Piezo-photocatalytic reduction of nitrates to N2 over silver dispersed on BaTiO3@TiO2.

This communication first achieved piezo-photocatalytic reduction of nitrates to N2 through designing an Ag2O/BaTiO3@TiO2 core-shell catalyst. The built-in electric field induced by piezoelectric polarization suppresses photoexcited carrier recombination, and simultaneously causes energy band tilting, leading to the generation of electrons with higher reducibility to directly trigger the NO3- reduction to ˙NO32-, even without hole scavengers.

Sirolimus-eluting iron bioresorbable scaffold versus cobalt-chromium everolimus-eluting stents in patients with coronary artery disease: rationale and design of the IRONMAN-II trial.

BACKGROUND: The previous first-in-human study established the preliminary safety and effectiveness of the novel thin-strut iron bioresorbable scaffold (IBS). The current study aims to directly compare the imaging and physiological efficacy, and clinical outcomes of IBS with contemporary metallic drug-eluting stents (DES). METHODS: A total of 518 patients were randomly allocated to treatment with IBS (257 patients) or metallic DES (261 patients) from 36 centers in China. The study is powered to test non-inferiority of the IBS compared with the metallic everolimus-eluting stent in terms of the primary endpoint of in-segment late lumen loss at 2 years, and major secondary endpoints as 2-year quantitative flow ratio and cross-sectional mean flow area measured by optical coherence tomography (OCT) (limited to the OCT subgroup, 25 patients in each group). CONCLUSION: This will be the first powered randomized trial investigating the safety and efficacy of the novel thin-strut IBS compared to a contemporary metallic DES. The findings will provide valuable evidence for future research of this kind and the application of metallic bioresorbable scaffolds.

Preoperative Quantitative Flow Ratio, Intraoperative Transit Time Flow Measurement Parameters, and Their Predictive Value for Short-Term Graft Failure After Coronary Artery Bypass Grafting.

BACKGROUND: Studies on the relationship between the preoperative quantitative flow ratio (QFR) and parameters of intraoperative transit time flow measurement (TTFM) are extremely rare. In addition, the predictive value of QFR and TTFM parameters for early internal mammary artery (IMA) failure after coronary artery bypass grafting still needs to be validated.Methods and Results: We retrospectively collected data from 510 patients who underwent in situ IMA grafting to the left anterior descending (LAD) artery at Fuwai Hospital. Spearman correlation coefficients between preoperative QFR of the LAD artery and intraoperative TTFM parameters of the IMA were -0.13 (P=0.004) for mean graft flow (Qm) and 0.14 (P=0.002) for the pulsatility index (PI). QFR and TTFM exhibited similar and good predictive value for early IMA failure (5.7% at 1 year), and they were better than percentage diameter stenosis (area under the curve 0.749 for QFR, 0.733 for Qm, 0.688 for PI, and 0.524 for percentage diameter stenosis). The optimal cut-off value of QFR was 0.765. Both univariate and multivariable regression analyses revealed that QFR >0.765, Qm ≤15 mL/min, and PI >3.0 independently contributed to early IMA failure. CONCLUSIONS: There were statistically significant correlations between preoperative QFR of the LAD artery and intraoperative TTFM parameters (Qm, PI) of the IMA. Preoperative QFR and intraoperative Qm and PI exhibited excellent predictive value for early IMA failure.

Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms.

The reversal of ubiquitination induced by members of the SidE effector family of Legionella pneumophila produces phosphoribosyl ubiquitin (PR-Ub) that is potentially detrimental to host cells. Here we show that the effector LnaB functions to transfer the AMP moiety from ATP to the phosphoryl moiety of PR-Ub to convert it into ADP-ribosylated ubiquitin (ADPR-Ub), which is further processed to ADP-ribose and functional ubiquitin by the (ADP-ribosyl)hydrolase MavL, thus maintaining ubiquitin homeostasis in infected cells. Upon being activated by Actin, LnaB also undergoes self-AMPylation on tyrosine residues. The activity of LnaB requires a motif consisting of Ser, His and Glu (S-HxxxE) present in a large family of toxins from diverse bacterial pathogens. Our study not only reveals intricate mechanisms for a pathogen to maintain ubiquitin homeostasis but also identifies a new family of enzymes capable of protein AMPylation, suggesting that this posttranslational modification is widely used in signaling during host-pathogen interactions.

