Pyruvate kinase M2 sustains cardiac mitochondrial quality surveillance in septic cardiomyopathy by regulating prohibitin 2 abundance via S91 phosphorylation.

The endogenous mitochondrial quality control (MQC) system serves to protect mitochondria against cellular stressors. Although mitochondrial dysfunction contributes to cardiac damage during many pathological conditions, the regulatory signals influencing MQC disruption during septic cardiomyopathy (SC) remain unclear. This study aimed to investigate the involvement of pyruvate kinase M2 (PKM2) and prohibitin 2 (PHB2) interaction followed by MQC impairment in the pathogenesis of SC. We utilized LPS-induced SC models in PKM2 transgenic (PKM2TG) mice, PHB2S91D-knockin mice, and PKM2-overexpressing HL-1 cardiomyocytes. After LPS-induced SC, cardiac PKM2 expression was significantly downregulated in wild-type mice, whereas PKM2 overexpression in vivo sustained heart function, suppressed myocardial inflammation, and attenuated cardiomyocyte death. PKM2 overexpression relieved sepsis-related mitochondrial damage via MQC normalization, evidenced by balanced mitochondrial fission/fusion, activated mitophagy, restored mitochondrial biogenesis, and inhibited mitochondrial unfolded protein response. Docking simulations, co-IP, and domain deletion mutant protein transfection experiments showed that PKM2 phosphorylates PHB2 at Ser91, preventing LPS-mediated PHB2 degradation. Additionally, the A domain of PKM2 and the PHB domain of PHB2 are required for PKM2-PHB2 binding and PHB2 phosphorylation. After LPS exposure, expression of a phosphorylation-defective PHB2S91A mutant negated the protective effects of PKM2 overexpression. Moreover, knockin mice expressing a phosphorylation-mimetic PHB2S91D mutant showed improved heart function, reduced inflammation, and preserved mitochondrial function following sepsis induction. Abundant PKM2 expression is a prerequisite to sustain PKM2-PHB2 interaction which is a key element for preservation of PHB2 phosphorylation and MQC, presenting novel interventive targets for the treatment of septic cardiomyopathy.

Neutrophil-derived PAD4 induces citrullination of CKMT1 exacerbates mucosal inflammation in inflammatory bowel disease.

Peptidyl arginine deiminase 4 (PAD4) plays a pivotal role in infection and inflammatory diseases by facilitating the formation of neutrophil extracellular traps (NETs). However, the substrates of PAD4 and its exact role in inflammatory bowel disease (IBD) remain unclear. In this study, we employed single-cell RNA sequencing (scRNA-seq) and substrate citrullination mapping to decipher the role of PAD4 in intestinal inflammation associated with IBD. Our results demonstrated that PAD4 deficiency alleviated colonic inflammation and restored intestinal barrier function in a dextran sulfate sodium (DSS)-induced colitis mouse model. scRNA-seq analysis revealed significant alterations in intestinal cell populations, with reduced neutrophil numbers and changes in epithelial subsets upon PAD4 deletion. Gene expression analysis highlighted pathways related to inflammation and epithelial cell function. Furthermore, we found that neutrophil-derived extracellular vesicles (EVs) carrying PAD4 were secreted into intestinal epithelial cells (IECs). Within IECs, PAD4 citrullinates mitochondrial creatine kinase 1 (CKMT1) at the R242 site, leading to reduced CKMT1 protein stability via the autophagy pathway. This action compromises mitochondrial homeostasis, impairs intestinal barrier integrity, and induces IECs apoptosis. IEC-specific depletion of CKMT1 exacerbated intestinal inflammation and apoptosis in mice with colitis. Clinical analysis of IBD patients revealed elevated levels of PAD4, increased CKMT1 citrullination, and decreased CKMT1 expression. In summary, our findings highlight the crucial role of PAD4 in IBD, where it modulates IECs plasticity via CKMT1 citrullination, suggesting that PAD4 may be a potential therapeutic target for IBD.

