Circadian Rhythms in Cardiovascular Metabolism.

Energetic demand and nutrient supply fluctuate as a function of time-of-day, in alignment with sleep-wake and fasting-feeding cycles. These daily rhythms are mirrored by 24-hour oscillations in numerous cardiovascular functional parameters, including blood pressure, heart rate, and myocardial contractility. It is, therefore, not surprising that metabolic processes also fluctuate over the course of the day, to ensure temporal needs for ATP, building blocks, and metabolism-based signaling molecules are met. What has become increasingly clear is that in addition to classic signal-response coupling (termed reactionary mechanisms), cardiovascular-relevant cells use autonomous circadian clocks to temporally orchestrate metabolic pathways in preparation for predicted stimuli/stresses (termed anticipatory mechanisms). Here, we review current knowledge regarding circadian regulation of metabolism, how metabolic rhythms are synchronized with cardiovascular function, and whether circadian misalignment/disruption of metabolic processes contribute toward the pathogenesis of cardiovascular disease.

The structure of NAD+ consuming protein Acinetobacter baumannii TIR domain shows unique kinetics and conformations.

Toll-like and interleukin-1/18 receptor/resistance (TIR) domain-containing proteins function as important signaling and immune regulatory molecules. TIR domain-containing proteins identified in eukaryotic and prokaryotic species also exhibit NAD+ hydrolase activity in select bacteria, plants, and mammalian cells. We report the crystal structure of the Acinetobacter baumannii TIR domain protein (AbTir-TIR) with confirmed NAD+ hydrolysis and map the conformational effects of its interaction with NAD+ using hydrogen-deuterium exchange-mass spectrometry. NAD+ results in mild decreases in deuterium uptake at the dimeric interface. In addition, AbTir-TIR exhibits EX1 kinetics indicative of large cooperative conformational changes, which are slowed down upon substrate binding. Additionally, we have developed label-free imaging using the minimally invasive spectroscopic method 2-photon excitation with fluorescence lifetime imaging, which shows differences in bacteria expressing native and mutant NAD+ hydrolase-inactivated AbTir-TIRE208A protein. Our observations are consistent with substrate-induced conformational changes reported in other TIR model systems with NAD+ hydrolase activity. These studies provide further insight into bacterial TIR protein mechanisms and their varying roles in biology.

Nitrative Modification of Caveolin-3: A Novel Mechanism of Cardiac Insulin Resistance and a Potential Therapeutic Target Against Ischemic Heart Failure in Prediabetic Animals.

BACKGROUND: Myocardial insulin resistance is a hallmark of diabetic cardiac injury. However, the underlying molecular mechanisms remain unclear. Recent studies demonstrate that the diabetic heart is resistant to other cardioprotective interventions, including adiponectin and preconditioning. The "universal" resistance to multiple therapeutic interventions suggests impairment of the requisite molecule(s) involved in broad prosurvival signaling cascades. Cav (Caveolin) is a scaffolding protein coordinating transmembrane signaling transduction. However, the role of Cav3 in diabetic impairment of cardiac protective signaling and diabetic ischemic heart failure is unknown. METHODS: Wild-type and gene-manipulated mice were fed a normal diet or high-fat diet for 2 to 12 weeks and subjected to myocardial ischemia and reperfusion. Insulin cardioprotection was determined. RESULTS: Compared with the normal diet group, the cardioprotective effect of insulin was significantly blunted as early as 4 weeks of high-fat diet feeding (prediabetes), a time point where expression levels of insulin-signaling molecules remained unchanged. However, Cav3/insulin receptor-ß complex formation was significantly reduced. Among multiple posttranslational modifications altering protein/protein interaction, Cav3 (not insulin receptor-ß) tyrosine nitration is prominent in the prediabetic heart. Treatment of cardiomyocytes with 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride reduced the signalsome complex and blocked insulin transmembrane signaling. Mass spectrometry identified Tyr73 as the Cav3 nitration site. Phenylalanine substitution of Tyr73 (Cav3Y73F) abolished 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride-induced Cav3 nitration, restored Cav3/insulin receptor-ß complex, and rescued insulin transmembrane signaling. It is most important that adeno-associated virus 9-mediated cardiomyocyte-specific Cav3Y73F reexpression blocked high-fat diet-induced Cav3 nitration, preserved Cav3 signalsome integrity, restored transmembrane signaling, and rescued insulin-protective action against ischemic heart failure. Last, diabetic nitrative modification of Cav3 at Tyr73 also reduced Cav3/AdipoR1 complex formation and blocked adiponectin cardioprotective signaling. CONCLUSIONS: Nitration of Cav3 at Tyr73 and resultant signal complex dissociation results in cardiac insulin/adiponectin resistance in the prediabetic heart, contributing to ischemic heart failure progression. Early interventions preserving Cav3-centered signalsome integrity is an effective novel strategy against diabetic exacerbation of ischemic heart failure.

