Accelerated biological aging mediated associations of ammonium, sulfate in fine particulate matter with liver cirrhosis.

BACKGROUND: Although both air pollution and aging are related to the development of liver cirrhosis, the role of biological aging in association of the mixture of fine particulate matter (PM2.5) and its constituents with liver cirrhosis was unknown. METHODS: This case-control retrospective study included 100 liver cirrhosis patients and 100 control subjects matched by age and sex. The concentrations of PM2.5 and its constituents were estimated for patients using machine-learning methods. The clinical biomarkers were used to calculate biological age using the Klemera-Doubalmethod (KDM) algorithms. Individual associations of PM2.5 and its constituents or biological age with liver cirrhosis were analyzed by generalized linear models. WQS and BKMR were applied to analyze association of mixture of PM2.5 and its constituents with liver cirrhosis. The mediation effect of biological age on associations of PM2.5 and its constituents with liver cirrhosis was further explored. RESULTS: we found that each 1-unit increment in NH4+, NO3-, SO42- and biological age were related to 3.618-fold (95%CI: 1.896, 6.904), 1.880-fold (95%CI: 1.319, 2.680), 2.955-fold (95%CI: 1.656, 5.272) and 1.244-fold (95%CI: 1.093, 1.414) increased liver cirrhosis. Both WQS and BKMR models showed that the mixture of PM2.5 and its constituents was related to increased liver cirrhosis. Furthermore, the mediated proportion of biological age on associations of NH4+ and SO42- with liver cirrhosis were 14.7 % and 14.6 %, respectively. CONCLUSIONS: Biological aging may partly explain the exposure to PM2.5 and its constituents in association with increased risk for liver cirrhosis, implying that delaying the aging process may be a key step for preventing PM2.5-related liver cirrhosis risk.

Melatonin alleviates endoplasmic reticulum stress and follicular granulosa cell apoptosis by regulating ATF4 to activate mTOR signaling pathway in chickens.

Follicular atresia in chickens reduces the number of follicles that can further develop, leading to decrease egg laying. Endoplasmic reticulum stress (ERS) can initiate a unique pathway inducing the apoptosis of follicular granulosa cells, thus reducing egg laying. Melatonin (MEL) is involved in the regulation of follicle development, ovulation, and oocyte maturation, and is closely related to follicle fate. Mammalian target of Rapamycin (mTOR) signaling pathway plays an important role in cell growth regulation, and that there is a possible crosstalk between melatonin and mTOR activity in granular cells maturation and ovulation. This study aimed to investigate whether MEL inhibits ERS and follicular granulosa cell apoptosis by regulating ATF4 to activate mTOR signaling pathway in chickens. Frist, we established an in vitro ERS cell model using tunicamycin (TM). The results showed that different concentrations of TM exhibited dose-dependent inhibition of cell activity and induction of granulosa cells (P<0.01). Therefore, we chose 5 µg/mL of TM and a treatment time for 6 h as the optimal concentration for the following experiments. Then we investigate whether melatonin can inhibit ERS. TM treatment decreased the cell viability and Bcl-2 expression, increasing ROS levels and the mRNA expression of Grp78, ATF4, CHOP, PERK, eIF-2α, and BAX (P<0.01), whereas TM+MEL treatment significantly inhibited these changes (P<0.01). Then we explored whether melatonin protects follicular granulosa cells from ERS-induced apoptosis through the mammalian target of rapamycin (mTOR) signaling pathway by regulating ATF4, we found that ATF4 knockdown inhibited ERS by decreasing the expression of ERS-related genes and proteins and activating mTOR signaling pathway by increasing the protein expression of p4E-BP1 and pT389-S6K (P<0.001), while these changes were promoted by TM+si-ATF4+MEL treatment (P<0.01). These results indicate that MEL could alleviate TM-induced ERS by regulating ATF4 to activate mTOR signaling pathway in follicular granulosa cells, thus providing a new perspective for prolonging the laying cycle in chickens.

Long-term remission and survival in patients with relapsed or refractory multiple myeloma after treatment with LCAR-B38M CAR T cells: 5-year follow-up of the LEGEND-2 trial.

