Organic-Inorganic Heterointerface-Expediting Electron Transfer Realizes Efficient Plasmonic Catalytic Sterilization via a Carbon-Dot Nanozyme.

Plasmonic nanozymes bring enticing prospects for catalytic sterilization by leveraging plasmon-engendered hot electrons. However, the interface between plasmons and nanozymes as the mandatory path of hot electrons receives little attention, and the mechanisms of plasmonic nanozymes still remain to be elucidated. Herein, a plasmonic carbon-dot nanozyme (FeCG) is developed by electrostatically assembling catalytic iron-doped carbon dots (Fe-CDs) with plasmonic gold nanorods. The energy harvesting and hot-electron migration are remarkably expedited by a spontaneous organic-inorganic heterointerface holding a Fermi level-induced interfacial electric field. The accumulated hot electrons are then fully utilized by conductive Fe-CDs to boost enzymatic catalysis toward overproduced reactive oxygen species. By synergizing with localized heating from hot-electron decay, FeCG achieves rapid and potent disinfection with an antibacterial efficiency of 99.6% on Escherichia coli within 5 min and is also effective (94.2%) against Staphylococcus aureus. Our work presents crucial insights into the organic-inorganic heterointerface in advanced plasmonic biocidal nanozymes.

Compound SJ-12 attenuates streptozocin-induced diabetic cardiomyopathy by stabilizing SERCA2a.

Heart failure (HF) is one of the major causes of death among diabetic patients. Although studies have shown that curcumin analog C66 can remarkably relieve diabetes-associated cardiovascular and kidney complications, the role of SJ-12, SJ-12, a novel curcumin analog, in diabetic cardiomyopathy and its molecular targets are unknown. 7-week-old male C57BL/6 mice were intraperitoneally injected with single streptozotocin (STZ) (160 mg/kg) to develop diabetic cardiomyopathy (DCM). The diabetic mice were then treated with SJ-12 via gavage for two months. Body weight, fast blood glucose, cardiac utrasonography, myocardial injury markers, pathological morphology of the heart, hypertrophic and fibrotic markers were assessed. The potential target of SJ-12 was evaluated via RNA-sequencing analysis. The O-GlcNAcylation levels of SP1 were detected via immunoprecipitation. SJ-12 effectively suppressed myocardial hypertrophy and fibrosis, thereby preventing heart dysfunction in mice with STZ-induced heart failure. RNA-sequencing analysis revealed that SJ-12 exerted its therapeutic effects through the modulation of the calcium signaling pathway. Furthermore, SJ-12 reduced the O-GlcNAcylation levels of SP1 by inhibiting O-linked N-acetylglucosamine transferase (OGT). Also, SJ-12 stabilized Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2a (SERCA2a), a crucial regulator of calcium homeostasis, thus reducing hypertrophy and fibrosis in mouse hearts and cultured cardiomyocytes. However, the anti-fibrotic effects of SJ-12 were not detected in SERCA2a or OGT-silenced cardiomyocytes, indicating that SJ-12 can prevent DCM by targeting OGT-dependent O-GlcNAcylation of SP1.These findings indicate that SJ-12 can exert cardioprotective effects in STZ-induced mice by reducing the O-GlcNAcylation levels of SP1, thus stabilizing SERCA2a and reducing myocardial fibrosis and hypertrophy. Therefore, SJ-12 can be used for the treatment of diabetic cardiomyopathy.

A single-cell characterised signature integrating heterogeneity and microenvironment of lung adenocarcinoma for prognostic stratification.

