PLIN5 Suppresses Lipotoxicity and Ferroptosis in Cardiomyocyte via Modulating PIR/NF-κB Axis.

Cardiomyocyte lipotoxicity and ferroptosis are the key to the development of diabetic cardiomyopathy (DCM). Perilipin 5 (PLIN5) is perceived as a significant target of DCM. This study aimed to focus on the role and mechanism of PLIN5 on lipotoxicity and ferroptosis in DCM.Following transfection, mouse cardiomyocytes HL-1 were induced by 0.1 mM palmitic acid (PA) to set up lipotoxic cardiomyocyte models. The cell viability and lipid accumulation were evaluated by cell counting kit-8 assay and Oil red O staining, respectively. Ferrous ion (Fe2+), glutathione (GSH), malondialdehyde (MDA), and reactive oxygen species (ROS) levels were determined to verify the effects of PLIN5 or Pirin (PIR) on ferroptosis. Quantitative real-time reverse transcription polymerase chain reaction or Western blot was performed for quantitative analysis.PLIN5 overexpression promoted the viability, GSH level, and expression of GPX4/PIR/intracellular P65, yet suppressed lipid accumulation, level of Fe2+/MDA/ROS, and expression of interleukin (IL) -1ß/IL-18/intranuclear P65 in PA-stimulated HL-1 cells. PIR silencing counteracted the roles of PLIN5 overexpression in PA-stimulated HL-1 cells.PLIN5 suppresses lipotoxicity and ferroptosis in cardiomyocyte via modulating PIR/NF-κB axis, hinting its potential as a therapeutic target in DCM.

Paraquat disrupts KIF5A-mediated axonal mitochondrial transport in midbrain neurons and its antagonism by melatonin.

Paraquat (PQ) is a broad-spectrum herbicide used worldwide and is a hazardous chemical to human health. Cumulative evidence strengthens the association between PQ exposure and the development of Parkinson's disease (PD). However, the underlying mechanism and effective interventions against PQ-induced neurotoxicity remain unclear. In this study, C57BL/6 J mice were treated with PQ (i.p., 10 mg/kg, twice a week) and melatonin (i.g., 20 mg/kg, twice a week) for 8 weeks. Results showed that PQ-induced motor deficits and midbrain dopaminergic neuronal damage in C57BL/6 J mice were protected by melatonin pretreatment. In isolated primary midbrain neurons and SK-N-SH cells, reduction of cell viability, elevation of total ROS levels, axonal mitochondrial transport defects and mitochondrial dysfunction caused by PQ were attenuated by melatonin. After screening of expression of main motors driving axonal mitochondrial transport, data showed that PQ-decreased KIF5A expression in mice midbrain and in SK-N-SH cell was antagonized by melatonin. Using the in vitro KIF5A-overexpression model, it was found that KIF5A overexpression inhibited PQ-caused neurotoxicity and mitochondrial dysfunction in SK-N-SH cells. In addition, application of MTNR1B (MT2) receptor antagonist, 4-P-PDOT, significantly counteracted the protection of melatonin against PQ-induced neurotoxicity. Further, Kif5a-knockdown diminished melatonin-induced alleviation of motor deficits and neuronal damage against PQ in C57BL/6 J mice. The present study establishes a causal link between environmental neurotoxicants exposure and PD etiology and provides effective interventive targets in the pathogenesis of PD.

Transcriptomic analysis provides insights into the molecular mechanism of melatonin-mediated cadmium tolerance in Medicago sativa L.

