Buried interface molecular hybrid for inverted perovskite solar cells.

Perovskite solar cells (PSCs) with an "inverted" architecture are a key pathway for commercializing this emerging photovoltaic technology due to the better power conversion efficiency (PCE) and operational stability as compared to the "normal" device structure. Specifically, PCEs of the inverted PSCs have exceeded 25% owing to the development of improved self-assembled molecules (SAMs)1-5 and passivation strategies6-8. Nevertheless, poor wettability and agglomerations of SAMs9-12 will cause interfacial losses, impeding further improvement in PCE and stability. Herein, we report on molecular hybrid at the buried interface in inverted PSCs by co-assembling a multiple carboxylic acid functionalized aromatic compound of 4,4',4''-nitrilotribenzoicacid (NA) with a popular SAM of [4-(3,6-dime-thyl-9H-carbazol-9-yl)butyl]phosphonic acid (Me-4PACz) to improve the heterojunction interface. The molecular hybrid of Me-4PACz with NA could substantially improve the interfacial characteristics. The resulting inverted PSCs demonstrated a record-certified steady-state efficiency of 26.54%. Crucially, this strategy aligns seamlessly with large-scale manufacturing, achieving the highest certified PCE for inverted mini-modules at 22.74% (aperture area: 11.1 cm2). Our device also maintained 96.1% of its initial PCE after more than 2,400 hours of 1-sun operation in ambient air.

Mechano-regulation of Peptide-MHC Class I Conformations Determines TCR Antigen Recognition.

TCRs recognize cognate pMHCs to initiate T cell signaling and adaptive immunity. Mechanical force strengthens TCR-pMHC interactions to elicit agonist-specific catch bonds to trigger TCR signaling, but the underlying dynamic structural mechanism is unclear. We combined steered molecular dynamics (SMD) simulation, single-molecule biophysical approaches, and functional assays to collectively demonstrate that mechanical force induces conformational changes in pMHCs to enhance pre-existing contacts and activates new interactions at the TCR-pMHC binding interface to resist bond dissociation under force, resulting in TCR-pMHC catch bonds and T cell activation. Intriguingly, cancer-associated somatic mutations in HLA-A2 that may restrict these conformational changes suppressed TCR-pMHC catch bonds. Structural analysis also indicated that HLA polymorphism might alter the equilibrium of these conformational changes. Our findings not only reveal critical roles of force-induced conformational changes in pMHCs for activating TCR-pMHC catch bonds but also have implications for T cell-based immunotherapy.

Dynamics of Endothelial Cell Generation and Turnover in Arteries During Homeostasis and Diseases.

BACKGROUND: Endothelial cell (EC) generation and turnover by self-proliferation contributes to vascular repair and regeneration. The ability to accurately measure the dynamics of EC generation would advance our understanding of cellular mechanisms of vascular homeostasis and diseases. However, it is currently challenging to evaluate the dynamics of EC generation in large vessels such as arteries because of their infrequent proliferation. METHODS: By using dual recombination systems based on Cre-loxP and Dre-rox, we developed a genetic system for temporally seamless recording of EC proliferation in vivo. We combined genetic recording of EC proliferation with single-cell RNA sequencing and gene knockout to uncover cellular and molecular mechanisms underlying EC generation in arteries during homeostasis and disease. RESULTS: Genetic proliferation tracing reveals that ≈3% of aortic ECs undergo proliferation per month in adult mice during homeostasis. The orientation of aortic EC division is generally parallel to blood flow in the aorta, which is regulated by the mechanosensing protein Piezo1. Single-cell RNA sequencing analysis reveals 4 heterogeneous aortic EC subpopulations with distinct proliferative activity. EC cluster 1 exhibits transit-amplifying cell features with preferential proliferative capacity and enriched expression of stem cell markers such as Sca1 and Sox18. EC proliferation increases in hypertension but decreases in type 2 diabetes, coinciding with changes in the extent of EC cluster 1 proliferation. Combined gene knockout and proliferation tracing reveals that Hippo/vascular endothelial growth factor receptor 2 signaling pathways regulate EC proliferation in large vessels. CONCLUSIONS: Genetic proliferation tracing quantitatively delineates the dynamics of EC generation and turnover, as well as EC division orientation, in large vessels during homeostasis and disease. An EC subpopulation in the aorta exhibits more robust cell proliferation during homeostasis and type 2 diabetes, identifying it as a potential therapeutic target for vascular repair and regeneration.

