Increase in Mitochondrial Mass of Lymphocyte Subsets in Anti-MDA5 and TIF1-γ-Positive Dermatomyositis Patients.

OBJECTIVES: The mitochondrial function in anti-MDA5 and TIF1-γ-positive dermatomyositis (DM) is relatively unknown. This study attempted to explore mitochondrial mass within the peripheral lymphocyte subsets of anti-MDA5 and TIF1-γ-positive DM. METHODS: This cross-sectional study enrolled 109 DM patients and 32 healthy controls (HCs). The mitochondrial mass of peripheral lymphocyte subsets was analyzed via flow cytometry using median fluorescence intensity assessment. RESULTS: Compared with HCs, there was an abnormal change in peripheral lymphocyte subsets in anti-MDA5 and anti-TIF1-γ-positive DM patients. Anti-MDA5 and anti-TIF1-γ-positive DM patients also exhibited a significantly elevated mitochondrial mass in peripheral lymphocyte subsets. Furthermore, anti-MDA5 antibody levels were positively associated with the mitochondrial mass of most lymphocyte subsets in anti-MDA5-positive DM patients. Univariate logistic regression analysis indicated that the increased mitochondrial mass in some peripheral lymphocyte subsets was related to the occurrence of anti-MDA5-positive DM and presence of anti-MDA5 antibodies. Similar results were obtained in anti-TIF1-γ-positive DM patients. CONCLUSIONS: Abnormal lymphocyte subset counts and percentages as well as altered mitochondrial mass in anti-MDA5 and TIF1-γ-positive DM patients were associated with anti-MDA5 and TIF1-γ antibodies. We believe that these results may provide novel mitochondria-based insights into DM pathogenesis.

Immune and inflammation features of severe and critical Omicron infected patients during Omicron wave in China.

OBJECTIVE: The current study aimed to investigate the baseline immune and inflammatory features and in-hospital outcomes of patients infected with the Omicron variant (PIWO) who presented with different disease severities during the first wave of mass Omicron infections in the Chinese population has occurred. METHOD: A cross-sectional study was conducted on 140 hospitalized PIWO between December 11, 2022, and February 16, 2023. The clinical features, antibodies against SARS-CoV-2, immune cells, and inflammatory cytokines among mildly, severely, and critically ill PIWO at baseline and during follow-up period were compared. RESULT: Patients with severe (n = 49) and critical (n = 35) disease were primarily male, needed invasive mechanical ventilation treatment, and exhibited higher mortality than those with mild disease (n = 56). During acute infection, SARS-CoV-2-specific antibody levels fluctuated with disease severity, serum antibodies increased and the incidence of severe cases decreased in critically ill PIWO over time. Antibody titers in severe or critical PIWO with no antibody responses at baseline did not increase significantly over time. Meanwhile, CD4+T cell, CD8+T cell, and natural killer cell counts were negatively correlated with disease severity, whereas interleukin (IL)-6 and IL-10 levels were positively correlated. In addition, combined diabetes, immunosuppressive therapy before infection, serum amyloid A, IL-10 and neutrophil counts were independently associated with severe and critical illness in PIWO. Among the 11 nonsurvivors, 8, 2, 1 died of respiratory failure, sudden cardiac death, and renal failure, respectively. Compared with survivors, nonsurvivors exhibited lower seropositivity of SARS-CoV-2-specific antibody, reduced CD3+T and CD4+T cell counts, and higher IL-2R, IL-6, IL-8, and IL-10 levels. Of note, lactate dehydrogenase was a significant risk factor of death in severe or critically ill PIWO. CONCLUSION: This present study assessed the dynamic changes of SARS-CoV-2-specific antibodies, immune cells and inflammatory indexes between severely and critically ill PIWO. Critical and dead PIWO featured compromised humoral immune response and excessive inflammation, which broadened the understanding of the pathophysiology of Omicron infection and provides warning markers for severe disease and poor prognosis.

The survival and complication profiles of the Compress® Endoprosthesis: A systematic review and meta-analysis.

