Viral reactivation in the lungs of patients with severe pneumonia is associated with increased mortality, a multicenter, retrospective study.

Viral reactivation is widespread in patients with severe pneumonia, yet the landscape of viral reactivation in the lungs is not well-known. This study aims to assess the landscape and clinical features of viral reactivation in the early onset of severe pneumonia in ICU patients. The clinical data from 97 patients were collected retrospectively from the intensive care units of five teaching hospitals between June 2018 and July 2021. Metagenomic next-generation sequencing (mNGS) of the bronchoalveolar lavage fluid (BALF) was performed at the onset of severe pneumonia. Cytomegalovirus (CMV), herpes simplex virus-1 (HSV-1), and Epstein-Barr virus (EBV) were the most common reactivated viruses in the lower respiratory tract of patients with severe pneumonia. After adjusting for the risk of confounding and competition of age, sex, sequential organ failure assessment, acute physiology chronic health assessment II and immunosuppression status, viral reactivation resulted in an overall 2.052-fold increase in 28-day all-cause mortality (95% CI: 1.004-4.194). This study showed that CMV, HSV-1, and EBV were the most common reactivated viruses in the lungs of patients with severe pneumonia. The existence of viral reactivations was associated with an increased risk of mortality. The simultaneous reactivation of multiple viruses needs to be considered in the design of clinical trials.

Mannose-binding lectin activates the nuclear factor-κB and renal inflammation in the progression of diabetic nephropathy.

Increased serum mannose-binding lectin (MBL) level has been proven to correlate with the development of diabetic nephropathy (DN). Here, we aim to find the role and mechanism of MBL involved in the progression of DN. Patients with DN were recruited and divided into two groups according to different rs1800450 genotypes of the MBL2 gene, and inflammatory profiles in monocytes/macrophages were compared between the two groups. MBL was given to treat macrophages, HK2, and HMC, and a co-culture transwell system was then employed. Renal inflammation and fibrosis parameters were measured after knocking down or overexpressing MBL genes in mice. Proinflammatory profile, manifesting as enhanced IL-1ß production and M1 polarization, was found in monocytes/macrophages from DN with a rs1800450 GG genotype of MBL2 gene who had higher MBL level, compared with those with a rs1800450 GA genotype. In mechanism, MBL directly induced inflammatory responses in macrophages, which promoted inflammatory and fibrotic markers in HK2 and HMCs during co-culture. Further experiments showed that MBL can promote macrophages transforming to the M1 subset mainly by activating the nuclear factor-κB pathway. After downregulation of MBL, the blood glucose, triglyceride, urine protein, injuries of glomerulus and tubules, and the degree of renal inflammation and fibrosis were ameliorated in db/db mice treated with AAV-MBL1/2-shRNA. Overexpression of MBL promoted macrophage infiltration in the kidney. In conclusion, MBL is a crucial mediator in the progression of DN via activating the nuclear factor-κB pathway in macrophages. This will serve as a genetic base for some patients with DN who have poor outcomes and provide a direction for the screening.

The predictive value of Berden's classification versus renal risk score for renal survival of Chinese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

OBJECTIVES: This study aims to compare the prognostic values of two histopathological classification, Berden's classification versus renal risk score (RRS) by Brix et al. for predicting renal survival in Chinese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (MPO-AAGN). METHODS: The medical records of 225 patients with MPO-AAGN diagnosed in our centre between February 2004 and December 2020 were retrospectively analysed. The predictive model of Berden's classification or RRS was established by Cox regression, respectively. The above two models were compared on aspects of discrimination, calibration, and decision curve analysis for predicting the 0.5-, 1-, 3-, and 5-year renal survival. RESULTS: After a median follow up of 38.99 months, 32.44% of patients developed end-stage renal disease (ESRD). In the Kaplan-Meier analysis, there were significant differences in renal survival among groups according to Berden's classification or RRS (both log-rank p<0.001). According to time-dependent receiver operating characteristic (ROC) curve analysis, the model based on RRS showed better discrimination ability than the model based on Berden's classification for predicting 0.5-, 1-, and 3-year renal survival. For calibration analysis, the model based on RRS showed worse calibration than the model based on Berden's classification for predicting 1- and 3-year renal survival. According to the decision curve analysis, the clinical decisions based on RRS could achieve more clinical benefits than those based on Berden's classification in predicting 0.5-, 1-, and 3-year renal survival. CONCLUSIONS: The model based on RRS has better predictive value for renal survival than Berden's classification in aspect of discrimination and clinical decision from 0.5- to 3-year renal survival.