Extracellular Matrix Disorganization Caused by ADAMTS16 Deficiency Leads to Bicuspid Aortic Valve With Raphe Formation.

BACKGROUND: A better understanding of the molecular mechanism of aortic valve development and bicuspid aortic valve (BAV) formation would significantly improve and optimize the therapeutic strategy for BAV treatment. Over the past decade, the genes involved in aortic valve development and BAV formation have been increasingly recognized. On the other hand, ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family members have been reported to be able to modulate cardiovascular development and diseases. The present study aimed to further investigate the roles of ADAMTS family members in aortic valve development and BAV formation. METHODS: Morpholino-based ADAMTS family gene-targeted screening for zebrafish heart outflow tract phenotypes combined with DNA sequencing in a 304 cohort BAV patient registry study was initially carried out to identify potentially related genes. Both ADAMTS gene-specific fluorescence in situ hybridization assay and genetic tracing experiments were performed to evaluate the expression pattern in the aortic valve. Accordingly, related genetic mouse models (both knockout and knockin) were generated using the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) method to further study the roles of ADAMTS family genes. The lineage-tracing technique was used again to evaluate how the cellular activity of specific progenitor cells was regulated by ADAMTS genes. Bulk RNA sequencing was used to investigate the signaling pathways involved. Inducible pluripotent stem cells derived from both BAV patients and genetic mouse tissue were used to study the molecular mechanism of ADAMTS. Immunohistochemistry was performed to examine the phenotype of cardiac valve anomalies, especially in the extracellular matrix components. RESULTS: ADAMTS genes targeting and phenotype screening in zebrafish and targeted DNA sequencing on a cohort of patients with BAV identified ADAMTS16 (a disintegrin and metalloproteinase with thrombospondin motifs 16) as a BAV-causing gene and found the ADAMTS16 p. H357Q variant in an inherited BAV family. Both in situ hybridization and genetic tracing studies described a unique spatiotemporal pattern of ADAMTS16 expression during aortic valve development. Adamts16+/- and Adamts16+/H355Q mouse models both exhibited a right coronary cusp-noncoronary cusp fusion-type BAV phenotype, with progressive aortic valve thickening associated with raphe formation (fusion of the commissure). Further, ADAMTS16 deficiency in Tie2 lineage cells recapitulated the BAV phenotype. This was confirmed in lineage-tracing mouse models in which Adamts16 deficiency affected endothelial and second heart field cells, not the neural crest cells. Accordingly, the changes were mainly detected in the noncoronary and right coronary leaflets. Bulk RNA sequencing using inducible pluripotent stem cells-derived endothelial cells and genetic mouse embryonic heart tissue unveiled enhanced FAK (focal adhesion kinase) signaling, which was accompanied by elevated fibronectin levels. Both in vitro inducible pluripotent stem cells-derived endothelial cells culture and ex vivo embryonic outflow tract explant studies validated the altered FAK signaling. CONCLUSIONS: Our present study identified a novel BAV-causing ADAMTS16 p. H357Q variant. ADAMTS16 deficiency led to BAV formation.

Fractional Flow Reserve or Intravascular Ultrasonography to Guide PCI.