BACKGROUND: The autologous anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M has been approved for the treatment of relapsed and refractory multiple myeloma in many countries across the world under the name ciltacabtagene autoleucel. LEGEND-2 was the first-in-human trial of LCAR-B38M and yielded deep and durable therapeutic responses. Here, we reported the outcomes in LEGEND-2 after a minimal 5-year follow-up. METHODS: Participants received an average dose of 0.5 × 106 cells/kg LCAR-B38M in split or single unfractionated infusions after cyclophosphamide-based lymphodepletion therapy. Investigator-assessed response, survival, safety and pharmacokinetics were evaluated. RESULTS: Seventy-four participants enrolled and had a median follow-up of 65.4 months. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 21.0% and 49.1%, with progressive flattening of the survival curves over time. Patients with complete response (CR) had longer PFS and OS, with 5-year rates of 28.4% and 65.7%, respectively. Twelve patients (16.2%) remained relapse-free irrespective of baseline high-risk cytogenetic abnormality and all had normal humoral immunity reconstituted. An ongoing CR closely correlated with several prognostic baseline indices including favorable performance status, immunoglobulin G subtype, and absence of extramedullary disease, as well as a combination cyclophosphamide and fludarabine preconditioning strategy. Sixty-two (83.8%) suffered progressive disease (PD) and/or death; however, 61.1% of PD patients could well respond to subsequent therapies, among which, the proteasome inhibitor-based regimens benefited the most. Concerning the safety, hematologic and hepatic function recovery were not significantly different between non-PD and PD/Death groups. A low rate of second primary malignancy (5.4%) and no severe virus infection were observed. The patients who tested positive for COVID-19 merely presented self-limiting symptoms. In addition, a sustainable CAR T population of one case with persistent remission was delineated, which was enriched with indolently proliferative and lowly cytotoxic CD4/CD8 double-negative functional T lymphocytes. CONCLUSIONS: These data, representing the longest follow-up of BCMA-redirected CAR T-cell therapy to date, demonstrate long-term remission and survival with LCAR-B38M for advanced myeloma. TRIAL REGISTRATION: LEGEND-2 was registered under the trial numbers NCT03090659, ChiCTRONH-17012285.

Immunotherapeutic value of NUSAP1 associated with bladder cancer through a comprehensive analysis of 33 human cancer cases.

To investigate the correlation between nucleolar spindle-associated protein 1 (NUSAP1) and cancer immunotherapy across 33 different types of human cancers. We conducted an analysis of The Cancer Genome Atlas (TCGA) database to retrieve gene expression data and clinical characteristics for 33 different cancer types. The immunotherapy cohorts encompassed GSE67501, GSE78220, and IMvigor210. Relevant information was extracted from the gene expression repository. We assessed the prognostic significance of NUSAP1 by examining various clinical parameters. The single-sample gene-set enrichment analysis (ssGSEA) method was utilized to gauge NUSAP1 activity and to contrast NUSAP1 transcriptome and protein levels. We delved into the correlation between NUSAP1 and various immune processes and components to gain insights into NUSAP1's role. We also discussed coherent pathways associated with NUSAP1 signal transduction and its impact on immunotherapy biomarkers. To authenticate and validate the differential expression patterns of NUSAP1 in bladder tumor tissues versus normal bladder counterparts, we utilized Western blotting (WB), real-time quantitative polymerase chain reaction (RT-qPCR), and immunohistochemistry (IHC) techniques. NUSAP1 exhibits overexpression across a spectrum of malignancies, and its expression levels correlate with overall survival (OS), disease-specific survival, and tumor stage in specific cancer types. Furthermore, NUSAP1 expression is linked to mutations, methylation patterns, and immunotherapy responses in human cancers. Meanwhile, our experiments, involving WB, RT-qPCR, and IHC, consistently demonstrated significantly higher NUSAP1 expression in bladder tumor tissues compared to normal controls. Our study underscores the potential of NUSAP1 as a promising prognostic indicator and immunotherapeutic target for a range of malignant tumors.

Exploring the role of histone deacetylase and histone deacetylase inhibitors in the context of multiple myeloma: mechanisms, therapeutic implications, and future perspectives.