Enhanced Thermoelectric Performance of N-Type PbSe Through Semi-Coherent Nanostructure by AgCuTe Alloying.

N-type PbSe thermoelectric materials encounter challenges in improving the power factor due to the single-band structure near the Fermi level, which obstructs typical band convergence. The primary strategy for enhancing the thermoelectric figure of merit (ZT) for n-type PbSe involves reducing lattice thermal conductivity (κlat) by introducing various defect structures. However, lattice mismatches resulting from internal defects within the matrix can diminish carrier mobility, thereby affecting electrical transport properties. In this study, n-type AgCuTe-alloyed PbSe systems achieve a peak ZT value of ≈1.5 at 773 K. Transmission electron microscopy reveals nanoprecipitates of Ag2Te, the room temperature second phase of AgCuTe, within the PbSe matrix. Meanwhile, a unique semi-coherent phase boundary is observed between the PbSe matrix and the Ag2Te nanoprecipitates. This semi-coherent phase interface effectively scatters low-frequency phonons while minimizing damage to carrier mobility. Additionally, the dynamic doping effect of Cu atoms from the decomposition of AgCuTe within the matrix further optimize the high-temperature thermoelectric performance. Overall, these factors significantly enhance the ZT across the whole temperature range. The ZT value of ≈1.5 indicates high competitiveness compared to the latest reported n-type PbSe materials, suggesting that these findings hold promise for advancing the development of efficient thermoelectric systems.

Ultra-high Q resonances based on zero group-velocity modes accompanied by bound states in the continuum in 2D photonic crystal slabs.

Optical resonators made of 2D photonic crystal (PhC) slabs provide efficient ways to manipulate light at the nanoscale through small group-velocity modes with low radiation losses. The resonant modes in periodic photonic lattices are predominantly limited by nonleaky guided modes at the boundary of the Brillouin zone below the light cone. Here, we propose a mechanism for ultra-high Q resonators based on the bound states in the continuum (BICs) above the light cone that have zero-group velocity (ZGV) at an arbitrary Bloch wavevector. By means of the mode expansion method, the construction and evolution of avoided crossings and Friedrich-Wintgen BICs are theoretically investigated at the same time. By tuning geometric parameters of the PhC slab, the coalescence of eigenfrequencies for a pair of BIC and ZGV modes is achieved, indicating that the waveguide modes are confined longitudinally by small group-velocity propagation and transversely by BICs. Using this mechanism, we engineer ultra-high Q nanoscale resonators that can significantly suppress the radiative losses, despite the operating frequencies above the light cone and the momenta at the generic k point. Our work suggests that the designed devices possess potential applications in low-threshold lasers and enhanced nonlinear effects.

Targeting Adiponectin Receptor 1 Phosphorylation Against Ischemic Heart Failure.