Cadmium (Cd), a toxic element, often makes a serious threat to plant growth and development. Previous studies found that melatonin (Mel) reduced Cd accumulation and reestablished the redox balance to alleviate Cd stress in Medicago sativa L., however, the complex molecular mechanisms are still elusive. Here, comparative transcriptome analysis and biochemical experiments were conducted to explore the molecular mechanisms of Mel in enhancing Cd tolerance. Results showed that 7237 differentially expressed genes (DEGs) were regulated by Mel pretreatment to Cd stress compared to the control condition in roots of Medicago sativa L. Besides, in comparison with Cd stress alone, Mel upregulated 1081 DEGs, and downregulated 1085 DEGs. These DEGs were mainly involved in the transcription and translation of genes and folding, sorting and degradation of proteins, carbohydrate metabolism, and hormone signal network. Application of Mel regulated the expression of several genes encoding ribosomal protein and E3 ubiquitin-protein ligase involved in folding, sorting and degradation of proteins. Moreover, transcriptomic analyse suggested that Mel might regulate the expression of genes encoding pectin lyase, UDP-glucose dehydrogenase, sucrose-phosphate synthase, hexokinase-1, and protein phosphorylation in the sugar metabolism. Therefore, these could promote sucrose accumulation and subsequently alleviate the Cd damage. In conclusion, above findings provided the mining of important genes and molecular basis of Mel in mitigating Cd tolerance and genetic cultivation of Medicago sativa L.

Chloride-induced corrosion of steel in concrete-insights from bimodal neutron and X-ray microtomography combined with ex-situ microscopy.

The steel-concrete interface (SCI) is known to play a major role in corrosion of steel in concrete, but a fundamental understanding is still lacking. One reason is that concrete's opacity complicates the study of internal processes. Here, we report on the application of bimodal X-ray and neutron microtomography as in-situ imaging techniques to elucidate the mechanism of steel corrosion in concrete. The study demonstrates that the segmentation of the specimen components of relevance-steel, cementitious matrix, aggregates, voids, corrosion products-obtained through bimodal X-ray and neutron imaging is more reliable than that based on the results of each of the two techniques separately. Further, we suggest the combination of tomographic in-situ imaging with ex-situ SEM analysis of targeted sections, selected based on the segmented tomograms. These in-situ and ex-situ characterization techniques were applied to study localized corrosion in a very early stage under laboratory chloride-exposure conditions, using reinforced concrete cores retrieved from a concrete bridge. Several interesting observations were made. First, the acquired images revealed the formation of several corrosion sites close to each other. Second, the morphology of the corrosion pits was relatively shallow. Finally, only about half of the total 31 corrosion initiation spots were in close proximity to interfacial macroscopic air voids, and > 90% of the more than 160 interfacial macroscopic air voids were free from corrosion. The findings have implications for the mechanistic understanding of corrosion of steel in concrete and suggest that multimodal in-situ imaging is a valuable technique for further related studies. Supplementary Information: The online version contains supplementary material available at 10.1617/s11527-024-02337-7.

Effect of Fluid Therapy in Early Morning on the Incidence of Post-Induction Hypotension During Non-Cardiac Surgery After Noon: A Single-Center Retrospective Study.

Purpose: Post-induction hypotension (PIH) is a common clinical phenomenon linked to increased morbidity and mortality in various non-cardiac surgeries. Patients with surgery in the afternoon may have preoperative hypovolemia caused by prolonged fasting and dehydration, which increases the risk of hypotension during the induction period. However, studies on the fluid therapy in early morning combating PIH remain inadequate. Therefore, we aimed to investigate the influence of prophylactic high-volume fluid in the early morning of the operation day on the incidence of PIH during non-cardiac surgery after noon. Patients and Methods: We reviewed the medical records of patients who underwent non-cardiac surgery after noon between October 2021 and October 2022. The patients were divided into two groups based on whether they received a substantial volume of intravenous fluid (high-volume group) or not (low-volume group) in the early morning of the surgery day. We investigated the incidence of PIH and intraoperative hypotension (IOH) as well as the accumulated duration of PIH in the first 15 minutes. In total, 550 patients were included in the analysis. Results: After propensity score matching, the incidence of PIH was 39.7% in the high-volume group and 54.1% in the low-volume group. Multivariate logistic regression analysis showed that patients in the high-volume group had lower incidence of hypotension after induction compared with the low-volume group (odds ratio, 0.55; 95% CI, 0.34-0.89; p = 0.016). The high-volume fluid infusion in the preoperative morning was significantly correlated with the decreased duration of PIH (p = 0.013), but no statistical difference was observed for the occurrence of IOH between the two groups (p = 0.075). Conclusion: The fluid therapy of more than or equal to 1000 mL in the early morning of the surgery day was associated with a decreased incidence of PIH compared with the low-volume group in patients undergoing non-cardiac surgery after noon.