Longitudinal Peripheral Blood Transcriptional Analysis Reveals Molecular Signatures of Disease Progression in COVID-19 Patients.

Coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some patients developing severe illness or even death. Disease severity has been associated with increased levels of proinflammatory cytokines and lymphopenia. To elucidate the atlas of peripheral immune response and pathways that might lead to immunopathology during COVID-19 disease course, we performed a peripheral blood RNA sequencing analysis of the same patient's samples collected from symptom onset to full recovery. We found that PBMCs at different disease stages exhibited unique transcriptome characteristics. We observed that SARS-CoV-2 infection caused excessive release of inflammatory cytokines and lipid mediators as well as an aberrant increase of low-density neutrophils. Further analysis revealed an increased expression of RNA sensors and robust IFN-stimulated genes expression but a repressed type I IFN production. SARS-CoV-2 infection activated T and B cell responses during the early onset but resulted in transient adaptive immunosuppression during severe disease state. Activation of apoptotic pathways and functional exhaustion may contribute to the reduction of lymphocytes and dysfunction of adaptive immunity, whereas increase in IL2, IL7, and IL15 may facilitate the recovery of the number and function of lymphocytes. Our study provides comprehensive transcriptional signatures of peripheral blood response in patients with moderate COVID-19.

Incidence and clinical features of HHV-7 detection in lower respiratory tract in patients with severe pneumonia: a multicenter, retrospective study.

PURPOSE: The significance of detecting human herpesvirus 7 (HHV-7) in the lower respiratory tract of patients with severe pneumonia is unclear. This study aims to evaluate the clinical characteristics and prognosis of detecting HHV-7 in the lower respiratory tract of patients with severe pneumonia. METHODS: Patients with severe pneumonia requiring invasive mechanical ventilation and underwent commercial metagenomic next-generation sequencing (mNGS) testing of bronchoalveolar lavage fluid from January 2019 to March 2023 were enrolled in 12 medical centers. Clinical data of patients were collected retrospectively, and propensity score matching was used for subgroup analysis and mortality assessment. RESULTS: In a total number of 721 patients, 45 cases (6.24%) were identified with HHV-7 positive in lower respiratory tract. HHV-7 positive patients were younger (59.2 vs 64.4, p = 0.032) and had a higher rate of co-detection with Cytomegalovirus (42.2% vs 20.7%, p = 0.001) and Epstein-Barr virus (35.6% vs 18.2%, p = 0.008). After propensity score matching for gender, age, SOFA score at ICU admission, and days from ICU admission to mNGS assay, there was no statistically significant difference in the 28-day mortality rate between HHV-7 positive and negative patients (46.2% vs 36.0%, p = 0.395). Multivariate Cox regression analysis adjusting for gender, age, and SOFA score showed that HHV-7 positive was not an independent risk factor for 28-day mortality (HR 1.783, 95%CI 0.936-3.400, p = 0.079). CONCLUSION: HHV-7 was detected in the lungs of 6.24% of patients with severe pneumonia. The presence of HHV-7 in patients with severe pneumonia requiring invasive mechanical ventilation is associated with a younger age and co-detected of Cytomegalovirus and Epstein-Barr virus. While HHV-7 positivity was not found to be an independent risk factor for mortality in this cohort, this result may have been influenced by the relatively small sample size of the study.