Background/purpose: This study aimed to summarize the survival and complication profiles of the compress® endoprosthesis (CPS) through a systematic review and meta-analysis. Methods: Online databases (PubMed, EMBASE and Web of Science) were searched from inception to November 2023. Trials were included that involved the use of CPS for endoprosthetic replacement in patients with massive segmental bone defects. Patients' clinical characteristics and demographic data were extracted using a standardized form. The methodological quality of included 13 non-comparative studies was assessed on basis of the Methodological Index for Non-Randomized Studies (MINORS). All the available Kaplan-Meier curves in the included studies were digitized and combined using Engauge-Digitizer software and the R Project for Statistical Computing. Results: The meta-analysis of thirteen included studies indicated: the all-cause failure rates of CPS were 26.3 % after surgery, in which the occurrence rates of aseptic loosening were 5.8 %. And the incidences of other complications were as follows: soft tissue failure (1.8 %), structure failure (8.2 %), infection (9.5 %), tumor progression (1.1 %). The 1-, 4-, and 8-year overall survival rates for all-cause failure with 95 % CI were 89 % (86 %-92 %), 75 % (71 %-79 %) and 65 % (60 %-70 %), respectively. The estimated mean survival time of all-cause failure was 145 months (95 % CI, 127-148 months), and the estimated median survival time of all-cause failure was 187 months (95 % CI, 135-198 months). The 1-, 4-, and 8-year overall survival rates of aseptic loosening with 95 % CI were 96 % (94 %-98 %), 91 % (87 %-95 %) and 88 % (83 %-93 %), respectively. The estimated mean survival time of aseptic loosening was 148 months (95 % CI, 137-153 months). Conclusion: CPS's innovative spring system promotes bone ingrowth by providing immediate and high-compression fixation, thereby reducing the risk of aseptic loosening caused by stress shielding and particle-induced osteolysis. CPS requires less residual bone mass for reconstructing massive segmental bone defects and facilitates easier revision due to its non-cemented fixation. In addition, the survival rate, estimated mean survival time, and complication rates of CPS are not inferior to those of common endoprosthesis.

SARS-CoV-2 Evolution: Immune Dynamics, Omicron Specificity, and Predictive Modeling in Vaccinated Populations.

Host immunity is central to the virus's spread dynamics, which is significantly influenced by vaccination and prior infection experiences. In this work, we analyzed the co-evolution of SARS-CoV-2 mutation, angiotensin-converting enzyme 2 (ACE2) receptor binding, and neutralizing antibody (NAb) responses across various variants in 822 human and mice vaccinated with different non-Omicron and Omicron vaccines is analyzed. The link between vaccine efficacy and vaccine type, dosing, and post-vaccination duration is revealed. The classification of immune protection against non-Omicron and Omicron variants is co-evolved with genetic mutations and vaccination. Additionally, a model, the Prevalence Score (P-Score) is introduced, which surpasses previous algorithm-based models in predicting the potential prevalence of new variants in vaccinated populations. The hybrid vaccination combining the wild-type (WT) inactivated vaccine with the Omicron BA.4/5 mRNA vaccine may provide broad protection against both non-Omicron variants and Omicron variants, albeit with EG.5.1 still posing a risk. In conclusion, these findings enhance understanding of population immunity variations and provide valuable insights for future vaccine development and public health strategies.

NK Cell Mitochondrial Membrane Potential-Associated Model Predicts Outcomes in Critically Ill Patients with COVID-19.

Purpose: This study investigated potential predictive models associated with natural killer (NK) cell mitochondrial membrane potential (MMP or ΔΨm) in predicting death among critically ill patients with COVID-19. Patients and Methods: We included 97 patients with COVID-19 of different severities attending Peking Union Medical College Hospital from December 2022 to January 2023. Patients were divided into three groups according to oxygen and mechanical ventilation use during specimen collection and were followed for survival and death at 3 months. The lymphocyte subpopulation MMP was detected via flow cytometry. We constructed a joint diagnostic model by integrating identified key indicators and generating receiver operating curves (ROCs) and evaluated its predictive performance for mortality risk in critically ill patients. Results: The NK-cell MMP median fluorescence intensity (MFI) was significantly lower in critically ill patients who died from COVID-19 (p<0.0001) and significantly and positively correlated with D-dimer content in critically ill patients (r=0.56, p=0.0023). The random forest model suggested that fibrinogen levels and NK-cell MMP MFI were the most important indicators. Integrating the above predictive models for the ROC yielded an area under the curve of 0.94. Conclusion: This study revealed the potential of combining NK-cell MMP with key clinical indicators (D-dimer and fibrinogen levels) to predict death among critically ill patients with COVID-19, which may help in early risk stratification of critically ill patients and improve patient care and clinical outcomes.