Tumor-targeted gypenoside nanodrug delivery system with double protective layers.

OBJECTIVES: Gypenoside (Gyp) is easily degraded in the gastrointestinal tract, resulting in its low bioavailability. We aimed to develop a tumor-targeted Gyp nanodrug delivery system and to investigate its antitumor effect in vitro. MATERIALS AND METHODS: We used Gyp as the therapeutic drug molecule, mesoporous silica (MSN) and liposome (Lipo) as the drug carrier and protective layers, and aptamer SYL3C as the targeting element to establish a tumor-targeted nanodrug delivery system (i.e., SYL3C-Lipo@Gyp-MSN). The characteristics of SYL3C-Lipo@Gyp-MSN were investigated, and its drug release performance, cell uptake, and antitumor activity in vitro were evaluated. RESULTS: A tumor-targeted Gyp nanodrug delivery system was successfully prepared. The SYL3C-Lipo@Gyp-MSN was spherical or ellipsoidal; had good dispersion, which enabled it to specifically target and kill the liver tumor cell HepG2; and effectively protected the early leakage of Gyp. CONCLUSIONS: We have established a tumor-targeted nanodrug delivery system that can target and kill liver cancer cells and may provide a strategy for preparing new nanodrug-loaded preparations of traditional Chinese medicine.

Ivermectin ameliorates acute myocarditis via the inhibition of importin-mediated nuclear translocation of NF-κB/p65.

BACKGROUND: Myocarditis is an important clinical issue which lacks specific treatment by now. Ivermectin (IVM) is an inhibitor of importin α/ß-mediated nuclear translocation. This study aimed to explore the therapeutic effects of IVM on acute myocarditis. METHODS: Mouse models of coxsackie B3 virus (CVB3) infection-induced myocarditis and experimental autoimmune myocarditis (EAM) were established to evaluate the effects of IVM. Cardiac functions were evaluated by echocardiography and Millar catheter. Cardiac inflammatory infiltration was assessed by histological staining. Cytometric bead array and quantitative real-time PCR were used to detect the levels of pro-inflammatory cytokines. The macrophages and their M1/M2 polarization were analyzed via flow cytometry. Protein expression and binding were detected by co-immunoprecipitation, Western blotting and histological staining. The underlying mechanism was verified in vitro using CVB3-infected RAW264.7 macrophages. Cyclic polypeptide (cTN50) was synthesized to selectively inhibit the nuclear translocation of NF-κB/p65, and CVB3-infected RAW264.7 cells were treated with cTN50. RESULTS: Increased expression of importin ß was observed in both models. IVM treatment improved cardiac functions and reduced the cardiac inflammation associated with CVB3-myocarditis and EAM. Furthermore, the pro-inflammatory cytokine (IL-1ß/IL-6/TNF-α) levels were downregulated via the inhibition of the nuclear translocation of NF-κB/p65 in macrophages. IVM and cTN50 treatment also inhibited the nuclear translocation of NF-κB/p65 and downregulated the expression of pro-inflammatory cytokines in RAW264.7 macrophages. CONCLUSIONS: Ivermectin inhibits the nuclear translocation of NF-κB/p65 and the expression of major pro-inflammatory cytokines in myocarditis. The therapeutic effects of IVM on viral and non-viral myocarditis models suggest its potential application in the treatment of acute myocarditis.

Bacterial cellulose-based hydrogel with regulated rehydration and enhanced antibacterial activity for wound healing.