Pharmacokinetics and bioequivalence studies of fluvoxamine maleate tablets in healthy Chinese subjects.

Fluvoxamine is a selective serotonin reuptake inhibitor commonly used for various types of depression. The purpose of this study was to evaluate the pharmacokinetics and bioequivalence of fluvoxamine maleate tablets orally on an empty stomach and after a meal in healthy adult Chinese subjects and to preliminarily evaluate their safety. A single-center, randomized, open-label, two-drug, two-period, crossover, single-dose trial protocol was designed. Sixty healthy Chinese participants were enrolled and randomly classified into fasting (n = 30) and fed groups (n = 30). Each week, subjects took fluvoxamine maleate tablets 50 mg orally once as a test preparation or as a reference preparation on an empty stomach/after meals. To evaluate the bioequivalence of test and reference tables, the concentration of fluvoxamine maleate in the plasma of the subjects at different time points after administration was detected by liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters including the maximum plasma drug concentration (Cmax ), the time to reach maximum concentration (Tmax ), the area under the plasma concentration-time curve from time 0 to the last measurable concentration (AUC0-t ) and the area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞ ) were calculated. Our data revealed that the 90% confidence intervals of the geometric mean ratio of the test or reference drugs for the Cmax , AUC0-t and AUC0-∞ fell within the acceptance range for bioequivalence (92.30-102.77%). The absorption, measured by AUC, did not show a significant difference between the two groups. There were no suspected serious adverse reactions or serious adverse events over the entire trial. Our results demonstrated that the test and reference tablets were bioequivalent under fasting and fed conditions.

Visual perception and linguistic abilities, not quantitative knowledge, count in geometric knowledge of kindergarten children.

Geometric knowledge is one of the important mathematical skills acquired by children at a young age and is a major area of future mathematical learning; however, there is no direct research on the factors influencing kindergarteners' early geometric knowledge. The pathways model to mathematics was modified to examine the cognitive mechanisms underlying geometric knowledge in Chinese kindergarten children aged 5-7 (n = 99). Quantitative knowledge, visual-spatial processing, and linguistic abilities were stepped into hierarchical multiple regression models. The results revealed that after age, sex, and nonverbal intelligence were statistically controlled, visual perception, phonological awareness, and rapid automatized naming in linguistic abilities significantly predicted the variation in geometric knowledge. For quantitative knowledge, neither dot comparison nor number comparison test could be a significant precursor of geometry skills. The findings indicate that visual perception and linguistic abilities, not quantitative knowledge, account for the geometric knowledge of kindergarten children.

A Cell Differentiation Trajectory-Related Signature for Predicting the Prognosis of Lung Adenocarcinoma.

Objective: To screen the cell differentiation trajectory-related genes and build a cell differentiation trajectory-related signature for predicting the prognosis of lung adenocarcinoma (LUAD). Methods: LUAD single cell mRNA expression profile, TCGA-LUAD transcriptome data were obtained from GEO and TCGA databases. Single-cell RNA-seq data were used for cell clustering and pseudotime analysis after dimensionality reduction analysis, and the cell differentiation trajectory-related genes were acquired after differential expression analysis conducted between the main branches. Then, the consensus clustering analysis was carried out on TCGA-LUAD samples, and the GSEA analysis was performed, then the differences on the expression levels of immune checkpoint genes and immunotherapy response were compared among clusters. The prognostic model was constructed, and the GSE42127 dataset was used to validate. A nomogram evaluation model was used to predict prognosis. Results: Two subsets with distinct differentiation states were found after cell differentiation trajectory analysis. TCGA-LUAD samples were divided into two cell differentiation trajectory-related gene-based clusters, GSEA found that cluster 1 was significantly related to 20 pathways, cluster 2 was significantly enriched in three pathways, and it was also shown that clusters could better predict immune checkpoint gene expression and immunotherapy response. A six cell differentiation-related genes-based prognostic signature was constructed, and the patients in the high-risk group had poorer prognosis than those in the low-risk group. Moreover, a nomogram was constructed based on the prognostic signature and clinicopathological features, and this nomogram had strong predictive performance and high accuracy. Conclusion: The cell differentiation-related signature and the prognostic nomogram could accurately predict survival.