Aridity threshold for alpine soil nitrogen isotope signature and ecosystem nitrogen cycling.

Determination of tipping points in nitrogen (N) isotope (δ15N) natural abundance, especially soil δ15N, with increasing aridity, is critical for estimating N-cycling dynamics and N limitation in terrestrial ecosystems. However, whether there are linear or nonlinear responses of soil δ15N to increases in aridity and if these responses correspond well with soil N cycling remains largely unknown. In this study, we investigated soil δ15N and soil N-cycling characteristics in both topsoil and subsoil layers along a drought gradient across a 3000-km transect of drylands on the Qinghai-Tibetan Plateau. We found that the effect of increasing aridity on soil δ15N values shifted from negative to positive with thresholds at aridity index (AI) = 0.27 and 0.29 for the topsoil and subsoil, respectively, although soil N pools and N transformation rates linearly decreased with increasing aridity in both soil layers. Furthermore, we identified markedly different correlations between soil δ15N and soil N-cycling traits above and below the AI thresholds (0.27 and 0.29 for topsoil and subsoil, respectively). Specifically, in wetter regions, soil δ15N positively correlated with most soil N-cycling traits, suggesting that high soil δ15N may result from the "openness" of soil N cycling. Conversely, in drier regions, soil δ15N showed insignificant relationships with soil N-cycling traits and correlated well with factors, such as soil-available phosphorus and foliage δ15N, demonstrating that pathways other than typical soil N cycling may dominate soil δ15N under drier conditions. Overall, these results highlight that different ecosystem N-cycling processes may drive soil δ15N along the aridity gradient, broadening our understanding of N cycling as indicated by soil δ15N under changing drought regimes. The aridity threshold of soil δ15N should be considered in terrestrial N-cycling models when incorporating 15N isotope signals to predict N cycling and availability under climatic dryness.

Law compliance decision making for autonomous vehicles on highways.

As autonomous driving advances, autonomous vehicles will share the road with human drivers. This requires autonomous vehicles to adhere to human traffic laws under safe conditions. Simultaneously, when confronted with dangerous situations, autonomous driving should also possess the capability to deviate from traffic laws to ensure safety. However, current autonomous vehicles primarily prioritize safety and collision avoidance in their decision-making and planning. This may lead to misunderstandings and distrust from human drivers in mixed traffic flow, and even accidents. To address this, this paper proposes a decoupled hierarchical framework for compliance safety decision-making. The framework primarily consists of two layers: the decision-making layer and the motion planning layer. In the decision-making layer, a candidate behavior set is constructed based on the scenario, and a dual layer admission assessment is utilized to filter out unsafe and non-compliant behaviors from the candidate sets. Subsequently, the optimal behavior is selected as the decision behavior according to the designed evaluation metrics. The decision-making layer ensures that the vehicle can meet lane safety requirements and comply with static traffic laws. In the motion planning layer, the surrounding vehicles and the road are modeled as safety potential fields and traffic laws potential fields. Combining the optimal decision behavior, they are incorporated into the cost function of the model predictive control to achieve compliant and safe trajectory planning. The planning layer ensures that the vehicle meets trajectory safety requirements and complies with dynamic traffic laws under safe conditions. Finally, four typical scenarios are used to evaluate the effectiveness of the proposed method. The results indicate that the proposed method can ensure compliance in safe conditions while also temporarily deviating from traffic laws in emergency situations to ensure safety.

Genetic drivers and cellular selection of female mosaic X chromosome loss.

Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals1,2, but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10 that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose female individuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion.

