Heterochromatin formation and remodeling by IRTKS condensates counteract cellular senescence.

Heterochromatin, a key component of the eukaryotic nucleus, is fundamental to the regulation of genome stability, gene expression and cellular functions. However, the factors and mechanisms involved in heterochromatin formation and maintenance still remain largely unknown. Here, we show that insulin receptor tyrosine kinase substrate (IRTKS), an I-BAR domain protein, is indispensable for constitutive heterochromatin formation via liquid‒liquid phase separation (LLPS). In particular, IRTKS droplets can infiltrate heterochromatin condensates composed of HP1α and diverse DNA-bound nucleosomes. IRTKS can stabilize HP1α by recruiting the E2 ligase Ubc9 to SUMOylate HP1α, which enables it to form larger phase-separated droplets than unmodified HP1α. Furthermore, IRTKS deficiency leads to loss of heterochromatin, resulting in genome-wide changes in chromatin accessibility and aberrant transcription of repetitive DNA elements. This leads to activation of cGAS-STING pathway and type-I interferon (IFN-I) signaling, as well as to the induction of cellular senescence and senescence-associated secretory phenotype (SASP) responses. Collectively, our findings establish a mechanism by which IRTKS condensates consolidate constitutive heterochromatin, revealing an unexpected role of IRTKS as an epigenetic mediator of cellular senescence.

Two-Dimensional Electrolyte Design: Broadening the Horizons of Functional Electrolytes in Lithium Batteries.

ConspectusSince their commercialization in the 1990s, lithium-ion batteries (LIBs) have been increasingly used in applications such as portable electronics, electric vehicles, and large-scale energy storage. The increasing use of LIBs in modern society has necessitated superior-performance LIB development, including electrochemical reversibility, interfacial stability, efficient kinetics, environmental adaptability, and intrinsic safety, which is difficult to simultaneously achieve in commercialized electrolytes. Current electrolyte systems contain a solution with Li salts (e.g., LiPF6) and solvents (e.g., ethylene carbonate and dimethyl carbonate), in which the latter dissolves Li salts and strongly interacts with Li+ (lithiophilic feature). Only lithiophilic agents can be functionally modified (e.g., additives and solvents), altering the bulk and interfacial behaviors of Li+ solvates. However, such approaches alter pristine Li+ solvation and electrochemical processes, making it difficult to strike a balance between the electrochemical performance and other desired electrolyte functions. This common electrolyte design in lithiophilic solvents shows strong coupling among formulation, coordination, electrochemistry, and electrolyte function. The invention of lithiophobic cosolvents (e.g., multifluorinated ether and fluoroaromatic hydrocarbons) has expanded the electrolyte design space to lithiophilic (interacts with Li+) and lithiophobic (interacts with solvents but not with Li+) dimensions. Functional modifications switch to lithiophobic cosolvents, affording superior properties (carried by lithiophobic cosolvents) with little impact on primary Li+ solvation (dictated by lithiophilic solvents). This electrolyte engineering technique based on lithiophobic cosolvents is the 2D electrolyte (TDE) principle, which decouples formulation, coordination, electrochemistry, and function. The molecular-scale understanding of TDEs is expected to accelerate electrolyte innovations in next-generation LIBs.This Account provides insights into recent advancements in electrolytes for superior LIBs from the perspective of lithiophobic agents (i.e., lithiophobic additives and cosolvents), establishing a generalized TDE principle for functional electrolyte design. In bulk electrolytes, a microsolvating competition emerges because of cosolvent-induced dipole-dipole and ion-dipole interactions, forming a loose solvation shell and a kinetically favorable electrolyte. At the electrode/electrolyte interface, the lithiophobic cosolvent affords reliable passivation and efficient desolvation, with interfacial compatibility and electrochemical reversibility even under harsh conditions. Based on this unique coordination chemistry, functional electrolytes are formulated without significantly sacrificing their electrochemical performance. First, lithiophobic cosolvents are used to tune Li+-solvent affinity and anion mobility, promoting Li+ diffusion and electrochemical kinetics of the electrolyte to benefit high-rate and low-temperature applications. Second, the lithiophobic cosolvent undergoes less thermally induced decomposition and constructs a thermally stable interphase in TDEs, affording electrolytes with high-temperature adaptability and cycling stability. Third, the lithiophobic cosolvent modifies the local Li+-solvent-anion topography, controlling electrolyte electrochemical reversibility to afford numerous promising solvents that cannot be used in common electrolyte design. Finally, the lithiophobic cosolvent mitigates detrimental crosstalk between flame retardants and carbonate solvents, improving the intrinsic electrolyte safety without compromising electrochemical performance, which broadens the horizons of electrolyte design by optimizing versatile cosolvents and solvents, inspiring new ideas in liquid electrochemistry in other battery systems.