Severe dawn phenomenon predicts long-term risk of all-cause mortality in patients with type 2 diabetes.

AIMS: The dawn phenomenon (DP) is an abnormal early morning blood glucose rise without nocturnal hypoglycaemia, which can be more easily and precisely assessed with continuous glucose monitoring (CGM). This prospective study aimed to explore the association between DP and the risk of all-cause mortality in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 5542 adult inpatients with type 2 diabetes in a single centre were analysed. The magnitude of DP (ΔG) was defined as the increment in the CGM-determined glucose value from nocturnal nadir (after 24:00) to prebreakfast. Participants were stratified into four groups by ΔG: ≤1.11, 1.12-3.33, 3.34-5.55, and >5.55 mmol/L. Cox proportional hazard regression models were used to evaluate the impact of DP on all-cause mortality risk. RESULTS: During a median follow-up of 9.4 years, 1083 deaths were identified. The restricted cubic spline revealed a nonlinear (p for nonlinearity = 0.002) relationship between ΔG and the risk of all-cause mortality. A multivariate-adjusted Cox regression model including glycated haemoglobin A1c (HbA1c) showed that ΔG > 5.55 mmol/L was associated with 30% (95% CI, 1.01-1.66) higher risk of all-cause mortality, as compared with ΔG 1.12-3.33 mmol/L. CONCLUSIONS: Higher ΔG is significantly related to an increased risk of all-cause mortality in type 2 diabetes, suggesting that severe DP should be given more attention as a part of glucose management to reduce the risk of long-term adverse outcomes.

Role of ESCCAL-1 in regulating exocytosis of AuNPs in human esophageal squamous carcinoma cells.

Exocytosis is a critical factor for designing efficient nanocarriers and determining cytotoxicity. However, the research on the exocytosis mechanism of nanoparticles, especially the role of long non-coding RNAs (lncRNAs), has not been reported. In this study, the exocytosis of AuNPs in the KYSE70 cells and the involved molecular pathways of exocytosis are analyzed. It demonstrates that nanoparticles underwent time-dependent release from the cells by exocytosis, and the release of ß-hexosaminidase confirms that AuNPs are excreted through lysosomes. Mechanistic studies reveal that lncRNA ESCCAL-1 plays a vital role in controlling the exocytosis of AuNPs through activation of the MAPK pathway, including the phosphorylation of ERK and JNK. The study implies that the ESCCAL-1-mediated pathway plays an important role in the exocytosis of AuNPs in KYSE70 cells. This finding has implications for the role of ESCCAL-1 on the drug resistance of esophagus cancer by controlling lysosome-mediated exocytosis.

The effect of budesonide-formoterol powder inhalation on cough and lung function following thoracoscopic pulmonary surgery: a retrospective cohort study.

OBJECTIVES: To explore whether portable budesonide-formoterol powder inhalation can ameliorate cough symptoms and improve pulmonary function recovery in patients who underwent thoracoscopic lung surgery. METHODS: Clinical data of patients who underwent thoracoscopic pulmonary resection at Henan Provincial People's Hospital between December 2022 and May 2023 were extracted. To evaluate the impact of continuous post-operative use of portable budesonide-formoterol powder inhalation, patients were divided into two groups: the control group and the case group. Next, we compared the Leicester cough score and pulmonary function indexes of the patients before surgery, one month and six month after the operation. RESULTS: A total of 188 cases were included, and the baseline demographic characteristics of both groups were well-balanced. The internal consistency of the LCQ-MC scale, as indicated by Cronbach's α coefficients, were all greater than 0.8, and there was no significant difference in LCQ-MC scores between the two groups before the operation (Z=-1.173, P=0.241). Postoperatively, the LCQ-MC score in the case group was significantly higher than that in the control group (18.66 vs. 16.79, P<0.01), with a notable statistically significant difference in the reduction of LCQ-MC scores between the two groups (1.32 vs. 3.30, P<0.01). Analysis of lung function revealed that patients in the case group exhibited significant improvements in FEV1/FVC, FVC, FEV1, PEF, MMEF75/25, MVV, DLCO and the RV/TLC indexes compared to the control group (P<0.01). CONCLUSIONS: Portable budesonide-formoterol powder inhalation can alleviate cough symptoms and promote pulmonary function recovery in patients following thoracoscopic lung surgery.