Integrative analysis of transcriptome, DNA methylome and chromatin accessibility reveals candidate therapeutic targets in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and is characterized by primary left ventricular hypertrophy usually caused by mutations in sarcomere genes. The mechanism underlying cardiac remodeling in HCM remains incompletely understood. An investigation of HCM through integrative analysis at multi-omics levels will be helpful for treating HCM. DNA methylation and chromatin accessibility, as well as gene expression, were assessed by nucleosome occupancy and methylome sequencing (NOMe-seq) and RNA-seq, respectively, using the cardiac tissues of HCM patients. Compared with those of the controls, the transcriptome, DNA methylome and chromatin accessibility of the HCM myocardium showed multifaceted differences. At the transcriptome level, HCM hearts returned to the fetal gene program through decreased sarcomeric and metabolic gene expression and increased extracellular matrix gene expression. In the DNA methylome, hypermethylated and hypomethylated differentially methylated regions (DMRs) were identified in HCM. At the chromatin accessibility level, HCM hearts showed changes in different genome elements. Several transcription factors (TFs), including SP1 and EGR1, exhibited a fetal-like pattern of binding motifs in nucleosome-depleted regions (NDRs) in HCM. In particular, the inhibition of SP1 or EGR1 in an HCM mouse model harboring sarcomere mutations markedly alleviated the HCM phenotype of the mutant mice and reversed fetal gene reprogramming. Overall, this study not only provides a high precision multi-omics map of HCM heart tissue but also sheds light on the therapeutic strategy by intervening the fetal gene reprogramming in HCM.

The prophylactic antiemetic therapies in management of differentiated thyroid cancer patients with radioactive iodine therapy: a single-center, non-randomized clinical trial.

Objective: The present study was to investigate three different single-drug regimens to show which was more effective to reduce radioactive iodine therapy (RAI) associated nausea and vomiting, and to compare the occurrence of long-term gastrointestinal diseases after RAI therapy. Method: We performed a single-center, non-randomized clinical trial among patients who underwent RAI therapy from March 2016 to July 2022. Enrolled patients were divided into four cohorts based on the date of the treatment. cohort 1, with no preventive antiemetics; cohort 2, received 20 mg of pantoprazole per day for 3 days; cohort 3, received a 10 mg metoclopramide tablet two times daily for 3 days; cohort 4, oral ondansetron, 8 mg, twice daily for 3 days. The primary endpoints were proportion of patients who experience vomiting episodes and nausea during the 7-day hospital period. Secondary end points included Functional Living Index Emesis (FLIE) quality-of life questionnaires and the occurrence of gastrointestinal diseases. Results: A total of 1755 patients were analyzed, comprised of 1299 (74.0%) women and 456 (26.0%) men, with a median age of 44 years (range 18-78 years). The characteristics of patient were similar within the four groups. 465 (26.4%) patients developed RAI-associated nausea, and 186 (14.4%) patients developed RAI-associated vomiting. The rate of nausea was significantly decreased in the patients who were taking ondansetron when compared with the other cohorts (P<0.05), while the rate of vomiting (≥6 episodes) was slightly lower. As secondary endpoint, FLIE measures ondansetron scored highly compared to other cohorts, from baseline (mean score of 110.53 ± 17.54) to day 7 (mean score of 105.56 ± 12.48). In addition, 48 (2.7%) patients were found to be with gastrointestinal diseases at the end of one year follow up. Multiple RAI therapy and higher dose of I-131 per body weight revealed a significantly independent risk factors of developing gastrointestinal disorders. Conclusions: In conclusion, the present study demonstrated that short-term ondansetron could be an effective prophylactic agent in controlling RAI-associated nausea and vomiting. Furthermore, the risk of developing gastrointestinal disorders was significantly higher for patients with multiple RAI therapy and higher dose of I-131 per body weight.

Comparison of multiple preservation and digestion methods for determination of tungsten concentrations in environmental media using ICP-MS.

Tungsten is an emerging environmental pollutant. However, a proved robust method for preserving and determining the concentrations of tungsten in environmental media is still lacking. This study examined and compared the suitability of classic methods and previously reported tungsten-oriented methods on preserving dissolved tungsten and recovering tungsten from soil/sediment matrix. Tungsten concentrations in the water samples and digestates were then determined by inductively coupled plasma mass spectrometry. Our data showed that the tungsten-oriented HF and alkaline preservatives indeed successfully maintained the stability of dissolved tungsten. Even when preserved using HNO3 or HCl, dissolved tungsten concentrations did not notably change in most of our water samples over the course of ∼4 months. Using glass containers for storing water samples also did not produce much difference from using high-density polyethylene containers. Our data further suggested that the addition of HF in digestion was important for tungsten solubilization from soil/sediment matrix. The digestion methods with HNO3/HCl/HF and HNO3/HF/NH4OH/EDTA both yielded quantitative recoveries of tungsten from certified reference materials and known synthetic samples, while the other tested methods had limited recoveries. The methods validated by this study could be used to accurately determine tungsten concentrations in environmental media and thereby to assess the fate and potential risks of tungsten.