Global airborne bacterial community-interactions with Earth's microbiomes and anthropogenic activities.

Airborne bacteria are an influential component of the Earth's microbiomes, but their community structure and biogeographic distribution patterns have yet to be understood. We analyzed the bacterial communities of 370 air particulate samples collected from 63 sites around the world and constructed an airborne bacterial reference catalog with more than 27 million nonredundant 16S ribosomal RNA (rRNA) gene sequences. We present their biogeographic pattern and decipher the interlacing of the microbiome co-occurrence network with surface environments of the Earth. While the total abundance of global airborne bacteria in the troposphere (1.72 × 1024 cells) is 1 to 3 orders of magnitude lower than that of other habitats, the number of bacterial taxa (i.e., richness) in the atmosphere (4.71 × 108 to 3.08 × 109) is comparable to that in the hydrosphere, and its maximum occurs in midlatitude regions, as is also observed in other ecosystems. The airborne bacterial community harbors a unique set of dominant taxa (24 species); however, its structure appears to be more easily perturbed, due to the more prominent role of stochastic processes in shaping community assembly. This is corroborated by the major contribution of surface microbiomes to airborne bacteria (averaging 46.3%), while atmospheric conditions such as meteorological factors and air quality also play a role. Particularly in urban areas, human impacts weaken the relative importance of plant sources of airborne bacteria and elevate the occurrence of potential pathogens from anthropogenic sources. These findings serve as a key reference for predicting planetary microbiome responses and the health impacts of inhalable microbiomes with future changes in the environment.

Switchable targeting of solid tumors by BsCAR T cells.

The development of chimeric antigen receptor (CAR) T cell therapy has become a critical milestone in modern oncotherapy. Despite the remarkable in vitro effectiveness, the problem of safety and efficacy of CAR T cell therapy against solid tumors is challenged by the lack of tumor-specific antigens required to avoid on-target off-tumor effects. Spatially separating the cytotoxic function of CAR T cells from tumor antigen recognition provided by protein mediators allows for the precise control of CAR T cell cytotoxicity. Here, the high affinity and capability of the bacterial toxin-antitoxin barnase-barstar system were adopted to guide CAR T cells to solid tumors. The complementary modules based on (1) ankyrin repeat (DARPin)-barnase proteins and (2) barstar-based CAR (BsCAR) were designed to provide switchable targeting to tumor cells. The alteration of the DARPin-barnase switches enabled the targeting of different tumor antigens with a single BsCAR. A gradual increase in cytokine release and tunable BsCAR T cell cytotoxicity was achieved by varying DARPin-barnase loads. Switchable BsCAR T cell therapy was able to eradicate the HER2+ ductal carcinoma in vivo. Guiding BsCAR T cells by DARPin-barnase switches provides a universal approach for a controlled multitargeted adoptive immunotherapy.

Capmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy.

BACKGROUND: Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. METHODS: To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. RESULTS: Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. CONCLUSIONS: We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.

Homocysteine-potentiated Kelch-like ECH-associated protein 1 promotes senescence of neuroblastoma 2a cells via inhibiting ubiquitination of ß-catenin.

Elevated serum homocysteine (Hcy) level is a risk factor for Alzheimer's disease (AD) and accelerates cell aging. However, the mechanism by which Hcy induces neuronal senescence remains largely unknown. In this study, we observed that Hcy significantly promoted senescence in neuroblastoma 2a (N2a) cells with elevated ß-catenin and Kelch-like ECH-associated protein 1 (KEAP1) levels. Intriguingly, Hcy promoted the interaction between KEAP1 and the Wilms tumor gene on the X chromosome (WTX) while hampering the ß-catenin-WTX interaction. Mechanistically, Hcy attenuated the methylation level of the KEAP1 promoter CpG island and activated KEAP1 transcription. However, a slow degradation rate rather than transcriptional activation contributed to the high level of ß-catenin. Hcy-upregulated KEAP1 competed with ß-catenin to bind to WTX. Knockdown of both ß-catenin and KEAP1 attenuated Hcy-induced senescence in N2a cells. Our data highlight a crucial role of the KEAP1-ß-catenin pathway in Hcy-induced neuronal-like senescence and uncover a promising target for AD treatment.