The survival nomograms for anti-neutrophil cytoplasmic antibody-associated glomerulonephritis patients with a follow-up of more than one year.

OBJECTIVES: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis with kidney injury, manifested as ANCA-associated glomerulonephritis (AAGN), often portends a poor prognosis of renal function and life survival in long term. METHODS: A cohort of 339 AAGN patients were enrolled retrospectively. These patients survived and were followed up for at least 12 months after diagnosis in our centre. Multivariate Cox regression analysis and nomogram models were performed to determine the risk factors associated with renal survival and patient survival. RESULTS: The median follow-up time of all 339 patients was 65.2 (IQR 45.1, 91.3) months and the median age was 61(IQR 53, 69) years. In order to analyse the impact of the factors on renal survival, we divided the patients into 2 groups: non-dialysis group (204 patients without dialysis at the final visit) and dialysis group (135 patients with maintaining dialysis). The patients in dialysis group had lower haemoglobin level, lower eGFR level, lower platelets count, more daily urine protein, and higher Birmingham Vasculitis Activity Score (BVAS) at admission than those in non-dialysis group. Multivariate Cox regression revealed that low haemoglobin (HR=0.977, 95%CI 0.965-0.990, p<0.001), low eGFR (HR=0.957, 95%CI 0.941-0.973, p<0.001) and high proteinuria (HR=1.139, 95%CI 1.055-1.230, p=0.001) at admission were independent risk factors for developing maintaining dialysis. A nomogram was established based on the results of multivariate Cox analysis and the internal bootstrap resampling approach showed the C-index of the nomogram was 0.83. Then we divided all patients into death group (n=99) and survival group (n=240). The patients in death group had older age, more hypertension, more chronic lung disease, lower platelets count, lower serum albumin, higher BVAS and lower eGFR at admission than those in survival group. Multivariate Cox regression revealed that the status of maintaining dialysis (HR 3.51, 95% CI 1.91-6.47, p<0.001) and old age (HR 1.07, 95% CI 1.04-1.09, p<0.001) were independent risk factors for all-cause mortality. Again, a nomogram was established and the C-index was 0.74. CONCLUSIONS: We analysed the independent risk factors for maintaining dialysis and all-cause mortality in AAGN patients with a follow-up of more than 12 months. The two proposed nomograms were of predictive value.

Construction of core-shell Fe3O4@GO-CoPc photo-Fenton catalyst for superior removal of tetracycline: The role of GO in promotion of H2O2 to •OH conversion.

A novel core-shell structured Fe3O4@GO-CoPc magnetic catalyst, which is with magnetite (Fe3O4) as the core, graphene oxide (GO) as the interlayer and cobalt-phthalocyanine (CoPc) as the shell, was successfully prepared and used as a heterogeneous photo-Fenton catalyst for tetracycline (TC) degradation in this work. The core-shell structure of the catalyst was confirmed by XRD, FTIR, SEM and TEM. BET and magnetic hysteresis loops measurements indicated that Fe3O4@GO-CoPc catalyst owned large specific surface area and could be easily recovered under an external magnetic field. Meanwhile, the experimental results of TC degradation demonstrated that the photo-Fenton efficiency of Fe3O4@GO-CoPc was excellent. When the reaction time was 120 min, TC could be degraded almost completely in the photo-Fenton system with Fe3O4@GO-CoPc. The high photo-Fenton catalytic activity of Fe3O4@GO-CoPc could be resulted from the effective transfer of photo-generated electrons between CoPc and Fe3O4 by GO. Moreover, the main reaction species, •OH, O2•-, 1O2 and h+, were verified by the analysis of active species in this system. Finally, the mechanism analyses and quantitative analysis results of active species indicated that the introduction of GO accelerated the cycle between Fe(II) and Fe(III) as well as improved the effective utilization of H2O2 (the efficiency of conversion of H2O2 to •OH).

