Cryo-electron tomography reveals the packaging pattern of RuBisCOs in Synechococcus ß-carboxysome.

Carboxysomes are large self-assembled microcompartments that serve as the central machinery of a CO2-concentrating mechanism (CCM). Biogenesis of carboxysome requires the fine organization of thousands of individual proteins; however, the packaging pattern of internal RuBisCOs remains largely unknown. Here we purified the intact ß-carboxysomes from Synechococcus elongatus PCC 7942 and identified the protein components by mass spectrometry. Cryo-electron tomography combined with subtomogram averaging revealed the general organization pattern of internal RuBisCOs, in which the adjacent RuBisCOs are mainly arranged in three distinct manners: head-to-head, head-to-side, and side-by-side. The RuBisCOs in the outermost layer are regularly aligned along the shell, the majority of which directly interact with the shell. Moreover, statistical analysis enabled us to propose an ideal packaging model of RuBisCOs in the ß-carboxysome. These results provide new insights into the biogenesis of ß-carboxysomes and also advance our understanding of the efficient carbon fixation functionality of carboxysomes.

PFOS-induced Sertoli cell injury through c-Jun N-terminal kinase (JNK) - a study by RNA-Seq.

Per- and polyfluoroalkyl substances (PFAS) are a family of "forever chemicals" including PFOS (perfluorooctane sulfonate). These toxic chemicals do not break down in the environment nor in our bodies. In the human body, PFOS and PFOA (perfluoroctanoic acid) have a half-life (T1/2) of about 4-5 years so low daily consumption of these chemicals can accumulate in the human body to a harmful level over a long period. Although the use of PFOS in consumer products was banned in the U.S. in 2022/2023, this forever chemical remains detectable in our tap water and food products. Every American tested has a high level of PFAS in their blood (https://cleanwater.org/pfas-forever-chemicals). In this report, we used a Sertoli cell blood-testis barrier (BTB) model with primary Sertoli cells cultured in vitro with an established functional tight junction (TJ)-permeability barrier that mimicked the BTB in vivo. Treatment of Sertoli cells with PFOS was found to perturb the TJ-barrier, which was the result of cytoskeletal disruption across the cell cytoplasm, disrupting actin and microtubule polymerization. These changes thus affected the proper localization of BTB-associated proteins at the BTB. Using RNA-Seq transcriptome profiling, bioinformatics analysis, and pertinent biochemical and cell biology techniques, it was discovered that PFOS-induced Sertoli cell toxicity through the c-Jun N-terminal kinase (JNK; also known as stress-activated protein kinase, SAPK) and its phosphorylated/active form p-JNK signaling pathway. More importantly, KB-R7943 mesylate (KB), a JNK/p-JNK activator, was capable of blocking PFOS-induced Sertoli cell injury, supporting the notion that PFOS-induced cell injury can possibly be therapeutically managed.

PDIA3 orchestrates effector T cell program by serving as a chaperone to facilitate the non-canonical nuclear import of STAT1 and PKM2.

Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide-isomerase A3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein (CRP) level and disease activity score 28 (DAS28). Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor (TCR) signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing Th1 and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings.

Mitoxantrone ameliorates ineffective erythropoiesis in a ß-thalassemia intermedia mouse model.

ß-thalassemia is a condition characterized by reduced or absent synthesis of ß-globin resulting from genetic mutations, leading to expanded and ineffective erythropoiesis. Mitoxantrone has been widely used clinically as an antitumor agent in light of its ability to inhibit cell proliferation. However, its therapeutic effect on expanded and ineffective erythropoiesis in ß-thalassemia is untested. We found that mitoxantrone decreased α-globin precipitates and ameliorated anemia, splenomegaly and ineffective erythropoiesis in the HbbTh3/+ mouse model of ß-thalassemia intermedia. The partially reversed ineffective erythropoiesis is a consequence of effects on autophagy as mitochondrial retention and protein levels of mTOR, P62 and LC3 in reticulocytes decreased in mitoxantrone-treated HbbTh3/+ mice. These data provide significant pre-clinical evidence for targeting autophagy as a novel therapeutic approach for ß-thalassemia.

Cross-species signaling pathways analysis inspire animal model selections for drug screening and target prediction in vascular aging diseases.