BACKGROUND: The high heterogeneity of tumour and the complexity of tumour microenvironment (TME) greatly impacted the tumour development and the prognosis of cancer in the era of immunotherapy. In this study, we aimed to portray the single cell-characterised landscape of lung adenocarcinoma (LUAD), and develop an integrated signature incorporating both tumour heterogeneity and TME for prognosis stratification. METHODS: Single-cell tagged reverse transcription sequencing (STRT-seq) was performed on tumour tissues and matched normal tissues from 14 patients with LUAD for immune landscape depiction and candidate key genes selection for signature construction. Kaplan-Meier survival analyses and in-vitro cell experiments were conducted to confirm the gene functions. The transcriptomic profile of 1949 patients from 11 independent cohorts including nine public datasets and two in-house cohorts were obtained for validation. FINDINGS: We selected 11 key genes closely related to cell-to-cell interaction, tumour development, T cell phenotype transformation, and Ma/Mo cell distribution, including HLA-DPB1, FAM83A, ITGB4, OAS1, FHL2, S100P, FSCN1, SFTPD, SPP1, DBH-AS1, CST3, and established an integrated 11-gene signature, stratifying patients to High-Score or Low-Score group for better or worse prognosis. Moreover, the prognostically-predictive potency of the signature was validated by 11 independent cohorts, and the immunotherapeutic predictive potency was also validated by our in-house cohort treated by immunotherapy. Additionally, the in-vitro cell experiments and drug sensitivity prediction further confirmed the gene function and generalizability of this signature across the entire RNA profile spectrum. INTERPRETATION: This single cell-characterised 11-gene signature might offer insights for prognosis stratification and potential guidance for treatment selection. FUNDING: Support for the study was provided by National key research and development project (2022YFC2505004, 2022YFC2505000 to Z.W. and J.W.), Beijing Natural Science Foundation (7242114 to J.X.), National Natural Science Foundation of China of China (82102886 to J.X., 81871889 and 82072586 to Z.W.), Beijing Nova Program (20220484119 to J.X.), NSFC general program (82272796 to J.W.), NSFC special program (82241229 to J.W.), CAMS Innovation Fund for Medical Sciences (2021-1-I2M-012, 2022-I2M-1-009 to Z.W. and J.W.), Beijing Natural Science Foundation (7212084 to Z.W.), CAMS Key lab of translational research on lung cancer (2018PT31035 to J.W.), Aiyou Foundation (KY201701 to J.W.). Medical Oncology Key Foundation of Cancer Hospital Chinese Academy of Medical Sciences (CICAMS-MOCP2022003 to J.X.).

Oncolytic mineralized bacteria as potent locally administered immunotherapeutics.

Oncolytic bacteria can trigger innate immune activity. However, the antitumour efficacy of inactivated bacteria is poor, and attenuated live bacteria pose substantial safety risks. Here we show that intratumourally injected paraformaldehyde-fixed bacteria coated with manganese dioxide potently activate innate immune activity, modulate the immunosuppressive tumour microenvironment and trigger tumour-specific immune responses and abscopal antitumour responses. A single intratumoural administration of mineralized Salmonella typhimurium suppressed the growth of multiple types of subcutaneous and orthotopic tumours in mice, rabbits and tree shrews and protected the cured animals against tumour rechallenge. We also show that mineralized bacteria can be administered via arterial embolization to treat orthotopic liver cancer in rabbits. Our findings support the further translational testing of oncolytic mineralized bacteria as potent and safe antitumour immunotherapeutics.

Genomic characteristics and immune landscape of super multiple primary lung cancer.

BACKGROUND: In recent years, a growing number of patients with multiple primary lung cancer (MPLC) are being diagnosed, and a subset of these patients is found to have a large number of lesions at the time of diagnosis, which are referred to as 'super MPLC'. METHODS: Here, we perform whole exome sequencing (WES) and immunohistochemistry (IHC) analysis of PD-L1 and CD8 on 212 tumor samples from 42 patients with super MPLC. FINDINGS: We report the genomic alteration landscape of super MPLC. EGFR, RBM10 and TP53 mutation and TERT amplification are important molecular events in the evolution of super MPLC. We propose the conception of early intrapulmonary metastasis, which exhibits different clinical features from conventional metastasis. The IHC analyses of PD-L1 and CD8 reveal a less inflamed microenvironment of super MPLC than that of traditional non-small cell lung cancer (NSCLC). We identify the potentially susceptible germline mutations for super MPLC. INTERPRETATION: Our study depicts the genomic characteristics and immune landscape, providing insights into the pathogenesis and possible therapeutic guidance of super MPLC. FUNDING: A full list of funding bodies that supported this study can be found in the Acknowledgements section.