Bacterial cellulose (BC) hydrogels are promising medical biomaterials that have been widely used for tissue repair, wound healing and cartilage engineering. However, the high water content of BC hydrogels increases the difficulty of storage and transportation. Moreover, they will lose their original hydrogel structure after dehydration, which severely limits their practical applications. Introducing the bio-based polyelectrolytes is expected to solve this problem. Here, we modified BC and combined it with quaternized chitosan (QCS) via a chemical reaction to obtain a dehydrated dialdehyde bacterial cellulose/quaternized chitosan (DBC/QCS) hydrogel with repeated swelling behavior and good antibacterial properties. The hydrogel can recover the initial state on the macro scale with a swelling ratio over 1000 % and possesses excellent antimicrobial properties against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) with a killing rate of 80.8 % and 81.3 %, respectively. In addition, the hydrogel has excellent biocompatibility, which is conducive to the stretching of L929 cells. After 14 d of in vivo wound modeling in rats, it was found that the hydrogel loaded with pirfenidone (PFD) could promote collagen deposition and accelerate wound healing with scar prevention. This rehydratable hydrogel can be stored and transported under dry conditions, which is promising for practical applications.

Head Impact Kinematics and Brain Tissue Strains in High School Lacrosse.

Male lacrosse and female lacrosse have differences in history, rules, and equipment. There is current debate regarding the need for enhanced protective headwear in female lacrosse like that worn by male lacrosse players. To inform this discussion, 17 high school lacrosse players (6 female and 11 male) wore the Stanford Instrumented Mouthguard during 26 competitive games over the 2021 season. Time-windowing and video review were used to remove false-positive recordings and verify head acceleration events (HAEs). The HAE rate in high school female lacrosse (0.21 per athlete exposure and 0.24 per player hour) was approximately 35% lower than the HAE rate in high school male lacrosse (0.33 per athlete exposure and 0.36 per player hour). Previously collected kinematics data from the 2019 high school male and female lacrosse season were combined with the newly collected 2021 kinematics data, which were used to drive a finite element head model and simulate 42 HAEs. Peak linear acceleration (PLA), peak angular velocity (PAV), and 95th percentile maximum principal strain (MPS95) of brain tissue were compared between HAEs in high school female and male lacrosse. Median values for peak kinematics and MPS95 of HAEs in high school female lacrosse (PLA, 22.3 g; PAV, 10.4 rad/s; MPS95, 0.05) were lower than for high school male lacrosse (PLA, 24.2 g; PAV, 15.4 rad/s; MPS95, 0.07), but the differences were not statistically significant. Quantifying a lower HAE rate in high school female lacrosse compared to high school male lacrosse, but similar HAE magnitudes, provides insight into the debate regarding helmets in female lacrosse. However, due to the small sample size, additional video-verified data from instrumented mouthguards are required.

Evolution of illness severity in hospital admissions due to COVID-19, Québec, Canada, January to April 2022.

Background: The coronavirus disease 2019 (COVID-19) severity is influenced by multiple factors, such as age, underlying medical conditions, individual immunity, infecting variant, and clinical practice. The highly transmissible Omicron variants resulted in decreased COVID-19 screening capacity, which limited disease severity surveillance. Objective: To report on the temporal evolution of disease severity among patients admitted to Québec hospitals due to COVID-19 between January 2, 2022, and April 23, 2022, which corresponded to the peak period of hospitalizations due to Omicron. Methods: Retrospective population-based cohort study of all hospital admissions due to COVID-19 in Québec, between January 2, 2022, and April 23, 2022. Study period was divided into four-week periods, corresponding roughly to January, February, March and April. Regression using Cox and Poisson generalized estimating equations (GEEs) was used to quantify temporal variations in length of stay and risk of complications (intensive care admission or in-hospital death) through time, using the Omicron peak (January 2022) as reference. Measures were adjusted for age, sex, vaccination status, presence of chronic diseases, and clustering by hospital. Results: During the study period, 9,178 of all 18,272 (50.2%) patients hospitalized with a COVID-19 diagnosis were admitted due to COVID-19. Of these, 1,026 (11.2%) were admitted to intensive care and 1,523 (16.6%) died. Compared to January, the risk of intensive care admission was 25% and 31% lower in March and April respectively, while in-hospital fatality continuously decreased by 45% lower in April. The average length of stay was temporarily lower in March (9%). Conclusion: Severity of admissions due to COVID-19 decreased in the first months of 2022, when predominant circulating variants were considered to be of similar severity. Monitoring hospital admissions due to COVID-19 can contribute to disease severity surveillance.

Enhanced oral and pulmonary delivery of biomacromolecules via amplified transporter targeting.