Palladium-Catalyzed Selective γ-Monoarylation of Free Amines Containing Symmetric γ-C-H Controlled by a Transient Directing Group.

We developed a new transient directing group, N-(2-benzoyl-4-chlorophenyl)-1,1,1-trifluoromethanesulfonamide, which can facilitate the γ-monoarylation of free amines containing symmetric γ-C-H bonds. A variety of amines containing symmetric and identical γ-C(sp3)-H and γ-C(sp2)-H reacted with a diverse range of aryl and heteroaryl iodides to provide γ-monoarylated products exclusively.

Integrated analyses highlight interactions between the three-dimensional genome and DNA, RNA and epigenomic alterations in metastatic prostate cancer.

The impact of variations in the three-dimensional structure of the genome has been recognized, but solid cancer tissue studies are limited. Here, we performed integrated deep Hi-C sequencing with matched whole-genome sequencing, whole-genome bisulfite sequencing, 5-hydroxymethylcytosine (5hmC) sequencing and RNA sequencing across a cohort of 80 biopsy samples from patients with metastatic castration-resistant prostate cancer. Dramatic differences were present in gene expression, 5-methylcytosine/5hmC methylation and in structural variation versus mutation rate between A and B (open and closed) chromatin compartments. A subset of tumors exhibited depleted regional chromatin contacts at the AR locus, linked to extrachromosomal circular DNA (ecDNA) and worse response to AR signaling inhibitors. We also identified topological subtypes associated with stark differences in methylation structure, gene expression and prognosis. Our data suggested that DNA interactions may predispose to structural variant formation, exemplified by the recurrent TMPRSS2-ERG fusion. This comprehensive integrated sequencing effort represents a unique clinical tumor resource.

An Atlas of Accessible Chromatin in Advanced Prostate Cancer Reveals the Epigenetic Evolution during Tumor Progression.

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease that resists therapy targeting androgen signaling, the primary driver of prostate cancer. mCRPC resists androgen receptor (AR) inhibitors by amplifying AR signaling or by evolving into therapy-resistant subtypes that do not depend on AR. Elucidation of the epigenetic underpinnings of these subtypes could provide important insights into the drivers of therapy resistance. In this study, we produced chromatin accessibility maps linked to the binding of lineage-specific transcription factors (TF) by performing assay for transposase-accessible chromatin sequencing on 70 mCRPC tissue biopsies integrated with transcriptome and whole-genome sequencing. mCRPC had a distinct global chromatin accessibility profile linked to AR function. Analysis of TF occupancy across accessible chromatin revealed 203 TFs associated with mCRPC subtypes. Notably, ZNF263 was identified as a putative prostate cancer TF with a significant impact on gene activity in the double-negative subtype (AR- neuroendocrine-), potentially activating MYC targets. Overall, this analysis of chromatin accessibility in mCRPC provides valuable insights into epigenetic changes that occur during progression to mCRPC. Significance: Integration of a large cohort of transcriptome, whole-genome, and ATAC sequencing characterizes the chromatin accessibility changes in advanced prostate cancer and identifies therapy-resistant prostate cancer subtype-specific transcription factors that modulate oncogenic programs.

Impaired acute-phase humoral immunity is the major factor predicting unfavorable outcomes in multiple myeloma patients with SARS-CoV-2 Omicron variants outbreak infection.

