Ribosome biogenesis is essential for hemogenic endothelial cells to generate hematopoietic stem cells.

Undergoing endothelial-to-hematopoietic transition, a small fraction of embryonic aortic endothelial cells specializes into hemogenic endothelial cells (HECs) and eventually gives rise to hematopoietic stem cells (HSCs). Previously, we found that the activity of ribosome biogenesis (RiBi) is highly enriched in the HSC-primed HECs compared with adjacent arterial endothelial cells; however, whether RiBi is required in HECs for the generation of HSCs remains to be determined. Here, we have found that robust RiBi is markedly augmented during the endothelial-to-hematopoietic transition in mouse. Pharmacological inhibition of RiBi completely impeded the generation of HSCs in explant cultures. Moreover, disrupting RiBi selectively interrupted the HSC generation potential of HECs rather than T1 pre-HSCs, which was in line with its influence on cell cycle activity. Further investigation revealed that, upon HEC specification, the master transcription factor Runx1 dramatically bound to the loci of genes involved in RiBi, thereby facilitating this biological process. Taken together, our study provides functional evidence showing the indispensable role of RiBi in generating HSCs from HECs, providing previously unreported insights that may contribute to the improvement of HSC regeneration strategies.

Attenuating midline thalamus bursting to mitigate absence epilepsy.

Advancing the mechanistic understanding of absence epilepsy is crucial for developing new therapeutics, especially for patients unresponsive to current treatments. Utilizing a recently developed mouse model of absence epilepsy carrying the BK gain-of-function channelopathy D434G, here we report that attenuating the burst firing of midline thalamus (MLT) neurons effectively prevents absence seizures. We found that enhanced BK channel activity in the BK-D434G MLT neurons promotes synchronized bursting during the ictal phase of absence seizures. Modulating MLT neurons through pharmacological reagents, optogenetic stimulation, or deep brain stimulation effectively attenuates burst firing, leading to reduced absence seizure frequency and increased vigilance. Additionally, enhancing vigilance by amphetamine, a stimulant medication, or physical perturbation also effectively suppresses MLT bursting and prevents absence seizures. These findings suggest that the MLT is a promising target for clinical interventions. Our diverse approaches offer valuable insights for developing next generation therapeutics to treat absence epilepsy.

Glaesserella parasuis serotype 4 exploits fibronectin via RlpA for tracheal colonization following porcine circovirus type 2 infection.

Porcine circovirus type 2 (PCV2) often causes disease through coinfection with other bacterial pathogens, including Glaesserella parasuis (G. parasuis), which causes high morbidity and mortality, but the role played by PCV2 and bacterial and host factors contributing to this process have not been defined. Bacterial attachment is assumed to occur via specific receptor-ligand interactions between adhesins on the bacterial cell and host proteins adsorbed to the implant surface. Mass spectrometry (MS) analysis of PCV2-infected swine tracheal epithelial cells (STEC) revealed that the expression of Extracellular matrix protein (ECM) Fibronectin (Fn) increased significantly on the infected cells surface. Importantly, efficient G. parasuis serotype 4 (GPS4) adherence to STECs was imparted by interactions with Fn. Furthermore, abrogation of adherence was gained by genetic knockout of Fn, Fn and Integrin ß1 antibody blocking. Fn is frequently exploited as a receptor for bacterial pathogens. To explore the GPS4 adhesin that interacts with Fn, recombinant Fn N-terminal type I and type II domains were incubated with GPS4, and the interacting proteins were pulled down for MS analysis. Here, we show that rare lipoprotein A (RlpA) directly interacts with host Fibronectin mediating GPS4 adhesion. Finally, we found that PCV2-induced Fibronectin expression and adherence of GPS4 were prevented significantly by TGF-ß signaling pathway inhibitor SB431542. Our data suggest the RlpA-Fn interaction to be a potentially promising novel therapeutic target to combat PCV2 and GPS4 coinfection.

Polymerization force-regulated actin filament-Arp2/3 complex interaction dominates self-adaptive cell migrations.