BACKGROUND: In patients with coronary artery disease who are being evaluated for percutaneous coronary intervention (PCI), procedures can be guided by fractional flow reserve (FFR) or intravascular ultrasonography (IVUS) for decision making regarding revascularization and stent implantation. However, the differences in clinical outcomes when only one method is used for both purposes are unclear. METHODS: We randomly assigned 1682 patients who were being evaluated for PCI for the treatment of intermediate stenosis (40 to 70% occlusion by visual estimation on coronary angiography) in a 1:1 ratio to undergo either an FFR-guided or IVUS-guided procedure. FFR or IVUS was to be used to determine whether to perform PCI and to assess PCI success. In the FFR group, PCI was to be performed if the FFR was 0.80 or less. In the IVUS group, the criteria for PCI were a minimal lumen area measuring either 3 mm2 or less or measuring 3 to 4 mm2 with a plaque burden of more than 70%. The primary outcome was a composite of death, myocardial infarction, or revascularization at 24 months after randomization. We tested the noninferiority of the FFR group as compared with the IVUS group (noninferiority margin, 2.5 percentage points). RESULTS: The frequency of PCI was 44.4% among patients in the FFR group and 65.3% among those in the IVUS group. At 24 months, a primary-outcome event had occurred in 8.1% of the patients in the FFR group and in 8.5% of those in the IVUS group (absolute difference, -0.4 percentage points; upper boundary of the one-sided 97.5% confidence interval, 2.2 percentage points; P = 0.01 for noninferiority). Patient-reported outcomes as reported on the Seattle Angina Questionnaire were similar in the two groups. CONCLUSIONS: In patients with intermediate stenosis who were being evaluated for PCI, FFR guidance was noninferior to IVUS guidance with respect to the composite primary outcome of death, myocardial infarction, or revascularization at 24 months. (Funded by Boston Scientific; FLAVOUR ClinicalTrials.gov number, NCT02673424.).

Reduced Mitochondrial Protein Translation Promotes Cardiomyocyte Proliferation and Heart Regeneration.

BACKGROUND: The importance of mitochondria in normal heart function are well recognized and recent studies have implicated changes in mitochondrial metabolism with some forms of heart disease. Previous studies demonstrated that knockdown of the mitochondrial ribosomal protein S5 (MRPS5) by small interfering RNA (siRNA) inhibits mitochondrial translation and thereby causes a mitonuclear protein imbalance. Therefore, we decided to examine the effects of MRPS5 loss and the role of these processes on cardiomyocyte proliferation. METHODS: We deleted a single allele of MRPS5 in mice and used left anterior descending coronary artery ligation surgery to induce myocardial damage in these animals. We examined cardiomyocyte proliferation and cardiac regeneration both in vivo and in vitro. Doxycycline treatment was used to inhibit protein translation. Heart function in mice was assessed by echocardiography. Quantitative real-time polymerase chain reaction and RNA sequencing were used to assess changes in transcription and chromatin immunoprecipitation (ChIP) and BioChIP were used to assess chromatin effects. Protein levels were assessed by Western blotting and cell proliferation or death by histology and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays. Adeno-associated virus was used to overexpress genes. The luciferase reporter assay was used to assess promoter activity. Mitochondrial oxygen consumption rate, ATP levels, and reactive oxygen species were also analyzed. RESULTS: We determined that deletion of a single allele of MRPS5 in mice results in elevated cardiomyocyte proliferation and cardiac regeneration; this observation correlates with improved cardiac function after induction of myocardial infarction. We identified ATF4 (activating transcription factor 4) as a key regulator of the mitochondrial stress response in cardiomyocytes from Mrps5+/- mice; furthermore, ATF4 regulates Knl1 (kinetochore scaffold 1) leading to an increase in cytokinesis during cardiomyocyte proliferation. The increased cardiomyocyte proliferation observed in Mrps5+/- mice was attenuated when one allele of Atf4 was deleted genetically (Mrps5+/-/Atf4+/-), resulting in the loss in the capacity for cardiac regeneration. Either MRPS5 inhibition (or as we also demonstrate, doxycycline treatment) activate a conserved regulatory mechanism that increases the proliferation of human induced pluripotent stem cell-derived cardiomyocytes. CONCLUSIONS: These data highlight a critical role for MRPS5/ATF4 in cardiomyocytes and an exciting new avenue of study for therapies to treat myocardial injury.

Mesenchymal stem cell-derived extracellular vesicles alleviate cervical cancer by delivering microRNA-331-3p to reduce LIM zinc finger domain containing 2 methylation in tumor cells.