Ligand-modified nanocarriers can promote oral or inhalative administration of macromolecular drugs across the intestinal or pulmonary mucosa. However, enhancing the unidirectional transport of the nanocarriers through "apical uptake→intracellular transport→basolateral exocytosis" route remains a hot topic and challenge in current research. Forskolin is a naturally occurring diterpenoid compound extracted from the roots of C. forskohlii. In our studies, we found that forskolin could increase the transcellular transport of butyrate-modified nanoparticles by 1.67-fold and 1.20-fold in Caco-2 intestinal epithelial cell models and Calu-3 lung epithelial cell models, respectively. Further mechanistic studies revealed that forskolin, on the one hand, promoted the cellular uptake of butyrate-modified nanoparticles by upregulating the expression of monocarboxylic acid transporter-1 (MCT-1) on the apical membrane. On the other hand, forskolin facilitated the binding of MCT-1 to caveolae, thereby mediating butyrate-modified nanoparticles hijacking caveolae to promote the basolateral exocytosis of butyrate-modified nanoparticles. Studies in normal mice model showed that forskolin could promote the transmucosal absorption of butyrate-modified nanoparticles by >2-fold, regardless of oral or inhalative administration. Using semaglutide as the model drug, both oral and inhalation delivery approaches demonstrated significant hypoglycemic effects in type 2 diabetes mice model, in which inhalative administration was more effective than oral administration. This study optimized the strategies aimed at enhancing the transmucosal absorption of ligand-modified nanocarriers in the intestinal or pulmonary mucosa.

Lipoic acid-mediated oral drug delivery system utilizing changes on cell surface thiol expression for the treatment of diabetes and inflammatory diseases.

Lipoic acid (LA), which has good safety and oral absorption, is obtained from various plant-based food sources and needs to be supplemented through human diet. Moreover, substances with a disulfide structure can enter cells through dynamic covalent disulfide exchange with thiol groups on the cell membrane surface. Based on these factors, we constructed LA-modified nanoparticles (LA NPs). Our results showed that LA NPs can be internalized into intestinal epithelial cells through surface thiols, followed by intracellular transcytosis via the endoplasmic reticulum-Golgi pathway. Further mechanistic studies indicated that disulfide bonds within the structure of LA play a critical role in this transport process. In a type I diabetes rat model, the oral administration of insulin-loaded LA NPs exhibited a more potent hypoglycemic effect, with a pharmacokinetic bioavailability of 5.42 ± 0.53%, representing a 1.6 fold enhancement compared to unmodified PEG NPs. Furthermore, a significant upregulation of surface thiols in inflammatory macrophages was reported. Thus, we turned our direction to investigate the uptake behavior of inflammatory macrophages with increased surface thiols towards LA NPs. Inflammatory macrophages showed a 2.6 fold increased uptake of LA NPs compared to non-inflammatory macrophages. Surprisingly, we also discovered that the antioxidant resveratrol facilitates the uptake of LA NPs in a concentration-dependent manner. This is mainly attributed to an increase in glutathione, which is involved in thiol uptake. Consequently, we employed LA NPs loaded with resveratrol for the treatment of colitis and observed a significant alleviation of colitis symptoms. These results suggest that leveraging the variations of thiol expression levels on cell surfaces under both healthy and diseased states through an oral drug delivery system mediated by the small-molecule nutrient LA can be employed for the treatment of diabetes and certain inflammatory diseases.

A commensal protozoan attenuates Clostridioides difficile pathogenesis in mice via arginine-ornithine metabolism and host intestinal immune response.