Histone deacetylase inhibitors (HDACis) are a significant category of pharmaceuticals that have developed in the past two decades to treat multiple myeloma. Four drugs in this category have received approval from the U.S. Food and Drug Administration (FDA) for use: Panobinonstat (though canceled by the FDA in 2022), Vorinostat, Belinostat and Romidepsin. The efficacy of this group of drugs is attributed to the disruption of many processes involved in tumor growth through the inhibition of histone deacetylase, and this mode of action leads to significant anti-multiple myeloma (MM) activity. In MM, inhibition of histone deacetylase has many downstream consequences, including suppression of NF-κB signaling and HSP90, upregulation of cell cycle regulators (p21, p53), and downregulation of antiapoptotic proteins including Bcl-2. Furthermore, HDACis have a variety of direct and indirect oxidative effects on cellular DNA. HDAC inhibitors enhance normal immune function, thereby decreasing the proliferation of malignant plasma cells and promoting autophagy. The various biological effects of inhibiting histone deacetylase have a combined or additional impact when used alongside other chemotherapeutic and targeted drugs for multiple myeloma. This helps to decrease resistance to treatment. Combination treatment regimens that include HDACis have become an essential part of the therapy for multiple myeloma. These regimens incorporate drugs from other important classes of anti-myeloma agents, such as immunomodulatory drugs (IMiDs), conventional chemotherapy, monoclonal antibodies, and proteasome inhibitors. This review provides a comprehensive evaluation of the clinical efficacy and safety data pertaining to the currently approved histone deacetylase inhibitors, as well as an explanation of the crucial function of histone deacetylase in multiple myeloma and the characteristics of the different histone deacetylase inhibitors. Moreover, it provides a concise overview of the most recent developments in the use of histone deacetylase inhibitors for treating multiple myeloma, as well as potential future uses in treatment.

Long-Term Thermal Stability of Ionic Surfactants for Improving Oil Production at High-Salinity High-Temperature Conditions.

Surfactants with stable chemical structures and robust ability are required to lower interfacial tension and stabilize emulsions for successful chemical injection applications. This work selected six surfactants, dodecyl carboxylic sodium (LAS), dodecyl sulfonate dodecyl sodium (SLS), dodecyl sulfate sodium (SDS), dodecyltrimethylammonium bromide (DTAB), 3-(N,N-dimethylmyristylammonio) propanesulfonate (SB3-14) and a sulfobetaine formulation (PCT-10), and systematically investigated the ionic-type effects on thermal stability at 95 °C for 150 days in high-salinity water (total dissolved solids (TDS) = 57,600 ppm). With characterizations of aged samples performed through a spinning drop tensiometer, high-performance liquid chromatography, and infrared spectroscopy, it can be seen that the long-term stability sequence of ionic surfactants in solutions is sulfobetaine ≈ quaternary ammonium > sulfonate > sulfate > carboxylate. The carboxylate possibly precipitates out from the solution in the acid form, and the sulfonate and sulfate decompositions are due to the hydrolysis of the anionic head, forming alcohol and NaHSO3/NaHSO4. Obvious decomposition of sulfobetaine and quaternary ammonium was not observed, but these molecules might suffer the elimination of the ionic head, forming the corresponding alkene and amine. The results also show that the dissolved oxygen in the solution preparation significantly sped up the degradation of sulfonates. At last, the emulsion stability tests of crude oil in surfactant solutions showed that sulfobetaine surfactants retained the highest emulsifying ability after thermal aging and thus are promising candidates for long-term chemical injection in high-temperature high-salinity reservoirs.

Brain magnetic resonance imaging findings in children with neurological complications of coronavirus disease 2019 (Omicron variant): a multicenter retrospective observational study.