Enhancing Electrode Performance through Triple Distribution Modulation of Active Material, Conductive Agent, and Porosity.

The increasing demand for large-scale energy storage propels the development of lithium-ion batteries with high energy and high power density. Low tortuosity electrodes with aligned straight channels have proved to be effective in building such batteries. However, manufacturing such low tortuosity electrodes in large scale remains extremely challenging. In contrast, high-performance electrodes with customized gradients of materials and porosity are possible to be made by industrial roll-to-roll coating process. Yet, the desired design of gradients combining materials and porosity is unclear for high-performance gradient electrodes. Here, triple gradient LiFePO4 electrodes (TGE) are fabricated featuring distribution modulation of active material, conductive agent, and porosity by combining suction filtration with the phase inversion method. The effects and mechanism of active material, conductive agent, and porosity distribution on electrode performance are analyzed by experiments. It is found that the electrode with a gradual increase of active material content from current collector to separator coupled with the distribution of conductive agent and porosity in the opposite direction, demonstrates the best rate capability, the fastest electrochemical reaction kinetics, and the highest utilization of active material. This work provides valuable insights into the design of gradient electrodes with high performance and high potential in application.

Association between atherogenic index of plasma and all-cause mortality and specific-mortality: a nationwide population­based cohort study.

BACKGROUND: Atherogenic index of plasma (AIP), a marker of atherosclerosis and cardiovascular disease (CVD). However, few studies have investigated association between AIP and all-cause mortality and specific-mortality in the general population. METHODS: This study included data from 14,063 American adults. The exposure variable was the AIP, which was defined as log10 (triglycerides/high-density lipoprotein cholesterol). The outcome variables included all-cause mortality and specific-mortality. Survey-weighted cox regressions were performed to evaluate the relation between AIP and all-cause mortality and specific-mortality. Weighted restricted cubic spline was conducted to examin the non-linear relationship. RESULTS: During 10 years of follow-up, we documented 2,077, 262, 854, and 476 cases of all-cause mortality, diabetes mortality, CVD mortality and cancer mortality, respectively. After adjustment for potential confounders, we found that atherogenic index of plasma (AIP) was significantly associated with an increased risk of diabetes mortality when comparing the highest to the lowest quantile of AIP in female (p for trend = 0.001) or participants older than 65 years (p for trend = 0.002). AIP was not significantly associated with all-cause mortality, CVD mortality and cancer mortality (p > 0.05). Moreover, a non-linear association was observed between AIP and all-cause mortality in a U-shape (p for non-linear = 0.0011), while a linear relationship was observed with diabetes mortality and non-diabetes mortality (p for linear < 0.0001). CONCLUSIONS: In this study, there is a no significant association between high AIP levels and a high risk of all-cause and cardiovascular mortality. Besides, a higher AIP was significantly associated with an increased risk of diabetes mortality, which only found in women older than 65 years. AIP was associated with all-cause mortality in a U-shape. This association could be explained by the finding that higher AIP predicted a higher risk of death from diabetes, and that lower AIP predicted a higher risk of death from non-diabetes causes.

We used a large national database and a prospective cohort study with a long follow-up period. Higher AIP was significantly associated with an increased risk of diabetes mortality, only in women older than 65 years. There is a no significant association between high AIP levels and a high risk of all-cause and cardiovascular mortality. AIP was associated with all-cause mortality in a U-shape. This finding suggest that controlling AIP levels may have a positive effect on reducing diabetes mortality.

Fine particulate matter contributes to COPD-like pathophysiology: experimental evidence from rats exposed to diesel exhaust particles.