Cells migrate by adapting their leading-edge behaviors to heterogeneous extracellular microenvironments (ECMs) during cancer invasions and immune responses. Yet it remains poorly understood how such complicated dynamic behaviors emerge from millisecond-scale assembling activities of protein molecules, which are hard to probe experimentally. To address this gap, we establish a spatiotemporal "resistance-adaptive propulsion" theory based on the interactions between Arp2/3 complexes and polymerizing actin filaments and a multiscale dynamic modeling system spanning from molecular proteins to the cell. We quantitatively find that cells can accurately self-adapt propulsive forces to overcome heterogeneous ECMs via a resistance-triggered positive feedback mechanism, dominated by polymerization-induced actin filament bending and the bending-regulated actin-Arp2/3 binding. However, for high resistance regions, resistance triggers a negative feedback, hindering branched filament assembly, which adapts cellular morphologies to circumnavigate the obstacles. Strikingly, the synergy of the two opposite feedbacks not only empowers the cell with both powerful and flexible migratory capabilities to deal with complex ECMs but also enables efficient utilization of intracellular proteins by the cell. In addition, we identify that the nature of cell migration velocity depending on ECM history stems from the inherent temporal hysteresis of cytoskeleton remodeling. We also show that directional cell migration is dictated by the competition between the local stiffness of ECMs and the local polymerizing rate of actin network caused by chemotactic cues. Our results reveal that it is the polymerization force-regulated actin filament-Arp2/3 complex binding interaction that dominates self-adaptive cell migrations in complex ECMs, and we provide a predictive theory and a spatiotemporal multiscale modeling system at the protein level.

Posterior parietal cortex predicts upcoming movement in dynamic sensorimotor control.

SignificanceMost studies in sensorimotor neurophysiology have utilized reactive movements to stationary goals pre-defined by sensory cues, but this approach is fundamentally incapable of determining whether the observed neural activity reflects current sensory stimuli or predicts future movements. In the present study, we recorded single-neuron activity from behaving monkeys engaged in a dynamic, flexible, stimulus-response contingency task that enabled us to distinguish activity co-varying with sensory inflow from that co-varying with motor outflow in the posterior parietal cortex.

Vacancy-Induced Anionic Electrons in Single-Metal Oxides and Their Possible Applications in Ammonia Synthesis.

Realizating of a low work function (WF) and room-temperature stability in electrides is highly desired for various applications, such as electron emitters, catalysts, and ion batteries. Herein, a criterion based on the electron localization function (ELF) and projected density of states (PDOS) in the vacancy of the oxide electride [Ca24Al28O64]4+(4e-) (C12A7) was adopted to screen out 13 electrides in single-metal oxides. By creating oxygen vacancies in nonelectride oxides, we find out 9 of them showed vacancy-induced anionic electrons. Considering the thermodynamic stability, two electrides with ordered vacancies, Nb3O3 and Ce4O3, stand out and show vacancy-induced zero-dimensional anionic electrons. Both exhibit low WFs, namely 3.1 and 2.3 eV for Nb3O3 and Ce4O3, respectively. In the case of Nb3O3, the ELF at oxygen vacancies decreases first and then increases during the decrease in the total number of electrons in self-consistent calculations due to Nb's multivalent state. Meanwhile, Ce4O3 displays promise for ammonia synthesis due to its low hydrogen diffusion barrier and low activation energy. Further calculations revealed that CeO with disordered vacancies at low concentrations also exhibits electride-like properties, suggesting its potential as a substitute for Ce4O3.

Evolution of High-Index Facets Pt Nanocrystals Induced by N-Defective Sites in the Integrated Electrode for Enhanced Methanol Oxidation.

Highly efficient and durable Pt electrocatalysts are the key to boost the performance of fuel cells. The high-index facets (HIF) Pt nanocrystals are regarded as excellent catalytic activity and stability catalysts. However, nucleation, growth and evolution of high-index facets Pt nanocrystals induced by defective sites is still a challenge. In this work, tetrahexahedron (THH) and hexactahedron (HOH) Pt nanocrystals are synthesized, which are loaded on the nitrogen-doped reduced graphene oxide (N-rGO) support of the integrated electrodes by the square wave pulse method. Experimental investigations and density functional theory (DFT) calculations are conducted to analyze the growth and evolution mechanism of HIF Pt nanocrystals on the graphene-derived carbon supports. It shows that the H adsorption on the N-rGO/CFP support can induce evolution of Pt nanocrystals. Moreover, the N-defective sites on the surface of N-rGO can lead to a slower growth of Pt nanocrystals than that on the surface of reduced graphene oxide (rGO). Pt/N-rGO/CFP (20 min) shows the highest specific activity in methanol oxidation, which is 1.5 times higher than that of commercial Pt/C. This research paves the way on the design and synthesis of HIF Pt nanocrystal using graphene-derived carbon materials as substrates in the future.