Signal enhancement ratio of multi-phase contrast-enhanced MRI: an imaging biomarker for survival in pancreatic adenocarcinoma.

OBJECTIVES: To evaluate signal enhancement ratio (SER) for tissue characterization and prognosis stratification in pancreatic adenocarcinoma (PDAC), with quantitative histopathological analysis (QHA) as the reference standard. METHODS: This retrospective study included 277 PDAC patients who underwent multi-phase contrast-enhanced (CE) MRI and whole-slide imaging (WSI) from three centers (2015-2021). SER is defined as (SIlt - SIpre)/(SIea - SIpre), where SIpre, SIea, and SIlt represent the signal intensity of the tumor in pre-contrast, early-, and late post-contrast images, respectively. Deep-learning algorithms were implemented to quantify the stroma, epithelium, and lumen of PDAC on WSIs. Correlation, regression, and Bland-Altman analyses were utilized to investigate the associations between SER and QHA. The prognostic significance of SER on overall survival (OS) was evaluated using Cox regression analysis and Kaplan-Meier curves. RESULTS: The internal dataset comprised 159 patients, which was further divided into training, validation, and internal test datasets (n = 60, 41, and 58, respectively). Sixty-five and 53 patients were included in two external test datasets. Excluding lumen, SER demonstrated significant correlations with stroma (r = 0.29-0.74, all p < 0.001) and epithelium (r = -0.23 to -0.71, all p < 0.001) across a wide post-injection time window (range, 25-300 s). Bland-Altman analysis revealed a small bias between SER and QHA for quantifying stroma/epithelium in individual training, validation (all within ± 2%), and three test datasets (all within ± 4%). Moreover, SER-predicted low stromal proportion was independently associated with worse OS (HR = 1.84 (1.17-2.91), p = 0.009) in training and validation datasets, which remained significant across three combined test datasets (HR = 1.73 (1.25-2.41), p = 0.001). CONCLUSION: SER of multi-phase CE-MRI allows for tissue characterization and prognosis stratification in PDAC. CLINICAL RELEVANCE STATEMENT: The signal enhancement ratio of multi-phase CE-MRI can serve as a novel imaging biomarker for characterizing tissue composition and holds the potential for improving patient stratification and therapy in PDAC. KEY POINTS: Imaging biomarkers are needed to better characterize tumor tissue in pancreatic adenocarcinoma. Signal enhancement ratio (SER)-predicted stromal/epithelial proportion showed good agreement with histopathology measurements across three distinct centers. Signal enhancement ratio (SER)-predicted stromal proportion was demonstrated to be an independent prognostic factor for OS in PDAC.

Clinical characteristics and prognosis of SARS-CoV-2 infection in lung transplant recipients.