BACKGROUND: Ambient fine particulate matter (PM2.5) is considered a plausible contributor to the onset of chronic obstructive pulmonary disease (COPD). Mechanistic studies are needed to augment the causality of epidemiologic findings. In this study, we aimed to test the hypothesis that repeated exposure to diesel exhaust particles (DEP), a model PM2.5, causes COPD-like pathophysiologic alterations, consequently leading to the development of specific disease phenotypes. Sprague Dawley rats, representing healthy lungs, were randomly assigned to inhale filtered clean air or DEP at a steady-state concentration of 1.03 mg/m3 (mass concentration), 4 h per day, consecutively for 2, 4, and 8 weeks, respectively. Pulmonary inflammation, morphologies and function were examined. RESULTS: Black carbon (a component of DEP) loading in bronchoalveolar lavage macrophages demonstrated a dose-dependent increase in rats following DEP exposures of different durations, indicating that DEP deposited and accumulated in the peripheral lung. Total wall areas (WAt) of small airways, but not of large airways, were significantly increased following DEP exposures, compared to those following filtered air exposures. Consistently, the expression of α-smooth muscle actin (α-SMA) in peripheral lung was elevated following DEP exposures. Fibrosis areas surrounding the small airways and content of hydroxyproline in lung tissue increased significantly following 4-week and 8-week DEP exposure as compared to the filtered air controls. In addition, goblet cell hyperplasia and mucus hypersecretions were evident in small airways following 4-week and 8-week DEP exposures. Lung resistance and total lung capacity were significantly increased following DEP exposures. Serum levels of two oxidative stress biomarkers (MDA and 8-OHdG) were significantly increased. A dramatical recruitment of eosinophils (14.0-fold increase over the control) and macrophages (3.2-fold increase) to the submucosa area of small airways was observed following DEP exposures. CONCLUSIONS: DEP exposures over the courses of 2 to 8 weeks induced COPD-like pathophysiology in rats, with characteristic small airway remodeling, mucus hypersecretion, and eosinophilic inflammation. The results provide insights on the pathophysiologic mechanisms by which PM2.5 exposures cause COPD especially the eosinophilic phenotype.

Syphilis susceptibility factors atlas: A wide-angled Mendelian randomization study.

OBJECTIVE: The pathogenic mechanisms of syphilis and the host defense mechanisms against syphilis remain poorly understood. Exploration of the susceptibility factors of syphilis may provide crucial clues for unraveling its underlying mechanisms. METHODS: A two-sample Mendelian Randomization framework was utilized, and the inverse-variance weighted method was used as the main analysis. All data was sourced from Genome-wide association studies datasets from 2015 to 2022 in Europe, and all participants were of European descent. Only summary-level statistics were used. Sensitivity analyses were conducted to evaluate the heterogeneity and pleiotropy of the datasets. RESULTS: Our study established 18 exposure factors (12 risk factors and 6 protective factors) for syphilis susceptibility. Twelve factors encompassing body mass index, waist circumference, darker natural skin, cooked vegetable intake, processed meat intake, diabetes mellitus, glucose regulation disorders, gout, autoimmune diseases, rheumatoid arthritis, diverticulitis, and longer menstrual cycles were found to increase susceptibility to syphilis. In contrast, 6 factors including easier skin tanning, blonde natural hair color, irritability, higher neuroticism scores, extended sleep duration, and delayed age at first sexual intercourse were connected to a reduced risk of syphilis infection (all P < 0.05). CONCLUSIONS: This study identified 18 influencing factors of syphilis susceptibility. These findings offered novel insights for further probing into the underlying pathogenic mechanisms of syphilis and underscored the importance of multifaceted prevention strategies against syphilis.

Association of sleep traits with myopia in children and adolescents: A meta-analysis and Mendelian randomization study.

PURPOSE: The association between sleep and myopia in children and adolescents has been reported, yet it remains controversial and inconclusive. This study aimed to investigate the influence of different sleep traits on the risk of myopia using meta-analytical and Mendelian randomization (MR) techniques. METHODS: The literature search was performed in August 31, 2023 based on PubMed, Embase, Web of Science, and Cochrane library. The meta-analysis of observational studies reporting the relationship between sleep and myopia was conducted. MR analyses were carried out to assess the causal impact of genetic pre-disposition for sleep traits on myopia. RESULTS: The results of the meta-analysis indicated a significant association between the risk of myopia and both short sleep duration [odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.08-1.42, P = 0.003] and long sleep duration (OR = 0.75, 95% CI = 0.66-0.86, P < 0.001). MR analyses revealed no significant causal associations of genetically determined sleep traits with myopia, including chronotype, sleep duration, short sleep duration and long sleep duration (all P > 0.05). CONCLUSIONS: No evidence was found to support a causal relationship between sleep traits and myopia. While sleep may not independently predict the risk of myopia, the potential impact of sleep on the occurrence and development of myopia cannot be disregarded.