Treatment patterns and clinical outcomes of patients with resectable non-small cell lung cancer receiving neoadjuvant immunochemotherapy: A large-scale, multicenter, real-world study (NeoR-World).

BACKGROUND: Neoadjuvant immunotherapy has ushered in a new era of perioperative treatment for resectable non-small cell lung cancer (NSCLC). However, large-scale data for verifying the efficacy and optimizing the therapeutic strategies of neoadjuvant immunochemotherapy in routine clinical practice are scarce. METHODS: NeoR-World (NCT05974007) was a multicenter, retrospective cohort study involving patients who received neoadjuvant immunotherapy plus chemotherapy or chemotherapy alone in routine clinical practice from 11 medical centers in China between January 2010 and March 2022. Propensity score matching was performed to address indication bias. RESULTS: A total of 408 patients receiving neoadjuvant immunochemotherapy and 684 patients receiving neoadjuvant chemotherapy were included. The pathologic complete response (pCR) and major pathologic response (MPR) rates of the real-world neoadjuvant immunochemotherapy cohort were 32.8% and 58.1%, respectively. Notably, patients with squamous cell carcinoma exhibited significantly higher pCR and MPR rates than those with adenocarcinoma (pCR, 39.2% vs 16.5% [P < .001]; MPR, 66.6% vs 36.5% [P < .001]), whereas pCR and MPR rates were comparable among patients receiving different neoadjuvant cycles. In addition, the 2-year rates of disease-free survival (DFS) and overall survival (OS) rate were 82.0% and 93.1%, respectively. Multivariate analyses identified adjuvant therapy as an independent prognostic factor for DFS (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.29-0.89; P = .018) and OS (HR, 0.28; 95% CI, 0.13-0.58; P < .001). A significantly longer DFS with adjuvant therapy was observed in patients with non-pCR or 2 neoadjuvant cycles. We observed significant benefits in pCR rate (32.4% vs 6.4%; P < .001), DFS (HR, 0.50; 95% CI, 0.38-0.68; P < .001) and OS (HR, 0.61; 95% CI, 0.40-0.94; P = .024) with immunotherapy plus chemotherapy compared to chemotherapy alone both in the primary propensity-matched cohort and across most key subgroups. CONCLUSIONS: The study validates the superior efficacy of neoadjuvant immunochemotherapy over chemotherapy alone for NSCLC. Adjuvant therapy could prolong DFS in patients receiving neoadjuvant immunochemotherapy, and patients with non-pCR or those who underwent 2 neoadjuvant cycles were identified as potential beneficiaries of adjuvant therapy.

Assessment of human leukocyte antigen-based neoantigen presentation to determine pan-cancer response to immunotherapy.

Despite the central role of human leukocyte antigen class I (HLA-I) in tumor neoantigen presentation, quantitative determination of presentation capacity remains elusive. Based on a pooled pan-cancer genomic dataset of 885 patients treated with immune checkpoint inhibitors (ICIs), we developed a score integrating the binding affinity of neoantigens to HLA-I, as well as HLA-I allele divergence, termed the HLA tumor-Antigen Presentation Score (HAPS). Patients with a high HAPS were more likely to experience survival benefit following ICI treatment. Analysis of the tumor microenvironment indicated that the antigen presentation pathway was enriched in patients with a high HAPS. Finally, we built a neural network incorporating factors associated with neoantigen production, presentation, and recognition, which exhibited potential for differentiating cancer patients likely to benefit from ICIs. Our findings highlight the clinical utility of evaluating HLA-I tumor antigen presentation capacity and describe how ICI response may depend on HLA-mediated immunity.