At the end of 2022, a huge tide of SARS-CoV-2 infection mainly Omicron BA.4/5 developed in China. Multiple myeloma (MM) patients suffered cancer deterioration and mortality from COVID-19, yet profound analyses of Omicron variants-induced immunity function are scarce. We presented a longitudinal study in 218 MM patients and 73 healthy controls (HCs), reporting the prognostic factors and dynamic humoral and cellular immune responses. Neutralizing antibody and interferon γ ELISpot assay of SARS-CoV-2 was tested at three time points: 2-4, 8-10, and 14-16 weeks after infections. Our data showed older age, active MM, relapsed/refractory MM (R/RMM), immunotherapy, comorbidity, and non-vaccination were risk factors associated with hospitalization. Severe humoral immunity impairment within 2-4 weeks was especially seen in patients with unvaccinated, older age, immunotherapy, R/RMM and comorbidities, while T-cell response was relatively intact. Although antibodies of Omicron variants reached positive levels in MM patients at 8-10 weeks, half lost effective antibody protection at 14-16 weeks. However, most seronegative patients (76.2% at 2-4 weeks, 83.3% at 8-10 weeks) could develop effective T-cell response. Notably, the inactivated wild-type vaccinated patients exhibited weaker humoral and cellular immunity only at 2-4 weeks, escalating to similar levels as those in HCs later. Our findings indicate impairment of humoral immunity at acute-phase after infection is the major factor correlated with hospitalization. One-month suspension of immune therapy is suggested to prevent serious infection. These results confirm the value of inactivated vaccine, but indicate the need for additional booster at 14-16 weeks after infection for high-risk MM population.

Supramolecular Modifying Nafion with Fluoroalkyl­Functionalized Polyoxometalate Nanoclusters for High­Selective Proton Conduction.

Fluoroalkyl-grafted polyoxometalate nanoclusters are used as supramolecular additives to precisely modify the ionic domains of Nafion, which can increase the proton conductivity and selectivity simultaneously. The resulting hybrid membranes show significantly enhanced power density in fuel cells and improved energy efficiency in vanadium flow batteries.

Integrative analysis of ultra-deep RNA-seq reveals alternative promoter usage as a mechanism of activating oncogenic programmes during prostate cancer progression.

Transcription factor (TF) proteins regulate gene activity by binding to regulatory regions, most importantly at gene promoters. Many genes have alternative promoters (APs) bound by distinct TFs. The role of differential TF activity at APs during tumour development is poorly understood. Here we show, using deep RNA sequencing in 274 biopsies of benign prostate tissue, localized prostate tumours and metastatic castration-resistant prostate cancer, that AP usage increases as tumours progress and APs are responsible for a disproportionate amount of tumour transcriptional activity. Expression of the androgen receptor (AR), the key driver of prostate tumour activity, is correlated with elevated AP usage. We identified AR, FOXA1 and MYC as potential drivers of AP activation. DNA methylation is a likely mechanism for AP activation during tumour progression and lineage plasticity. Our data suggest that prostate tumours activate APs to magnify the transcriptional impact of tumour drivers, including AR and MYC.

Significance of immunoglobulins synthesis with central nervous system involvement in Neuro-Behçet's disease.

OBJECTIVES: Demyelination and immunocyte-infiltrated lesions have been found in neuro-Behçet's disease (NBD) pathology. Lacking satisfying laboratory biomarkers in NBD impedes standard clinical diagnostics. We aim to explore the ancillary indicators for NBD diagnosis unveiling its potential etiology. METHODS: 28 NBD with defined diagnosis, 29 patients with neuropsychiatric lupus erythematosus, 30 central nervous system idiopathic inflammatory demyelination diseases (CNS-IIDD), 30 CNS infections, 30 cerebrovascular diseases, and 30 noninflammatory neurological diseases (NIND) were retrospectively enrolled. Immunoglobulins (Ig) in serum and cerebral spinal fluid (CSF) were detected by immunonephelometry and myelin basic protein (MBP) by quantitative enzyme-linked immunosorbent assay. RESULTS: IgA index is almost twice enhanced in NBD than NIND with an accuracy of 0.8488 in differential diagnosis, the sensitivity and specificity of which were 75.00 % and 90.00 % when the cutoff was > 0.6814. The accuracy of CSF Ig and quotient of Ig all exceed 0.90 in discerning NBD with damaged and intact blood-brain barrier (BBB). Clustering analyses divided NBD into two different phenotypes: one with BBB damage has lower Ig synthesis, the other with extra-synthesis in parenchymal sites but with intact BBB. MBP index is significantly correlated with kappa (KAP) index and lambda (LAM) index (r = 0.358, 0.575, P < 0.001), hinting the NBD pathogenesis of CNS demyelination in triggering excessive intrathecal Ig productions and humoral responses. CONCLUSIONS: IgA index acts as a potential diagnostic indicator in differentiating NBD from NIND and CNS-IIDD. Excessive immunoglobulin production induced by CNS inflammation and demyelination might be latent immunopathogenesis of NBD.