Mango wiggler as a novel insertion device providing a large and symmetrical imaging field of view.

A novel insertion device is introduced, designated as the Mango wiggler, designed for synchrotron radiation (SR) imaging that provides a large field of view. This innovative device is constructed from two orthogonal planar wigglers with a small difference in their period lengths, eliciting the phase difference of the magnetic fields to incrementally transitions from 0 to π/2. Such a configuration enlarges the vertical divergence of the light source, as with the horizontal divergence. The appellation `Mango wiggler' derives from the distinctive mango-shaped contour of its radiation field. A comprehensive suite of theoretical analyses and simulations has been executed to elucidate the radiation properties of the Mango wiggler, employing SPECTRA and Mathematica as calculation tools. In conjunction with the ongoing construction of the High Energy Photon Source in Beijing a practical Mango wiggler device has been fabricated for utilization in SR imaging applications. Theoretical analyses were applied to this particular Mango wiggler to yield several theoretical conclusions, and several simulations were performed according to the measured magnetic field results.

African Swine Fever Virus Cysteine Protease pS273R Inhibits Type I Interferon Signaling by Mediating STAT2 Degradation.

African swine fever virus (ASFV) is a large DNA virus that causes African swine fever (ASF), an acute and hemorrhagic disease in pigs with lethality rates of up to 100%. To date, how ASFV efficiently suppress the innate immune response remains enigmatic. In this study, we identified ASFV cysteine protease pS273R as an antagonist of type I interferon (IFN). Overexpression of pS273R inhibited JAK-STAT signaling triggered by type I IFNs. Mechanistically, pS273R interacted with STAT2 and recruited the E3 ubiquitin ligase DCST1, resulting in K48-linked polyubiquitination at K55 of STAT2 and subsequent proteasome-dependent degradation of STAT2. Furthermore, such a function of pS273R in JAK-STAT signaling is not dependent on its protease activity. These findings suggest that ASFV pS273R is important to evade host innate immunity. IMPORTANCE ASF is an acute disease in domestic pigs caused by infection with ASFV. ASF has become a global threat with devastating economic and ecological consequences. To date, there are no commercially available, safe, and efficacious vaccines to prevent ASFV infection. ASFV has evolved a series of strategies to evade host immune responses, facilitating its replication and transmission. Therefore, understanding the immune evasion mechanism of ASFV is helpful for the development of prevention and control measures for ASF. Here, we identified ASFV cysteine protease pS273R as an antagonist of type I IFNs. ASFV pS273R interacted with STAT2 and mediated degradation of STAT2, a transcription factor downstream of type I IFNs that is responsible for induction of various IFN-stimulated genes. pS273R recruited the E3 ubiquitin ligase DCST1 to enhance K48-linked polyubiquitination of STAT2 at K55 in a manner independent of its protease activity. These findings suggest that pS273R is important for ASFV to escape host innate immunity, which sheds new light on the mechanisms of ASFV immune evasion.

Proinflammatory phenotype of B10 and B10pro cells elicited by TNF-α in rheumatoid arthritis.