OTUD1 promotes isoprenaline- and myocardial infarction-induced heart failure by targeting PDE5A in cardiomyocytes.

Heart failure represents a major cause of death worldwide. Recent research has emphasized the potential role of protein ubiquitination/deubiquitination protein modification in cardiac pathology. Here, we investigate the role of the ovarian tumor deubiquitinase 1 (OTUD1) in isoprenaline (ISO)- and myocardial infarction (MI)-induced heart failure and its molecular mechanism. OTUD1 protein levels were raised markedly in murine cardiomyocytes after MI and ISO treatment. OTUD1 deficiency attenuated myocardial hypertrophy and cardiac dysfunction induced by ISO infusion or MI operation. In vitro, OTUD1 knockdown in neonatal rat ventricular myocytes (NRVMs) attenuated ISO-induced injuries, while OTUD1 overexpression aggravated the pathological changes. Mechanistically, LC-MS/MS and Co-IP studies showed that OTUD1 bound directly to the GAF1 and PDEase domains of PDE5A. OTUD1 was found to reverse K48 ubiquitin chain in PDE5A through cysteine at position 320 of OTUD1, preventing its proteasomal degradation. PDE5A could inactivates the cGMP-PKG-SERCA2a signaling axis which dysregulate the calcium handling in cardiomyocytes, and leading to the cardiomyocyte injuries. In conclusion, OTUD1 promotes heart failure by deubiquitinating and stabilizing PDE5A in cardiomyocytes. These findings have identified PDE5A as a new target of OTUD1 and emphasize the potential of OTUD1 as a target for treating heart failure.

Comparison of efficacy discrepancy between early-phase clinical trials and phase III trials of PD-1/PD-L1 inhibitors.

BACKGROUND: Phase III clinical trials are pivotal for evaluating therapeutics, yet a concerning failure rate has been documented, particularly impacting oncology where accelerated approvals of immunotherapies are common. These failures are predominantly attributed to a lack of therapeutic efficacy, indicating overestimation of results from phase II studies. Our research aims to systematically assess overestimation in early-phase trials involving programmed cell death-1 (PD-1)/programmed cell death-ligand 1(PD-L1) inhibitors compared with phase III trials and identify contributing factors. METHODS: We matched 51 pairs of early-phase and phase III clinical trials from a pool of over 9,600 PD-1/PD-L1 inhibitor trials. The matching criteria included identical treatment regimens, cancer types, treatment lines, and biomarker enrichment strategies. To assess overestimation, we compared the overall response rates (ORR) between early-phase and phase III trials. We established independent variables related to eligibility criteria, and trial design features of participants to analyze the factors influencing the observed discrepancy in efficacy between the two phases through univariable and multivariable logistic analyses. RESULT: Early-phase trial outcomes systematically overestimated the subsequent phase III results, yielding an odds ratio (OR) comparing ORR in early-phase versus phase III: 1.66 (95% CI: 1.43 to 1.92, p<0.05). This trend of inflated ORR was consistent across trials testing PD-1/PD-L1 monotherapies and combination therapies involving PD-1/PD-L1. Among the examined factors, the exclusion of patients with autoimmune diseases was significantly associated with the disparity in efficacy between early-phase trials and phase III trials (p=0.023). We calculated a Ward statistic of 2.27 to validate the effectiveness of the model. CONCLUSION: These findings underscore the tendency of overestimation of efficacy in early-phase trials involving immunotherapies. The observed differences could be attributed to variations in the inclusion of patients with autoimmune disorders in early-phase trials. These insights have the potential to inform stakeholders in the future development of cancer immunotherapies.

JOSD2 mediates isoprenaline-induced heart failure by deubiquitinating CaMKIIδ in cardiomyocytes.