Lightweight, Low-Cost Co2SiO4@diatomite Core-Shell Composite Material for High-Efficiency Microwave Absorption.

The porous and biomimetic cobalt silicate@diatomite (Co2SiO4@diatomite) was successfully synthesized by a two-step method, including the hydrothermal method and calcination to improve the electromagnetic wave absorption property. Different hydrothermal times were well-tuned for Co2SiO4@diatomite composites with different loadings of Co2SiO4. Interestingly, the Co2SiO4@diatomite composites (6 h, 25 wt%) had a smaller minimum reflection loss. Moreover, the minimum reflection loss (RLmin) could reach -12.03 dB at 16.64 GHz and the matched absorber thickness was 10 mm, while the effective absorption bandwidth (EAB, RL ≤ -10 dB) could be 1.92 GHz. In principle, such findings indicate that Co2SiO4@diatomite nanocomposites could be a promising candidate for high-efficiency microwave absorption capability.

Anti-inflammatory capacity of Apremilast in human chondrocytes is dependent on SOX-9.

BACKGROUND AND PURPOSE: Osteoarthritis (OA) impacts the quality of life in middle-aged and elderly people by inducing immobility. The severe inflammation in chondrocytes is reported to be related to the development and process of OA. The present study aims to investigate the protective effects of Apremilast on injured chondrocytes induced by interleukin-1α (IL-1α) and the underlying mechanism. METHODS: 10 ng/mL IL-1α was used to induce the in vitro injured chondrocytes. QRT-PCR was used to evaluate the expression level of Sry-type high-mobility-group box 9 (SOX-9), collagen type II alpha-1 gene (COL2A1), Aggrecan (ACAN) and collagen type X alpha 1 chain (COL10A1). SiRNA technology was utilized to knock down the expression of SOX-9 in the chondrocytes. The expression of SOX-9 was determined by Western Blot assay and/or immunofluorescence assay. Western Blot was used to evaluate the expression level of phosphorylated cyclic AMP response element binding (CREB). RESULTS: SOX9, Col2a1 and Acan were significantly up-regulated and Col10a1 was significantly down-regulated in the chondrocytes by Apremilast in a dose-dependent manner. IL-1α induced the injured chondrocytes by decreasing the expression of SOX9, Col2a1, Acan and increasing the expression of Col10a1, which were greatly reversed by Apremilast. By silencing SOX-9, the effects of Apremilast on SOX9 and marker genes were abolished. Phosphorylated CREB was up-regulated by Apremilast in a time-dependent manner. The up-regulated SOX-9 by Apremilast was reversed by the protein kinase A (PKA)/CREB pathway inhibitor H89. CONCLUSION: Apremilast may protect chondrocytes from inflammation by up-regulating SOX9.

[A new nor-sesquiterpene from Cassia occidentalis and its bioactivity].

The phytochemistry investigation on the Cassia occidentalis, a Dai Medicine, was carried out. The C. occidentalis was extracted with ethanol and then partitioned with EtOAc. The EtOAc soluble materials were subjected repeatedly to column chromatography on silica gel and preparative RP-HPLC, leading to isolation of a nor-sesquiterpene, 3-isopropyl-1,6-dimethoxy-5-methyl-naphthalen-7-ol (1), and a sesquiterpene, 2,7-dihydroxy-4-isopropyl-6-methyl-naphthalene-1-carbaldehyde (2). Their structures were determined by means of spectroscopic studies. Compound 1 is a new compound. Compound 2 is also isolated from C. occidentalis for the first time. In addition, the cytotoxicity of compound 1 for NB4, A549, SHSY5Y, PC3, and MCF7 cells line was assayed by using the MTT method, and it displayed potential cytotoxicity for the tested cancer cell-line with IC50 valves of (1.8±0.2), (1.2±0.2), (0.9±0.1), (2.2±0.3), (2.6±0.3) µmol•L⁻¹, respectively.