OBJECTIVES: B10 and B10pro cells suppress immune responses via secreting interleukin (IL)-10. However, their regulators and underlying mechanisms, especially in human autoimmune diseases, are elusive. This study aimed to address these questions in rheumatoid arthritis (RA), one of the most common highly disabling autoimmune diseases. METHODS: The frequencies and functions of B10 and B10pro cells in healthy individuals and patients with RA were first analysed. The effects of proinflammatory cytokines, particularly tumour necrosis factor (TNF)-α on the quantity, stability and pathogenic phenotype of these cells, were then assessed in patients with RA before and after anti-TNF therapy. The underlying mechanisms were further investigated by scRNA-seq database reanalysis, transcriptome sequencing, TNF-α-/- and B cell-specific SHIP-1-/- mouse disease model studies. RESULTS: TNF-α was a key determinant for B10 cells. TNF-α elicited the proinflammatory feature of B10 and B10pro cells by downregulating IL-10, and upregulating interferon-γ and IL-17A. In patients with RA, B10 and B10pro cells were impaired with exacerbated proinflammatory phenotype, while anti-TNF therapy potently restored their frequencies and immunosuppressive functions, consistent with the increased B10 cells in TNF-α-/- mice. Mechanistically, TNF-α diminished B10 and B10pro cells by inhibiting their glycolysis and proliferation. TNF-α also regulated the phosphatidylinositol phosphate signalling of B10 and B10pro cells and dampened the expression of SHIP-1, a dominant phosphatidylinositol phosphatase regulator of these cells. CONCLUSIONS: TNF-α provoked the proinflammatory phenotype of B10 and B10pro cells by disturbing SHIP-1 in RA, contributing to the disease development. Reinstating the immunosuppressive property of B10 and B10pro cells might represent novel therapeutic approaches for RA.

Compressive forces stabilize microtubules in living cells.

Microtubules are cytoskeleton components with unique mechanical and dynamic properties. They are rigid polymers that alternate phases of growth and shrinkage. Nonetheless, the cells can display a subset of stable microtubules, but it is unclear whether microtubule dynamics and mechanical properties are related. Recent in vitro studies suggest that microtubules have mechano-responsive properties, being able to stabilize their lattice by self-repair on physical damage. Here we study how microtubules respond to cycles of compressive forces in living cells and find that microtubules become distorted, less dynamic and more stable. This mechano-stabilization depends on CLASP2, which relocates from the end to the deformed shaft of microtubules. This process seems to be instrumental for cell migration in confined spaces. Overall, these results demonstrate that microtubules in living cells have mechano-responsive properties that allow them to resist and even counteract the forces to which they are subjected, being a central mediator of cellular mechano-responses.

African swine fever virus I267L acts as an important virulence factor by inhibiting RNA polymerase III-RIG-I-mediated innate immunity.

ASFV is a large DNA virus that is highly pathogenic in domestic pigs. How this virus is sensed by the innate immune system as well as why it is so virulent remains enigmatic. In this study, we show that the ASFV genome contains AT-rich regions that are recognized by the DNA-directed RNA polymerase III (Pol-III), leading to viral RNA sensor RIG-I-mediated innate immune responses. We further show that ASFV protein I267L inhibits RNA Pol-III-RIG-I-mediated innate antiviral responses. I267L interacts with the E3 ubiquitin ligase Riplet, disrupts Riplet-RIG-I interaction and impairs Riplet-mediated K63-polyubiquitination and activation of RIG-I. I267L-deficient ASFV induces higher levels of interferon-ß, and displays compromised replication both in primary macrophages and pigs compared with wild-type ASFV. Furthermore, I267L-deficiency attenuates the virulence and pathogenesis of ASFV in pigs. These findings suggest that ASFV I267L is an important virulence factor by impairing innate immune responses mediated by the RNA Pol-III-RIG-I axis.

The prevalence of Human Immunodeficiency Virus infection among voluntary blood donors in mainland China: A systematic review and meta-analysis.

Human immunodeficiency virus (HIV) infection through transfusion has been an imperative challenge for blood safety. Despite the implementation of screening strategies, there was still the residual risk of transfusion-transmitted HIV. Considering that the prevalence of HIV infection in blood donors is significant for evaluating blood safety and potential risks to the population, meta-analysis was applied to investigate the HIV prevalence among voluntary blood donors during the past 27 years to characterize the epidemiology and related risk factors of HIV in blood donors. The literature concerning the HIV screening reactive rate and prevalence in Chinese voluntary blood donors was collected through the systematic searching of four electronic databases. After integrating data, following the Preferred Reporting of Items for Systematic Reviews and Meta-Analyses guidelines, data manipulation and statistical analyses were conducted by Stata 12.0. The results indicated that overall HIV prevalence was 0.0178% (95% confidence interval [CI], 0.0169%-0.0187%) with a remarkable rise, which varied from 2000 (0.0034%) to 2015 (0.027%). The HIV window period infection rate was 0.0475‱ (95% CI, 0.0304‱-0.0646‱). Importantly, subgroup analysis revealed the heterogeneity in gender, occupations, education and donation frequency. With the effective control of HIV transmission through blood, HIV prevalence declined in China to some extent in recent years, and the characteristics of HIV epidemic in some provinces have drastically changed. However, remaining relatively high HIV prevalence and overall increased trend of HIV prevalence since the 21th century demonstrates the potential residual risk of blood transfusion, and the whole society is supposed to pay close attention to HIV infection.