BACKGROUND: Despite significantly reduced acute myocardial infarction (MI) mortality in recent years, ischemic heart failure continues to escalate. Therapeutic interventions effectively reversing pathological remodeling are an urgent unmet medical need. We recently demonstrated that AdipoR1 (APN [adiponectin] receptor 1) phosphorylation by GRK2 (G-protein-coupled receptor kinase 2) contributes to maladaptive remodeling in the ischemic heart. The current study clarified the underlying mechanisms leading to AdipoR1 phosphorylative desensitization and investigated whether blocking AdipoR1 phosphorylation may restore its protective signaling, reversing post-MI remodeling. METHODS: Specific sites and underlying molecular mechanisms responsible for AdipoR1 phosphorylative desensitization were investigated in vitro (neonatal and adult cardiomyocytes). The effects of AdipoR1 phosphorylation inhibition upon APN post-MI remodeling and heart failure progression were investigated in vivo. RESULTS: Among 4 previously identified sites sensitive to GRK2 phosphorylation, alanine substitution of Ser205 (AdipoR1S205A), but not other 3 sites, rescued GRK2-suppressed AdipoR1 functions, restoring APN-induced cell salvage kinase activation and reducing oxidative cell death. The molecular investigation followed by functional determination demonstrated that AdipoR1 phosphorylation promoted clathrin-dependent (not caveolae) endocytosis and lysosomal-mediated (not proteasome) degradation, reducing AdipoR1 protein level and suppressing AdipoR1-mediated cytoprotective action. GRK2-induced AdipoR1 endocytosis and degradation were blocked by AdipoR1S205A overexpression. Moreover, AdipoR1S205E (pseudophosphorylation) phenocopied GRK2 effects, promoted AdipoR1 endocytosis and degradation, and inhibited AdipoR1 biological function. Most importantly, AdipoR1 function was preserved during heart failure development in AdipoR1-KO (AdipoR1 knockout) mice reexpressing hAdipoR1S205A. APN administration in the failing heart reversed post-MI remodeling and improved cardiac function. However, reexpressing hAdipoR1WT in AdipoR1-KO mice failed to restore APN cardioprotection. CONCLUSIONS: Ser205 is responsible for AdipoR1 phosphorylative desensitization in the failing heart. Blockade of AdipoR1 phosphorylation followed by pharmacological APN administration is a novel therapy effective in reversing post-MI remodeling and mitigating heart failure progression.

Ischemic Heart-Derived Small Extracellular Vesicles Impair Adipocyte Function.

BACKGROUND: Patients with acute myocardial infarction suffer systemic metabolic dysfunction via incompletely understood mechanisms. Adipocytes play critical role in metabolic homeostasis. The impact of acute myocardial infarction upon adipocyte function is unclear. Small extracellular vesicles (sEVs) critically contribute to organ-organ communication. Whether and how small extracellular vesicle mediate post-MI cardiomyocyte/adipocyte communication remain unknown. METHODS: Plasma sEVs were isolated from sham control (Pla-sEVSham) or 3 hours after myocardial ischemia/reperfusion (Pla-sEVMI/R) and incubated with adipocytes for 24 hours. Compared with Pla-sEVSham, Pla-sEVMI/R significantly altered expression of genes known to be important in adipocyte function, including a well-known metabolic regulatory/cardioprotective adipokine, APN (adiponectin). Pla-sEVMI/R activated 2 (PERK-CHOP and ATF6 [transcription factor 6]-EDEM [ER degradation enhancing alpha-mannosidase like protein 1] pathways) of the 3 endoplasmic reticulum (ER) stress pathways in adipocytes. These pathological alterations were also observed in adipocytes treated with sEVs isolated from adult cardiomyocytes subjected to in vivo myocardial ischemia/reperfusion (MI/R) (Myo-sEVMI/R). Bioinformatic/RT-qPCR analysis demonstrates that the members of miR-23-27-24 cluster are significantly increased in Pla-sEVMI/R, Myo-sEVMI/R, and adipose tissue of MI/R animals. Administration of cardiomyocyte-specific miR-23-27-24 sponges abolished adipocyte miR-23-27-24 elevation in MI/R animals, supporting the cardiomyocyte origin of adipocyte miR-23-27-24 cluster. In similar fashion to Myo-sEVMI/R, a miR-27a mimic activated PERK-CHOP and ATF6-EDEM-mediated ER stress. Conversely, a miR-27a inhibitor significantly attenuated Myo-sEVMI/R-induced ER stress and restored APN production. RESULTS: An unbiased approach identified EDEM3 (ER degradation enhancing alpha-mannosidase like protein 3) as a novel downstream target of miR-27a. Adipocyte EDEM3 deficiency phenocopied multiple pathological alterations caused by Myo-sEVMI/R, whereas EDEM3 overexpression attenuated Myo-sEVMI/R-resulted ER stress. Finally, administration of GW4869 or cardiomyocyte-specific miR-23-27-24 cluster sponges attenuated adipocyte ER stress, improved adipocyte endocrine function, and restored plasma APN levels in MI/R animals. CONCLUSIONS: We demonstrate for the first time that MI/R causes significant adipocyte ER stress and endocrine dysfunction by releasing miR-23-27-24 cluster-enriched small extracellular vesicle. Targeting small extracellular vesicle-mediated cardiomyocyte-adipocyte pathological communication may be of therapeutic potential to prevent metabolic dysfunction after MI/R.

