic GVHD symptoms in a number of organs, which were effectively managed. Our findings suggest that HSCT is a feasible strategy for reconstituting the immune system in TYK2-deficient patients; however, the factors associated with GVHD and autoimmune thyroiditis development in TYK2-deficient patients undergoing HSCT warrant further investigation.

Lymphocyte counts predict optimal timing of chemotherapy reinitiation after antivirus treatment for herpes zoster in children with leukemia.

Herpes zoster (HZ) is rare in healthy children, but more prevalent in those with leukemia. Optimal timing of chemotherapy reinitiation after HZ treatment is challenging because chemotherapy suppresses immunity and increases risk of HZ relapse. We aimed to optimize the timing of chemotherapy reinitiation after HZ therapy in children with leukemia. The study included 31 children with acute leukemia and HZ infection. General information, clinical symptoms, laboratory test results, duration of HZ treatment, and prognosis were compared with those of children with leukemia alone. Correlation analysis was performed for 20 children who restarted chemotherapy after HZ treatment. Of 31 children with leukemia and HZ, 67.74% had lesions at multiple sites. The median time from chemotherapy initiation to HZ onset was 14.1 (1.5-29.5) months. Among 27 children included in the follow-up, there was one case of HZ relapse. After excluding children who did not continue chemotherapy after HZ treatment, the median interval between completion of HZ therapy and chemotherapy reinitiation in the remaining 20 children was 8.00 (- 3 to 27) days. Lymphocyte counts (LY#) on restarting chemotherapy correlated inversely with HZ lesion healing time (p < 0.05). LY# at the time of HZ onset were lower than those pre- and post-onset, and lower than those in the control group (p < 0.05). In conclusion, children with leukemia have a good HZ prognosis, but an increased risk of HZ recurrence. LY# at the time of chemotherapy reinitiation may be a useful indicator for selecting the optimal interval between antiviral therapy completion and chemotherapy reinitiation.

Risk factors and survival outcomes in children with early cardiotoxicity after allogeneic hematopoietic stem cell transplantation.

Cardiotoxicity in children is a potentially fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT); therefore, early identification of risk factors can improve patient prognosis. However, there are few data on the clinical characteristics of early-stage cardiotoxicity in children after allo-HSCT. We conducted a retrospective single-center study of pediatric patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) between January 2016 and December 2022 at the Children's Hospital Affiliated with Chongqing Medical University to evaluate the clinical characteristics of early cardiac events (ECEs) after allo-HSCT and their impact on survival outcomes. We enrolled 444 patients who underwent allo-HSCT-304 males (68%) and 140 females (32%)-with a median age of 3.3 years (1.8-6.5 years) at transplantation. We found that 73 patients (16.4%) had ECEs after allo-HSCT. The ECEs included valvular disease (n = 46), pericardial effusion (n = 38), arrhythmia (n = 9), heart failure (n = 16), and dilated cardiomyopathy (n = 1). Female sex, age ≥ 6 years, body mass index (BMI) < 16 kg/m2 and HLA-type mismatches were risk factors for ECEs. We designed a stratified cardiac risk score that included these risk factors, and the higher the score was, the greater the cumulative incidence of ECEs. The occurrence of an ECE was closely associated with a lower overall survival (OS) rate and greater nonrelapse mortality (NRM). In addition, stratified analysis based on the number of combined ECEs showed that the greater the number of combined ECEs was, the more significant the negative impact on OS rates.

Prediction of tumor lysis syndrome in childhood acute lymphoblastic leukemia based on machine learning models: a retrospective study.