Antibiotic-induced dysbiosis is a major risk factor for Clostridioides difficile infection (CDI), and fecal microbiota transplantation (FMT) is recommended for treating CDI. However, the underlying mechanisms remain unclear. Here, we show that Tritrichomonas musculis (T.mu), an integral member of the mouse gut commensal microbiota, reduces CDI-induced intestinal damage by inhibiting neutrophil recruitment and IL-1ß secretion, while promoting Th1 cell differentiation and IFN-γ secretion, which in turn enhances goblet cell production and mucin secretion to protect the intestinal mucosa. T.mu can actively metabolize arginine, not only influencing the host's arginine-ornithine metabolic pathway, but also shaping the metabolic environment for the microbial community in the host's intestinal lumen. This leads to a relatively low ornithine state in the intestinal lumen in C. difficile-infected mice. These changes modulate C. difficile's virulence and the host intestinal immune response, and thus collectively alleviating CDI. These findings strongly suggest interactions between an intestinal commensal eukaryote, a pathogenic bacterium, and the host immune system via inter-related arginine-ornithine metabolism in the regulation of pathogenesis and provide further insights for treating CDI.

A nomogram for predicting the risk of cerebral vasospasm after neurosurgical clipping in patients with aneurysmal subarachnoid hemorrhage.

Purpose: Cerebral vasospasm (CVS) is a common complication that occurs after neurosurgical clipping of intracranial aneurysms in patients with aSAH. This complication can lead to clinical deterioration and a poor prognosis. The aim of this study is to explore the risk factors for CVS in aSAH patients who have undergone neurosurgical clipping, develop a nomogram for CVS, and evaluate its performance. Methods: Patients with aSAH who underwent neurosurgical clipping in the Department of Neurosurgery from January 2018 to January 2023 were selected as the subjects of this research. The clinical data of these patients were retrospectively analyzed. Logistic multivariate regression analysis was employed to identify the independent risk factors of CVS. A clinical prediction model in the form of a nomogram for CVS was developed using the R programming language and subsequently evaluated for its performance and quality. Results: A total of 156 patients with aSAH were included in the analysis, comprising 109 patients in the training set and 47 patients in the validation set. In the training cohort, 27 patients (24.77%) developed CVS after neurosurgical clipping, while in the validation cohort, 15 patients (31.91%) experienced CVS. Multivariate regression analysis revealed that age, Hcy, WBC, glucose/potassium ratio, aneurysm location, and modified Fisher grade were independent risk factors for CVS. The nomogram exhibited excellent discriminative performance in both the training set (AUC = 0.885) and the validation set (AUC = 0.906). Conclusion: CVS was a prevalent complication following neurosurgical clipping in patients with aSAH, with a highly intricate pathogenesis and pathophysiological course. Early prediction of CVS represented a significant challenge in clinical practice. In this study, age, Hcy, WBC, glucose/potassium ratio, aneurysm location, and modified Fisher grade emerged as independent risk factors for CVS. The resulting nomogram demonstrated substantial predictive value.

Predicting pharmacodynamic effects through early drug discovery with artificial intelligence-physiologically based pharmacokinetic (AI-PBPK) modelling.

A mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model links the concentration-time profile of a drug with its therapeutic effects based on the underlying biological or physiological processes. Clinical endpoints play a pivotal role in drug development. Despite the substantial time and effort invested in screening drugs for favourable pharmacokinetic (PK) properties, they may not consistently yield optimal clinical outcomes. Furthermore, in the virtual compound screening phase, researchers cannot observe clinical outcomes in humans directly. These uncertainties prolong the process of drug development. As incorporation of Artificial Intelligence (AI) into the physiologically based pharmacokinetic/pharmacodynamic (PBPK) model can assist in forecasting pharmacodynamic (PD) effects within the human body, we introduce a methodology for utilizing the AI-PBPK platform to predict the PK and PD outcomes of target compounds in the early drug discovery stage. In this integrated platform, machine learning is used to predict the parameters for the model, and the mechanism-based PD model is used to predict the PD outcome through the PK results. This platform enables researchers to align the PK profile of a drug with desired PD effects at the early drug discovery stage. Case studies are presented to assess and compare five potassium-competitive acid blocker (P-CAB) compounds, after calibration and verification using vonoprazan and revaprazan.

Identifying central symptom clusters and correlates in patients with lung cancer post-chemotherapy: A network analysis.