Diffusion-/perfusion-weighted imaging fusion to automatically identify stroke within 4.5 h.

OBJECTIVES: We aimed to develop machine learning (ML) models based on diffusion- and perfusion-weighted imaging fusion (DP fusion) for identifying stroke within 4.5 h, to compare them with DWI- and/or PWI-based ML models, and to construct an automatic segmentation-classification model and compare with manual labeling methods. METHODS: ML models were developed from multimodal MRI datasets of acute stroke patients within 24 h of clear symptom onset from two centers. The processes included manual segmentation, registration, DP fusion, feature extraction, and model establishment (logistic regression (LR) and support vector machine (SVM)). A segmentation-classification model (X-Net) was proposed for automatically identifying stroke within 4.5 h. The area under the receiver operating characteristic curve (AUC), sensitivity, Dice coefficients, decision curve analysis, and calibration curves were used to evaluate model performance. RESULTS: A total of 418 patients (≤ 4.5 h: 214; > 4.5 h: 204) were evaluated. The DP fusion model achieved the highest AUC in identifying the onset time in the training (LR: 0.95; SVM: 0.92) and test sets (LR: 0.91; SVM: 0.90). The DP fusion-LR model displayed consistent positive and greater net benefits than other models across a broad range of risk thresholds. The calibration curve demonstrated the good calibration of the DP fusion-LR model (average absolute error: 0.049). The X-Net model obtained the highest Dice coefficients (DWI: 0.81; Tmax: 0.83) and achieved similar performance to manual labeling (AUC: 0.84). CONCLUSIONS: The automatic segmentation-classification models based on DWI and PWI fusion images had high performance in identifying stroke within 4.5 h. CLINICAL RELEVANCE STATEMENT: Perfusion-weighted imaging (PWI) fusion images had high performance in identifying stroke within 4.5 h. The automatic segmentation-classification models based on DWI and PWI fusion images could provide clinicians with decision-making guidance for acute stroke patients with unknown onset time. KEY POINTS: • The diffusion/perfusion-weighted imaging fusion model had the best performance in identifying stroke within 4.5 h. • The X-Net model had the highest Dice and achieved performance close to manual labeling in segmenting lesions of acute stroke. • The automatic segmentation-classification model based on DP fusion images performed well in identifying stroke within 4.5 h.

Dysfunctional APPL1-Mediated Epigenetic Regulation in Diabetic Vascular Injury.

BACKGROUND: APN (adiponectin) and APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) are potent vasculoprotective molecules, and their deficiency (eg, hypoadiponectinemia) contributes to diabetic vascular complications. However, the molecular mechanisms that govern their vasculoprotective genes as well as their alteration by diabetes remain unknown. METHODS: Diabetic medium-cultured rat aortic endothelial cells, mouse aortic endothelial cells from high-fat-diet animals, and diabetic human aortic endothelial cells were used for molecular/cellular investigations. The in vivo concept-prove demonstration was conducted using diabetic vascular injury and diabetic hindlimb ischemia models. RESULTS: In vivo animal experiments showed that APN replenishment caused APPL1 nuclear translocation, resulting in an interaction with HDAC (histone deacetylase) 2, which inhibited HDAC2 activity and increased H3Kac27 levels. Based on transcriptionome pathway-specific real-time polymerase chain reaction profiling and bioinformatics analysis, Angpt1 (angiopoietin 1), Ocln (occludin), and Cav1 (caveolin 1) were found to be the top 3 vasculoprotective genes suppressed by diabetes and rescued by APN in an APPL1-dependent manner. APN reverses diabetes-induced inhibition of Cav1 interaction with APPL1. APN-induced Cav1 expression was not affected by Angpt1 or Ocln deficiency, whereas APN-induced APPL1 nuclear translocation or upregulation of Angpt1/Ocln expression was abolished in the absence of Cav1 both in vivo and in vitro, suggesting Cav1 is upstream molecule of Angpt1/Ocln in response to APN administration. Chromatin immunoprecipitation-qPCR (quantitative polymerase chain reaction) demonstrated that APN caused significant enrichment of H3K27ac in Angpt1 and Ocln promoter region, an effect blocked by APPL1/Cav1 knockdown or HDAC2 overexpression. The protective effects of APN on the vascular system were attenuated by overexpression of HDAC2 and abolished by knocking out APPL1 or Cav1. The double knockdown of ANGPT1/OCLN blunted APN vascular protection both in vitro and in vivo. Furthermore, in diabetic human endothelial cells, HDAC2 activity is increased, H3 acetylation is decreased, and ANGPT1/OCLN expression is reduced, suggesting that the findings have important translational implications. CONCLUSIONS: Hypoadiponectinemia and dysregulation of APPL1-mediated epigenetic regulation are novel mechanisms leading to diabetes-induced suppression of vasculoprotective gene expression. Diabetes-induced pathological vascular remodeling may be prevented by interventions promoting APPL1 nuclear translocation and inhibiting HDAC2.