Prolonged stimulation of ß-adrenergic receptor (ß-AR) can lead to sympathetic overactivity that causes pathologic cardiac hypertrophy and fibrosis, ultimately resulting in heart failure. Recent studies suggest that abnormal protein ubiquitylation may contribute to the pathogenesis of cardiac hypertrophy and remodeling. In this study, we demonstrated that deficiency of a deubiquitinase, Josephin domain-containing protein 2 (JOSD2), ameliorated isoprenaline (ISO)- and myocardial infarction (MI)-induced cardiac hypertrophy, fibrosis, and dysfunction both in vitro and in vivo. Conversely, JOSD2 overexpression aggravated ISO-induced cardiac pathology. Through comprehensive mass spectrometry analysis, we identified that JOSD2 interacts with Calcium-calmodulin-dependent protein kinase II (CaMKIIδ). JOSD2 directly hydrolyzes the K63-linked polyubiquitin chains on CaMKIIδ, thereby increasing the phosphorylation of CaMKIIδ and resulting in calcium mishandling, hypertrophy, and fibrosis in cardiomyocytes. In vivo experiments showed that the cardiac remodeling induced by JOSD2 overexpression could be reversed by the CaMKIIδ inhibitor KN-93. In conclusion, our study highlights the role of JOSD2 in mediating ISO-induced cardiac remodeling through the regulation of CaMKIIδ ubiquitination, and suggests its potential as a therapeutic target for combating the disease. Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary. All have been checked.

Isoproterenol induces MD2 activation by ß-AR-cAMP-PKA-ROS signalling axis in cardiomyocytes and macrophages drives inflammatory heart failure.

Cardiac inflammation contributes to heart failure (HF) induced by isoproterenol (ISO) through activating ß-adrenergic receptors (ß-AR). Recent evidence shows that myeloid differentiation factor 2 (MD2), a key protein in endotoxin-induced inflammation, mediates inflammatory heart diseases. In this study, we investigated the role of MD2 in ISO-ß-AR-induced heart injuries and HF. Mice were infused with ISO (30 mg·kg-1·d-1) via osmotic mini-pumps for 2 weeks. We showed that MD2 in cardiomyocytes and cardiac macrophages was significantly increased and activated in the heart tissues of ISO-challenged mice. Either MD2 knockout or administration of MD2 inhibitor L6H21 (10 mg/kg every 2 days, i.g.) could prevent mouse hearts from ISO-induced inflammation, remodelling and dysfunction. Bone marrow transplantation study revealed that both cardiomyocyte MD2 and bone marrow-derived macrophage MD2 contributed to ISO-induced cardiac inflammation and injuries. In ISO-treated H9c2 cardiomyocyte-like cells, neonatal rat primary cardiomyocytes and primary mouse peritoneal macrophages, MD2 knockout or pre-treatment with L6H21 (10 µM) alleviated ISO-induced inflammatory responses, and the conditioned medium from ISO-challenged macrophages promoted the hypertrophy and fibrosis in cardiomyocytes and fibroblasts. We demonstrated that ISO induced MD2 activation in cardiomyocytes via ß1-AR-cAMP-PKA-ROS signalling axis, and induced inflammatory responses in macrophages via ß2-AR-cAMP-PKA-ROS axis. This study identifies MD2 as a key inflammatory mediator and a promising therapeutic target for ISO-induced heart failure.

Impact of doxycycline on Clostridioides difficile infection in patients hospitalized with community-acquired pneumonia.

BACKGROUND: Antibiotic use is a significant risk factor associated with Clostridioides difficile (C difficile) infection (CDI). Community-acquired pneumonia (CAP) is a common infection leading to hospital admission and the use of antibiotics that are highly associated with CDI. It has been proposed that doxycycline, a tetracycline antibiotic, may be protective against CDI. METHODS: A retrospective analysis was conducted in hospitalized patients in Veterans Affairs Hospitals across the United States to determine if doxycycline was associated with a decreased risk of CDI. The primary outcome was the development of CDI within 30 days of initiation of doxycycline or azithromycin, as part of a standard pneumonia regimen. RESULTS: Approximately 156,107 hospitalized patients who received care at a Veterans Affairs Hospital and were diagnosed with CAP during the study timeframe were included. A 17% decreased risk of CDI was identified with doxycycline compared to azithromycin when used with ceftriaxone for the treatment of pneumonia (P = .03). In patients who had a prior history of CDI, doxycycline decreased the incidence of CDI by 45% (odds ratio 0.55; P = .02). CONCLUSIONS: Doxycycline is associated with a lower risk of CDI compared to azithromycin when used for atypical coverage in CAP. Thus, patients who are at such risk may benefit from doxycycline as a first-line agent for atypical coverage, rather than the use of a macrolide antibiotic, if Legionella is not of concern.

