p53 Acetylation Exerts Critical Roles in Pressure Overload-Induced Coronary Microvascular Dysfunction and Heart Failure in Mice.

BACKGROUND: Coronary microvascular dysfunction (CMD) has been shown to contribute to cardiac hypertrophy and heart failure (HF) with preserved ejection fraction. At this point, there are no proven treatments for CMD. METHODS: We have shown that histone acetylation may play a critical role in the regulation of CMD. By using a mouse model that replaces lysine with arginine at residues K98, K117, K161, and K162R of p53 (p534KR), preventing acetylation at these sites, we test the hypothesis that acetylation-deficient p534KR could improve CMD and prevent the progression of hypertensive cardiac hypertrophy and HF. Wild-type and p534KR mice were subjected to pressure overload by transverse aortic constriction to induce cardiac hypertrophy and HF. RESULTS: Echocardiography measurements revealed improved cardiac function together with a reduction of apoptosis and fibrosis in p534KR mice. Importantly, myocardial capillary density and coronary flow reserve were significantly improved in p534KR mice. Moreover, p534KR upregulated the expression of cardiac glycolytic enzymes and Gluts (glucose transporters), as well as the level of fructose-2,6-biphosphate; increased PFK-1 (phosphofructokinase 1) activity; and attenuated cardiac hypertrophy. These changes were accompanied by increased expression of HIF-1α (hypoxia-inducible factor-1α) and proangiogenic growth factors. Additionally, the levels of SERCA-2 were significantly upregulated in sham p534KR mice, as well as in p534KR mice after transverse aortic constriction. In vitro, p534KR significantly improved endothelial cell glycolytic function and mitochondrial respiration and enhanced endothelial cell proliferation and angiogenesis. Similarly, acetylation-deficient p534KR significantly improved coronary flow reserve and rescued cardiac dysfunction in SIRT3 (sirtuin 3) knockout mice. CONCLUSIONS: Our data reveal the importance of p53 acetylation in coronary microvascular function, cardiac function, and remodeling and may provide a promising approach to improve hypertension-induced CMD and to prevent the transition of cardiac hypertrophy to HF.

Ferrostatin-1 specifically targets mitochondrial iron-sulfur clusters and aconitase to improve cardiac function in Sirtuin 3 cardiomyocyte knockout mice.

AIMS: Ferroptosis is a form of iron-regulated cell death implicated in ischemic heart disease. Our previous study revealed that Sirtuin 3 (SIRT3) is associated with ferroptosis and cardiac fibrosis. In this study, we tested whether the knockout of SIRT3 in cardiomyocytes (SIRT3cKO) promotes mitochondrial ferroptosis and whether the blockade of ferroptosis would ameliorate mitochondrial dysfunction. METHODS AND RESULTS: Mitochondrial and cytosolic fractions were isolated from the ventricles of mice. Cytosolic and mitochondrial ferroptosis were analyzed by comparison to SIRT3loxp mice. An echocardiography study showed that SIRT3cKO mice developed heart failure as evidenced by a reduction of EF% and FS% compared to SIRT3loxp mice. Comparison of mitochondrial and cytosolic fractions of SIRT3cKO and SIRT3loxp mice revealed that, upon loss of SIRT3, mitochondrial, but not cytosolic, total lysine acetylation was significantly increased. Similarly, acetylated p53 was significantly upregulated only in the mitochondria. These data demonstrate that SIRT3 is the primary mitochondrial deacetylase. Most importantly, loss of SIRT3 resulted in significant reductions of frataxin, aconitase, and glutathione peroxidase 4 (GPX4) in the mitochondria. This was accompanied by a significant increase in levels of mitochondrial 4-hydroxynonenal. Treatment of SIRT3cKO mice with the ferroptosis inhibitor ferrostatin-1 (Fer-1) for 14 days significantly improved preexisting heart failure. Mechanistically, Fer-1 treatment significantly increased GPX4 and aconitase expression/activity, increased mitochondrial iron­sulfur clusters, and improved mitochondrial membrane potential and Complex IV activity. CONCLUSIONS: Inhibition of ferroptosis ameliorated cardiac dysfunction by specifically targeting mitochondrial aconitase and iron­sulfur clusters. Blockade of mitochondrial ferroptosis may be a novel therapeutic target for mitochondrial cardiomyopathies.