Copper-catalyzed asymmetric 1,2-arylboration of enamines: access to chiral borate-containing 3,3'-disubstituted isoindolinones.

An enantioselective copper-catalyzed 1,2-arylboration reaction of enamines has been developed by employing (R)-xyl-BINAP as a chiral ligand. A number of chiral borate-containing 3,3'-disubstituted isoindolinones were obtained in moderate to good yields and good to excellent enantioselectivities from the reactions of N-(o-iodobenzoyl)enamines and bis(pinacolato)diboron (B2pin2) under mild reaction conditions. Synthetic transformations of the products were conducted to demonstrate the practicality of this reaction.

Seasonal and Spatial Fluctuations of Reactive Oxygen Species in Riparian Soils and Their Contributions on Organic Carbon Mineralization.

Reactive oxygen species (ROS) are ubiquitous in the natural environment and play a pivotal role in biogeochemical processes. However, the spatiotemporal distribution and production mechanisms of ROS in riparian soil remain unknown. Herein, we performed uninterrupted monitoring to investigate the variation of ROS at different soil sites of the Weihe River riparian zone throughout the year. Fluorescence imaging and quantitative analysis clearly showed the production and spatiotemporal variation of ROS in riparian soils. The concentration of superoxide (O2•-) was 300% higher in summer and autumn compared to that in other seasons, while the highest concentrations of 539.7 and 20.12 µmol kg-1 were observed in winter for hydrogen peroxide (H2O2) and hydroxyl radicals (•OH), respectively. Spatially, ROS production in riparian soils gradually decreased along with the stream. The results of the structural equation and random forest model indicated that meteorological conditions and soil physicochemical properties were primary drivers mediating the seasonal and spatial variations in ROS production, respectively. The generated •OH significantly induced the abiotic mineralization of organic carbon, contributing to 17.5-26.4% of CO2 efflux. The obtained information highlighted riparian zones as pervasive yet previously underestimated hotspots for ROS production, which may have non-negligible implications for carbon turnover and other elemental cycles in riparian soils.

Adverse events of tissue plasminogen activators in acute myocardial infarction patients: a real-world and pharmacovigilance database analysis.

BACKGROUND: Tissue plasminogen activator (tPA) is recommended as the preferred thrombolytic therapy for acute myocardial infarction (AMI). This study aimed to explore tPA-related adverse events (AEs) reported in the United States Food and Drug Administration Adverse Event Reporting System (FAERS), assess the potential safety of three preferred tPA therapies for treating AMI, and provide guidance for selecting tPA for prehospital thrombolysis. METHOD: Four algorithms, including ROR, PRR, BCPNN, and MGPS, were used to quantify the signals of Tenecteplase, Reteplase, and Alteplase related AEs and compare the differential degrees of the three tPA-associated AEs in the actual data. RESULT: We detected 18 signals of Tenecteplase-induced AE, 29 signals of Reteplase-induced AE, and 22 signals of Alteplase-induced AE. Among the three drugs, Tenecteplase had the highest signal intensity for intracranial hemorrhage-related AE, followed by Alteplase. Besides, Reteplase had the highest signal intensity for procedure-related AE and Alteplase had the highest signal intensity for arrhythmia-related AE. The time-onset analysis indicates that we should be vigilant for AEs, especially within the first week and the first 1-2 days after medication. CONCLUSION: This study identified and compared the signals of AE related to Tenecteplase, Reteplase, and Alteplase in AMI patients.

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

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

Neuron-derived exosomes mediate sevoflurane-induced neurotoxicity in neonatal mice via transferring lncRNA Gas5 and promoting M1 polarization of microglia.