SMURF1 controls the PPP3/calcineurin complex and TFEB at a regulatory node for lysosomal biogenesis.

Macroautophagy/autophagy is a homeostatic process in response to multiple signaling, such as the lysosome-dependent recycling process of cellular components. Starvation-induced MTOR inactivation and PPP3/calcineurin activation were shown to promote the nuclear translocation of TFEB. However, the mechanisms via which signals from endomembrane damage are transmitted to activate PPP3/calcineurin and orchestrate autophagic responses remain unknown. This study aimed to show that autophagy regulator SMURF1 controlled TFEB nuclear import for transcriptional activation of the lysosomal biogenesis. We showed that blocking SMURF1 affected lysosomal biogenesis in response to lysosomal damage by preventing TFEB nuclear translocation. It revealed galectins recognized endolysosomal damage, and led to recruitment of SMURF1 and the PPP3/calcineurin apparatus on lysosomes. SMURF1 interacts with both LGALS3 and PPP3CB to form the LGALS3-SMURF1-PPP3/calcineurin complex. Importantly, this complex further stabilizes TFEB, thereby activating TFEB for lysosomal biogenesis. We determined that LLOMe-mediated TFEB nuclear import is dependent on SMURF1 under the condition of MTORC1 inhibition. In addition, SMURF1 is required for PPP3/calcineurin activity as a positive regulator of TFEB. SMURF1 controlled the phosphatase activity of the PPP3CB by promoting the dissociation of its autoinhibitory domain (AID) from its catalytic domain (CD). Overexpression of SMURF1 showed similar effects as the constitutive activation of PPP3CB. Thus, SMURF1, which bridges environmental stress with the core autophagosomal and autolysosomal machinery, interacted with endomembrane sensor LGALS3 and phosphatase PPP3CB to control TFEB activation.Abbreviations: ATG: autophagy-related; LLOMe: L-Leucyl-L-Leucine methyl ester; ML-SA1: mucolipin synthetic agonist 1; MTOR: mechanistic target of rapamycin kinase; PPP3CB: protein phosphatase 3 catalytic subunit beta; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; TFEB: transcription factor EB.

Research advances in mechanism of antiangiogenic therapy combined with immune checkpoint inhibitors for treatment of non-small cell lung cancer.

Immunotherapy has changed the treatment strategy of non-small cell lung cancer (NSCLC) in recent years, among which anti-PD-1/PD-L1 antibodies are the most used. However, the majority of patients with NSCLC do not derive benefit from immune checkpoint inhibitors (ICIs). Vascular abnormalities are a hallmark of most solid tumors and facilitate immune evasion. Thus, combining antiangiogenic therapies might increase the effectiveness of anti-PD-1/PD-L1 antibodies. In this paper, the mechanisms of anti-angiogenic agents combined with anti-PD-1/PD-L1 antibodies are illustrated, moreover, relevant clinical studies and predictive immunotherapeutic biomarkers are summarized and analyzed, in order to provide more treatment options for NSCLC patients.

Real-Time Road Intersection Detection in Sparse Point Cloud Based on Augmented Viewpoints Beam Model.