Background: Tumor lysis syndrome (TLS) often occurs early after induction chemotherapy for acute lymphoblastic leukemia (ALL) and can rapidly progress. This study aimed to construct a machine learning model to predict the risk of TLS using clinical indicators at the time of ALL diagnosis. Methods: This observational cohort study was conducted at the National Clinical Research Center for Child Health and Disease. Data were collected from pediatric ALL patients diagnosed between December 2008 and December 2021. Four machine learning models were constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) to select key clinical indicators for model construction. Results: The study included 2,243 pediatric ALL patients, and the occurrence of TLS was 8.87%. A total of 33 indicators with missing values ≤30% were collected, and 12 risk factors were selected through LASSO regression analysis. The CatBoost model with the best performance after feature screening was selected to predict the TLS of ALL patients. The CatBoost model had an AUC of 0.832 and an accuracy of 0.758. The risk factors most associated with TLS were the absence of potassium, phosphorus, aspartate transaminase (AST), white blood cell count (WBC), and urea levels. Conclusion: We developed the first TLS prediction model for pediatric ALL to assist clinicians in risk stratification at diagnosis and in developing personalized treatment protocols. This study is registered on the China Clinical Trials Registry platform (ChiCTR2200060616). Clinical trial registration: https://www.chictr.org.cn/, identifier ChiCTR2200060616.

Engineering functional materials through bacteria-assisted living grafting.

Functionalizing materials with biomacromolecules such as enzymes has broad applications in biotechnology and biomedicine. Here, we introduce a grafting method mediated by living cells to functionalize materials. We use polymeric scaffolds to trap engineered bacteria and micron-sized particles with chemical groups serving as active sites for grafting. The bacteria synthesize the desired protein for grafting and autonomously lyse to release it. The released functional moieties are locally grafted onto the active sites, generating the materials engineered by living grafting (MELGs). MELGs are resilient to perturbations because of both the bonding and the regeneration of functional domains synthesized by living cells. The programmability of the bacteria enables us to fabricate MELGs that can respond to external input, decompose a pollutant, reconstitute synthetic pathways for natural product synthesis, and purify mismatched DNA. Our work establishes a bacteria-assisted grafting strategy to functionalize materials with a broad range of biological activities in an integrated, flexible, and modular manner. A record of this paper's transparent peer review process is included in the supplemental information.

New Analogues of Amides and Quinolinones Produced by Streptomyces sp. YIM S01983.

Streptomide (1), a new amide analogue, streptomynone (2), a new quinolinone, and ten known compounds including three aliphatic acids (3-5), two amides (6-7), four cyclic dipeptides (8-11), and an adenosine (12) were isolated from the fermentation broth of Streptomyces sp. YIM S01983 isolated from a sediment sample collected in Bendong Village, Huadong Town, Chuxiong, China. Their structures were determined by analysis of the 1D/2D-NMR and HR-ESI-MS spectra. Compound 12 presented weak antimicrobial activities against Candida albicans and Aligenes faecalis (MIC=64 µg/mL). Compounds 7 and 12 showed weak cytotoxic activity against MHCC97H.

Effect of allogeneic hematopoietic stem cell transplantation for chronic granulomatous disease in children: A multicentre, retrospective cohort study in China.

Chronic granulomatous disease (CGD) in children is a rare primary immunodeficiency disorder that can lead to life-threatening infections and inflammatory complications. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is increasingly being used to treat severe CGD in children. We conducted a multicenter retrospective analysis of children with CGD who were treated with allo-HSCT at four pediatric hematopoietic stem cell transplant centers in China from September 2005 to December 2019. The study included a total of 171 patients (169 males and 2 females). The median age at the time of transplantation was 6.1 (0-16.4) years. Among them, 154 patients had X-linked recessive inheritance caused by CYBB gene mutations, 12 patients were autosomal recessive, 1 patient had DNAH11 and HYDIN gene mutations, and 4 patients had no gene mutations. The median follow-up period was 36.3 (1.9-79) months. All participating patients were applied to myeloablative conditioning (MAC) regimens. The rates of OS, EFS, and GEFS within three years were 87.5%, 85.3%, and 75.2%, respectively. The total graft failure and the total mortality rate were 5.3% and 11.1%. The cumulative incidence of acute GVHD was 53.8% and the incidence of chronic GVHD was 12.9%, The incidence of chronic GVHD was higher for patients who received unrelated donor cord blood stem cell transplantation (UD-CB) (P = 0.001). Chronic GVHD and coinfections are the risk factors for OS and EFS in patients with CGD after receiving allo-HSCT. UD-CB is a risk factor for EFS and the presence of pneumonia before transplantation is a risk factor for OS. In conclusion, through this study, we have demonstrated that allo-HSCT has excellent efficacy in the treatment of CGD in children, especially, RD-haplo is associated with a lower rate of graft failure incidence and mortality than the treatment modalities of other donor type. Therefore, allo-HSCT is strongly recommended when a well-matched donor is available. If a well-matched donor is not available, the HLA-mismatched donor should be carefully evaluated, and the conditioning regimen modified accordingly.