Insight into the generation of toxic by-products during UV/H2O2 degradation of carbamazepine: Mechanisms, N-transformation and toxicity.

Carbamazepine (CBZ) is a widely used anticonvulsant drug that has been detected in aquatic environments. This study investigated the toxicity of its by-products (CBZ-BPs), which may surpass CBZ. Unlike the previous studies, this study offered a more systematic approach to identifying toxic BPs and inferring degradation pathways. Furthermore, quadrupole time-of-flight (QTOF) and density functional theory (DFT) calculations were employed to analyze CBZ-BP structures and degradation pathways. Evaluation of total organic carbon (TOC) and total nitrogen (TN) mineralization rates, revealed carbon (C) greater susceptibility to mineralization compared with nitrogen (N). Furthermore, three rules were established for CBZ decarbonization and N removal during degradation, observing the transformation of aromatic compounds into aliphatic hydrocarbons and stable N-containing organic matter over time. Five potentially highly toxic BPs were screened from 14 identified BPs, with toxicity predictions guiding the selection of commercial standards for quantification and true toxicity testing. Additionally, BP207 emerged as the most toxic, supported by the predictive toxicity accumulation model (PTAM). Notably, highly toxic BPs feature an acridine structure, indicating its significant contribution to toxicity. These findings offered valuable insights into the degradation mechanisms of emerging contaminants and the biosafety of aquatic environments during deep oxidation.

Time-resolved map of serum metabolome profiling in D-galactose-induced aging rats with exercise intervention.

Exercise, an intervention with wide-ranging effects on the whole body, has been shown to delay aging. Due to aging and exercise as modulator of metabolism, a picture of how exercise delayed D-galactose (D-gal)-induced aging in a time-resolved manner was presented in this paper. The mapping of molecular changes in response to exercise has become increasingly accessible with the development of omics techniques. To explore the dynamic changes during exercise, the serum of rats and D-gal-induced aging rats before, during, and after exercise was analyzed by untargeted metabolomics. The variation of metabolites was monitored to reveal the specific response to D-gal-induced senescence and exercise in multiple pathways, especially the basal amino acid metabolism, including glycine serine and threonine metabolism, cysteine and methionine metabolism, and tryptophan metabolism. The homeostasis was disturbed by D-gal and maintained by exercise. The paper was expected to provide a theoretical basis for the study of anti-aging exercise.

The correlation of interstitial change with renal prognosis in patients with myeloperoxidase-ANCA-associated glomerulonephritis: a single-center retrospective analysis.

OBJECTS: We aim to explore the correlation between active/chronic tubulointerstitial injury and renal survival, and to compare their predictive value in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN). METHOD: A total of 225 patients with MPO-AAGN diagnosed between February 2004 and December 2020 were included. Survival and univariate/multivariate Cox regression analyses were used to analyze the prognostic value of interstitial inflammation and interstitial fibrosis/tubular atrophy (IF/TA). RESULTS: Of the 225 patients, 73 (32.4%) patients developed end-stage renal disease (ESRD) requiring maintenance dialysis. Interstitial inflammation>50% and IF/TA>50% were important predictors for ESRD in MPO-AAGN in multivariate Cox regression analysis adjusted by age, gender, estimated glomerular filtration rate (eGFR)≤15 ml/min/1.73m2, and normal glomeruli% (classified by <25%, 25-50%, >50%). Furthermore, we conducted stratified Cox regression analysis and found different results in the subgroups of eGFR>15 ml/min/1.73m2 and eGFR≤15 ml/min/1.73m2. Interstitial inflammation>50% and IF/TA>50% were significant risk factors for ESRD in the subgroup of eGFR>15 ml/min/1.73m2, but not or less significant in the subgroup of eGFR≤15 ml/min/1.73m2. Similarly, the survival analysis according to interstitial inflammation>50%/≤50% and IF/TA>50%/≤50% showed significant differences in the subgroup of eGFR>15 ml/min/1.73m2, but not or less significant in the subgroup of eGFR≤15 ml/min/1.73m2. CONCLUSIONS: Interstitial inflammation>50% and IF/TA>50% were prognostic factors for renal survival in MPO-AAGN. In particular, interstitial inflammation and IF/TA had a better predictive ability in the subgroup of eGFR>15 ml/min/1.73m2. Key Points • Interstitial inflammation>50% and IF/TA>50% can help to predict renal survival in MPO-AAGN. • Both interstitial inflammation and IF/TA had a better predictive ability in the subgroup of eGFR>15 ml/min/1.73m2 than those in the subgroup of eGFR≤15 ml/min/1.73m2.