Road intersection is a kind of important navigation landmark, while existing detection methods exhibit clear limitations in terms of their robustness and efficiency. A real-time algorithm for road intersection detection and location in large-scale sparse point clouds is proposed in this paper. Different from traditional approaches, our method establishes the augmented viewpoints beam model to perceive the road bifurcation structure. Explicitly, the spatial features from point clouds are jointly extracted in various viewpoints in front of the robot. In addition, the evaluation metrics are designed to self-assess the quality of detection results, enabling our method to optimize the detection process in real time. Considering the scarcity of datasets for intersection detection, we also collect and annotate a VLP-16 point cloud dataset specifically for intersections, called NCP-Intersection. Quantitative and qualitative experiments demonstrate that the proposed method performs favorably against the other parallel methods. Specifically, our method performs an average precision exceeding 90% and an average processing time of approximately 88 ms/frame.

20(S)-ginsenoside Rh2 inhibits angiotensin-2 mediated cardiac remodeling and inflammation associated with suppression of the JNK/AP-1 pathway.

BACKGROUND: Enhanced levels of angiotensin-2 (Ang-II) causes hypertensive heart failure (HHF) through non-hemodynamical and hemodynamical alterations. 20(S)-ginsenoside Rh2 (20(S)-Rh2) is a natural ginseng compound with numerous cardiovascular benefits. This investigation elucidates the influence of 20(S)-Rh2 on Ang-II-induced heart failure and cardiac alterations. METHODS: Ang-II was administered in C57BL/6 mice for 4 weeks to induce HHF. In the last 2 weeks of treatment, 20(S)-Rh2 was orally administered in mice to assess the potential 20(S)-Rh2 mechanism. Subsequently, RNA sequencing was carried out. RESULTS: It was indicated that 20(S)-Rh2 suppresses myocardial fibrosis, hypertrophy, and inflammation, thereby inhibiting cardiac disruption in Ang-II-challenged mice without affecting blood pressure. According to the RNA sequencing data, this cardio-protective effect was linked with the (JNK)/AP 1 pathway. 20(S)-Rh2 alleviated heart tissue and cardiomyocytes inflammation by inhibiting the Ang-II-mediated JNK/AP-1 pathway. Within cardiomyocytes, JNK or AP-1 absence abolished the anti-inflammatory effects of 20(S)-Rh2. CONCLUSION: This study investigation indicated that 20(S)-Rh2 prevents cardiovascular dysfunction induced by Ang-II induced by decreasing JNK-regulated inflammatory responses, providing evidence for its use as an efficient regimen for HHF.

Spatial-temporal distribution characteristics of pollutants of heavy-duty diesel vehicles in urban road networks: a case study of Kunming City.

With the continuous promotion of urbanization in China, the economic level of small and medium-sized cities has been further improved. The transportation industry is crucial in promoting urban-rural integration and construction. Still, motor vehicle emissions also bring air pollution problems to cities, with heavy-duty diesel vehicle emissions severely impacting the urban environment. This study used a bottom-up approach to analyze the spatial emission characteristics of heavy-duty diesel vehicles under different road types in Kunming, a typical medium-sized city in China. A high-resolution emission inventory (1 km × 1 km) of heavy-duty diesel vehicles was developed using the vehicle emission inventory model (VEIN) and ArcGIS, and the vehicle emission standards were determined by the Weibull survival rate curve. The VEIN emission model was optimized using a velocity correction curve. The results showed that heavy-duty vehicles had a more significant impact on the emissions during the morning and evening peak hours, with low emission levels during the day and high emission levels at night and early morning. The total daily emissions of carbon monoxide (CO), hydrocarbons (HC), nitrogen oxides (NOx), and particulate matter (PM10 and PM2.5) from heavy-duty diesel vehicles in Motorway, Trunk, Primary, Secondary, and Tertiary were 14.44 tons, 5.26 tons, 4.78 tons, 7.02 tons, and 3.83 tons, respectively. China III heavy-duty diesel vehicles mainly contributed to CO, HC, NOx, and PM emissions. This study can be used as an essential reference for controlling the exhaust emissions of HDDVs in Kunming.