Age is a significant contributing factor to the occurrence and progression of cardiovascular disease (CVD). Pharmacological treatment can effectively alleviate CVD symptoms caused by aging. However, 90% of the drugs have failed in clinics because of the loss of drug effects or the occurrence of the side effects. One of the reasons is the disparity between animal models used and the actual physiological levels in humans. Therefore, we integrated multiple datasets from single-cell and bulk-seq RNA-sequencing data in rats, monkeys, and humans to identify genes and pathways with consistent/differential expression patterns across these three species. An approach called "Cross-species signaling pathway analysis" was developed to select suitable animal models for drug screening. The effectiveness of this method was validated through the analysis of the pharmacological predictions of four known anti-vascular aging drugs used in animal/clinical experiments. The effectiveness of drugs was consistently observed between the models and clinics when they targeted pathways with the same trend in our analysis. However, drugs might have exhibited adverse effects if they targeted pathways with opposite trends between the models and the clinics. Additionally, through our approach, we discovered four targets for anti-vascular aging drugs, which were consistent with their pharmaceutical effects in literatures, showing the value of this approach. In the end, software was established to facilitate the use of "Cross-species signaling pathway analysis." In sum, our study suggests utilizing bioinformatics analysis based on disease characteristics can help in choosing more appropriate animal models.

Effects of temporal changes in resting heart rate on future diabetes-related outcomes.

Background and aims: Most studies have analyzed the relationship between resting heart rate (RHR) measured at only one time point and future clinical events. The current study aims to investigate the impact of long-term RHR changes on future clinical outcomes in a decade-long cohort with type 2 diabetes mellitus (T2DM). Methods: The two-staged follow-up involved 2,513 T2DM participants. The first stage (2008-2014) intended to identify levels and trends in RHR changes, while the second stage (2014-2018) attempted to collect new occurrence records of clinical results. Cox proportional hazards models were applied to predict hazard ratios (HRs), along with 95% confidence interval (CI) for the correlation between RHR changes and future events. Results: There is no significant correlation between baseline RHR levels and long-term clinical events. According to the range of RHR change, compared with the stable RHR group, the adjusted HRs for cardiovascular events and all-cause death in the large increase group were 3.40 (95% CI: 1.33-8.71, p=0.010) and 3.22 (95% CI: 1.07-9.64, p=0.037), respectively. While the adjusted HRs for all-cause death and major adverse cardiac and cerebrovascular events (MACCE) in the moderate decrease group were 0.55 (95% CI: 0.31-0.96, p=0.037) and 0.51 (95% CI: 0.26-0.98, p=0.046). According to the trend of RHR, compared with the normal-normal group, the adjusted HRs for composite endpoint events and cerebrovascular events in the normal-high group were 1.64 (95% CI: 1.00-2.68, p=0.047) and 2.82 (95% CI: 1.03-7.76, p=0.043), respectively. Conclusion: Changes in RHR had predictive value for long-term clinical events in diabetic populations. Individuals with significantly elevated RHR over a particular period of time showed an increased risk of adverse events.

The role of tumor-associated macrophages in the radioresistance of esophageal cancer cells via regulation of the VEGF-mediated angiogenic pathway.

Tumor-associated macrophages (TAMs) are known to promote tumor growth, invasion, metastasis, and protumor angiogenesis, but the role of TAMs in evading radiotherapy in esophagus cancer remains unclear. In this study, we first induced TAMs from human monocytes (THP-1) and identified using immunofluorescence and Western blotting assays. We then co-cultured them with human esophageal cancer cell lines. CCK-8, colony formation, Transwell, scratch test, and TUNEL assays showed that TAMs could promote proliferation, survival rate, invasion, migration, and radioresistance and could inhibit apoptosis of the esophageal squamous carcinoma cell lines KYSE-150 and TE-1 before and after radiotherapy both in vivo and in vitro. Using LV-VEGFA-RNAi lentiviral vectors, we also found that TAMs could increase the expression of VEGFA and that inhibition of VEGFA could inhibit the biological function caused by TAMs. Finally, a Western blotting assay was used to evaluate the expression of various factors underlying the mechanism of TAMs. VEGFA, MAPK, P-MAPK, BCL-2, and Snail proteins were found to be overexpressed in co-cultured groups, whereas after VEGFA inhibition, MAPK, P-MAPK, BCL-2, and Snail proteins were found to be significantly downregulated in the radiotherapy group. These study results offer important information regarding the mechanism of radioresistance in esophageal cancer.