Targeting Cancer Mitochondria by Inducing an Abnormal Mitochondrial Unfolded Protein Response Leads to Tumor Suppression.

The mitochondrial unfolded protein response (UPRmt) is a pivotal cellular mechanism that ensures mitochondrial homeostasis and cellular survival under stress conditions. This study investigates the role of UPRmt in modulating the response of nasopharyngeal carcinoma cells to cisplatin-induced stress. We report that the inhibition of UPRmt via AEB5F exacerbates cisplatin cytotoxicity, as evidenced by increased lactate dehydrogenase (LDH) release and apoptosis, characterized by a surge in TUNEL-positive cells. Conversely, the activation of UPRmt with oligomycin attenuates these effects, preserving cell viability and reducing apoptotic markers. Immunofluorescence assays reveal that UPRmt activation maintains mitochondrial membrane potential and ATP production in the presence of cisplatin, countering the rise in reactive oxygen species (ROS) and inhibiting caspase-9 activation. These findings suggest that UPRmt serves as a cytoprotective mechanism in cancer cells, mitigating cisplatin-induced mitochondrial dysfunction and apoptosis. The data underscore the therapeutic potential of modulating UPRmt to improve the efficacy and reduce the side effects of cisplatin chemotherapy. This study provides a foundation for future research on the exploitation of UPRmt in cancer treatment, with the aim of enhancing patient outcomes by leveraging the cellular stress response pathways.

Role of Emerin in regulating fibroblast differentiation and migration at the substrate of stiffness coupled topology.

In hypertrophic scars, the differentiation and migration of fibroblasts are influenced by the extracellular matrix microenvironment, which includes factors such as stiffness, restraint, and tensile force. These mechanical stresses incite alterations in cell behavior, accompanied by cytoskeletal protein reorganization. However, the role of nucleo-skeletal proteins in this context remains underexplored. In this study, we use a polyacrylamide hydrogel (PAA) to simulate the mechanical stress experienced by cells in scar tissue and investigate the impact of Emerin on cell behavior. We utilize atomic force microscopy (AFM) and RNA interference technology to analyze cell differentiation, migration, and stiffness. Our findings reveal that rigid substrates and cellular restriction elevate Emerin expression and diminish differentiation. Conversely, reducing Emerin expression leads to attenuated cell differentiation, where stiffness and constraining factors exert no notable influence. Furthermore, a softening of cells and an enhanced migration rate are also markedly observed. These observations indicate that variations in nuclear skeletal proteins, prompted by diverse matrix microenvironments, play a pivotal role in the pathogenesis of hypertrophic scars (HSs). This research offers novel insights and a reference point for understanding scar fibrosis formation mechanisms and preventing fibrosis.

Design, synthesis, and in vitro gene transfer efficacy of novel ionizable cholesterol derivatives.