Sevoflurane exposure during rapid brain development induces neuronal apoptosis and causes memory and cognitive deficits in neonatal mice. Exosomes that transfer genetic materials including long non-coding RNAs (lncRNAs) between cells play a critical role in intercellular communication. However, the lncRNAs found in exosomes derived from neurons treated with sevoflurane and their potential role in promoting neurotoxicity remain unknown. In this study, we investigated the role of cross-talk of newborn mouse neurons with microglial cells in sevoflurane-induced neurotoxicity. Mouse hippocampal neuronal HT22 cells were exposed to sevoflurane, and then co-cultured with BV2 microglial cells. We showed that sevoflurane treatment markedly increased the expression of the lncRNA growth arrest-specific 5 (Gas5) in neuron-derived extracellular vesicles, which inhibited neuronal proliferation and induced neuronal apoptosis by promoting M1 polarization of microglia and the release of inflammatory cytokines. We further revealed that the exosomal lncRNA Gas5 significantly upregulated Foxo3 as a competitive endogenous RNA of miR-212-3p in BV2 cells, and activated the NF-κB pathway to promote M1 microglial polarization and the secretion of inflammatory cytokines, thereby exacerbating neuronal damage. In neonatal mice, intracranial injection of the exosomes derived from sevoflurane-treated neurons into the bilateral hippocampi significantly increased the proportion of M1 microglia, inhibited neuronal proliferation and promoted apoptosis, ultimately leading to neurotoxicity. Similar results were observed in vitro in BV2 cells treated with the CM from HT22 cells after sevoflurane exposure. We conclude that sevoflurane induces the transfer of lncRNA Gas5-containing exosomes from neurons, which in turn regulates the M1 polarization of microglia and contributes to neurotoxicity. Thus, modulating the expression of lncRNA Gas5 or the secretion of exosomes could be a strategy for addressing sevoflurane-induced neurotoxicity.

Association between dietary diversity changes and frailty among Chinese older adults: findings from a nationwide cohort study.

BACKGROUND: Dietary diversity has been suggested as a potential preventive measure against frailty in older adults, but the effect of changes in dietary diversity on frailty is unclear. This study was conducted to examine the association between the dietary diversity score (DDS) and frailty among older Chinese adults. METHODS: A total of 12,457 adults aged 65 years or older were enrolled from three consecutive and nonoverlapping cohorts from the Chinese Longitudinal Healthy Longevity Survey (the 2002 cohort, the 2005 cohort, and the 2008 cohort). DDS was calculated based on nine predefined food groups, and DDS changes were assessed by comparing scores at baseline and the first follow-up survey. We used 39 self-reported health items to assess frailty. Cox proportional hazard models were performed to examine the association between DDS change patterns and frailty. RESULTS: Participants with low-to-low DDS had the highest frailty incidence (111.1/1000 person-years), while high-to-high DDS had the lowest (41.1/1000 person-years). Compared to the high-to-high group of overall DDS pattern, participants in other DDS change patterns had a higher risk of frailty (HRs ranged from 1.25 to 2.15). Similar associations were observed for plant-based and animal-based DDS. Compared to stable DDS changes, participants with an extreme decline in DDS had an increased risk of frailty, with HRs of 1.38 (1.24, 1.53), 1.31 (1.19, 1.44), and 1.29 (1.16, 1.43) for overall, plant-based, and animal-based DDS, respectively. CONCLUSIONS: Maintaining a lower DDS or having a large reduction in DDS was associated with a higher risk of frailty among Chinese older adults. These findings highlight the importance of improving a diverse diet across old age for preventing frailty in later life.

Association of insomnia symptoms and trajectories with the risk of functional disability: a prospective cohort study.

BACKGROUND: There is limited understanding regarding prospective associations of insomnia symptoms and trajectories with functional disability. We aimed to investigate the associations of insomnia symptoms and trajectories with functional disability. METHOD: A total of 13 197 participants were eligible from the Health and Retirement Study. Insomnia symptoms included non-restorative sleep, difficulty initiating sleep, early morning awakening, and difficulty maintaining sleep. We also identified four distinct trajectories of insomnia symptoms: low, decreasing, increasing, and high insomnia symptoms. Functional status was assessed through activities of daily living (ADL) and instrumental activities of daily living (IADL). RESULTS: Participants experiencing one (HR, 1.21; 95% CI, 1.13-1.29), two (HR, 1.43; 95% CI, 1.29-1.57), or three to four (HR, 1.41; 95% CI, 1.25-1.60) insomnia symptoms had a higher risk of ADL disability than asymptomatic respondents. Similarly, participants with one or more insomnia symptoms had a higher risk of IADL disability. Furthermore, using the trajectory with low insomnia symptoms as the reference, decreasing insomnia symptoms (HR, 1.22; 95% CI, 1.12-1.34), increasing insomnia symptoms (HR, 1.21; 95% CI, 1.05-1.41), and high insomnia symptoms (HR, 1.36; 95% CI, 1.18-1.56) were all associated with an increased risk of ADL disability. CONCLUSION: Both a single measurement and dynamic trajectory of insomnia symptoms are associated with the onset of ADL disability. Increased awareness and management of insomnia symptoms may contribute to the prevention of functional disability occurrence.