Meiotic transcriptional reprogramming mediated by cell-cell communications in humans and mice revealed by scATAC-seq and scRNA-seq.

Meiosis is a highly complex process significantly influenced by transcriptional regulation. However, studies on the mechanisms that govern transcriptomic changes during meiosis, especially in prophase I, are limited. Here, we performed single-cell ATAC-seq of human testis tissues and observed reprogramming during the transition from zygotene to pachytene spermatocytes. This event, conserved in mice, involved the deactivation of genes associated with meiosis after reprogramming and the activation of those related to spermatogenesis before their functional onset. Furthermore, we identified 282 transcriptional regulators (TRs) that underwent activation or deactivation subsequent to this process. Evidence suggested that physical contact signals from Sertoli cells may regulate these TRs in spermatocytes, while secreted ENHO signals may alter metabolic patterns in these cells. Our results further indicated that defective transcriptional reprogramming may be associated with non-obstructive azoospermia (NOA). This study revealed the importance of both physical contact and secreted signals between Sertoli cells and germ cells in meiotic progression.

Retinoic acid tiers mitochondrial metabolism to Sertoli Cell-Mediated efferocytosis via a non-RAR-dependent mechanism.

Efferocytosis of massive non-viable germ cells by Sertoli cells (SCs), the specialized phagocytes, is essential for maintaining testis homeostasis. What elusive is the contribution of mitochondrial metabolism to this energy-consuming process, as SC has a preference of aerobic glycolysis. All-trans retinoic acid (ATRA, hereafter referred to as RA) is a well-known morphogen that primarily acts through the nuclear RA receptor (RAR). It sustains SC blood-testisbarrier integrity, and it's SC-derived RA sets the timing of meiotic commitment. In this study, we revisited RA in SC biology, from the perspective of SC-mediated efferocytosis. We provide evidence that RA induces transcriptional programming of multiple regulators involved in efferocytosis, which thereby represses SC-mediated efferocytosis, via a RAR-independent mechanism, as blocking pan-RAR activity fails to rescue RA-induced defective efferocytosis. RA-treated SCs exhibit alternations in mitochondrial dynamics and metabolism, and the hindered efferocytosis can be rescued by stimulating mitochondrial OXPHOS via pharmacological targeting of AMPK and PDK. We thus prefer to propose a signaling axis of RA-mitochondrial metabolism-efferocytosis. Our study uncovers a hitherto unappreciated role of RA in SC biology and tiers mitochondria metabolism to SC-mediated efferocytosis, contributing a deeper understanding of SC in male reproduction.

General Fabrication of Robust Alloyed Metal Anodes for High-Performance Metal Batteries.

Revitalizing metal anodes for rechargeable batteries confronts challenges such as dendrite formation, limited cyclicity, and suboptimal energy density. Despite various efforts, a practical fabrication method for dendrite-free metal anodes remains unavailable. Herein, focusing on Li as exemplar, a general strategy is reported to enhance reversibility of the metal anodes by forming alloyed metals, which is achieved by induction heating of 3D substrate, lithiophilic metals, and Li within tens of seconds. It is demonstrated that preferred alloying interactions between substrates and lithiophilic metals created a lithiophilic metal-rich region adjacent to the substrate, serving as ultrastable lithiophilic host to guide dendrite-free deposition, particularly during prolonged high-capacity cycling. Simultaneously, an alloying between lithiophilic metals and Li creates a Li-rich region adjacent to electrolyte that reduces nucleation overpotential and constitutes favorable electrolyte-Li interface. The resultant composite Li anodes paired with high areal loading LiNi0.8Co0.1Mn0.1O2 cathodes achieve superior cycling stability and remarkable energy density above 1200 Wh L-1 (excluding packaging). Furthermore, this approach shows broader applicability to other metal anodes plagued by dendrite-related challenges, such as Na and Zn. Overall, this work paves the way for development of commercially viable metal-based batteries that offer a combination of safety, high energy density, and durability.

Identifications of novel host cell factors that interact with the receptor binding domain of the SARS-CoV-2 spike protein.