Trim27 aggravates airway inflammation and oxidative stress in asthmatic mice via potentiating the NLRP3 inflammasome.

Asthma is a prevalent chronic respiratory disease, yet understanding its ecology and pathogenesis remains a challenge. Trim27, a ubiquitination ligase belonging to the TRIM (tripartite motif-containing) family, has been implicated in regulating multiple pathophysiological processes such as inflammation, oxidative stress, apoptosis, and cell proliferation. However, the role of Trim27 in asthma has not been investigated. Our study found that Trim27 expression significantly increases in the airway epithelium of asthmatic mice. Knockdown of Trim27 expression effectively relieved ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) and lung tissue histopathological changes. Moreover, Trim27 knockdown exhibited a significant reduction in airway inflammation and oxidative stress in asthmatic mice, and in vitro analysis confirmed the favorable effect of Trim27 deletion on inflammation and oxidative stress in mouse airway epithelial cells. Furthermore, our study revealed that deletion of Trim27 in MLE12 cells significantly decreased NLRP3 inflammasome activation, as evidenced by reduced expression of NLRP3, ASC, and pro-IL-1ß mRNA. This downregulation was reversed when Trim27, but not its mutant lacking ubiquitination ligase activity, was replenished in these cells. Consistent with these findings, protein levels of NLRP3, pro-caspase-1, pro-IL-1ß, cleaved-caspase-1, and cleaved-IL-1ß were higher in Trim27-replenished cells compared to cells expressing Trim27C/A. Functionally, the downregulation of IL-1ß and IL-18 levels induced by Trim27 deletion was rescued by replenishing Trim27. Overall, our findings provide evidence that Trim27 contributes to airway inflammation and oxidative stress in asthmatic mice via NLRP3 inflammasome activation, providing crucial insights into potential therapeutic interventions targeting Trim27 as a way to treat asthma.

A self-cleaning photocatalytic membrane loaded with Bi2O2CO3/In(OH)3 S-scheme heterojunction composites for removing tetracycline from aqueous solutions.

Bi2O2CO3/In(OH)3 (BON) photocatalysts were synthesized by a one-pot method and loaded onto polyvinylidene fluoride (PVDF) membranes to obtain a Bi2O2CO3/In(OH)3/PVDF (BON-M) catalytic membrane system. The catalytic membranes demonstrated complete degradation of tetracycline within 40 min under visible light. They demonstrated robust photocatalytic activity across a broad pH range (5-11) and in the presence of coexisting ions. The membranes demonstrated excellent self-cleaning performance. Following exposure to light, the irreversible contamination decreased from 27.1% to 4.7% and the membrane's permeability was almost completely restored. Moreover, the charge transfer mechanism at the S-scheme heterojunction interface of BON was demonstrated by Density functional theory and in-situ X-ray Photoelectron Spectroscopy characterisation, and the active sites involved in tetracycline's degradation were identified. Meanwhile, the mechanism of the "anemone effect" of BON-M was demonstrated in conjunction with Electron paramagnetic resonance, and the intrinsic Some factors enhancing the membranes' photocatalytic activity are specified.

Muscle-specific PGC-1α modulates mitochondrial oxidative stress in aged sarcopenia through regulating Nrf2.