SlCathB2 as a negative regulator mediates a novel regulatory pathway upon high-temperature stress response in tomato.

High-temperature stress (HS) is a major abiotic stress that affects the yield and quality of plants. Cathepsin B-like protease 2 (CathB2) has been reported to play a role in developmental processes and stress response, but its involvement in HS response has not been identified. Here, overexpression, virus-induced gene silencing (VIGS)and RNA-sequencing analysis were performed to uncover the functional characteristics of SlCathB2-1 and SlCathB2-2 genes for HS response in tomato. The results showed that overexpression of SlCathB2-1 and SlCathB2-2 resulted in reduced heat tolerance of tomato to HS while silencing the genes resulted in enhanced heat tolerance. RNA-sequencing analysis revealed that the heat shock proteins (HSPs) exhibited higher expression in WT than in SlCathB2-1 and SlCathB2-2 overexpression lines. Furthermore, the possible molecular regulation mechanism underlying SlCathB2-1 and SlCathB2-2-mediated response to HS was investigated. We found that SlCathB2-1 and SlCathB2-2 negatively regulated antioxidant capacity by regulating a set of genes involved in antioxidant defence and reactive oxygen species (ROS) signal transduction. We also demonstrated that SlCathB2-1 and SlCathB2-2 positively regulated ER-stress-induced PCD (ERSID) by regulating unfolded protein response (UPR) gene expression. Furthermore, SlCathB2-1 and SlCathB2-2 interacting with proteasome subunit beta type-4 (PBA4) was identified in the ERSID pathway using yeast two-hybrid (Y2H) analysis and bimolecular fluorescence complementation (BiFC) screening. Overall, the study identified both SlCathB2-1 and SlCathB2-2 as new negative regulators to HS and presented a new HS response pathway. This provided the foundation for the construction of heat-tolerant molecular mechanisms and breeding strategies aiming to improve the thermotolerance of tomato plants.

Acceptance, safety, and immunogenicity of a booster dose of inactivated SARS-CoV-2 vaccine in patients with primary biliary cholangitis.

Inactivated coronavirus disease 2019 (COVID-19) vaccines showed impaired immunogenicity in some autoimmune diseases, but it remains unclear in primary biliary cholangitis (PBC). This study aimed to explore the antibody response to the inactivated COVID-19 vaccine in individuals with PBC, as well as to evaluate coverage, safety, and attitudes toward the COVID-19 vaccine among them. Two cohorts of patients with PBC were enrolled in this study. One cohort was arranged to evaluate the immunogenicity of the inactivated COVID-19 vaccine, another cohort participated in an online survey. The titers of the anti-receptor-binding domain (RBD)-specific immunoglobulin G (IgG), neutralizing antibody (NAb) toward severe acute respiratory syndrome coronavirus 2 wild-type, and NAb toward Omicron BA.4/5 subvariants were detected to assess antibody response from the vaccine. After booster vaccination for more than six months, patients with PBC had significantly lowered levels of anti-RBD-specific IgG compared to HCs, and the inhibition rates of NAb toward wild-type also declined in individuals with PBC. The detected levels of NAb toward Omicron BA.4/5 were below the positive threshold in patients with PBC and HCs. Laboratory parameters did not significantly correlate with any of the three antibodies. The online survey revealed that 24% of patients with PBC received three COVID-19 vaccines, while 63% were unimmunized. Adverse effect rates after the first, second, and third vaccine doses were 6.1%, 10.3%, and 9.5%, respectively. Unvaccinated patients with PBC were more worried about the safety of the vaccine than those who were vaccinated (P = 0.004). As a result, this study fills the immunological assessment gap in patients with PBC who received inactivated COVID-19 vaccines.