The aim of this study is to investigate if extracellular vesicles (EVs) from bone marrow mesenchymal stem cells (BMSCs) deliver microRNA (miR)-331-3p to regulate LIM zinc finger domain containing 2 (LIMS2) methylation in cervical cancer cells. Cervical cancer cells were incubated with EVs from BMSCs with altered expression of miR-331-3p, DNA methyltransferase 3 alpha (DNMT3A) or/and LIMS2 and then subjected to 5-ethynyl-2'-deoxyuridine, Transwell, flow cytometry and western blotting analyses. Dual-luciferase reporter assay was conducted to verify the binding between miR-331-3p and DNMT3A. A xenograft model was established to evaluate the effect of BMSC-derived EV-miR-331-3p on cervical tumor growth. miR-331-3p was lowly and DNMT3A was highly expressed in cervical cancer. BMSC-derived EVs delivered miR-331-3p to control the behaviors of cervical cancer cells. miR-331-3p inhibited the expression of DNMT3A by binding DNMT3A mRNA. DNMT3A promoted LIMS2 methylation and reduced the expression of LIMS2. Overexpression of DNMT3A or silencing of LIMS2 in BMSCs counteracted the tumor suppressive effects of miR-331-3p. BMSC-derived EV-miR-331-3p also inhibited the growth of cervical tumors in vivo. BMSC-derived EVs alleviate cervical cancer partially by delivering miR-331-3p to reduce DNMT3A-dependent LIMS2 methylation in tumor cells.

AntDAS-GCMS: A New Comprehensive Data Analysis Platform for GC-MS-Based Untargeted Metabolomics with the Advantage of Addressing the Time Shift Problem.

Over the years, a number of state-of-the-art data analysis tools have been developed to provide a comprehensive analysis of data collected from gas chromatography-mass spectrometry (GC-MS). Unfortunately, the time shift problem remains unsolved in these tools. Here, we developed a novel comprehensive data analysis strategy for GC-MS-based untargeted metabolomics (AntDAS-GCMS) to perform total ion chromatogram peak detection, peak resolution, time shift correction, component registration, statistical analysis, and compound identification. Time shift correction was specifically optimized in this work. The information on mass spectra and elution profiles of compounds was used to search for inherent landmarks within analyzed samples to resolve the time shift problem across samples efficiently and accurately. The performance of our AntDAS-GCMS was comprehensively investigated by using four complex GC-MS data sets with various types of time shift problems. Meanwhile, AntDAS-GCMS was compared with advanced GC-MS data analysis tools and classic time shift correction methods. Results indicated that AntDAS-GCMS could achieve the best performance compared to the other methods.

Effect of Potential on the Nanostructure Dynamics of Ethylammonium Nitrate at a Graphite Electrode.

Video-rate atomic force microscopy (AFM) is used to study the near-surface nanostructure dynamics of the ionic liquid ethylammonium nitrate (EAN) at a highly oriented pyrolytic graphite (HOPG) electrode as a function of potential in real-time for the first time. The effects of varying the surface potential and adding 10 wt% water on the nanostructure diffusion coefficient are probed. For both EAN and the 90 wt% EAN-water mixture, disk-like features ≈9 nm in diameter and 1 nm in height form above the Stern layer at all potentials. The nanostructure diffusion coefficient increases with potential (from OCP -0.5 V to OCP +0.5 V) and with added water. Nanostructure dynamics depends on both the magnitude and direction of the potential change. Upon switching the potential from OCP -0.5 V to OCP +0.5 V, a substantial increase in the diffusion coefficients is observed, likely due to the absence of solvophobic interactions between the nitrate (NO3 - ) anions and the ethylammonium (EA+ ) cations in the near-surface region. When the potential is reversed, EA+ is attracted to the Stern layer to replace NO3 - , but its movement is hindered by solvophobic attractions. The outcomes will aid applications, including electrochemical devices, catalysts, and lubricants.

Nanostructure and Dynamics of Aprotic Ionic Liquids at Graphite Electrodes as a Function of Potential.