BACKGROUND: Aged sarcopenia is characterized by loss of skeletal muscle mass and strength, and mitochondrial dysregulation in skeletal myocyte is considered as a major factor. Here, we aimed to analyze the effects of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) on mitochondrial reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2) in aged skeletal muscles. METHODS: C2C12 cells were stimulated by 50 µM 7ß-hydroxycholesterol (7ß-OHC) to observe the changes of cellular ROS, mitochondrial ROS, and expression of PGC-1α and Nrf2. Different PGC-1α expression in cells was established by transfection with small interfering RNA (siRNA) or plasmids overexpressing PGC-1α (pEX-3-PGC-1α). The effects of different PGC-1α expression on cellular ROS, mitochondrial ROS and Nrf2 expression were measured in cells. Wild type (WT) mice and PGC-1α conditional knockout (CKO) mice were used to analyze the effects of PGC-1α on aged sarcopenia and expression of Nrf2 and CD38 in gastrocnemius muscles. Diethylmaleate, a Nrf2 activator, was used to analyze the connection between PGC-1α and Nrf2 in cells and in mice. RESULTS: In C2C12 cells, the expressions of PGC-1α and Nrf2 were declined by the 7ß-OHC treatment or PGC-1α silence. Moreover, PGC-1α silence increased the harmful ROS and decreased the Nrf2 protein expression in the 7ß-OHC-treated cells. PGC-1α overexpression decreased the harmful ROS and increased the Nrf2 protein expression in the 7ß-OHC-treated cells. Diethylmaleate treatment decreased the harmful ROS in the 7ß-OHC-treated or PGC-1α siRNA-transfected cells. At the same age, muscle-specific PGC-1α deficiency aggravated aged sarcopenia, decreased Nrf2 expression and increased CD38 expression in gastrocnemius muscles compared with the WT mice. Diethylmaleate treatment improved the muscle function and decreased the CD38 expression in the old two genotypes. CONCLUSIONS: Our study demonstrated that PGC-1α modulated mitochondrial oxidative stress in aged sarcopenia through regulating Nrf2.

Prediction of small intracranial aneurysm rupture status based on combined Clinical-Radiomics model.

Background: Accumulating small unruptured intracranial aneurysms are detected due to the improved quality and higher frequency of cranial imaging, but treatment remains controversial. While surgery or endovascular treatment is effective for small aneurysms with a high risk of rupture, such interventions are unnecessary for aneurysms with a low risk of rupture. Consequently, it is imperative to accurately identify small aneurysms with a low risk of rupture. The purpose of this study was to develop a clinically practical model to predict small aneurysm ruptures based on a radiomics signature and clinical risk factors. Methods: A total of 293 patients having an aneurysm with a diameter of less than 5 mm, including 199 patients (67.9 %) with a ruptured aneurysm and 94 patients (32.1 %) without a ruptured aneurysm, were included in this study. Digital subtraction angiography or surgical treatment was required in all cases. Data on the clinical risk factors and the features on computed tomography angiography images associated with the aneurysm rupture status were collected simultaneously. We developed a clinical-radiomics model to predict aneurysm rupture status using multivariate logistic regression analysis. The combined clinical-radiomics model was constructed by nomogram analysis. The diagnostic performance, clinical utility, and model calibration were evaluated by operating characteristic curve analysis, decision curve analysis, and calibration analysis. Results: A combined clinical-radiomics model (Area Under Curve [AUC], 0.85; 95 % confidence interval [CI], 0.757-0.947) showed effective performance in the operating characteristic curve analysis. In the validation cohort, the performance of the combined model was better than that of the radiomics model (AUC, 0.75; 95 % CI, 0.645-0.865; Delong's test p-value = 0.01) and the clinical model (AUC, 0.74; 95 % CI, 0.625-0.851; Delong's test p-value <0.01) alone. The results of the decision curve, nomogram, and calibration analyses demonstrated the clinical utility and good fitness of the combined model. Conclusion: Our study demonstrated the effectiveness of a clinical-radiomics model for predicting rupture status in small aneurysms.

Incremental value of myocardial global longitudinal strain in predicting major adverse cardiac events among patients with hypertrophic cardiomyopathy.

OBJECTIVES: Endocardial global longitudinal strain (endo-GLS) measured with echocardiography (echo) has been demonstrated to be associated with myocardial fibrosis (MF) and is a prognostic predictor in patients with hypertrophic cardiomyopathy (HCM). Late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) imaging showed that MF is primarily located in the myocardial layer of the extremely hypertrophic septal or ventricular wall. We hypothesized that GLS of the myocardial layer (myo-GLS) is more strongly correlated with the extent of LGE (%LGE) and is a more powerful prognostic factor than endo-GLS. METHODS: A total of 177 inpatients (54.0 [IQR: 43.0, 64.0] years, female 37.3%) with HCM were retrospectively included from May 2019 to April 2021. Among them, 162 patients underwent echocardiographic examination and contrast-enhanced CMR within 7 days. Myo-GLS and %LGE were blindly assessed in a core laboratory. All the patients were followed after they were discharged. RESULTS: During a mean follow-up of 33.77 [IQR 30.05, 35.40] months, 14 participants (7.91%) experienced major adverse cardiac events (MACE). The MACE (+) group showed lower absolute endo-GLS and myo-GLS than the MACE (-) group. Myo-GLS was more associated with %LGE (r = -.68, P < .001) than endo-GLS (r = -.64, P < .001). Cox multivariable analysis indicated that absolute myo-GLS was independently associated with MACE (adjusted hazard ratio = .75, P < .05). Myo-GLS was better than endo-GLS at detecting MACE (+) patients (-8.64%, AUC .939 vs. - 16.375%, AUC .898, P < .05). CONCLUSIONS: Myo-GLS is a stronger predictor of MACE than endo-GLS in patients with HCM and is highly correlated with %LGE.