Evaluating sequential and allosteric activation models in IKs channels with mutated voltage sensors.

The ion-conducting IKs channel complex, important in cardiac repolarization and arrhythmias, comprises tetramers of KCNQ1 α-subunits along with 1-4 KCNE1 accessory subunits and calmodulin regulatory molecules. The E160R mutation in individual KCNQ1 subunits was used to prevent activation of voltage sensors and allow direct determination of transition rate data from complexes opening with a fixed number of 1, 2, or 4 activatable voltage sensors. Markov models were used to test the suitability of sequential versus allosteric models of IKs activation by comparing simulations with experimental steady-state and transient activation kinetics, voltage-sensor fluorescence from channels with two or four activatable domains, and limiting slope currents at negative potentials. Sequential Hodgkin-Huxley-type models approximately describe IKs currents but cannot explain an activation delay in channels with only one activatable subunit or the hyperpolarizing shift in the conductance-voltage relationship with more activatable voltage sensors. Incorporating two voltage sensor activation steps in sequential models and a concerted step in opening via rates derived from fluorescence measurements improves models but does not resolve fundamental differences with experimental data. Limiting slope current data that show the opening of channels at negative potentials and very low open probability are better simulated using allosteric models of activation with one transition per voltage sensor, which implies that movement of all four sensors is not required for IKs conductance. Tiered allosteric models with two activating transitions per voltage sensor can fully account for IKs current and fluorescence activation kinetics in constructs with different numbers of activatable voltage sensors.

The distribution of intestinal flora after hematopoietic stem cell transplantation in children.

BACKGROUND: This prospective study aimed to comprehensively understand the changes in intestinal flora at different stages after hematopoietic stem cell transplantation (HSCT) in pediatric patients and to analyze the effect of intestinal flora on acute graft versus host disease (aGVHD), especially on gastrointestinal graft versus host disease (GI GVHD). METHODS: A total of 32 children with primary diseases of primary immunodeficiency disease (PID) and thalassemia were included. 16S sequencing was used to characterize the microbiota layout at three time points peri-transplant including pre-transplant, Day +3, and Day +30. RESULTS: By comparing the intestinal flora of children with GI GVHD and those without GI GVHD, it suggests that in children with GI GVHD, the distribution of intestinal flora after transplantation was more variable and more chaotic (chao1 index, Friedman test, p = .029). Besides, Veillonella and Ruminococcaceae were more abundant before transplantation, Bifidobacteriaceae and Bacillales were more abundant after transplantation. Comparing children with PID and thalassemia, it was found that the destruction of gut microbiota diversity was more significant in children with thalassemia after transplantation. The comparison of children with 0-I° aGVHD and II-III° aGVHD indicates that children with II-III° aGVHD had more Bilophila before transplantation than children with 0-I° aGVHD. Additionally, exploratory analyses to evaluate correlations between clinical characteristics (medications, immune cell recovery, etc.) and microbiome features were also performed. CONCLUSIONS: This study has synthetically shown the distribution of intestinal flora after allo-HSCT, and some characteristic bacteria at different stages that may serve as potential biomarkers were screened out additionally, perhaps providing clues for the prevention and treatment of the disease.

Predictive model for early death risk in pediatric hemophagocytic lymphohistiocytosis patients based on machine learning.