SARS-CoV-2 entry into host cells is facilitated by the interaction between the receptor binding domain of its spike protein (CoV2-RBD) and host cell receptor, ACE2, promoting viral membrane fusion. The virus also uses endocytic pathways for entry, but the mediating host factors remain largely unknown. It is also unknown whether mutations in the RBD of SARS-CoV-2 variants promote interactions with additional host factors to promote viral entry. Here, we used the GST pull-down approach to identify novel surface-located host factors that bind to CoV2-RBD. One of these factors, SH3BP4, regulates internalization of CoV2-RBD in an ACE2-independent, but integrin- and clathrin-dependent manner, and mediates SARS-CoV-2 pseudovirus entry, suggesting that SH3BP4 promotes viral entry via the endocytic route. Many of the identified factors, including SH3BP4, ADAM9 and TMEM2, show stronger affinity to CoV2-RBD than to RBD of the less infective SARS-CoV, suggesting SARS-CoV-2-specific utilization. We also found factors preferentially binding to the RBD of the SARS-CoV-2 Delta variant, potentially enhancing its entry. These data identify the repertoire of host cell surface factors that function in the events leading to entry of SARS-CoV-2.

L(1)10Bb serves as a conservative determinant for soma-germline communications via cellular non-autonomous effects within the testicular stem cell niche.

The testicular stem cell niche is the central regulator of spermatogenesis in Drosophila melanogaster. However, the underlying regulatory mechanisms are unclear. This study demonstrated the crucial role of lethal (1) 10Bb [l(1)10Bb] in regulating the testicular stem cell niche. Dysfunction of l(1)10Bb in early-stage cyst cells led to male fertility disorders and compromised cyst stem cell maintenance. Moreover, the dysfunction of l(1)10Bb in early-stage cyst cells exerted non-autonomous effects on germline stem cell differentiation, independently of hub signals. Notably, our study highlights the rescue of testicular defects through ectopic expression of L(1)10Bb and the human homologous protein BUD31 homolog (BUD31). In addition, l(1)10Bb dysfunction in early-stage cyst cells downregulated the expression of spliceosome subunits in the Sm and the precursor RNA processing complexes. Collectively, our findings established l(1)10Bb as a pivotal factor in the modulation of Drosophila soma-germline communications within the testicular stem cell niche.

Simultaneously enhancing toluene adsorption and regeneration process by hierarchical pore in activated coke: a combined experimental and adsorption kinetic modeling study.

Activated coke is a type of commonly used adsorbent for benzene series VOCs such as toluene, but traditional microporous activated coke usually faces the challenge of poor regeneration performance. Herein, based on self-made activated cokes with typical pore configuration, we found that adsorption and regeneration of toluene can be simultaneously enhanced by constructing hierarchical pore in activated coke. Correlations of pore configuration with toluene adsorption capacity and regeneration efficiency reveal that micropore contributes for strong toluene adsorption; meso-macropore provides mass transfer channel for toluene desorption and regeneration process. Hierarchical porous activated coke prepared from Zhundong subbituminous coal not only achieves the highest toluene adsorption capacity of 340.92 mg·g-1, but also can retain more than 90% of initial adsorption capacity after five adsorption-regeneration cycles. By contrast, micropore-dominant activated cokes can only retain 70% of initial adsorption capacity. Adsorption kinetic modelling on adsorption breakthrough curves shows that hierarchical porous activated coke prepared from Zhundong subbituminous coal exhibits high adsorption and diffusion rate constants of 14.39 and 33.45 min-1, respectively, much higher than those of micropore-dominant activated cokes. Due to the accelerated surface adsorption and diffusion processes induced by meso-macropore, toluene adsorption and regeneration behavior can be simultaneously improved. Results from this work validated the role of pore hierarchy in toluene adsorption-regeneration process, providing guidance for designing high-performance activated coke with synergistically improved toluene adsorption capacity and regeneration performance.

Effects of different doses of intranasal dexmedetomidine on related complications and parents' satisfaction in anesthetized children: a systematic review.