Ablation of ERO1A induces lethal endoplasmic reticulum stress responses and immunogenic cell death to activate anti-tumor immunity.

Immunophenotyping of the tumor microenvironment (TME) is essential for enhancing immunotherapy efficacy. However, strategies for characterizing the TME exhibit significant heterogeneity. Here, we show that endoplasmic reticular oxidoreductase-1α (ERO1A) mediates an immune-suppressive TME and attenuates the response to PD-1 blockade. Ablation of ERO1A in tumor cells substantially incites anti-tumor T cell immunity and promotes the efficacy of aPD-1 in therapeutic models. Single-cell RNA-sequencing analyses confirm that ERO1A correlates with immunosuppression and dysfunction of CD8+ T cells along anti-PD-1 treatment. In human lung cancer, high ERO1A expression is associated with a higher risk of recurrence following neoadjuvant immunotherapy. Mechanistically, ERO1A ablation impairs the balance between IRE1α and PERK signaling activities and induces lethal unfolded protein responses in tumor cells undergoing endoplasmic reticulum stress, thereby enhancing anti-tumor immunity via immunogenic cell death. These findings reveal how tumor ERO1A induces immunosuppression, highlighting its potential as a therapeutic target for cancer immunotherapy.

Superhydrophobic and Photocatalytic Synergistic Self-Cleaning Coating Constructed by Hierarchically Structured Flower-like Hollow SiO2@TiO2 Spheres with Oxygen Vacancies.

The self-cleaning coating has both superhydrophobic physical and photocatalytic chemical self-cleaning properties, which has attracted the wide attention of researchers in recent years. First, the flower-like hollow SiO2@TiO2 spheres with oxygen vacancies (rFHSTs) were prepared by the liquid-phase reduction method, in which several different functional components were integrated. Meanwhile, the influence mechanisms of the physical structure and chemical composition on the photocatalytic properties are discussed in detail. The results proved that rFHSTs exhibited the enhanced photoresponse range and photocatalytic degradation performance in visible light because of the synergistic effect of the microstructure (internal cavity, 3D flower-like nanosheet), SiO2/TiO2 heterojunction structure, and oxygen vacancies. After that, superhydrophobic modified rFHSTs were used as fillers to fabricate PVA/PFDTS-rFHSTs composite coatings with both physical and chemical self-cleaning properties. The self-cleaning performances and principles of the composite coating were examined and explored. The results showed that the low surface energy of the hydrophobic chain segment, the inherent particle effect, and the photocatalytic activity of rFHSTs were responsible for the superhydrophobic and photocatalytic effects, finally endowing the composite coating with self-cleaning performance. In short, this study is profound for the development and application of self-cleaning coatings with both physical and chemical performances.

Positive-Negative Receptive Field Reasoning for Omni-Supervised 3D Segmentation.

Hidden features in the neural networks usually fail to learn informative representation for 3D segmentation as supervisions are only given on output prediction, while this can be solved by omni-scale supervision on intermediate layers. In this paper, we bring the first omni-scale supervision method to 3D segmentation via the proposed gradual Receptive Field Component Reasoning (RFCR), where target Receptive Field Component Codes (RFCCs) is designed to record categories within receptive fields for hidden units in the encoder. Then, target RFCCs will supervise the decoder to gradually infer the RFCCs in a coarse-to-fine categories reasoning manner, and finally obtain the semantic labels. To purchase more supervisions, we also propose an RFCR-NL model with complementary negative codes (i.e., Negative RFCCs, NRFCCs) with negative learning. Because many hidden features are inactive with tiny magnitudes and make minor contributions to RFCC prediction, we propose Feature Densification with a centrifugal potential to obtain more unambiguous features, and it is in effect equivalent to entropy regularization over features. More active features can unleash the potential of omni-supervision method. We embed our method into three prevailing backbones, which are significantly improved in all three datasets on both fully and weakly supervised segmentation tasks and achieve competitive performances.