Atomic force microscope (AFM) videos reveal the near-surface nanostructure and dynamics of the ionic liquids (ILs) 1-butyl-3-methylimidazolium dicyanamide (BMIM DCA) and 1-hexyl-3-methylimidazolium dicyanamide (HMIM DCA) above highly oriented pyrolytic graphite (HOPG) electrodes as a function of surface potential. Molecular dynamics (MD) simulations reveal the molecular-level composition of the nanostructures. In combination, AFM and MD show that the near-surface aggregates form via solvophobic association of the cation alkyl chains at the electrode interface. The diffusion coefficients of interfacial nanostructures are ≈0.01 nm2 s-1 and vary with the cation alkyl chain length and the surface potential. For each IL, the nanostructure diffusion coefficients are similar at open-circuit potential (OCP) and OCP + 1V, but BMIM DCA moves about twice as fast as HMIM DCA. At negative potentials, the diffusion coefficient decreases for BMIM DCA and increases for HMIM DCA. When the surface potential is switched from negative to positive, a sudden change in the direction of the nanostructure motion is observed for both BMIM DCA and HMIM DCA. No transient dynamics are noted following other potential jumps. This study provides a new fundamental understanding regarding the dynamics of electrochemically stable ILs at electrodes vital for the rational development of IL-based electrochemical devices.

Comparison of downsizing strategy (HANGZHOU Solution) and standard annulus sizing strategy in type 0 bicuspid aortic stenosis patients undergoing transcatheter aortic valve replacement: Rationale and design of a randomized clinical trial.

BACKGROUND: There has not been a consensus on the prothesis sizing strategy in type 0 bicuspid aortic stenosis (AS) patients undergoing transcatheter aortic valve replacement (TAVR). Modifications to standard annular sizing strategies might be required due to the distinct anatomical characteristics. We have devised a downsizing strategy for TAVR using a self-expanding valve specifically for patients with type 0 bicuspid AS. The primary aim of this study is to compare the safety and efficacy of downsizing strategy with the Standard Annulus Sizing Strategy in TAVR for patients with type 0 bicuspid AS. TRIAL DESIGN: It is a prospective, multi-center, superiority, single-blinded, randomized controlled trial comparing the Down Sizing and Standard Annulus Sizing Strategy in patients with type 0 bicuspid aortic stenosis undergoing transcatheter aortic valve replacement. Eligible participants will include patients with severe type 0 bicuspid AS, as defined by criteria such as mean gradient across aortic valve ≥40 mmHg, peak aortic jet velocity ≥4.0 m/s, aortic valve area (AVA) ≤1.0 cm², or AVA index ≤0.6 cm2/m2. These patients will be randomly assigned, in a 1:1 ratio, to either the Down Sizing Strategy group or the Standard Sizing Strategy group. In the Down Sizing Strategy group, a valve one size smaller will be implanted if the "waist sign" manifests along with less than mild regurgitation during balloon pre-dilatation. The primary end point of the study is a composite of VARC-3 defined device success, absence of both permanent pacemaker implantation due to high-degree atrioventricular block and new-onset complete left bundle branch block. CONCLUSION: This study will compare the safety and efficacy of Down Sizing Strategy with the Standard Annulus Sizing Strategy and provide valuable insights into the optimal approach for sizing in TAVR patients with type 0 bicuspid AS. We hypothesize that the Down Sizing Strategy will demonstrate superiority when compared to the Standard Annulus Sizing Strategy. (Down Sizing Strategy (HANGZHOU Solution) vs Standard Sizing Strategy TAVR in Bicuspid Aortic Stenosis (Type 0) (TAILOR-TAVR), NCT05511792).

A modified Carpentier classification in transcatheter edge-to-edge repair for mitral regurgitation.

Mitral regurgitation (MR) is the most common heart valve disease, and transcatheter edge-to-edge repair (TEER) has been recommended as a therapy for severe MR patients by guidelines. The classic Carpentier classification used to guide surgical mitral valve repair but is inadequate for mitral TEER (M-TEER). We herein proposed a new modified Carpentier classification named after "type + segment," which is suitable for M-TEER. We shared our strategies in M-TEER procedure for screening and performing the M-TEER according to the new modified Carpentier classification.

Percutaneous left atrial appendage closure with SeaLA device in non-valvular atrial fibrillation.