BACKGROUND: An increasing rate of encephalopathy associated with coronavirus disease 2019 (COVID-19) has been observed among children. However, the literature on neuroimaging data in children with COVID-19 is limited. OBJECTIVE: To analyze brain magnetic resonance imaging (MRI) of pediatric COVID-19 patients with neurological complications. MATERIALS AND METHODS: This multicenter retrospective observational study analyzed clinical (n=102, 100%) and neuroimaging (n=93, 91.2%) data of 102 children with COVID-19 infections and comorbid acute neurological symptoms. These children were hospitalized at five pediatric intensive care units (PICUs) in China between December 1, 2022, and January 31, 2023. RESULTS: All patients were positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as detected via reverse transcriptase polymerase chain reaction. About 75.7% of the children were infected with the Omicron variant BF.7 strain. Brain MRI was performed 1-12 days following the onset of neurological symptoms, which revealed acute neuroimaging findings in 74.2% (69/93) of cases, including evidence of acute necrotizing encephalopathy (33/69, 47.8%), encephalitis (31/69, 44.9%), reversible splenial lesion syndrome (3/69, 4.3%), reversible posterior leukoencephalopathy (1/69, 1.4%), and hippocampal atrophy (1/69, 1.4%). CONCLUSIONS: Overall, these data highlighted five neuroimaging patterns associated with the outbreak of the SARS-CoV-2 Omicron variant, with acute necrotizing encephalopathy being the most common of these neuroimaging findings. Rarely, the brain MRI of these pediatric COVID-19 patients also demonstrate hippocampal atrophy.

Synergistic integration of histone deacetylase inhibitors apparently enhances the cytokine-induced killer cell efficiency in multiple myeloma via the NKG2D pathway.

Objectives: The rapid recognition of epigenetic manipulation's potential in restricting cancer cell capabilities spurred translational initiatives, including histone deacetylase inhibitors (HDACis). Clinical trials on multiple myeloma (MM) demonstrated substantial benefits of HDACis, coupled with promising outcomes from cytokine-induced killer cell (CIK) immunotherapy. Intriguingly, the unexplored synergy of HDACis and CIK cell immunotherapy in MM prompted our study. Methods: We examined clinically relevant HDACis (panobinostat/LBH589 and romidepsin) alongside CIK cells derived from peripheral blood mononuclear cells across diverse MM cell lines (U266, RPMI8226, OPM-2 and NCI-H929). Utilising various in vitro methodologies, we investigated how HDACis enhance CIK cell lysis of myeloma cells through NKG2D/NKG2D ligand interactions. Results: The results of our analysis indicated several key findings. (1) Enhanced cytotoxicity of CIK cells in MM cells when combined with HDACis. (2) Significant increase in apoptosis, suggesting HDACis and CIK may together enhance apoptotic effects in specific MM cell lines. (3) Elevated IFN-γ secretion and alterations in granzyme B secretion because of the independent activity of HDACis. (4) Notably, HDACis increased the expression of MICA/B and ULBP2, crucial for inducing antitumor cytotoxicity of NKT cells. Validation through NKG2D receptor blocking in CIK cells with a purified mouse antihuman NKG2D antibody further supported our findings. Conclusions: Our analyses provide sufficient evidence to consider this clinically forgotten instance (HDACis-CIK cell combination) as a therapeutic priority for MM treatment. Furthermore, we suggest that NKG2D/NKG2D-ligand interactions activating NK/NKT cells may contribute to enhanced myeloma cell lysis in response to HDACis treatment by CIK cells.

Evolution of Endogenous Retroviruses in the Subfamily of Caprinae.

The interest in endogenous retroviruses (ERVs) has been fueled by their impact on the evolution of the host genome. In this study, we used multiple pipelines to conduct a de novo exploration and annotation of ERVs in 13 species of the Caprinae subfamily. Through analyses of sequence identity, structural organization, and phylogeny, we defined 28 ERV groups within Caprinae, including 19 gamma retrovirus groups and 9 beta retrovirus groups. Notably, we identified four recent and potentially active groups prevalent in the Caprinae genomes. Additionally, our investigation revealed that most long noncoding genes (lncRNA) and protein-coding genes (PC) contain ERV-derived sequences. Specifically, we observed that ERV-derived sequences were present in approximately 75% of protein-coding genes and 81% of lncRNA genes in sheep. Similarly, in goats, ERV-derived sequences were found in approximately 74% of protein-coding genes and 75% of lncRNA genes. Our findings lead to the conclusion that the majority of ERVs in the Caprinae genomes can be categorized as fossils, representing remnants of past retroviral infections that have become permanently integrated into the genomes. Nevertheless, the identification of the Cap_ERV_20, Cap_ERV_21, Cap_ERV_24, and Cap_ERV_25 groups indicates the presence of relatively recent and potentially active ERVs in these genomes. These particular groups may contribute to the ongoing evolution of the Caprinae genome. The identification of putatively active ERVs in the Caprinae genomes raises the possibility of harnessing them for future genetic marker development.