Background: Hemophagocytic Lymphohistiocytosis (HLH) is a rare and life-threatening disease in children, with a high early mortality rate. This study aimed to construct machine learning model to predict the risk of early death using clinical indicators at the time of HLH diagnosis. Methods: This observational cohort study was conducted at the National Clinical Research Center for Child Health and Disease. Data was collected from pediatric HLH patients diagnosed by the HLH-2004 protocol between January 2006 and December 2022. Six machine learning models were constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) to select key clinical indicators for model construction. Results: The study included 587 pediatric HLH patients, and the early mortality rate was 28.45 %. The logistic and XGBoost model with the best performance after feature screening were selected to predict early death of HLH patients. The logistic model had an AUC of 0.915 and an accuracy of 0.863, while the XGBoost model had an AUC of 0.889 and an accuracy of 0.829. The risk factors most associated with early death were the absence of immunochemotherapy, decreased TC levels, increased BUN and total bilirubin, and prolonged TT. We developed an online calculator tool for predicting the probability of early death in children with HLH. Conclusions: We developed the first web-based early mortality prediction tool for pediatric HLH to assist clinicians in risk stratification at diagnosis and in developing personalized treatment protocols. This study is registered on the China Clinical Trials Registry platform (ChiCTR2200061315).

Wireless, battery-free, multifunctional integrated bioelectronics for respiratory pathogens monitoring and severity evaluation.

The rapid diagnosis of respiratory virus infection through breath and blow remains challenging. Here we develop a wireless, battery-free, multifunctional pathogenic infection diagnosis system (PIDS) for diagnosing SARS-CoV-2 infection and symptom severity by blow and breath within 110 s and 350 s, respectively. The accuracies reach to 100% and 92% for evaluating the infection and symptom severity of 42 participants, respectively. PIDS realizes simultaneous gaseous sample collection, biomarker identification, abnormal physical signs recording and machine learning analysis. We transform PIDS into other miniaturized wearable or portable electronic platforms that may widen the diagnostic modes at home, outdoors and public places. Collectively, we demonstrate a general-purpose technology for rapidly diagnosing respiratory pathogenic infection by breath and blow, alleviating the technical bottleneck of saliva and nasopharyngeal secretions. PIDS may serve as a complementary diagnostic tool for other point-of-care techniques and guide the symptomatic treatment of viral infections.

A generic binding pocket for small molecule IKs activators at the extracellular inter-subunit interface of KCNQ1 and KCNE1 channel complexes.

The cardiac IKs ion channel comprises KCNQ1, calmodulin, and KCNE1 in a dodecameric complex which provides a repolarizing current reserve at higher heart rates and protects from arrhythmia syndromes that cause fainting and sudden death. Pharmacological activators of IKs are therefore of interest both scientifically and therapeutically for treatment of IKs loss-of-function disorders. One group of chemical activators are only active in the presence of the accessory KCNE1 subunit and here we investigate this phenomenon using molecular modeling techniques and mutagenesis scanning in mammalian cells. A generalized activator binding pocket is formed extracellularly by KCNE1, the domain-swapped S1 helices of one KCNQ1 subunit and the pore/turret region made up of two other KCNQ1 subunits. A few residues, including K41, A44 and Y46 in KCNE1, W323 in the KCNQ1 pore, and Y148 in the KCNQ1 S1 domain, appear critical for the binding of structurally diverse molecules, but in addition, molecular modeling studies suggest that induced fit by structurally different molecules underlies the generalized nature of the binding pocket. Activation of IKs is enhanced by stabilization of the KCNQ1-S1/KCNE1/pore complex, which ultimately slows deactivation of the current, and promotes outward current summation at higher pulse rates. Our results provide a mechanistic explanation of enhanced IKs currents by these activator compounds and provide a map for future design of more potent therapeutically useful molecules.

Retrospective study of risk factors for pericardial effusion after haematopoietic stem cell transplantation in children.