ABSTACTThe medicinal properties of genetic drugs are highly dependent on the design of delivery systems. Ionizable cationic lipids are considered core materials in delivery systems. However, there has not yet been a widespread consensus on the relationship between the wide diversity of lipid structure design and gene delivery efficiency. The aims of the research work were to synthesize ionizable cholesterol derivatives (iChol-lipids) and to evaluate their potential applications as gene delivery vector. A series of iChol-lipids with different head groups were synthesized with carbamate bond spacer. The chemical structures were characterized by 1H NMR, MS, melting range, and pKa. The interactions between iChol-lipids and MALAT1-siRNA were studied by molecular dynamics simulations and compared with market available DC-Chol, which revealed that hydrogen bonds, salt-bridge, and electrostatic interaction were probably involved. The self-assemble behaviors of these lipids were intensively investigated and evaluated by dynamic laser scattering in the presence of different helper lipids and PEGylated lipids. Their plasmid binding ability, transfection efficiency, hemolytic toxicity, and cytotoxicity were fully studied. IZ-Chol-LNPs was proved to be highly potential to effectively complex with DNA, and endosome escape mechanisms mediated by proton sponge effect was verified by pH-sensitive fluorescence probe BCFL.

Global integrative meta-analysis of the responses in soil organic carbon stock to biochar amendment.

Applying biochar to soil has been recognized as a promising practice of climate-smart agriculture, with considerable potential in enhancing soil organic carbon (SOC) sequestration. Previous studies showed that biochar-induced increases in SOC stock varied substantially among experiments, while the explanatory factors responsible for such variability are still not well assessed. Here, we conducted an integrative meta-analysis of the magnitude and efficiency of biochar-induced change in SOC stock, using a database including 476 field measurements at 101 sites across the globe. Biochar amendment increased SOC stock by 6.13 ± 1.62 (95% confidence interval, CI) and 7.01 ± 1.11 (95% CI) Mg C ha-1, respectively, compared to their unfertilized (R0) and mineral nitrogen (N) fertilized (Rn) references. Of which approx. 52% (R0) and 50% (Rn) were contributed directly by biochar-C input. Corresponding biochar carbon efficiencies in R0 and Rn datasets were estimated as 58.20 ± 10.37% and 65.58 ± 9.26% (95% CI), respectively. The change magnitude of SOC stock increased significantly (p < 0.01) with the increasing amount of biochar-C input, while carbon efficiency of biochar showed an opposite trend. Biochar amendment sequestered larger amounts of SOC with higher efficiency in acidic and loamy soils than in alkaline and sandy soils. Biochar amendments with higher C/N ratio caused higher SOC increase than those with lower C/N ratio. Random forest (RF) algorithm showed that accumulative biochar-C input, soil pH, and biochar C/N ratio were the three most-important factors regulating the SOC stock responses. Overall, these results suggest that applying high C/N ratio biochar in acidic soils is a recommendable agricultural practice from the perspective of enhancing organic carbon.

Synergistic Ag/g-C3N4 H2O2 System for Photocatalytic Degradation of Azo Dyes.

Graphitic carbon nitride (g-C3N4), known for being nontoxic, highly stable, and environmentally friendly, is extensively used in photocatalytic degradation technologies. Silver nanoparticles effectively capture the photogenerated electrons in g-C3N4, enhancing the photocatalytic efficiency. This study primarily focused on synthesizing graphitic carbon nitride via thermal polymerization and depositing noble metal silver onto g-C3N4 through photoreduction. Methyl orange (MO) and methylene blue (MB) were targeted as the pollutants in the photocatalytic experiments under visible light in conjunction with a H2O2 system. The characteristics peaks, structure, and morphology were analyzed using Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), and scanning electron microscopy (SEM). g-C3N4 loaded with 6% Ag exhibited superior photocatalytic performance; the photocatalytic fraction of the degraded materials of the MO and MB solutions reached 100% within 70 and 80 min, respectively, upon adding 1 mL and 2 mL of H2O2. ·OH and ·O2- were the primary active free radicals in the dye degradation process within the synergistic system. Stability tests also demonstrated that the photocatalyst maintained good reusability under the synergistic system.

Monson's sphere in Chinese young adult females with individual normal occlusion: a preliminary study using digital models.