Objective: This study aimed to investigate the clinical manifestations and prognosis of lung transplant (LTx) recipients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the coronavirus disease (COVID-19) pandemic. Methods: The research participants were LTx recipients who underwent surgery and were regularly followed up at our center. From 1 December 2022 to 28 February 2023, during the COVID-19 pandemic in China, research participants were interviewed either online or in person. SARS-CoV-2 nucleic acid or self-tested antigens were detected according to accessibility. Diagnosis and treatment were performed according to the Diagnosis and Treatment Plan for COVID-19 (10th edition) issued by the National Health Commission of the People's Republic of China. Hospitalized patients underwent chest imaging examinations, routine blood tests, biomarkers for infection and inflammation, and biochemical tests, all of which were taken and recorded. Data were analyzed to describe the features of COVID-19 in LTx recipients. Results: In total, 52 patients were enrolled in this study, comprising 48 men and 4 women, with a mean age of 51.71 ± 11.67 years. By 1 December 2022, the mean survival period was 33.87 ± 25.97 months, of which 84.61% of the patients (44/52) had a survival period longer than 12 months. The SARS-CoV-2 infection rate in these LTx recipients was 82.69% (43/52), with 3.85% (2/52) of the infected recipients being asymptomatic, 50.00% (26/52) of the infected recipients experiencing mild COVID-19, 11.54% (6/52) having moderate COVID-19, and 17.31% (9/52) having severe or critical COVID-19. The mortality rate among severe and critical patients was 66.67% (6/9). Conclusion: LTx recipients in this cohort exhibited a notable susceptibility to SARS-CoV-2, with 82.69% of individuals diagnosed with COVID-19. Moreover, the mortality rate among critically ill patients was high.

Different Evolutionary Trends of Galloanseres: Mitogenomics Analysis.

The two existing clades of Galloanseres, orders Galliformes (landfowl) and Anseriformes (waterfowl), exhibit dramatically different evolutionary trends. Mitochondria serve as primary sites for energy production in organisms, and numerous studies have revealed their role in biological evolution and ecological adaptation. We assembled the complete mitogenome sequences of two species of the genus Aythya within Anseriformes: Aythya baeri and Aythya marila. A phylogenetic tree was constructed for 142 species within Galloanseres, and their divergence times were inferred. The divergence between Galliformes and Anseriformes occurred ~79.62 million years ago (Mya), followed by rapid evolution and diversification after the Middle Miocene (~13.82 Mya). The analysis of selective pressure indicated that the mitochondrial protein-coding genes (PCGs) of Galloanseres species have predominantly undergone purifying selection. The free-ratio model revealed that the evolutionary rates of COX1 and COX3 were lower than those of the other PCGs, whereas ND2 and ND6 had faster evolutionary rates. The CmC model also indicated that most PCGs in Anseriformes exhibited stronger selective constraints. Our study suggests that the distinct evolutionary trends and energy requirements of Galliformes and Anseriformes drive different evolutionary patterns in the mitogenome.

Effect of Mo and Cr on the Microstructure and Properties of Low-Alloy Wear-Resistant Steels.

Low-alloy wear-resistant steel often requires the addition of trace alloy elements to enhance its performance while also considering the cost-effectiveness of production. In order to comparatively analyze the strengthening mechanisms of Mo and Cr elements and further explore economically feasible production processes, we designed two types of low-alloy wear-resistant steels, based on C-Mn series wear-resistant steels, with individually added Mo and Cr elements, comparing and investigating the roles of the alloying elements Mo and Cr in low-alloy wear-resistant steels. Utilizing JMatPro software to calculate Continuous Cooling Transformation (CCT) curves, conducting thermal simulation quenching experiments using a Gleeble-3800 thermal simulator, and employing equipment such as a metallographic microscope, transmission electron microscope, and tensile testing machine, this study comparatively investigated the influence of Mo and Cr on the microstructural transformation and mechanical properties of low-alloy wear-resistant steels under different cooling rates. The results indicate that the addition of the Mo element in low-alloy wear-resistant steel can effectively suppress the transformation of ferrite and pearlite, reduce the martensitic transformation temperature, and lower the critical cooling rate for complete martensitic transformation, thereby promoting martensitic transformation. Adding Cr elements can reduce the austenite transformation zone, decrease the rate of austenite formation, and promote the occurrence of low-temperature phase transformation. Additionally, Mo has a better effect on improving the toughness of low-temperature impact, and Cr has a more significant improvement in strength and hardness. The critical cooling rates of C-Mn-Mo steel and C-Mn-Cr steel for complete martensitic transition are 13 °C/s and 24 °C/s, respectively. With the increase in the cooling rate, the martensitic tissues of the two experimental steels gradually refined, and the characteristics of the slats gradually appeared. In comparison, the C-Mn-Mo steel displays a higher dislocation density, accompanied by dislocation entanglement phenomena, and contains a small amount of residual austenite, while granular ε-carbides are clearly precipitated in the C-Mn-Cr steel. The C-Mn-Mo steel achieves its best performance at a cooling rate of 25 °C/s, whereas the C-Mn-Cr steel only needs to increase the cooling rate to 35 °C/s to attain a similar comprehensive performance to the C-Mn-Mo steel.