EEBR induces Caspase-1-dependent pyroptosis through the NF-κB/NLRP3 signalling cascade in non-small cell lung cancer.

Lung cancer is a leading cause of cancer-related deaths worldwide. Recent studies have identified pyroptosis, a type of programmed cell death, as a critical process in the development and progression of lung cancer. In this study, we investigated the effect of EEBR, a new compound synthesized by our team, on pyroptosis in non-small cell lung cancer cells (NSCLC) and the underlying molecular mechanisms. Our results demonstrated that EEBR significantly reduced the proliferation and metastasis of NSCLC cells in vitro. Moreover, EEBR-induced pyroptosis in NSCLC cells, as evidenced by cell membrane rupture, the release of cytokines such as interleukin-18 and interleukin-1 beta and the promotion of Gasdermin D cleavage in a Caspase-1-dependent manner. Furthermore, EEBR promoted the nuclear translocation of NF-κB and upregulated the protein level of NLRP3. Subsequent studies revealed that EEBR-induced pyroptosis was suppressed by the inhibition of NF-κB. Finally, EEBR effectively suppressed the growth of lung cancer xenograft tumours by promoting NSCLC pyroptosis in animal models. Taken together, our findings suggest that EEBR induces Caspase-1-dependent pyroptosis through the NF-κB/NLRP3 signalling cascade in NSCLC, highlighting its potential as a candidate drug for NSCLC treatment.

Balanced Solution versus Normal Saline in Predicted Severe Acute Pancreatitis: A Stepped Wedge Cluster Randomized Trial.

OBJECTIVE: To compare the effect of balanced multielectrolyte solutions(BMES) versus normal saline(NS) for intravenous fluid on chloride levels and clinical outcomes.in patients with predicted severe acute pancreatitis (pSAP). SUMMARY BACKGROUND DATA: Isotonic crystalloids are recommended for initial fluid therapy in acute pancreatitis, but whether the use of BMES in preference to NS confers clinical benefits is unknown. METHODS: In this multicenter, stepped-wedge, cluster-randomized trial, we enrolled patients with pSAP (APACHE II score ≥8 and C-reactive protein >150 mg/L) admitted within 72 hours of the advent of symptoms. The study sites were randomly assigned to staggered start dates for one-way crossover from the NS phase (NS for intravenous fluid) to the BMES phase(Sterofudin for intravenous fluid). The primary endpoint was the serum chloride concentration on trial day3. Secondary endpoints included a composite of clinical and laboratory measures. RESULTS: Overall, 259 patients were enrolled from eleven sites to receive NS(n=147) or BMES(n=112). On trial day3, the mean chloride level was significantly lower in patients who received BMES(101.8 mmol/L(SD4.8) versus 105.8 mmol/L(SD5.9), difference -4.3 mmol/L [95%CI -5.6 to -3.0 mmol/L];P<0.001). For secondary endpoints, patients who received BMES had less systemic inflammatory response syndrome(19/112,17.0% versus 43/147,29.3%, P=0.024) and increased organ failure-free days (3.9 d(SD2.7) versus 3.5days(SD2.7), P<0.001) by trial day7. They also spent more time alive and out of ICU(26.4 d(SD5.2) versus 25.0days(SD6.4), P=0.009) and hospital(19.8 d(SD6.1) versus16.3days(SD7.2), P<0.001) by trial day30. CONCLUSIONS: Among patients with pSAP, using BMES in preference to NS resulted in a significantly more physiological serum chloride level, which was associated with multiple clinical benefits(Trial registration number: ChiCTR2100044432).

Superconductivity in Ca-intercalated bilayer graphene: C2CaC2.