Cytochrome P450 CYP736A12 is crucial for Trichoderma asperellum-induced alleviation of phoxim phytotoxicity and reduction of pesticide residue in tomato roots.

Trichoderma can enhance the metabolism of organophosphate pesticides in plants, but the mechanism is unclear. Here, we performed high-throughput transcriptome sequencing of roots upon Trichoderma asperellum (TM) inoculation and phoxim (P) application in tomato (Solanum lycopersicum L.). A total of 4059 differentially expressed genes (DEGs) were obtained, including 2110 up-regulated and 1949 down-regulated DEGs in P vs TM+P. COG and KOG analysis indicated that DEGs were mainly enriched in signal transduction mechanisms. We then focused on the pesticide detoxification pathway and screened out cytochrome P450 CYP736A12 as a putative gene for functional analysis. We suppressed the expression of CYP736A12 in tomato plants by virus-induced gene silencing and analyzed tissue-specific phoxim residues, oxidative stress markers, glutathione pool, GST activity and related gene expression. Silencing CYP736A12 significantly increased phoxim residue and induced oxidative stress in tomato plants, by attenuating the TM-induced increased activity of antioxidant and detoxification enzymes, redox homeostasis and transcripts of detoxification genes including CYP724B2, GSH1, GSH2, GR, GPX, GST1, GST2, GST3, and ABC. The study revealed a critical mechanism by which TM promotes the metabolism of phoxim in tomato roots, which can be useful for further understanding the Trichoderma-induced xenobiotic detoxification and improving food safety.

Polyoxometalate-based reticular materials for proton conduction: from rigid frameworks to flexible networks.

Proton conductors play a crucial role in energy and electronic technologies, thus attracting extensive research interest. Recently, reticular chemistry has propelled the development of reticular materials with framework or network structures, which can offer tunable proton transport pathways to achieve optimal conducting performance. Polyoxometalates (POMs), as a class of highly proton-conducting units, have been integrated into these reticular materials using various linkers. This leads to the creation of hybrid proton conductors with structures varying from rigid crystalline frameworks to flexible networks, showing adjustable proton transport behaviors and mechanical properties. This Frontier article highlights the advancements in POM-based reticular materials for proton conduction and provides insights for designing advanced proton conductors for practical applications.

Nuclear receptor NURR1 functions to promote stemness and epithelial-mesenchymal transition in prostate cancer via its targeting of Wnt/ß-catenin signaling pathway.

Dysregulated activation of Wnt/ß-catenin signaling pathway is a frequent or common event during advanced progression of multiple cancers. With this signaling activation, it enhances their tumorigenic growth and facilitates metastasis and therapy resistance. Advances show that this signaling pathway can play dual regulatory roles in the control of cellular processes epithelial-mesenchymal transition (EMT) and cancer stemness in cancer progression. Aberrant activation of Wnt/ß-catenin signaling pathway is shown to be common in prostate cancer and also castration-resistant prostate cancer (CRPC). However, the transcriptional regulators of this pathway in prostate cancer are still not well characterized. NURR1 (NR4A2) is an orphan nuclear receptor and plays an important role in the development of dopaminergic neurons. Previously, we have shown that NURR1 exhibits an upregulation in isolated prostate cancer stem-like cells (PCSCs) and a xenograft model of CRPC. In this study, we further confirmed that NURR1 exhibited an upregulation in prostate cancer and also enhanced expression in prostate cancer cell lines. Functional and molecular analyses showed that NURR1 could act to promote both in vitro (cancer stemness and EMT) and also in vivo oncogenic growth of prostate cancer cells (metastasis and castration resistance) via its direct transactivation of CTNNB1 (ß-catenin) and activation of ß-catenin to mediate the activation of Wnt/ß-catenin signaling pathway. Moreover, we also demonstrated that NURR1 activity in prostate cancer cells could be modulated by small molecules, implicating that NURR1 could be a potential therapeutic target for advanced prostate cancer management.

COVID-19 vaccination willingness among people living with HIV in Shijiazhuang, China: a cross-sectional survey.