OBJECTIVES: The clinical efficacy and safety of a novel left atrial appendage (LAA) occluder of the SeaLA closure system in patients with nonvalvular atrial fibrillation (NVAF) were reported. BACKGROUND: Patients with NVAF are at a higher risk of stroke compared to healthy individuals. Left atrial appendage closure (LAAC) has emerged as a prominent strategy for reducing the risk of thrombosis in individuals with NVAF. METHODS: A prospective, multicenter study was conducted in NVAF patients with a high risk of stroke. RESULTS: The LAAC was successfully performed in 163 patients. The mean age was 66.93 ± 7.92 years, with a mean preoperative CHA2DS2-VASc score of 4.17 ± 1.48. One patient with residual flow >3 mm was observed at the 6-month follow-up, confirmed by TEE. During the follow-up, 2 severe pericardiac effusions were noted, and 2 ischemic strokes were observed. Four device-related thromboses were resolved after anticoagulation treatment. There was no device embolism. CONCLUSIONS: The LAAC with the SeaLA device demonstrates encouraging feasibility, safety, and efficacy outcomes.

2024 Statement from Asia expert operators on transcatheter pulmonary valve replacement.

Transcatheter pulmonary valve replacement (TPVR), also known as percutaneous pulmonary valve implantation, refers to a minimally invasive technique that replaces the pulmonary valve by delivering an artificial pulmonary prosthesis through a catheter into the diseased pulmonary valve under the guidance of X-ray and/or echocardiogram while the heart is still beating not arrested. In recent years, TPVR has achieved remarkable progress in device development, evidence-based medicine proof and clinical experience. To update the knowledge of TPVR in a timely fashion, and according to the latest research and further facilitate the standardized and healthy development of TPVR in Asia, we have updated this consensus statement. After systematical review of the relevant literature with an in-depth analysis of eight main issues, we finally established eight core viewpoints, including indication recommendation, device selection, perioperative evaluation, procedure precautions, and prevention and treatment of complications.

Flavin Containing Monooxygenase 2 Prevents Cardiac Fibrosis via CYP2J3-SMURF2 Axis.

BACKGROUND: Cardiac fibrosis is a common pathological feature associated with adverse clinical outcome in postinjury remodeling and has no effective therapy. Using an unbiased transcriptome analysis, we identified FMO2 (flavin-containing monooxygenase 2) as a top-ranked gene dynamically expressed following myocardial infarction (MI) in hearts across different species including rodents, nonhuman primates, and human. However, the functional role of FMO2 in cardiac remodeling is largely unknown. METHODS: Single-nuclei transcriptome analysis was performed to identify FMO2 after MI; FMO2 ablation rats were generated both in genetic level using the CRISPR-cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) technology and lentivirus-mediated manner. Gain-of-function experiments were conducted using postn-promoter FMO2, miR1a/miR133a-FMO2 lentivirus, and enzymatic activity mutant FMO2 lentivirus after MI. RESULTS: A significant downregulation of FMO2 was consistently observed in hearts after MI in rodents, nonhuman primates, and patients. Single-nuclei transcriptome analysis showed cardiac expression of FMO2 was enriched in fibroblasts rather than myocytes. Elevated spontaneous tissue fibrosis was observed in the FMO2-null animals without external stress. In contrast, fibroblast-specific expression of FMO2 markedly reduced cardiac fibrosis following MI in rodents and nonhuman primates associated with diminished SMAD2/3 phosphorylation. Unexpectedly, the FMO2-mediated regulation in fibrosis and SMAD2/3 signaling was independent of its enzymatic activity. Rather, FMO2 was detected to interact with CYP2J3 (cytochrome p450 superfamily 2J3). Binding of FMO2 to CYP2J3 disrupted CYP2J3 interaction with SMURF2 (SMAD-specific E3 ubiquitin ligase 2) in cytosol, leading to increased cytoplasm to nuclear translocation of SMURF2 and consequent inhibition of SMAD2/3 signaling. CONCLUSIONS: Loss of FMO2 is a conserved molecular signature in postinjury hearts. FMO2 possesses a previously uncharacterized enzyme-independent antifibrosis activity via the CYP2J3-SMURF2 axis. Restoring FMO2 expression exerts potent ameliorative effect against fibrotic remodeling in postinjury hearts from rodents to nonhuman primates. Therefore, FMO2 is a potential therapeutic target for treating cardiac fibrosis following injury.