APTAnet: an atom-level peptide-TCR interaction affinity prediction model.

The prediction of affinity between TCRs and peptides is crucial for the further development of TIL (Tumor-Infiltrating Lymphocytes) immunotherapy. Inspired by the broader research of drug-protein interaction (DPI), we propose an atom-level peptide-TCR interaction (PTI) affinity prediction model APTAnet using natural language processing methods. APTAnet model achieved an average ROC-AUC and PR-AUC of 0.893 and 0.877, respectively, in ten-fold cross-validation on 25,675 pairs of PTI data. Furthermore, experimental results on an independent test set from the McPAS database showed that APTAnet outperformed the current mainstream models. Finally, through the validation on 11 cases of real tumor patient data, we found that the APTAnet model can effectively identify tumor peptides and screen tumor-specific TCRs.

Clinical Features Post Anterior Cruciate Ligament Reconstruction Associated with Structural Alterations in Corticospinal Tract.

CONTEXT: Structural evidence for corticospinal tract (CST) abnormality between patients with ACLR and healthy controls, and the relationships between CST structure and clinical features of the patients (e.g., objective sensorimotor outcomes, postoperative duration) are lacking. OBJECTIVES: To investigate whether the structural features of CST 1) differ between patients with ACLR and healthy controls, and 2) were associated with clinical features in patients following ACLR. DESIGN: Cross-sectional study. SETTING: Sports medicine laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty-six patients who had undergone ACLR and twenty-six healthy controls were enrolled in this cross-sectional investigation. MAIN OUTCOME MEASURE(S): Using the CST as the region of interest, we performed diffusion tensor imaging to measure the microstructure of white matter tracts. Between-group comparisons and correlation analyses with clinical features in patients with ACLR were performed. RESULTS: The patients with ACLR showed significant, moderate lower fractional anisotropy (FA, Cohen's d = -0.666, 95% CIs -1.221 to -0.104), lower axial diffusivity (AD, Cohen's d = -0.526, 95% CIs -1.077 to 0.030), and higher radial diffusivity (RD, Cohen's d = 0.514, 95% CIs -0.042 to 1.064) when compared to that of healthy controls, with the RD values being significantly correlated with the postoperative duration (r = 0.623, p < 0.001) after controlling the age, sex, and BMI in patients with ACLR. CONCLUSIONS: This study revealed that patients with ACLR have impaired integrity (lower FA values and higher RD values) in the CST contralateral to the ACLR injured limb in comparison with healthy controls. Decreased integrity (higher RD) of the CST in patients was significantly associated with longer postoperative duration, which hinted that impaired structural integrity of the CST may be a maladaptive process of neuroplasticity in ACLR.

DeepMicroClass sorts metagenomic contigs into prokaryotes, eukaryotes and viruses.