Single-cell transcriptomics reveals writers of RNA modification-mediated immune microenvironment and cardiac resident Macro-MYL2 macrophages in heart failure.

BACKGROUND: Heart failure (HF), which is caused by cardiac overload and injury, is linked to significant mortality. Writers of RNA modification (WRMs) play a crucial role in the regulation of epigenetic processes involved in immune response and cardiovascular disease. However, the potential roles of these writers in the immunological milieu of HF remain unknown. METHODS: We comprehensively characterized the expressions of 28 WRMs using datasets GSE145154 and GSE141910 to map the cardiac immunological microenvironment in HF patients. Based on the expression of WRMs, the immunological cells in the datasets were scored. RESULTS: Single-cell transcriptomics analysis (GSE145154) revealed immunological dysregulation in HF as well as differential expression of WRMs in immunological cells from HF and non-HF (NHF) samples. WRM-scored immunological cells were positively correlated with the immunological response, and the high WRM score group exhibited elevated immunological cell infiltration. WRMs are involved in the differentiation of T cells and myeloid cells. WRM scores of T cell and myeloid cell subtypes were significantly reduced in the HF group compared to the NHF group. We identified a myogenesis-related resident macrophage population in the heart, Macro-MYL2, that was characterized by an increased expression of cardiomyocyte structural genes (MYL2, TNNI3, TNNC1, TCAP, and TNNT2) and was regulated by TRMT10C. Based on the WRM expression pattern, the transcriptomics data (GSE141910) identified two distinct clusters of HF samples, each with distinct functional enrichments and immunological characteristics. CONCLUSION: Our study demonstrated a significant relationship between the WRMs and immunological microenvironment in HF, as well as a novel resident macrophage population, Macro-MYL2, characterized by myogenesis. These results provide a novel perspective on the underlying mechanisms and therapeutic targets for HF. Further experiments are required to validate the regulation of WRMs and Macro-MYL2 macrophage subtype in the cardiac immunological milieu.

ASH2L upregulation contributes to diabetic endothelial dysfunction in mice through STEAP4-mediated copper uptake.

Endothelial dysfunction is a common complication of diabetes mellitus (DM) and contributes to the high incidence and mortality of cardiovascular and cerebrovascular diseases. Aberrant epigenetic regulation under diabetic conditions, including histone modifications, DNA methylation, and non-coding RNAs (ncRNAs) play key roles in the initiation and progression of diabetic vascular complications. ASH2L, a H3K4me3 regulator, triggers genetic transcription, which is critical for physiological and pathogenic processes. In this study we investigated the role of ASH2L in mediating diabetic endothelial dysfunction. We showed that ASH2L expression was significantly elevated in vascular tissues from diabetic db/db mice and in rat aortic endothelial cells (RAECs) treated with high glucose medium (11 and 22 mM). Knockdown of ASH2L in RAECs markedly inhibited the deteriorating effects of high glucose, characterized by reduced oxidative stress and inflammatory responses. Deletion of endothelial ASH2L in db/db mice by injection of an adeno-associated virus (AAV)-endothelial specific system carrying shRNA against Ash2l (AAV-shAsh2l) restored the impaired endothelium-dependent relaxations, and ameliorated DM-induced vascular dysfunction. We revealed that ASH2L expression activated reductase STEAP4 transcription in vitro and in vivo, which consequently elevated Cu(I) transportation into ECs by the copper transporter CTR1. Excess copper produced by STEAP4-mediated copper uptake triggered oxidative stress and inflammatory responses, resulting in endothelial dysfunction. Our results demonstrate that hyperglycemia triggered ASH2L-STEAP4 axis contributes to diabetic endothelial dysfunction by modulating copper uptake into ECs and highlight the therapeutic potential of blocking the endothelial ASH2L in the pathogenesis of diabetic vascular complications.