Objective: This study aims to investigate the network structures of symptoms and symptom clusters in patients with lung cancer post-chemotherapy, with a focus on identifying the central symptom cluster. Understanding the central cluster is crucial for targeted and effective symptom management. Methods: Symptom occurrence and severity were assessed using the Memorial Symptom Assessment Scale (MSAS). Principal component analysis (PCA) was employed to explore symptom clusters, while network analysis unveiled the network structure and pinpointed the central symptom cluster. Results: The study included 512 patients with lung cancer. Four distinct symptom clusters emerged: sickness behavior, psychological, lung cancer-specific, and epithelial. The sickness behavior symptom cluster was identified as the central symptom cluster. Conclusions: This research designates the sickness behavior symptom cluster as central in post-chemotherapy patients with lung cancer, offering valuable insights for clinical nurses in devising more effective symptom management strategies. Trial registration: ChiCTR2300070944 (Chinese Clinical Trial Register).

Predictive value of NT-proBNP and hs-TnT for outcomes after pediatric congenital cardiac surgery.

BACKGROUND: The available evidence regarding the predictive value of troponins and natriuretic peptides for early postoperative outcomes in pediatrics is limited, controversial, and based on small sample sizes. We aimed to investigate the association of N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) with the in-hospital adverse outcomes after congenital cardiac surgeries. METHODS: A secondary analysis based on a prospective study of pediatric congenital heart disease (CHD) patients was conducted to investigate the association of NT-proBNP and hs-TnT tested within 6 hours postoperatively with in-hospital adverse events. A multivariate logistic regression analysis with a minimum P value approach was used to identify the optimal thresholds of NT-proBNP and hs-TnT for risk stratification. RESULTS: NT-proBNP and hs-TnT are positively correlated with cardiopulmonary bypass time, mechanical ventilation duration, and pediatric intensive care unit stay. The predictive performance of NT-proBNP is excellent for adverse events in both patients younger than 1 year [area under the curve (AUC): 0.771, 0.693-0.850] and those older than 1 year (AUC: 0.839, 0.757-0.922). However, hs-TnT exhibited a satisfactory predictive value solely in patients aged over 1 year. (AUC: 0.784, 0.717-0.852). NT-proBNP levels of 2000 to 10000 ng/L [Odds Ratio (OR): 3.79, 1.47-9.76) and exceeding 10000 ng/L (OR: 12.21, 3.66-40.80) were associated with a higher risk of postoperative adverse events in patients younger than 1 year. Patients older than 1 year, with NT-proBNP higher than 500 ng/L (OR: 15.09, 6.05-37.66) or hs-TnT greater than 1200 ng/L (OR: 5.50, 1.47-20.59), had a higher incidence of postoperative adverse events. CONCLUSIONS: NT-proBNP and hs-TnT tested within postoperative 6 hours demonstrated significant predictive value for postoperative adverse events in CHD patients older than 1 year. However, among CHD patients younger than 1 year, only NT-proBNP exhibited commendable predictive performance for postoperative adverse events.

Radiofrequency radiation reshapes tumor immune microenvironment into antitumor phenotype in pulmonary metastatic melanoma by inducing active transformation of tumor-infiltrating CD8+ T and NK cells.

Immunosuppression by the tumor microenvironment is a pivotal factor contributing to tumor progression and immunotherapy resistance. Priming the tumor immune microenvironment (TIME) has emerged as a promising strategy for improving the efficacy of cancer immunotherapy. In this study we investigated the effects of noninvasive radiofrequency radiation (RFR) exposure on tumor progression and TIME phenotype, as well as the antitumor potential of PD-1 blockage in a model of pulmonary metastatic melanoma (PMM). Mouse model of PMM was established by tail vein injection of B16F10 cells. From day 3 after injection, the mice were exposed to RFR at an average specific absorption rate of 9.7 W/kg for 1 h per day for 14 days. After RFR exposure, lung tissues were harvested and RNAs were extracted for transcriptome sequencing; PMM-infiltrating immune cells were isolated for single-cell RNA-seq analysis. We showed that RFR exposure significantly impeded PMM progression accompanied by remodeled TIME of PMM via altering the proportion and transcription profile of tumor-infiltrating immune cells. RFR exposure increased the activation and cytotoxicity signatures of tumor-infiltrating CD8+ T cells, particularly in the early activation subset with upregulated genes associated with T cell cytotoxicity. The PD-1 checkpoint pathway was upregulated by RFR exposure in CD8+ T cells. RFR exposure also augmented NK cell subsets with increased cytotoxic characteristics in PMM. RFR exposure enhanced the effector function of tumor-infiltrating CD8+ T cells and NK cells, evidenced by increased expression of cytotoxic molecules. RFR-induced inhibition of PMM growth was mediated by RFR-activated CD8+ T cells and NK cells. We conclude that noninvasive RFR exposure induces antitumor remodeling of the TIME, leading to inhibition of tumor progression, which provides a promising novel strategy for TIME priming and potential combination with cancer immunotherapy.