Tolterodine ameliorates inflammatory response and ferroptosis against LPS in human bladder epithelial cells.

Bacterial endotoxin lipopolysaccharide (LPS)-induced inflammatory response and ferroptosis play an important role in urinary tract infections. Tolterodine has been used as a urinary tract antispasmodic and anticholinergic agent. However, the effects of Tolterodine against LPS-induced insults in human bladder epithelial cells (hBECs) have not been reported before. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase release assays to determine the cell viability, reactive oxygen species (ROS) and malondialdehyde level detection were used to determine the level of oxidative stress, enzyme-linked immunosorbent assay and Western blot analysis were used to detect the protein level. In the current study, we found that Tolterodine ameliorated LPS-induced production of ROS and lipid oxidation in hBECs. Interestingly, Tolterodine inhibited the production of interleukin 6, interleukin-1ß, and tumor necrosis factor α. Also, Tolterodine reduced the levels of Fe2+ and suppressed ferroptosis by reducing the levels of glutathione peroxidase 4, prostaglandin-endoperoxide synthase 2, and acyl-CoA synthetase long-chain family member 4 in LPS-challenged bladder epithelial cells. Mechanistically, it was shown that Tolterodine restored the nuclear factor E2-related factor 2 (Nrf2)/nuclear factor-κB signaling. Importantly, inhibition of Nrf2 with its specific inhibitor ML385 abolished the protective effects of Tolterodine in the inflammatory response and ferroptosis, suggesting that the effects of Tolterodine are mediated by Nrf2. Based on these findings, we conclude that Tolterodine might serve as a promising agent for the treatment of LPS-induced bladder inflammation.

Hesperetin derivative 2a inhibits lipopolysaccharide-induced acute liver injury in mice via downregulation of circDcbld2.

Acute liver injury (ALI) is a complex, life-threatening inflammatory liver disease, and persistent liver damage leads to rapid decline and even failure of liver function. However, the pathogenesis of ALI is still not fully understood, and no effective treatment has been discovered. Recent evidence shows that many circular RNAs (circRNAs) are associated with the occurrence of liver diseases. In this study we investigated the mechanisms of occurrence and development of ALI in lipopolysaccharide (LPS)-induced ALI mice. We found that expression of the circular RNA circDcbld2 was significantly elevated in the liver tissues of ALI mice and LPS-treated RAW264.7 cells. Knockdown of circDcbld2 markedly alleviates LPS-induced inflammatory responses in ALI mice and RAW264.7 cells. We designed and synthesized a series of hesperidin derivatives for circDcbld2, and found that hesperetin derivative 2a (HD-2a) at the concentrations of 2, 4, 8 µM effectively inhibited circDcbld2 expression in RAW264.7 cells. Administration of HD-2a (50, 100, 200 mg/kg. i.g., once 24 h in advance) effectively relieved LPS-induced liver dysfunction and inflammatory responses. RNA sequencing analysis revealed that the anti-inflammatory and hepatoprotective effects of HD-2a were mediated through downregulating circDcbld2 and suppressing the JAK2/STAT3 pathway. We conclude that HD-2a downregulates circDcbld2 to inhibit the JAK2/STAT3 pathway, thereby inhibiting the inflammatory responses in ALI. The results suggest that circDcbld2 may be a potential target for the prevention and treatment of ALI, and HD-2a may have potential as a drug for the treatment of ALI.

The effects of pre-cue posterior alpha on post-cue alpha activity and target processing in visual spatial attention tasks with instructional and probabilistic cues.

The electroencephalography alpha-band (8-13 Hz) activity may represent a crucial neural substrate of visual spatial attention. However, factors likely contributing to alpha activity have not been adequately addressed, which impedes understanding its functional roles. We investigated whether pre-cue alpha power was associated with post-cue alpha activity in 2 independent experiments (n = 30 each) with different cueing strategies (instructional vs. probabilistic) by median-splitting subjects (between-subject) or trials (within-subject) according to pre-cue alpha. In both experiments, only subjects with higher pre-cue alpha showed significant post-cue alpha desynchronization and alpha lateralization, while whether trials had higher or lower pre-cue alpha affected post-cue alpha desynchronization but not alpha lateralization. Furthermore, significant attentional modulation of target processing indexed by N1 component was observed in subjects and trials regardless of higher or lower pre-cue alpha in the instructional cueing experiment. While in the probabilistic cueing experiment, N1 attentional modulation was only observed in higher pre-cue alpha subjects and lower pre-cue alpha trials. In summary, by demonstrating the effects of pre-cue alpha and cueing strategy on post-cue alpha activity and target processing, our results suggest the necessity of considering these 2 contributing factors when investigating the functional roles of alpha activity in visual spatial attention.