BACKGROUND: This study investigated the characteristics of Monson's sphere in Chinese young adult females with individual normal occlusion to provide a reference for oral rehabilitation in prosthodontic and orthodontic treatments. METHODS: Points at the dental cusps and incisal edges were selected from 51 digital mandibular dental models of Chinese young adult females (aged 18-22 years) with individual normal occlusion. Monson's spheres were fitted to the selected points based on the least-squares principle and the radii were calculated. The deviation of each selected point from its relative spherical surface was also calculated. The radii and deviations of these points were examined using conventional descriptive statistics and distributions of the most deviated points inside and outside the spheres were analyzed. RESULTS: The mean radius of Monson's sphere in Chinese young adult females was 79.60 ± 14.13 mm. The deviation of each selected point from its relative sphere surface was 0.38 ± 0.30 mm. The maximum deviations inside and outside the sphere were 0.93 ± 0.25 mm and 0.95 ± 0.30 mm, respectively. The most deviated points outside the spheres were mainly distributed at the distolingual cusps of the mandibular second permanent molars (31.37%), while those inside the spheres were mainly distributed at the mesiolingual cusps of the mandibular first permanent molars (45.10%). CONCLUSIONS: The radius of Monson's sphere in Chinese young adult females was smaller than the classic four-inch value suggested by Monson. Deviation was observed from all selected points to their Monson's sphere surface, with the most deviated points distributed primarily in the molar region.

Orthodontic camouflage treatment of a hyperdivergent adolescent patient with anterior open bite and TMD: a case report.

BACKGROUND: In orthodontics, anterior open bite is a common malocclusion that recurs frequently. Because the causes of anterior open bite are so varied, medical professionals must create customized treatment programs for each patient based on their unique etiology. Through the lowering of the posterior teeth, closure of the anterior teeth gap, and cooperation with intermaxillary traction, the treatment plan outlined in this case study sought to achieve a stable occlusion. CASE PRESENTATION: This case report aims to describe an orthodontic camouflage treatment of a 15-year-old female patient with anterior open bite, arch width discrepancy and a history of temporomandibular joint disorder. The patient was treated with intermaxillary vertical elastics and the multiple edgewise arch wire (MEAW) approach. A satisfactory occlusion with a neutral molar relationship was attained after 29 months of orthodontic therapy. The condylography recording showed that this patient's occlusion tended to be more stable both before and after our treatment. The purpose of this case study is to provide an overview of an orthodontic camouflage treatment for a female patient, who had a history of temporomandibular joint disease, anterior open bite, and arch width disparity. CONCLUSIONS: Our results demonstrated that more attention should be paid to levelling the occlusal plane, intrusion of the molars, decompression of temporomandibular joints and the etiology factors of malocclusion during the orthodontic period for those patients with anterior open bite.

Hypoadiponectinemia-induced upregulation of microRNA449b downregulating Nrf-1 aggravates cardiac ischemia-reperfusion injury in diabetic mice.

Diabetes enhances myocardial ischemic/reperfusion (MI/R) injury via an incompletely understood mechanism. Adiponectin (APN) is a cardioprotective adipokine suppressed by diabetes. However, how hypoadiponectinemia exacerbates cardiac injury remains incompletely understood. Dysregulation of miRNAs plays a significant role in disease development. However, whether hypoadiponectinemia alters cardiac miRNA profile, contributing to diabetic heart injury, remains unclear. Methods and Results: Wild-type (WT) and APN knockout (APN-KO) mice were subjected to MI/R. A cardiac microRNA profile was determined. Among 23 miRNAs increased in APN-KO mice following MI/R, miR-449b was most significantly upregulated (3.98-fold over WT mice). Administrating miR-449b mimic increased apoptosis, enlarged infarct size, and impaired cardiac function in WT mice. In contrast, anti-miR-449b decreased apoptosis, reduced infarct size, and improved cardiac function in APN-KO mice. Bioinformatic analysis predicted 73 miR-449b targeting genes, and GO analysis revealed oxidative stress as the top pathway regulated by these genes. Venn analysis followed by luciferase assay identified Nrf-1 and Ucp3 as the two most important miR-449b targets. In vivo administration of anti-miR-449b in APN-KO mice attenuated MI/R-stimulated superoxide overproduction. In vitro experiments demonstrated that high glucose/high lipid and simulated ischemia/reperfusion upregulated miR-449b and inhibited Nrf-1 and Ucp3 expression. These pathological effects were attenuated by anti-miR-449b or Nrf-1 overexpression. In a final attempt to validate our finding in a clinically relevant model, high-fat diet (HFD)-induced diabetic mice were subjected to MI/R and treated with anti-miR-449b or APN. Diabetes significantly increased miR-449b expression and downregulated Nrf-1 and Ucp3 expression. Administration of anti-miR-449b or APN preserved cardiac Nrf-1 expression, reduced cardiac oxidative stress, decreased apoptosis and infarct size, and improved cardiac function. Conclusion: We demonstrated for the first time that hypoadiponectinemia upregulates miR-449b and suppresses Nrf-1/Ucp3 expression, promoting oxidative stress and exacerbating MI/R injury in this population. Dysregulated APN/miR-449b/oxidative stress pathway is a potential therapeutic target against diabetic MI/R injury.