Low-Cytotoxic Core-Sheath ZnO NWs@TiO2-xNy Triggered Piezo-photocatalytic Antibacterial Activity.

Sonophotodynamic antimicrobial therapy (SPDAT) is recognized as a highly efficient biomedical treatment option, known for its versatility and remarkable healing outcomes. Nevertheless, there is a scarcity of sonophotosensitizers that demonstrate both low cytotoxicity and exceptional antibacterial effectiveness in clinical applications. In this paper, a novel ZnO nanowires (NWs)@TiO2-xNy core-sheath composite was developed, which integrates the piezoelectric effect and heterojunction to build dual built-in electric fields. Remarkably, it showed superb antibacterial effectiveness (achieving 95% within 60 min against S. aureus and ∼100% within 40 min against E. coli, respectively) when exposed to visible light and ultrasound. Due to the continuous interference caused by light and ultrasound, the material's electrostatic equilibrium gets disrupted. The modification in electrical properties facilitates the composite's ability to attract bacterial cells through electrostatic forces. Moreover, Zn-O-Ti and Zn-N-Ti bonds formed at the interface of ZnO NWs@TiO2-xNy, further enhancing the dual internal electric fields to accelerate the excited carrier separation to generate more reactive oxygen species (ROS), and thereby boosting the antimicrobial performance. In addition, the TiO2 layer limited Zn2+ dissolution into solution, leading to good biocompatibility and low cytotoxicity. Lastly, we suggest a mechanistic model to offer practical direction for the future development of antibacterial agents that are both low in toxicity and high in efficacy. In comparison to the traditional photodynamic therapy systems, ZnO NWs@TiO2-xNy composites exhibit super piezo-photocatalytic antibacterial activity with low toxicity, which shows great potential for clinical application as an antibacterial nanomaterial.

Revisiting the Potency of Tbx2 Expression in Transforming Outer Hair Cells into Inner Hair Cells at Multiple Ages In Vivo.

The mouse auditory organ cochlea contains two types of sound receptors: inner hair cells (IHCs) and outer hair cells (OHCs). Tbx2 is expressed in IHCs but repressed in OHCs, and neonatal OHCs that misexpress Tbx2 transdifferentiate into IHC-like cells. However, the extent of this switch from OHCs to IHC-like cells and the underlying molecular mechanism remain poorly understood. Furthermore, whether Tbx2 can transform fully mature adult OHCs into IHC-like cells is unknown. Here, our single-cell transcriptomic analysis revealed that in neonatal OHCs misexpressing Tbx2, 85.6% of IHC genes, including Slc17a8, are upregulated, but only 38.6% of OHC genes, including Ikzf2 and Slc26a5, are downregulated. This suggests that Tbx2 cannot fully reprogram neonatal OHCs into IHCs. Moreover, Tbx2 also failed to completely reprogram cochlear progenitors into IHCs. Lastly, restoring Ikzf2 expression alleviated the abnormalities detected in Tbx2+ OHCs, which supports the notion that Ikzf2 repression by Tbx2 contributes to the transdifferentiation of OHCs into IHC-like cells. Our study evaluates the effects of ectopic Tbx2 expression on OHC lineage development at distinct stages of either male or female mice and provides molecular insights into how Tbx2 disrupts the gene expression profile of OHCs. This research also lays the groundwork for future studies on OHC regeneration.

PGC-1α participates in regulating mitochondrial function in aged sarcopenia through effects on the Sestrin2-mediated mTORC1 pathway.