Objectives: The COVID-19 pandemic imposed an enormous disease and economic burden worldwide. SARS-CoV-2 vaccination is essential to containing the pandemic. People living with HIV (PLWH) may be more vulnerable to severe COVID-19 outcomes; thus, understanding their vaccination willingness and influencing factors is helpful in developing targeted vaccination strategies. Methods: A cross-sectional study was conducted between 15 June and 30 August 2022 in Shijiazhuang, China. Variables included socio-demographic characteristics, health status characteristics, HIV-related characteristics, knowledge, and attitudes toward COVID-19 vaccination and COVID-19 vaccination status. Multivariable logistic regression was used to confirm factors associated with COVID-19 vaccination willingness among PLWH. Results: A total of 1,428 PLWH were included, with a 90.48% willingness to receive the COVID-19 vaccination. PLWH were more unwilling to receive COVID-19 vaccination for those who were female or had a fair/poor health status, had an allergic history and comorbidities, were unconvinced and unsure about the effectiveness of vaccines, were unconvinced and unsure about the safety of vaccines, were convinced and unsure about whether COVID-19 vaccination would affect ART efficacy, or did not know at least a type of domestic COVID-19 vaccine. Approximately 93.00% of PLWH have received at least one dose of the COVID-19 vaccine among PLWH, and 213 PLWH (14.92%) reported at least one adverse reaction within 7 days. Conclusion: In conclusion, our study reported a relatively high willingness to receive the COVID-19 vaccination among PLWH in Shijiazhuang. However, a small number of PLWH still held hesitancy; thus, more tailored policies or guidelines from the government should be performed to enhance the COVID-19 vaccination rate among PLWH.

Omicron BA.4/5 neutralization and cell-mediated immune responses in relation to baseline immune status and breakthrough infection among PLWH: A follow-up cohort study.

There is a paucity of data on hybrid immunity (vaccination plus breakthrough infection [BI]), especially cell-mediated responses to Omicron among immunosuppressed patients. We aim to investigate humoral and cellular responses to Omicron BA.4/5 among people living with HIV (PLWH) with/without BIs, the most prevalent variant of concern after the reopening of China. Based on our previous study, we enrolled 77 PLWH with baseline immune status of severe acute respiratory syndrome coronavirus 2 specific antibodies after inactivated vaccination. "Correlates of protection," including serological immunoassays, T cell phenotypes and memory B cells (MBC) were determined in PLWH without and with BI, together with 16 PLWH with reinfections. Higher inhibition rate of neutralizing antibodies (NAb) against BA.4/5 was elicited among PLWH with BI than those without. Omicron-reactive IL4+ CD8+ T cells were significantly elevated in PLWH experienced postvaccine infection contrasting with those did not. NAb towards wild type at baseline was associated with prolonged negative conversion time for PLWH whereas intermediate MBCs serve as protecting effectors. We uncovered that hybrid immunity intensified more protection on BA.4/5 than vaccination did. Strengthened surveillance on immunological parameters and timely clinical intervention on PLWH deficient in protection would reduce the severity and mortality in the context of coexistence with new Omicron subvariants.

Large tandem duplications in cancer result from transcription and DNA replication collisions.

Despite the abundance of somatic structural variations (SVs) in cancer, the underlying molecular mechanisms of their formation remain unclear. Here, we use 6,193 whole-genome sequenced tumors to study the contributions of transcription and DNA replication collisions to genome instability. After deconvoluting robust SV signatures in three independent pan-cancer cohorts, we detect transcription-dependent replicated-strand bias, the expected footprint of transcription-replication collision (TRC), in large tandem duplications (TDs). Large TDs are abundant in female-enriched, upper gastrointestinal tract and prostate cancers. They are associated with poor patient survival and mutations in TP53, CDK12, and SPOP. Upon inactivating CDK12, cells display significantly more TRCs, R-loops, and large TDs. Inhibition of G2/M checkpoint proteins, such as WEE1, CHK1, and ATR, selectively inhibits the growth of cells deficient in CDK12. Our data suggest that large TDs in cancer form due to TRCs, and their presence can be used as a biomarker for prognosis and treatment.