Cardiovascular diseases burden attributable to ambient PM2.5 pollution from 1990 to 2019: A systematic analysis for the global burden of disease study 2019.

BACKGROUND: Ambient PM2.5 pollution (APMP2.5) was the leading environmental risk factor for cardiovascular diseases (CVDs) worldwide. An up-to-date comprehensive study is needed to provide global epidemiological patterns. METHODS: Detailed data on CVDs burden attributable to APMP2.5 were obtained from the Global Burden of Disease Study (GBD) 2019. We calculated the estimated annual percentage change (EAPC) to assess temporal trends in age-standardized rates of deaths and disability-adjusted life years (DALYs) over 30 years. RESULTS: Globally, CVDs attributable to APMP2.5 resulted in 2.48 million deaths and 60.91 million DALYs, with an increase of 122%, respectively from 1990 to 2019. In general, men suffered markedly higher burden than women, but the gap will likely turn narrow. As for age distribution, CVDs deaths and DALYs attributable to APMP2.5 mainly occurred in the elder group (>70 years). Low- and middle-income regions endured the higher CVDs burden due to the higher exposure to APMP2.5, and the gap may potentially expand further compared with high-income regions. For regions, the highest age-standardized rates of APMP2.5-related CVDs deaths and DALYs were observed mainly in Central Asia, while the lowest was observed in Australasia. At the national level, countries with the largest ASDR decline were clustered in western Europe, while Equatorial Guinea, Timor-Leste and Bhutan exhibited relatively rapid increases over this period. CONCLUSIONS: The global CVDs burden attributable to APMP2.5 has contributed to the heterogeneity of spatial and temporal distribution. APMP2.5-related CVDs deaths have largely shifted from higher SDI regions to those with a lower SDI. Globally, APMP2.5-attributable CVDs pose a significant threat to public health and diseases burden has increased over time, particularly in male, old-aged populations. The governments and health systems should take measures to reduce air pollution to impede this rising trend.

Genetic and pharmacological inhibition of GRPR protects against acute kidney injury via attenuating renal inflammation and necroptosis.

Gastrin-releasing peptide (GRP) binds to its receptor (GRP receptor [GRPR]) to regulate multiple biological processes, but the function of GRP/GRPR axis in acute kidney injury (AKI) remains unknown. In the present study, GRPR is highly expressed by tubular epithelial cells (TECs) in patients or mice with AKI, while histone deacetylase 8 may lead to the transcriptional activation of GRPR. Functionally, we uncovered that GRPR was pathogenic in AKI, as genetic deletion of GRPR was able to protect mice from cisplatin- and ischemia-induced AKI. This was further confirmed by specifically deleting the GRPR gene from TECs in GRPRFlox/Flox//KspCre mice. Mechanistically, we uncovered that GRPR was able to interact with Toll-like receptor 4 to activate STAT1 that bound the promoter of MLKL and CCL2 to induce TEC necroptosis, necroinflammation, and macrophages recruitment. This was further confirmed by overexpressing STAT1 to restore renal injury in GRPRFlox/Flox/KspCre mice. Concurrently, STAT1 induced GRP synthesis to enforce the GRP/GRPR/STAT1 positive feedback loop. Importantly, targeting GRPR by lentivirus-packaged small hairpin RNA or by treatment with a novel GRPR antagonist RH-1402 was able to inhibit cisplatin-induced AKI. In conclusion, GRPR is pathogenic in AKI and mediates AKI via the STAT1-dependent mechanism. Thus, targeting GRPR may be a novel therapeutic strategy for AKI.