OBJECTIVES: The clinical characteristics, risk factors and survival prognosis of pericardial effusion (PE) after haematopoietic stem cell transplantation (HSCT) in children were investigated. METHODS: Clinical data of children who underwent HSCT at the Children's Hospital Affiliated with Chongqing Medical University from January 2016 to December 2022 were analysed retrospectively. Cox proportional hazards regression and the Kaplan-Meier method were used to analyse the risk factors for post-HSCT PE and its impact on outcomes, respectively. RESULTS: We enrolled 452 patients with HSCT: 307 males and 145 females, with a median age of 3.4 (1.8 to 6.5) years at transplantation. Forty-five patients (10%) had PE within a median time of 25 (10.5 to 44) days, 42 (93%) within 100 days. Three patients with large PE were treated with pericardiocentesis and drainage, while the others were treated conservatively. Of the 45 patients with PE, 24 survived, and their PE disappeared after treatment. Graft-versus-host disease (GVHD) grade, abnormal pre-HSCT electrocardiogram, hepatic veno-occlusive disease (HVOD), pulmonary infection and Epstein-Barr virus (EBV) infection were risk factors for PE. The overall survival (OS) rates at 1, 3, and 5 years were 86.0%, 84.2%, and 82.3%, respectively. PE had a significant negative effect on OS after HSCT (P < 0.0001). Particularly, one patient with large PE died of pericardial tamponade. CONCLUSIONS: Post-HSCT PE usually occurred within 100 days. GVHD grade, abnormal pre-HSCT electrocardiogram, HVOD, pulmonary infection and EBV infection were closely related to PE. PE had a significant negative effect on OS rate.

Effects of straw and plastic film mulching on microbial functional genes involved in soil nitrogen cycling.

Introduction: Microorganisms regulate soil nitrogen (N) cycling in cropping systems. However, how soil microbial functional genes involved in soil N cycling respond to mulching practices is not well known. Methods: We collected soil samples from a spring maize field mulched with crop straw (SM) and plastic film (FM) for 10-year and with no mulching (CK) in the Loess Plateau. Microbial functional genes involved in soil N cycling were quantified using metagenomic sequencing. We collected soil samples from a spring maize field mulched with crop straw (SM) and plastic film (FM) for 10-year and with no mulching (CK) in the Loess Plateau. Microbial functional genes involved in soil N cycling were quantified using metagenomic sequencing. Results: Compared to that in CK, the total abundance of genes involved in soil N cycling increased in SM but had no significant changes in FM. Specifically, SM increased the abundances of functional genes that involved in dissimilatory nitrate reduction to ammonium (nirB, napA, and nrfA), while FM decreased the abundances of functional genes that involved in ammonification (ureC and ureA) in comparison with CK. Other genes involved in assimilatory nitrate reduction, denitrification, and ammonia assimilation, however, were not significantly changed with mulching practices. The nirB and napA were derived from Proteobacteria (mainly Sorangium), and the ureC was derived from Actinobacteria (mainly Streptomyces). Mental test showed that the abundance of functional genes that involved in dissimilatory nitrate reduction was positively correlated with the contents of soil microbial biomass N, potential N mineralization, particulate organic N, and C fractions, while ammonification related gene abundance was positively correlated with soil pH, microbial biomass C and N, and mineral N contents. Discussion: Overall, this study showed that SM could improve soil N availability and promote the soil N cycling by increasing the abundance of functional genes that involved in DNRA, while FM reduced the abundance of functional genes that involved in ammonification and inhibited soil N cycling.

Differential analysis of immune reconstitution after allogeneic hematopoietic stem cell transplantation in children with Wiskott-Aldrich syndrome and chronic granulomatous disease.