Deciphering and advancing CAR T-cell therapy with single-cell sequencing technologies.

Chimeric antigen receptor (CAR) T-cell therapy has made remarkable progress in cancer immunotherapy, but several challenges with unclear mechanisms hinder its wide clinical application. Single-cell sequencing technologies, with the powerful unbiased analysis of cellular heterogeneity and molecular patterns at unprecedented resolution, have greatly advanced our understanding of immunology and oncology. In this review, we summarize the recent applications of single-cell sequencing technologies in CAR T-cell therapy, including the biological characteristics, the latest mechanisms of clinical response and adverse events, promising strategies that contribute to the development of CAR T-cell therapy and CAR target selection. Generally, we propose a multi-omics research mode to guide potential future research on CAR T-cell therapy.

Identification of nsLTP family in Chinese white pear (Pyrus bretschneideri) reveals its potential roles in russet skin formation.

MAIN CONCLUSION: Identification of PbLTP genes in pear and functional characterization of PbLTP4 in the transport of suberin monomers of russet skin formation. Non-specific lipid-transfer protein (nsLTP) is an abundant and diverse alkaline small molecule protein in the plant kingdom with complex and diverse biophysiological functions, such as transfer of phospholipids, reproductive development, pathogen defence and abiotic stress response. Up to now, only a tiny fraction of nsLTPs have been functionally identified, and the distribution of nsLTPs in pear (Pyrus bretschneideri) (PbLTPs) has not been fully characterized. In this study, the genome-wide analysis of the nsLTP gene family in the pear genome identified 67 PbLTP proteins, which could be divided into six types (1, 2, C, D, E, and G). Similar intron/exon structural patterns were observed in the same type, strongly supporting their close evolutionary relationship. In addition, PbLTP4 was highly expressed in russet pear skin compared with green skin, which was located in the plasma membrane. Coexpression network analysis showed that PbLTP4 closely related to suberin biosynthetic genes. The biological function of PbLTP4 in promoting suberification has been demonstrated by overexpression in Arabidopsis. Identification of suberin monomers showed that PbLTP4 promotes suberification by regulating 9,12-octadecadienoic acid and hexadecanoic acid transport. These results provide helpful insights into the characteristics of PbLTP genes and their biological function in the transport of suberin monomers of russet skin formation.

MIR-107/HMGB1/FGF-2 axis responds to excessive mechanical stretch to promote rapid repair of vascular endothelial cells.

The increase of vascular wall tension can lead to endothelial injury during hypertension, but its potential mechanism remains to be studied. Our results of previous study showed that HUVECs could induce changes in HMGB1/RAGE to resist abnormal mechanical environments in pathological mechanical stretching. In this study, we applied two different kinds of mechanical tension to endothelial cells using the in vitro mechanical loading system FlexCell-5000T and focused on exploring the expression of miR-107 related pathways in HUVECs with excessive mechanical tension. The results showed that miR-107 negatively regulated the expression of the HMGB1/RAGE axis under excessive mechanical tension. Excessive mechanical stretching reduced the expression of miR-107 in HUVECs, and increased the expression of the HMGB1/RAGE axis. When miR-107 analog was transfected into HUVECs with lipo3000 reagent, the overexpression of miR-107 slowed down the increase of the HMGB1/RAGE axis caused by excessive mechanical stretching. At the same time, the overexpression of miR-107 inhibited the proliferation and migration of HUVECs to a certain extent. On the contrary, when miR-107 was silent, the proliferation and migration of HUVECs showed an upward trend. In addition, the study also showed that under excessive mechanical tension, miR-107 could regulate the expression of FGF-2 by HMGB1. In conclusion, these findings suggest that pathological mechanical stretching promote resistance to abnormal mechanical stimulation on HUVECs through miR-107/HMGB1/RAGE/FGF-2 pathway, thus promote vascular repair after endothelial injury. The suggest that miR-107 is a potential therapeutic target for hypertension.