Knowledge, attitudes and practices among medical workers toward outpatient diabetes information platform.

BACKGROUND: This study aimed to assess the knowledge, attitudes and practices among medical workers toward outpatient diabetes information platform. METHODS: This web-based cross-sectional study was conducted between May 2023 and June 2023 at the First Hospital of Zhangjiakou, China. A self-designed questionnaire was developed to collect demographic information of medical workers, and assess their knowledge, attitudes and practices toward outpatient diabetes information platform. RESULTS: A total of 685 questionnaires were collected. Among the participants, 603 (88.03%) were female, 432 (63.07%) work in a tertiary hospital, 548 (80.00%) have a bachelor degree, 270 (39.42%) of them work in the department of internal medicine and 315 (45.99%) of them received previous training on outpatient diabetes information platform. The mean knowledge, attitudes and practices scores were 4.32 ± 1.27 (possible range: 0-6), 56.76 ± 5.72 (possible range: 14-70), and 32.22 ± 8.42 (possible range: 9-45), respectively. 350 (51.09%) of them have sufficient knowledge, 168 (24.53%) have positive attitudes and 395 (57.66%) have active practices. Pearson correlation analysis showed that knowledge was positively correlated with attitudes (r = 0.397, P < 0.001), and attitudes were positively correlated with practices (r = 0.306, P < 0.001). Multivariate analysis showed that primary hospital (OR = 0.32, 95% CI: 0.14-0.71, P = 0.005), secondary hospital (OR = 0.48, 95% CI: 0.32-0.72, P < 0.001), doctor (OR = 2.44, 95% CI: 1.39-4.28, P = 0.002) were independently associated with sufficient knowledge. Knowledge (OR = 1.49, 95% CI: 1.29-1.73, P < 0.001), community hospital staff (OR = 0.21, 95% CI: 0.05-0.88, P = 0.032) were independently associated with positive attitudes. Attitudes (OR = 1.13, 95% CI: 1.09-1.17, P < 0.001), junior college (OR = 1.72, 95% CI: 1.07-2.77, P = 0.026) were independently associated with active practices. The structural equation model demonstrated that knowledge had a direct effect on attitudes (path coefficient = 0.521, P < 0.001), and attitudes had a direct effect on practices (path coefficient = 0.542, P < 0.001). Moreover, the type of hospital had a direct effect on knowledge (path coefficient = 0.085, P < 0.001). Additionally, previous training on the outpatient diabetes platform had direct effects on attitudes (path coefficient = 0.191, P < 0.001) and practices (path coefficient = 0.184, P < 0.001). CONCLUSION: These findings revealed that medical workers have insufficient knowledge, positive attitudes and inactive practices toward the outpatient diabetes information platform. Comprehensive training programs are needed to improve medical staff's practices in this area.

Research progress of the chemokine/chemokine receptor axes in the oncobiology of multiple myeloma (MM).

BACKGROUND: The incidence of multiple myeloma (MM), a type of blood cancer affecting monoclonal plasma cells, is rising. Although new drugs and therapies have improved patient outcomes, MM remains incurable. Recent studies have highlighted the crucial role of the chemokine network in MM's pathological mechanism. Gaining a better understanding of this network and creating an overview of chemokines in MM could aid in identifying potential biomarkers and developing new therapeutic strategies and targets. PURPOSE: To summarize the complicated role of chemokines in MM, discuss their potential as biomarkers, and introduce several treatments based on chemokines. METHODS: Pubmed, Web of Science, ICTRP, and Clinical Trials were searched for articles and research related to chemokines. Publications published within the last 5 years are selected. RESULTS: Malignant cells can utilize chemokines, including CCL2, CCL3, CCL5, CXCL7, CXCL8, CXCL12, and CXCL13 to evade apoptosis triggered by immune cells or medication, escape from bone marrow and escalate bone lesions. Other chemokines, including CXCL4, CCL19, and CXCL10, may aid in recruiting immune cells, increasing their cytotoxicity against cancer cells, and inducing apoptosis of malignant cells. CONCLUSION: Utilizing anti-tumor chemokines or blocking pro-tumor chemokines may provide new therapeutic strategies for managing MM. Inspired by developed CXCR4 antagonists, including plerixafor, ulocuplumab, and motixafortide, more small molecular antagonists or antibodies for pro-tumor chemokine ligands and their receptors can be developed and used in clinical practice. Along with inhibiting pro-tumor chemokines, studies suggest combining chemokines with chimeric antigen receptor (CAR)-T therapy is promising and efficient.