SNORD3A Regulates STING Transcription to Promote Ferroptosis in Acute Kidney Injury.

Acute kidney injury (AKI) signifies a sudden and prolonged decline in kidney function characterized by tubular cell death and interstitial inflammation. Small nucleolar RNAs (snoRNAs) play pivotal roles in oxidative stress and inflammation, and may play an important role in the AKI process, which remains elusive. an elevated expression of Snord3a is revealed in renal tubules in response to AKI and demonstrates that Snord3a deficiency alleviates renal injury in AKI mouse models. Notably, the deficiency of Snord3a exhibits a mitigating effect on the stimulator of interferon genes (STING)-associated ferroptosis phenotypes and the progression of tubular injury. Mechanistically, Snord3a is shown to regulate the STING signaling axis via promoting STING gene transcription; administration of Snord3a antisense oligonucleotides establishes a significant therapeutic advantage in AKI mouse models. Together, the findings elucidate the transcription regulation mechanism of STING and the crucial roles of the Snord3a-STING axis in ferroptosis during AKI, underscoring Snord3a as a potential prognostic and therapeutic target for AKI.

Deep immunoglobulin repertoire sequencing depicts a comprehensive atlas of spike-specific antibody lineages shared among COVID-19 convalescents.

Neutralizing antibodies are a key component in protective humoral immunity against SARS-CoV-2. Currently, available technologies cannot track epitope-specific antibodies in global antibody repertoires. Thus, the comprehensive repertoire of spike-specific neutralizing antibodies elicited by SARS-CoV-2 infection is not fully understood. We therefore combined high-throughput immunoglobulin heavy chain (IgH) repertoire sequencing, and structural and bioinformatics analysis to establish an antibodyomics pipeline, which enables tracking spike-specific antibody lineages that target certain neutralizing epitopes. We mapped the neutralizing epitopes on the spike and determined the epitope-preferential antibody lineages. This analysis also revealed numerous overlaps between immunodominant neutralizing antibody-binding sites and mutation hotspots on spikes as observed so far in SARS-CoV-2 variants. By clustering 2677 spike-specific antibodies with 360 million IgH sequences that we sequenced, a total of 329 shared spike-specific antibody clonotypes were identified from 33 COVID-19 convalescents and 24 SARS-CoV-2-naïve individuals. Epitope mapping showed that the shared antibody responses target not only neutralizing epitopes on RBD and NTD but also non-neutralizing epitopes on S2. The immunodominance of neutralizing antibody response is determined by the occurrence of specific precursors in human naïve B-cell repertoires. We identified that only 28 out of the 329 shared spike-specific antibody clonotypes persisted for at least 12 months. Among them, long-lived IGHV3-53 antibodies are likely to evolve cross-reactivity to Omicron variants through accumulating somatic hypermutations. Altogether, we created a comprehensive atlas of spike-targeting antibody lineages in COVID-19 convalescents and antibody precursors in human naïve B cell repertoires, providing a valuable reference for future vaccine design and evaluation.