BACKGROUND: Mitochondrial dysregulation in skeletal myocytes is considered a major factor in aged sarcopenia. In this study, we aimed to study the effects of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) on Sestrin2-mediated mechanistic target of rapamycin complex 1 (mTORC1) in aged skeletal muscles. METHODS: C2C12 myoblasts were stimulated by 50 µM 7ß-hydroxycholesterol (7ß-OHC) to observe the changes of DNA damage, mitochondrial membrane potential (Δψm), mitochondrial ROS and PGC-1α protein. The PGC-1α silence in the C2C12 cells was established by siRNA transfection. The levels of DNA damage, Δψm, mitochondrial ROS, Sestrin2 and p-S6K1/S6K1 proteins were observed after the PGC-1α silence in the C2C12 cells. Recombinant Sestrin2 treatment was used to observe the changes of DNA damage, Δψm, mitochondrial ROS and p-S6K1/S6K1 protein in the 7ß-OHC-treated or PGC-1α siRNA-transfected C2C12 cells. Wild-type (WT) mice and muscle-specific PGC-1α conditional knockout (MKO) mice, including young and old, were used to analyse the effects of PGC-1α on muscle function and the levels of Sestrin2 and p-S6K1 in the white gastrocnemius muscles. Recombinant Sestrin2 was administrated to analyse its effects on muscle function in the old WT mice and old MKO mice. RESULTS: 7ß-OHC treatment induced DNA damage, mitochondrial dysfunction and decrease of PGC-1α protein in the C2C12 cells. PGC-1α silence also induced DNA damage and mitochondrial dysfunction in the C2C12 cells. Additionally, PGC-1α silence or 7ß-OHC treatment decreased the levels of Sestrin2 and p-S6K1/S6K1 protein in the C2C12 cells. Recombinant Sestrin2 treatment significantly improved the DNA damage and mitochondrial dysfunction in the 7ß-OHC-treated or PGC-1α siRNA-transfected C2C12 cells. At the same age, muscle-specific PGC-1α deficiency aggravated aged sarcopenia and decreased the levels of Sestrin2 and p-S6K1 in the white gastrocnemius muscles when compared to the WT mice. Recombinant Sestrin2 treatment improved muscle function and increased p-S6K1 levels in the old two genotypes. CONCLUSION: This research demonstrates that PGC-1α participates in regulating mitochondrial function in aged sarcopenia through effects on the Sestrin2-mediated mTORC1 pathway.

The burden and management competency of cardiomyopathies in China: a nationwide survey study.

Background: The public health burden of cardiomyopathies and competency in their management by health agencies in China are not well understood. Methods: This study adopted a multi-stage sampling method for hospital selection. In the first stage, nationwide tertiary hospital recruitment was performed. As a result, 88 hospitals with the consent of the director of cardiology and access to an established electronic medical records system, were recruited. In the second stage, we sampled 66 hospitals within each geographic-economic stratification through a random sampling process. Data on (1) the outpatient and inpatient visits for cardiomyopathies between 2017 and 2021 and (2) the competency in the management of patients with cardiomyopathies, were collected. The competency of a hospital to provide cardiomyopathy care was evaluated using a specifically devised scale. Findings: The outpatient and inpatient visits for cardiomyopathies increased between 2017 and 2021 by 38.6% and 33.0%, respectively. Most hospitals had basic facilities for cardiomyopathy assessment. However, access to more complex procedures was limited, and the integrated management pathway needs improvement. Only 4 (6.1%) of the 66 participating hospitals met the criteria for being designated as a comprehensive cardiomyopathy center, and only 29 (43.9%) could be classified as a primary cardiomyopathy center. There were significant variations in competency between hospitals with different administrative and economic levels. Interpretation: The health burden of cardiomyopathies has increased significantly between 2017 and 2021 in China. Although most tertiary hospitals in China can offer basic cardiomyopathy care, more advanced facilities are not yet universally available. Moreover, inconsistencies in the management of cardiomyopathies across hospitals due to differing administrative and economic levels warrants a review of the nation allocation of medical resources. Funding: This work was supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2023-I2M-1-001) and the National High Level Hospital Clinical Research Funding (2022-GSP-GG-17).