Sequence classification facilitates a fundamental understanding of the structure of microbial communities. Binary metagenomic sequence classifiers are insufficient because environmental metagenomes are typically derived from multiple sequence sources. Here we introduce a deep-learning based sequence classifier, DeepMicroClass, that classifies metagenomic contigs into five sequence classes, i.e. viruses infecting prokaryotic or eukaryotic hosts, eukaryotic or prokaryotic chromosomes, and prokaryotic plasmids. DeepMicroClass achieved high performance for all sequence classes at various tested sequence lengths ranging from 500 bp to 100 kbps. By benchmarking on a synthetic dataset with variable sequence class composition, we showed that DeepMicroClass obtained better performance for eukaryotic, plasmid and viral contig classification than other state-of-the-art predictors. DeepMicroClass achieved comparable performance on viral sequence classification with geNomad and VirSorter2 when benchmarked on the CAMI II marine dataset. Using a coastal daily time-series metagenomic dataset as a case study, we showed that microbial eukaryotes and prokaryotic viruses are integral to microbial communities. By analyzing monthly metagenomes collected at HOT and BATS, we found relatively higher viral read proportions in the subsurface layer in late summer, consistent with the seasonal viral infection patterns prevalent in these areas. We expect DeepMicroClass will promote metagenomic studies of under-appreciated sequence types.

Ultrafast Carrier Relaxation Dynamics in a Nodal-Line Semimetal PtSn4.

Topological Dirac nodal-line semimetals host topologically nontrivial electronic structure with nodal-line crossings around the Fermi level, which could affect the photocarrier dynamics and lead to novel relaxation mechanisms. Herein, by using time- and angle-resolved photoemission spectroscopy, we reveal the previously inaccessible linear dispersions of the bulk conduction bands above the Fermi level in a Dirac nodal-line semimetal PtSn4, as well as the momentum and temporal evolution of the gapless nodal lines. A surprisingly ultrafast relaxation dynamics within a few hundred femtoseconds is revealed for photoexcited carriers in the nodal line. Theoretical calculations suggest that such ultrafast carrier relaxation is attributed to the multichannel scatterings among the complex metallic bands of PtSn4 via electron-phonon coupling. In addition, a unique dynamic relaxation mechanism contributed by the highly anisotropic Dirac nodal-line electronic structure is also identified. Our work provides a comprehensive understanding of the ultrafast carrier dynamics in a Dirac nodal-line semimetal.

Caveolin-1 scaffolding domain-derived peptide enhances erectile function by regulating oxidative stress, mitochondrial dysfunction, and apoptosis of corpus cavernosum smooth muscle cells in rats with cavernous nerve injury.

AIM: Increased corpus cavernosum smooth muscle cells (CCSMCs) apoptosis in the penis due to cavernous nerve injury (CNI) is a crucial contributor to erectile dysfunction (ED). Caveolin-1 scaffolding domain (CSD)-derived peptide has been found to exert potential antiapoptotic properties. However, whether CSD peptide can alleviate CCSMCs apoptosis and ED in CNI rats remains unknown. The study aimed to determine whether CSD peptide can improve bilateral CNI-induced ED (BCNI-ED) by enhancing the antiapoptotic processes of CCSMCs. MAIN METHODS: Fifteen 10-week-old male Sprague-Dawley (SD) rats were randomly classified into three groups: sham surgery (Sham) group and BCNI groups that underwent saline or CSD peptide treatment respectively. At 3 weeks postoperatively, erectile function was assessed and the penis tissue was histologically examined. Furthermore, an in vitro model of CCSMCs apoptosis was established using transforming growth factor-beta 1 (TGF-ß1) to investigate the mechanism of CSD peptide in treating BCNI-ED. KEY FINDINGS: In BCNI rats, CSD peptide significantly prevented ED and decreased oxidative stress, the Bax/Bcl-2 ratio, and the levels of caspase3. TGF-ß1-treated CCSMCs exhibited severe oxidative stress, mitochondrial dysfunction, and apoptosis. However, CSD peptide partially reversed these alterations. SIGNIFICANCE: Exogenous CSD peptide could improve BCNI-ED by inhibiting oxidative stress, the Bax/Bcl-2 ratio, and caspase3 expression in penile tissue. The underlying mechanism might involve the regulatory effects of CSD peptide on oxidative stress, mitochondrial dysfunction, and apoptosis of CCSMCs following CNI. This study highlights CSD peptide as an effective therapy for post-radical prostatectomy ED (pRP-ED).