Ntsr1 contributes to pulmonary hypertension by enhancing endoplasmic reticulum stress via JAK2-STAT3-Thbs1 signaling.

Pulmonary hypertension (PH) is a severe clinical syndrome with pulmonary vascular remodeling and poor long-term prognosis. Neurotensin receptor 1 (Ntsr1), serve as one of the G protein-coupled receptors (GPCRs), implicates in various biological processes, but the potential effects of Ntsr1 in PH development are unclear. The Sugen/Hypoxia (SuHx) or monocrotaline (MCT) induced rat PH model was used in our study and the PH rats showed aggravated pulmonary artery remodeling and increased right ventricular systolic pressure (RVSP). Our results revealed that Ntsr1 induced endoplasmic reticulum (ER) stress response via ATF6 activation contributed to the development of PH. Moreover, RNA-sequencing (RNA-seq) and phosphoproteomics were performed and the Ntsr1-JAK2-STAT3-thrombospondin 1 (Thbs1)-ATF6 signaling was distinguished as the key pathway. In vitro, pulmonary artery smooth muscle cells (PASMCs) under hypoxia condition showed enhanced proliferation and migration properties, which could be inhibited by Ntsr1 knockdown, JAK2 inhibitor (Fedratinib) treatment, STAT3 inhibitior (Stattic) treatment, Thbs1 knockdown or ATF6 knockdown. In addition, adeno-associated virus 1 (AAV1) were used to knockdown the expression of Ntsr1, Thbs1 or ATF6 in rats and reversed the phenotype of PH. In summary, our results reveal that Ntsr1-JAK2-STAT3-Thbs1 pathway can induce enhanced ER stress via ATF6 activation and increased PASMC proliferation and migration capacities, which can be mechanism of the pulmonary artery remodeling and PH. Targeting Ntsr1 might be a novel therapeutic strategy to ameliorate PH.

Cost-effectiveness analysis of different anesthesia strategies for transperineal MRI/US fusion prostate biopsy.

ABSTRACT: This study aims to conduct a cost-effectiveness analysis of three different anesthesia strategies, namely chatting while under local anesthesia (Chat-LA), total intravenous anesthesia (TIVA), and general anesthesia with laryngeal mask airway (GA-LMA), employed in transperineal magnetic resonance imaging (MRI)/ultrasound (US) fusion prostate biopsy (TP-MUF-PB). A retrospective study was conducted involving 1202 patients who underwent TP-MUF-PB from June 2016 to April 2023 at The First Affiliated Hospital of Soochow University (Suzhou, China). Clinical data and outcomes, including total costs, complications, and quality-adjusted life years (QALYs), were compared. Probability sensitivity and subgroup analyses were also performed. Chat-LA was found to be the most cost-effective option, outperforming both TIVA and GA-LMA. However, subgroup analyses revealed that in younger patients (under 65 years old) and those with smaller prostate volumes (<40 ml), TIVA emerged as a more cost-effective strategy. While Chat-LA may generally be the most cost-effective and safer anesthesia method for TP-MUF-PB, personalization of anesthesia strategies is crucial, considering specific patient demographics such as age and prostate volume.

Zbtb16 increases susceptibility of atrial fibrillation in type 2 diabetic mice via Txnip-Trx2 signaling.

Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia, and recent epidemiological studies suggested type 2 diabetes mellitus (T2DM) is an independent risk factor for the development of AF. Zinc finger and BTB (broad-complex, tram-track and bric-a-brac) domain containing 16 (Zbtb16) serve as transcriptional factors to regulate many biological processes. However, the potential effects of Zbtb16 in AF under T2DM condition remain unclear. Here, we reported that db/db mice displayed higher AF vulnerability and Zbtb16 was identified as the most significantly enriched gene by RNA sequencing (RNA-seq) analysis in atrium. In addition, thioredoxin interacting protein (Txnip) was distinguished as the key downstream gene of Zbtb16 by Cleavage Under Targets and Tagmentation (CUT&Tag) assay. Mechanistically, increased Txnip combined with thioredoxin 2 (Trx2) in mitochondrion induced excess reactive oxygen species (ROS) release, calcium/calmodulin-dependent protein kinase II (CaMKII) overactivation, and spontaneous Ca2+ waves (SCWs) occurrence, which could be inhibited through atrial-specific knockdown (KD) of Zbtb16 or Txnip by adeno-associated virus 9 (AAV9) or Mito-TEMPO treatment. High glucose (HG)-treated HL-1 cells were used to mimic the setting of diabetic in vitro. Zbtb16-Txnip-Trx2 signaling-induced excess ROS release and CaMKII activation were also verified in HL-1 cells under HG condition. Furthermore, atrial-specific Zbtb16 or Txnip-KD reduced incidence and duration of AF in db/db mice. Altogether, we demonstrated that interrupting Zbtb16-Txnip-Trx2 signaling in atrium could decrease AF susceptibility via reducing ROS release and CaMKII activation in the setting of T2DM.

Adsorption performance of mineral-carbon adsorbents derived from coal gasification fine ash: Prepared via low-temperature alkali fusion method.

To address the solid waste challenges associated with coal gasification fine ash, this study conducted a low-temperature alkali fusion de-ashing treatment to transform coal gasification fine ash into mineral-carbon adsorbent. The preparation process was simplified without grinding, carbonization and high-temperature (500-800 °C) activation treatment. The results demonstrate a positive linear correlation between the ash removal rate of the samples (measured during the preparation process, i.e., low-temperature alkaline fusion treatment of coal gasification fine ash) and their maximum equilibrium adsorption capacity for methylene blue. For the samples with an ash removal rate of 95.71 %, which exhibit a maximum adsorption capacity of 161.36 mg/g for methylene blue. The adsorption behavior of methylene blue on mineral-carbon adsorbent was a monolayer adsorption on the surface of homogeneous medium, involving both physical and chemical adsorption. The main adsorb rate-controlling steps for the samples with ash removal rates of 27.91-59.33 % and 95.71 % were the intra particle diffusion process and the liquid film diffusion process, respectively. The adsorption mechanism of methylene blue on the surface of mineral-carbon adsorbent involved electrostatic attraction and hydrogen bonding. The aforementioned results demonstrated the potential of coal gasification fine ash as an adsorbent material, providing new options for promoting the resource utilization and high-value applications of coal gasification fine ash.

Light-enhanced catalytic activity of stable and large gold nanoparticles in homocoupling reactions.

Validating the direct photocatalytic activity of colloidal plasmonic nanoparticles is challenging due to their limited stability and needed support materials that can often contribute to the chemical reactions. Stable gold nanoparticles (AuNPs) with tunable sizes are prepared across porous polymer particles without any chemical bonds where the resulting composite particles exhibit intense surface plasmon resonances (SPRs) in the visible region. These composite particles are then tested as photocatalysts under a broadband solar-simulated light source to examine the contribution degree of photothermal heating and SPR coming from the incorporated AuNPs in the C-C bond forming homocoupling reaction. Generally, the thermal and photothermal heating are the main driving force to increase the reactivity of relatively smaller AuNPs (~ 44 nm in diameter) with a narrower SPR band. However, the SPR-induced catalytic activity is much greater for the composite particles containing larger AuNPs (~ 87 nm in diameter) with a broader SPR. As the polymer particle matrix does not influence the catalytic activity (e.g., inducing charge delocalization and/or separation), the unique SPR role of the colloidal AuNPs in the catalytic reaction is assessable under light irradiation. This study experimentally demonstrates the possibility of evaluating the direct contribution of SPRs to photocatalytic chemical reactions.