Disruption of a kasB homolog gene (kasB) causes attenuation of cell invasion and virulence of Nocardia seriolae.

Nocardia seriolae is the primary aetiological agent of nocardiosis in fish, which causes mass mortality in freshwater and marine fish. ß-ketoacyl-ACP synthase (KAS) is one of the essential enzymes in the synthesis of mycolic acids (MASs) in Mycobacterium spp. and has been chosen as the target for therapeutic intervention in mycobacterial diseases. In the present study, a kasB homologue gene (kasB) was identified in the genome of N. seriolae, and the gene-deficient mutant (ΔkasB) was generated based on a clinical isolate, XSYC-Ns. Compared to the wild-type (WT) strain, the ΔkasB showed a measurably growth defect in vitro but retained the acid-fastness in acid-fast staining. Observation of the cell ultrastructure showed some alterations in the cell wall of the ΔkasB strain. Compared to its original strain, the cell wall lipid layer seemed sparser, and a wider electron-transparent zone was observed in the cell wall of ΔkasB strain. Moreover, the ΔkasB strain showed impaired ability of cell invasion as well as intracellular survival in the cell line originating from the head-kidney of the large yellow croaker (LYC-hK), compared to its original strain. In addition, the deficiency of ΔkasB significantly attenuated the virulence of N. seriolae in largemouth bass. The present study suggested that the ΔkasB gene might be involved in the synthesis of extracellular cell-wall lipids in N. seriolae and play a crucial role in its pathogenicity.

Prototype Learning for Medical Time Series Classification via Human-Machine Collaboration.

Deep neural networks must address the dual challenge of delivering high-accuracy predictions and providing user-friendly explanations. While deep models are widely used in the field of time series modeling, deciphering the core principles that govern the models' outputs remains a significant challenge. This is crucial for fostering the development of trusted models and facilitating domain expert validation, thereby empowering users and domain experts to utilize them confidently in high-risk decision-making contexts (e.g., decision-support systems in healthcare). In this work, we put forward a deep prototype learning model that supports interpretable and manipulable modeling and classification of medical time series (i.e., ECG signal). Specifically, we first optimize the representation of single heartbeat data by employing a bidirectional long short-term memory and attention mechanism, and then construct prototypes during the training phase. The final classification outcomes (i.e., normal sinus rhythm, atrial fibrillation, and other rhythm) are determined by comparing the input with the obtained prototypes. Moreover, the proposed model presents a human-machine collaboration mechanism, allowing domain experts to refine the prototypes by integrating their expertise to further enhance the model's performance (contrary to the human-in-the-loop paradigm, where humans primarily act as supervisors or correctors, intervening when required, our approach focuses on a human-machine collaboration, wherein both parties engage as partners, enabling more fluid and integrated interactions). The experimental outcomes presented herein delineate that, within the realm of binary classification tasks-specifically distinguishing between normal sinus rhythm and atrial fibrillation-our proposed model, albeit registering marginally lower performance in comparison to certain established baseline models such as Convolutional Neural Networks (CNNs) and bidirectional long short-term memory with attention mechanisms (Bi-LSTMAttns), evidently surpasses other contemporary state-of-the-art prototype baseline models. Moreover, it demonstrates significantly enhanced performance relative to these prototype baseline models in the context of triple classification tasks, which encompass normal sinus rhythm, atrial fibrillation, and other rhythm classifications. The proposed model manifests a commendable prediction accuracy of 0.8414, coupled with macro precision, recall, and F1-score metrics of 0.8449, 0.8224, and 0.8235, respectively, achieving both high classification accuracy as well as good interpretability.