Multiple molecular and cellular mechanisms of the antitumour effect of dihydromyricetin (Review).

Dihydromyricetin (DHM) is a natural flavonoid compound with multiple antitumour effects, including inhibition of proliferation, promotion of apoptosis, inhibition of invasion and migration, clearance of reactive oxygen species (ROS) and induction of autophagy. For example, DHM can effectively block the progression of the tumour cell cycle and inhibit cell proliferation. In different types of cancer cells, DHM can regulate the PI3K/Akt pathway, mTOR, and NF-κB pathway components, such as p53, and endoplasmic reticulum stress can alter the accumulation of ROS or induce autophagy to promote the apoptosis of tumour cells. In addition, when DHM is used in combination with various known chemotherapy drugs, such as paclitaxel, nedaplatin, doxorubicin, oxaliplatin and vinblastine, it can increase the sensitivity of tumour cells to DHM and increase the therapeutic effect of chemotherapy drugs. In the present review, the multiple molecular and cellular mechanisms underlying the antitumour effect of DHM, as well as its ability to increase the effects of various traditional antitumour drugs were summarized. Through the present review, it is expected by the authors to draw attention to the potential of DHM as an antitumour drug and provide valuable references for the clinical translation of DHM research and the development of related treatment strategies.

Tuning A-Site Cation Deficiency in Pr0.5La0.5BaCo2O5+ δ Perovskite to Realize Large-Scale Hydrogen Evolution at 2000 mA cm-2.

Industrial-level hydrogen production from the water electrolysis requires reducing the overpotential (η) as much as possible at high current density, which is closely related to intrinsic activity of the electrocatalysts. Herein, A-site cation deficiency engineering is proposed to screen high-performance catalysts, demonstrating effective Pr0.5- xLa0.5BaCo2O5+ δ (P0.5- xLBC) perovskites toward alkaline hydrogen evolution reaction (HER). Among all perovskite compositions, Pr0.4La0.5BaCo2O5+ δ (P0.4LBC) exhibits superior HER performance along with unique operating stability at large current densities (J = 500-2000 mA cm-2 geo). The overpotential of ≈636 mV is achieved in P0.4LBC at 2000 mA cm-2 geo, which outperforms commercial Pt/C benchmark (≈974 mV). Furthermore, the Tafel slope of P0.4LBC (34.1 mV dec-1) is close to that of Pt/C (35.6 mV dec-1), reflecting fast HER kinetics on the P0.4LBC catalyst. Combined with experimental and theoretical results, such catalytic activity may benefit from enhanced electrical conductivity, enlarged Co-O covalency, and decreased desorption energy of H* species. This results highlight effective A-site cation-deficient strategy for promoting electrochemical properties of perovskites, highlighting potential water electrolysis at ampere-level current density.

Optimizing antigen selection for the development of tuberculosis vaccines.

Tuberculosis (TB) remains a prevalent global infectious disease caused by genetically closely related tubercle bacilli in Mycobacterium tuberculosis complex (MTBC). For a century, the Bacillus Calmette-Guérin (BCG) vaccine has been the primary preventive measure against TB. While it effectively protects against extrapulmonary forms of pediatric TB, it lacks consistent efficacy in providing protection against pulmonary TB in adults. Consequently, the exploration and development of novel TB vaccines, capable of providing broad protection to populations, have consistently constituted a prominent area of interest in medical research. This article presents a concise overview of the novel TB vaccines currently undergoing clinical trials, discussing their classification, protective efficacy, immunogenicity, advantages, and limitations. In vaccine development, the careful selection of antigens that can induce strong and diverse specific immune responses is essential. Therefore, we have summarized the molecular characteristics, biological function, immunogenicity, and relevant studies associated with the chosen antigens for TB vaccines. These insights gained from vaccines and immunogenic proteins will inform the development of novel mycobacterial vaccines, particularly mRNA vaccines, for effective TB control.