Objective: To investigate similarities and differences in immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). Method: We retrospectively analyzed the lymphocyte subpopulations and the serum level of various immune-related protein or peptide on Days 15, 30, 100, 180 and 360 post-transplantation in 70 children with WAS and 48 children with CGD who underwent allo-HSCT at the Transplantation Center of the Department of Hematology-Oncology, Children's Hospital of Chongqing Medical University from January 2007 to December 2020, and we analyzed the differences in the immune reconstitution process between the two groups. Results: ① The WAS group had higher lymphocyte subpopulation counts than the CGD group. ② Among children aged 1-3 years who underwent transplantation, the WAS group had higher lymphocyte subpopulation counts than the CGD group. ③ Further comparisons were performed between children with non-umbilical cord blood transplantation (non-UCBT) and children with umbilical cord blood transplantation (UCBT) in the WAS group. On Day 15 and 30 post-transplantation, the non-UCBT group had higher B-cell counts than the UCBT group. On the remaining time points post-transplantation, the UCBT group had higher lymphocyte subpopulation counts than the non-UCBT group. ④ Comparisons were performed between children with non-UCBT in the WAS group and in the CGD group, the lymphocyte subpopulation counts were higher in the WAS group compared to the CGD group. ⑤ On Day 100 post-transplantation, the CGD group had higher C3 levels than the WAS group. On Day 360 post-transplantation, the CGD group had higher IgA and C4 levels than the WAS group. Conclusion: ① The rate of immunity recovery was faster in children within the WAS group compared to those children within the CGD group, which may be attributed to the difference of percentage undergoing UCBT and primary diseases. ② In the WAS group, the non-UCBT group had higher B-cell counts than the UCBT group at Day 15 and 30 post-transplantation, however, the UCBT group had higher B-cell counts than the non-UCBT group at Day 100 and 180 post-transplantation, suggesting that cord blood has strong B-cell reconstitution potentiality after transplantation.

Vaccine-induced protection against SARS-CoV-2 requires IFN-γ-driven cellular immune response.

The overall success of worldwide mass vaccination in limiting the negative effect of the COVID-19 pandemics is inevitable, however, recent SARS-CoV-2 variants of concern, especially Omicron and its sub-lineages, efficiently evade humoral immunity mounted upon vaccination or previous infection. Thus, it is an important question whether these variants, or vaccines against them, induce anti-viral cellular immunity. Here we show that the mRNA vaccine BNT162b2 induces robust protective immunity in K18-hACE2 transgenic B-cell deficient (µMT) mice. We further demonstrate that the protection is attributed to cellular immunity depending on robust IFN-γ production. Viral challenge with SARS-CoV-2 Omicron BA.1 and BA.5.2 sub-variants induce boosted cellular responses in vaccinated µMT mice, which highlights the significance of cellular immunity against the ever-emerging SARS-CoV-2 variants evading antibody-mediated immunity. Our work, by providing evidence that BNT162b2 can induce significant protective immunity in mice that are unable to produce antibodies, thus highlights the importance of cellular immunity in the protection against SARS-CoV-2.

Circulating CXCR5+ natural killer cells are expanded in patients with myasthenia gravis.

Objectives: Myasthenia gravis (MG) is a classic autoantibody-mediated disease in which pathogenic antibodies target postsynaptic membrane components, causing fluctuating skeletal muscle weakness and fatigue. Natural killer (NK) cells are heterogeneous lymphocytes that have gained increasing attention owing to their potential roles in autoimmune disorders. This study will investigate the relationship between the distinct NK cell subsets and MG pathogenesis. Methods: A total of 33 MG patients and 19 healthy controls were enrolled in the present study. Circulating NK cells, their subtypes and follicular helper T cells were analysed by flow cytometry. Serum acetylcholine receptor (AChR) antibody levels were determined by ELISA. The role of NK cells in the regulation of B cells was verified using a co-culture assay. Results: Myasthenia gravis patients with acute exacerbations had a reduced number of total NK cells, CD56dim NK cells and IFN-γ-secreting NK cells in the peripheral blood, while CXCR5+ NK cells were significantly elevated. CXCR5+ NK cells expressed a higher level of ICOS and PD-1 and a lower level of IFN-γ than those in CXCR5- NK cells and were positively correlated with Tfh cell and AChR antibody levels. In vitro experiments demonstrated that NK cells suppressed plasmablast differentiation while promoting CD80 and PD-L1 expression on B cells in an IFN-γ-dependent manner. Furthermore, CXCR5- NK cells inhibited plasmablast differentiation, while CXCR5+ NK cells could more efficiently promote B cell proliferation. Conclusion: These results reveal that CXCR5+ NK cells exhibit distinct phenotypes and functions compared with CXCR5- NK cells and might participate in the pathogenesis of MG.