Neutrophil activation and clonal CAR-T re-expansion underpinning cytokine release syndrome during ciltacabtagene autoleucel therapy in multiple myeloma.

Cytokine release syndrome (CRS) is the most common complication of chimeric antigen receptor redirected T cells (CAR-T) therapy. CAR-T toxicity management has been greatly improved, but CRS remains a prime safety concern. Here we follow serum cytokine levels and circulating immune cell transcriptomes longitudinally in 26 relapsed/refractory multiple myeloma patients receiving the CAR-T product, ciltacabtagene autoleucel, to understand the immunological kinetics of CRS. We find that although T lymphocytes and monocytes/macrophages are the major overall cytokine source in manifest CRS, neutrophil activation peaks earlier, before the onset of severe symptoms. Intracellularly, signaling activation dominated by JAK/STAT pathway occurred prior to cytokine cascade and displayed regular kinetic changes. CRS severity is accurately described and potentially predicted by temporal cytokine secretion signatures. Notably, CAR-T re-expansion is found in three patients, including a fatal case characterized by somatic TET2-mutation, clonal expanded cytotoxic CAR-T, broadened cytokine profiles and irreversible hepatic toxicity. Together, our findings show that a latent phase with distinct immunological changes precedes manifest CRS, providing an optimal window and potential targets for CRS therapeutic intervention and that CAR-T re-expansion warrants close clinical attention and laboratory investigation to mitigate the lethal risk.

Crystallographic and biochemical analyses of a far-red allophycocyanin to address the mechanism of the super-red-shift.

Far-red absorbing allophycocyanins (APC), identified in cyanobacteria capable of FRL photoacclimation (FaRLiP) and low-light photoacclimation (LoLiP), absorb far-red light, functioning in energy transfer as light-harvesting proteins. We report an optimized method to obtain high purity far-red absorbing allophycocyanin B, AP-B2, of Chroococcidiopsis thermalis sp. PCC7203 by synthesis in Escherichia coli and an improved purification protocol. The crystal structure of the trimer, (PCB-ApcD5/PCB-ApcB2)3, has been resolved to 2.8 Å. The main difference to conventional APCs absorbing in the 650-670 nm range is a largely flat chromophore with the co-planarity extending, in particular, from rings BCD to ring A. This effectively extends the conjugation system of PCB and contributes to the super-red-shifted absorption of the α-subunit (λmax = 697 nm). On complexation with the ß-subunit, it is even further red-shifted (λmax, absorption = 707 nm, λmax, emission = 721 nm). The relevance of ring A for this shift is supported by mutagenesis data. A variant of the α-subunit, I123M, has been generated that shows an intense FR-band already in the absence of the ß-subunit, a possible model is discussed. Two additional mechanisms are known to red-shift the chromophore spectrum: lactam-lactim tautomerism and deprotonation of the chromophore that both mechanisms appear inconsistent with our data, leaving this question unresolved.

Spatial separation of nitrifiers and denitrifiers promotes selection and enrichment of polyhydroxyalkanoates storing mixed cultures fed by crude glycerol and propionate wastewater.

Polyhydroxyalkanoates (PHA) recovery from industrial wastewater has been highlighted as a promising strategy for a circular bioeconomy. However, the high and varying level of nitrogen in wastewater makes enrichment of mixed microbial culture (MMC) low efficiency. In this study, spatial separation of nitrifiers and denitrifiers was adopted by adding biocarriers in MMC and decreasing the sludge retention time (SRT) to accelerate the enrichment of PHA-storing MMC fed by mixed wastewater containing glycerol and propionate. Nitrifiers and denitrifiers were sustained on biocarriers, obtaining a high total inorganic nitrogen removal and allowing a more efficient selective pressure of a high carbon and nitrogen ratio (C/N) under low SRT conditions. The maximum PHA cell content and relative abundance of PHA-storing bacteria were increased to 60.51 % (SRT 6 d) and 49.62 % (SRT 6 d) with the decrease of SRT, respectively. This study demonstrates an efficient way to highly enrich PHA-storing MMC from crude glycerol, which provide a relevant technical support for high-efficiency enrichment of PHA-storing bacteria in low C/N wastewater.