Indomethacin restrains cytoplasmic nucleic acid-stimulated immune responses by inhibiting the nuclear translocation of IRF3.

The recognition of cytosolic nucleic acid triggers the DNA/RNA sensor-IRF3 axis-mediated production of type I interferons (IFNs), which are essential for antiviral immune responses. However, the inappropriate activation of these signaling pathways is implicated in autoimmune conditions. Here, we report that indomethacin, a widely used nonsteroidal anti-inflammatory drug, inhibits nucleic acid-triggered IFN production. We found that both DNA- and RNA-stimulated IFN expression can be effectively blocked by indomethacin. Interestingly, indomethacin also prohibits the nuclear translocation of IRF3 following cytosolic nucleic acid recognition. Importantly, in cell lines and a mouse model of Aicardi-Goutières syndrome, indomethacin administration blunts self-DNA-induced autoimmune responses. Thus, our study reveals a previously unknown function of indomethacin and provides a potential treatment for cytosolic nucleic acid-stimulated autoimmunity.

Histologic and biomechanical comparison of fascia lata autograft, acellular dermal xenograft, and synthetic patch for bridging massive rotator cuff tear in a rabbit model.

Background: Bridging repair has emerged as a promising and reliable treatment strategy for the massive rotator cuff tears (MRCTs). However, there remains a lack of evidence on which bridging graft provides the better repair results, and a dearth of animal studies comparing bridging repairs with different grafts. The purpose of this study was to evaluate the histological and biomechanical outcomes of commonly used grafts (autologous fascia lata (FL), acellular dermal matrix graft (ADM), and polyethylene terephthalate (PET) patch). Methods: A total of 66 male New Zealand White Rabbits were used to mimic a model of unilateral chronic MRCTs. The rabbits were randomly divided into three groups: (1) FL group, which underwent bridging repair with autologous FL; (2) ADM group, which underwent bridging with ADM; and (3) PET group, which underwent bridging with PET patch. Tissue samples were collected and subjected to histological analysis using Hematoxylin and eosin, Picrosirius red, Safranin O/Fast green staining, and Immunostaining. Collagen diameter and fibril density in the regenerated tendon was analyzed with transmission electron microscopy (TEM). Additionally, biomechanical tests were performed at 6 and 12 weeks after repair. Results: The regenerated tendon successfully reattached to the footprint in all experimental groups. At 6 weeks after repair, the FL group had a significantly higher Modified Tendon Histological Evaluation (MTHE) score at the regenerated tendon than the PET group (13.2 ± 1.64 vs 9.6 ± 1.95, respectively; P = 0.038). The picrosirius red staining results showed that the FL group had a significantly higher type I collagen content than the ADM and PET groups at 6 weeks, and this difference was sustained with the PET group at 12 weeks (P < 0.05). Immunofluorescence analysis against CD68 indicated that the number of macrophage infiltrates was significantly lower in the FL group than in the ADM and PET groups (P < 0.05). At 12 weeks after repair, the area of Safranin O metachromasia was significant greater in ADM group than that in the PET group (P = 0.01). The FL group showed a significantly larger collagen diameter in the regenerated tendon than the PET group (P < 0.05), as indicated by TEM results. Furthermore, the FL group resulted in a greater failure load (at 6 weeks; 118.40 ± 16.70 N vs 93.75 ± 9.06 N, respectively; P = 0.019) and elastic modulus (at 6 weeks; 12.28 ± 1.94 MPa vs 9.58 ± 0.79 MPa, respectively; P = 0.024; at 12 weeks; 15.02 ± 2.36 MPa vs 11.63 ± 1.20 MPa, respectively; P = 0.032) than the ADM group. Conclusions: This study demonstrated that all three grafts could successfully bridging chronic MRCTs in a rabbit model. However, autologous FL promoted tendon regeneration and maturation, and enhanced the tensile properties of the tendon-to-bone complex when compared with ADM and PET grafts.