Efficient DNA Coding Algorithm for Polymerase Chain Reaction Amplification Information Retrieval.

Polymerase Chain Reaction (PCR) amplification is widely used for retrieving information from DNA storage. During the PCR amplification process, nonspecific pairing between the 3' end of the primer and the DNA sequence can cause cross-talk in the amplification reaction, leading to the generation of interfering sequences and reduced amplification accuracy. To address this issue, we propose an efficient coding algorithm for PCR amplification information retrieval (ECA-PCRAIR). This algorithm employs variable-length scanning and pruning optimization to construct a codebook that maximizes storage density while satisfying traditional biological constraints. Subsequently, a codeword search tree is constructed based on the primer library to optimize the codebook, and a variable-length interleaver is used for constraint detection and correction, thereby minimizing the likelihood of nonspecific pairing. Experimental results demonstrate that ECA-PCRAIR can reduce the probability of nonspecific pairing between the 3' end of the primer and the DNA sequence to 2-25%, enhancing the robustness of the DNA sequences. Additionally, ECA-PCRAIR achieves a storage density of 2.14-3.67 bits per nucleotide (bits/nt), significantly improving storage capacity.

Differential drivers on the occurrence of antibiotic resistance genes in agricultural soils and crops: Evidence from the different fertilization regimes.

Organic fertilizer application caused bacterial resistance contamination in farming systems has been widely documented, and long-term fertilization will exacerbate the migration of antibiotic resistance genes (ARGs) to crops and humans. However, it remains unclear whether a combined pattern of chemical and organic fertilizer application can arrest the high prevalence of ARGs in soil-crop. Here we investigated the ARGs occurrence under different fertilization regimes, and explored the mechanisms by which micro-ecological shifts and geochemical factors in modulating the ARGs fate in soil and crop. The results showed that the soil ARGs abundance was highest under 100% organic fertilizer, while the highest ARGs abundance in crops was observed at 100% chemical fertilizer. Application of organic fertilizers with more than 50% ration intensified the soil accumulation and migration of tetA, sul1, sul2 and macA genes. And, multidrug_transporter, macA and sul1 were co-shared in soil and crop, where ARGs potential hosts differed complete in the two, suggesting that these ARGs may be transferred across media by horizontal transfer. Procrustes analysis revealed that soil microbial community was significantly correlated with ARG hosts, and soil microbial evolutionary pathway was congruent with antibiotic resistance, suggesting that fertilizers affect soil ARGs abundance mainly by altering soil microbial composition and their ecological evolutionary trajectories. While, no significant correlation was observed between endophytes and crop ARG host. Structural equations demonstrated that soil nutrients and crop growth characteristics contributed largely to the prevalence of crop ARGs. This outcome will provide new insights into the high prevalence of ARGs in soil and crop, and offer fertilizer recommendations for effectively curbing antibiotic-resistance contamination in farming systems.

[Genetic study of a rare Chinese pedigree with a recombination occurring between the HLA-A/C loci in both parents].

OBJECTIVE: To analyze a Chinese pedigree with a recombination occurring between the HLA-A/C loci in both parents. METHODS: A patient who was planning to undergo hematopoietic stem cell transplantation due to "aplastic anemia" in February 2022 was selected as the study subject. Peripheral blood samples were collected from the patient, his parents and brother. HLA-A/C/B/DRB1/DQB1 high-resolution typing was carried out by using sequence-based typing and sequence-specific oligonucleotides. The recombination was identified by pedigree analysis. The HLA haplotype of each individual was identified by genealogical analysis. The parentage possibility was determined by short tandem repeat analysis. HLA-A/C/B/DRB1/DRB345/DQA1/DQB1/DPA1/DPB1 were determined with next-generation high-throughput sequence-based typing. The recombination sites were analyzed by family study. RESULTS: The high parentage possibilities of the family was confirmed by short tandem repeat analysis. Recombination was found between the HLA-A*24:02 A*33:03/C*14:03 in the paternally transmitted haplotype, whilst HLA-A*01:01 A*03:01/C*08:02 was found in the maternally transmitted haplotype, which had resulted in two novel HLA haplotypes in the proband. CONCLUSION: A rare case with simultaneous recombination of the paternal and maternal HLA-A/C loci has been discovered, which may facilitate further study of the mechanisms of the HLA recombination.