BACKGROUND: Agitation/delirium is commonly seen in children after anesthesia, and a proper dose of dexmedetomidine can prevent this complication. This study aimed to investigate the effects of different doses of Dexmedetomidine (DEX) on agitation/delirium and other complications in anesthetized children, providing clinical evidence for dose recommendations of DEX. METHODS: This study was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A systematic search was conducted in the Cochrane Library, PubMed, Web of Science, and EMBASE. Two independent researchers performed literature screening, data extraction, and assessed the methodological quality. Data analysis was conducted using R and STATA 16.0. RESULTS: In the final analysis, 20 randomized controlled trials (RCTs) involving 2521 children were included. The results showed that in comparison to normal saline, 1 µg/kg, 1.5 µg/kg, and 2 µg/kg intranasal DEX significantly reduced the incidence of post-anesthetic emergence agitation in children with the most effective dose being 2 µg/kg (SUCRA = 0.91). Compared with normal saline, 1 µg/kg, 1.5 µg/kg, and 2 µg/kg intranasal DEX reduced patient's need for postoperative analgesia, with the most effective dose being 1.5 µg/kg (SUCRA = 0.78). However, 1 µg/kg DEX performed the best in reducing Pediatric Anaesthesia Emergence Delirium (PAED) Scale score (SUCRA = 0.88). CONCLUSION: Compared with normal saline, intranasal administration of 2 µg/kg DEX and 1.5 µg/kg DEX are the optimal doses to reduce the incidence of agitation and the need for postoperative pain relief in children under general anesthesia. Given effectiveness and safety, intranasal use of 1 µg/kg DEX appears to be the most effective dosage for anesthetized children.

Triptolide exposure triggers testicular vacuolization injury by disrupting the Sertoli cell junction and cytoskeletal organization via the AKT/mTOR signaling pathway.

BACKGROUND: Despite the known reproductive toxicity induced by triptolide (TP) exposure, the regulatory mechanism underlying testicular vacuolization injury caused by TP remains largely obscure. METHODS: Male mice were subjected to TP at doses of 15, 30, and 60 µg/kg for 35 consecutive days. Primary Sertoli cells were isolated from 20-day-old rat testes and exposed to TP at concentrations of 0, 40, 80, 160, 320, and 640 nM. A Biotin tracer assay was conducted to assess the integrity of the blood-testis barrier (BTB). Transepithelial electrical resistance (TER) assays were employed to investigate BTB function in primary Sertoli cells. Histological structures of the testes and epididymides were stained with hematoxylin and eosin (H&E). The expression and localization of relevant proteins or pathways were assessed through Western blotting or immunofluorescence staining. RESULTS: TP exposure led to dose-dependent testicular injuries, characterized by a decreased organ coefficient, reduced sperm concentration, and the formation of vacuolization damage. Furthermore, TP exposure disrupted BTB integrity by reducing the expression levels of tight junction (TJ) proteins in the testes without affecting basal ectoplasmic specialization (basal ES) proteins. Through the TER assay, we identified that a TP concentration of 160 nM was optimal for elucidating BTB function in primary Sertoli cells, correlating with reductions in TJ protein expression. Moreover, TP exposure induced changes in the distribution of the BTB and cytoskeleton-associated proteins in primary Sertoli cells. By activating the AKT/mTOR signaling pathway, TP exposure disturbed the balance between mTORC1 and mTORC2, ultimately compromising BTB integrity in Sertoli cells. CONCLUSION: This investigation sheds light on the impacts of TP exposure on testes, elucidating the mechanism by which TP exposure leads to testicular vacuolization injury and offering valuable insights into comprehending the toxic effects of TP exposure on testes.

Melatonin ameliorates 10-hydroxycamptothecin-induced oxidative stress and apoptosis via autophagy-regulated p62/Keap1/Nrf2 pathway in mouse testicular cells.

10-Hydroxycamptothecin (HCPT) is a widely used clinical anticancer drug but has a significant side effect profile. Melatonin has a beneficial impact on the chemotherapy of different cancer cells and reproductive processes, but the effect and underlying molecular mechanism of melatonin's involvement in the HCPT-induced side effects in cells, especially in the testicular cells, are poorly understood. In this study, we found that melatonin therapy significantly restored HCPT-induced testicular cell damage and did not affect the antitumor effect of HCPT. Further analysis found that melatonin therapy suppressed HCPT-induced DNA damage associated with ataxia-telangiectasia mutated- and Rad3-related and CHK1 phosphorylation levels in the testis. Changes in apoptosis-associated protein levels (Bax, Bcl-2, p53, and Cleaved caspase-3) and in reactive oxygen species-associated proteins (Nrf2 and Keap1) and index (malondialdehyde and glutathione) suggested that melatonin treatment relieved HCPT-induced cell apoptosis and oxidative damage, respectively. Mechanistically, melatonin-activated autophagy proteins (ATG7, Beclin1, and LC3bII/I) may induce p62-dependent autophagy to degrade Keap1, eliciting Nrf2 from Keap1-Nrf2 interaction to promote antioxidant enzyme expression such as HO-1, which would salvage HCPT-induced ROS production and mitochondrial dysfunction. Collectively, this study reveals that melatonin therapy may protect testicular cells from HCPT-induced damage via the activation of autophagy, which alleviates oxidative stress, mitochondrial dysfunction, and cell apoptosis.