Single-Nucleus Multiomic Analyses Identifies Gene Regulatory Dynamics of Phenotypic Modulation in Human Aneurysmal Aortic Root.

Aortic root aneurysm is a potentially life-threatening condition that may lead to aortic rupture and is often associated with genetic syndromes, such as Marfan syndrome (MFS). Although studies with MFS animal models have provided valuable insights into the pathogenesis of aortic root aneurysms, this understanding of the transcriptomic and epigenomic landscape in human aortic root tissue remains incomplete. This knowledge gap has impeded the development of effective targeted therapies. Here, this study performs the first integrative analysis of single-nucleus multiomic (gene expression and chromatin accessibility) and spatial transcriptomic sequencing data of human aortic root tissue under healthy and MFS conditions. Cell-type-specific transcriptomic and cis-regulatory profiles in the human aortic root are identified. Regulatory and spatial dynamics during phenotypic modulation of vascular smooth muscle cells (VSMCs), the cardinal cell type, are delineated. Moreover, candidate key regulators driving the phenotypic modulation of VSMC, such as FOXN3, TEAD1, BACH2, and BACH1, are identified. In vitro experiments demonstrate that FOXN3 functions as a novel key regulator for maintaining the contractile phenotype of human aortic VSMCs through targeting ACTA2. These findings provide novel insights into the regulatory and spatial dynamics during phenotypic modulation in the aneurysmal aortic root of humans.

Fascia Lata Autografts Achieve Interface Healing With the Supraspinatus Muscle Histologically and Mechanically in a Rat Supraspinatus Tendon Reconstruction Model for Massive Irreparable Rotator Cuff Tears.

PURPOSE: To evaluate the histologic healing process and mechanical characteristics of the interface between a fascia lata autograft and supraspinatus muscle by establishing a supraspinatus tendon reconstruction model for chronic massive irreparable rotator cuff tears (MIRCTs). METHODS: A total of 40 rats were studied. Eight rats were killed to establish an intact control group, and the other rats were first established as a chronic MIRCT model and then developed as the supraspinatus tendon reconstruction model. Histology, fatty infiltration, mechanics, and open field test for the interface between the fascia lata autograft and muscle were assessed at 2, 4, 8, and 16 weeks postoperatively. RESULTS: Histologically, the interface between the fascia lata autograft and muscle gradually regenerated structural characteristics similar to the normal muscle-tendon interface by 16 weeks postoperatively. The amount of collagen I and III increased significantly during the healing time and stabilized at 8 weeks postoperatively. Fatty infiltration was obvious in the supraspinatus muscle 4 weeks after establishing the MIRCT model. However, the degree of fatty infiltration in the supraspinatus muscle gradually decreased after supraspinatus tendon reconstruction and stabilized at 8 weeks postoperatively. The ultimate failure force and ultimate stress gradually increased from 2 to 16 weeks and reached the level of the intact control tendon at 16 weeks postoperatively (P = .086). The movability of the forepaw returned to normal in the open field test (P = .907). CONCLUSIONS: In this rat supraspinatus tendon reconstruction model, fascia lata autografts showed good interface healing with the supraspinatus muscle, and fatty infiltration in the supraspinatus muscle was histologically decreased. The interface between the fascia lata autograft and muscle showed mechanical strength similar to the anatomic muscle-tendon interface. CLINICAL RELEVANCE: A supraspinatus tendon reconstruction technique using fascia lata autografts might be a good histologic and biomechanical option for treating MIRCTs.