[A unicenter real-world study of the correlation factors for complete clinical response in idiopathic inflammatory myopathies].

OBJECTIVE: To investigate the correlation factors of complete clinical response in idiopathic inflammatory myopathies (IIMs) patients receiving conventional treatment. METHODS: Patients diagnosed with IIMs hospitalized in Peking University People's Hospital from January 2000 to June 2023 were included. The correlation factors of complete clinical response to conventional treatment were identified by analyzing the clinical characteristics, laboratory features, peripheral blood lymphocytes, immunological indicators, and therapeutic drugs. RESULTS: Among the 635 patients included, 518 patients finished the follow-up, with an average time of 36.8 months. The total complete clinical response rate of IIMs was 50.0% (259/518). The complete clinical response rate of dermatomyositis (DM), anti-synthetase syndrome (ASS) and immune-mediated necrotizing myopathy (IMNM) were 53.5%, 48.9% and 39.0%, respectively. Fever (P=0.002) and rapid progressive interstitial lung disease (RP-ILD) (P=0.014) were observed much more frequently in non-complete clinical response group than in complete clinical response group. The aspartate transaminase (AST), lactate dehydrogenase (LDH), D-dimer, erythrocyte sedimentation rate (ESR), C-reaction protein (CRP) and serum ferritin were significantly higher in non-complete clinical response group as compared with complete clinical response group. As for the treatment, the percentage of glucocorticoid received and intravenous immunoglobin (IVIG) were significantly higher in non-complete clinical response group than in complete clinical response group. Risk factor analysis showed that IMNM subtype (P=0.007), interstitial lung disease (ILD) (P=0.001), eleva-ted AST (P=0.012), elevated serum ferritin (P=0.016) and decreased count of CD4+T cells in peripheral blood (P=0.004) might be the risk factors for IIMs non-complete clinical response. CONCLUSION: The total complete clinical response rate of IIMs is low, especially for IMNM subtype. More effective intervention should be administered to patients with ILD, elevated AST, elevated serum ferritin or decreased count of CD4+T cells at disease onset.

Dynamics of T follicular helper cells in patients with rheumatic diseases and subsequent antibody responses in a three-dose immunization regimen of CoronaVac.

Given increased acceptance of the CoronaVac, there is an unmet need to assess the safety and immunogenic changes of CoronaVac in patients with rheumatic diseases (RD). Here we comprehensively analysed humoral and cellular responses in patient with RD after a three-dose immunization regimen of CoronaVac. RD patients with stable condition and/or low disease activity (n = 40) or healthy controls (n = 40) were assigned in a 1:1 ratio to receive CoronaVac (Sinovac). The prevalence of anti-receptor binding domain (RBD) antibodies and neutralizing antibodies was similar between healthy control (HC) and RD patients after the second and the third vaccination. However, the titers of anti-RBD IgG and neutralizing antibodies were significantly lower in RD patients compared to HCs (p < 0.05), which was associated with an impaired T follicular helper (Tfh) cell response. Among RD patients, those who generated an antibody response displayed a significantly higher Tfh cells compared to those who failed after the first and the second vaccination (p < 0.05). Interestingly, subjects with a negative serological response displayed a similar Tfh memory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides as their anti-RBD IgG positive counterpart, and all (4/4) of the non-responders in HCs, and 62.5% (5/8) of the non-responders in patients with RD displayed a positive serological response following the third dose. No serious adverse events were observed. In conclusion, our findings support SARS-CoV-2 vaccination in patients with RD with stable and/or low disease activity. The impaired ability in generating vaccine-specific antibodies in patients with RD was associated with a reduction in Tfh cells induction. The window of vaccination times still needs to be explored in future studies. Clinical trial registration: This trial was registered with ChiCTR2100049138.