Rapid identification and determination of adulteration in medicinal Arnebiae Radix by combining near infrared spectroscopy with chemometrics.

The medicinal Arnebia Radix (AR) is one of widely-used Chinese herbal medicines (CHMs), usually adulterated with non-medicinal species that seriously compromise the quality of AR and affect patients' health. Detection of these adulterants is usually performed by using expensive and time-consuming analytical instruments. In this study, a rapid, non-destructive, and effective method was proposed to identify and determine the adulteration in the medicinal AR by near-infrared (NIR) spectroscopy coupled with chemometrics. 37 batches of medicinal AR samples originated from Arnebia euchroma (Royle) Johnst., 11 batches of non-medicinal AR samples including Onosma paniculatum Bur. et Franch and Arnebia benthamii (Wall. ex G. Don) Johnston, and 72 batches of adulterated AR samples were characterized by NIR spectroscopy. The data driven-soft independent modeling by class analogy (DD-SIMCA) and partial least squares-discriminant analysis (PLS-DA) were separately used to differentiate the authentic from adulterated AR samples. Then the PLS and support vector machine (SVM) were applied to predict the concentration of the adulteration in the adulterated AR samples, respectively. As a result, the classification accuracies of DD-SIMCA and PLS-DA models were 100% for the calibration set, and 96.7% vs. 100% for the prediction set. Moreover, the relative prediction deviation (RPD) values of PLS models reached 11.38 and 7.75 for quantifying two adulterants species, which were obviously superior to the SVM models. It can be concluded that the NIR spectroscopy coupled with chemometrics is feasible to identify the authentic from adulterated AR samples and quantify the adulteration in adulterated AR samples.

Identifying and Addressing the Spiritual Needs of Older Adults in Care Facilities: Administrators of Chinese Nursing Homes Relate Their Perspectives.

Addressing the spiritual needs of older adults is a central component of holistic service provision. Using a qualitative description design, this study identified: (1) common spiritual needs among Chinese nursing home residents, including the needs of residents with dementia, (2) the process staff use to identify these needs when residents are unable to verbalize them, and (3) the strategies staff implement to meet the identified needs. Semi-structured interviews were conducted with 21 nursing home administrators. Analysis produced five themes, including the need for older adults to express their faith, receive love and care, have contact with their children, interact with others, and participate in activities. For residents with dementia who are unable to verbalize their concerns, staff used two primary strategies to identify spiritual needs: careful observation and communication with family members. To address the identified spiritual needs, multiple strategies were offered including arranging clergy visits and personalizing care.

STUB1 is acetylated by KAT5 and alleviates myocardial ischemia-reperfusion injury through LATS2-YAP-ß-catenin axis.

Myocardial ischemia-reperfusion injury (MIRI) is involved in the pathogenesis of multiple cardiovascular diseases. This study elucidated the biological function of lysine acetyltransferase 5 (KAT5) in cardiomyocyte pyroptosis during MIRI. Oxygen-glucose deprivation/reoxygenation and left anterior descending coronary artery ligation were used to establish MIRI models. Here we show, KAT5 and STIP1 homology and U-box-containing protein 1 (STUB1) were downregulated, while large tumor suppressor kinase 2 (LATS2) was upregulated in MIRI models. KAT5/STUB1 overexpression or LATS2 silencing repressed cardiomyocyte pyroptosis. Mechanistically, KAT5 promoted STUB1 transcription via acetylation modulation, and subsequently caused ubiquitination and degradation of LATS2, which activated YAP/ß-catenin pathway. Notably, the inhibitory effect of STUB1 overexpression on cardiomyocyte pyroptosis was abolished by LATS2 overexpression or KAT5 depletion. Our findings suggest that KAT5 overexpression inhibits NLRP3-mediated cardiomyocyte pyroptosis to relieve MIRI through modulation of STUB1/LATS2/YAP/ß-catenin axis, providing a potential therapeutic target for MIRI.