The deposition and intercalation of metal atoms can induce superconductivity in monolayer and bilayer graphenes. For example, it has been experimentally proved that Li-deposited graphene is a superconductor with critical temperature Tc of 5.9 K, Ca-intercalated bilayer graphene C6CaC6 and K-intercalated epitaxial bilayer graphene C8KC8 are superconductors with Tc of 2-4 K and 3.6 K, respectively. However, the Tc of them are relatively low. To obtain higher Tc in graphene-based superconductors, here we predict a new Ca-intercalated bilayer graphene C2CaC2, which shows higher Ca concentration than the C6CaC6. It is proved to be thermodynamically and dynamically stable. The electronic structure, electron-phonon coupling (EPC) and superconductivity of C2CaC2 are investigated based on first-principles calculations. The EPC of C2CaC2 mainly comes from the coupling between the electrons of C-pz orbital and the high- and low-frequency vibration modes of C atoms. The calculated EPC constant λ of C2CaC2 is 0.75, and the superconducting Tc is 18.9 K, which is much higher than other metal-intercalated bilayer graphenes. By further applying -4% biaxial compressive strain to C2CaC2, the Tc can be boosted to 26.6 K. Thus, the predicted C2CaC2 provides a new platform for realizing superconductivity with the highest Tc in bilayer graphenes.

ErbB4 deficiency exacerbates olfactory dysfunction in an early-stage Alzheimer's disease mouse model.

Olfactory dysfunction is increasingly recognized as an early indicator of Alzheimer's disease (AD). Aberrations in GABAergic function and the excitatory/inhibitory (E/I) balance within the olfactory bulb (OB) have been implicated in olfactory impairment during the initial stages of AD. While the neuregulin 1 (NRG1)/ErbB4 signaling pathway is known to regulate GABAergic transmission in the brain and is associated with various neuropsychiatric disorders, its specific role in early AD-related olfactory impairment remains incompletely understood. This study demonstrated that olfactory dysfunction preceded cognitive decline in young adult APP/PS1 mice and was characterized by reduced levels of NRG1 and ErbB4 in the OB. Further investigation revealed that deletion of ErbB4 in parvalbumin interneurons reduced GABAergic transmission and increased hyperexcitability in mitral and tufted cells (M/Ts) in the OB, thereby accelerating olfactory dysfunction in young adult APP/PS1 mice. Additionally, ErbB4 deficiency was associated with increased accumulation of Aß and BACE1-mediated cleavage of APP, along with enhanced CDK5 signaling in the OB. NRG1 infusion into the OB was found to enhance GABAergic transmission in M/Ts and alleviate olfactory dysfunction in young adult APP/PS1 mice. These findings underscore the critical role of NRG1/ErbB4 signaling in regulating GABAergic transmission and E/I balance within the OB, contributing to olfactory impairment in young adult APP/PS1 mice, and provide novel insights for early intervention strategies in AD. This work has shown that ErbB4 deficiency increased the burden of Aß, impaired GABAergic transmission, and disrupted the E/I balance of mitral and tufted cells (M/Ts) in the OB, ultimately resulting in olfactory dysfunction in young adult APP/PS1 mice. NRG1 could enhance GABAergic transmission, rescue E/I imbalance in M/Ts, and alleviate olfactory dysfunction in young adult APP/PS1 mice. OB: olfactory bulb, E/I: excitation/inhibition, Pr: probability of release, PV: parvalbumin interneurons, Aß: ß-amyloid, GABA: gamma-aminobutyric acid.

Effect of Model-Based Iterative Reconstruction on Image Quality of Chest Computed Tomography for COVID-19 Pneumonia.

PURPOSE: This study aimed to compare the image quality of chest computed tomography (CT) scans for COVID-19 pneumonia using forward-projected model-based iterative reconstruction solution-LUNG (FIRST-LUNG) with filtered back projection (FBP) and hybrid iterative reconstruction (HIR). METHOD: The CT images of 44 inpatients diagnosed with COVID-19 pneumonia between December 2022 and June 2023 were retrospectively analyzed. The CT images were reconstructed using FBP, HIR, and FIRST-LUNG-MILD/STANDARD/STRONG. The CT values and noise of the lumen of the main trachea and erector spine muscle were measured for each group. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. Subjective evaluations included overall image quality, noise, streak artifact, visualization of normal lung structures, and abnormal CT features. One-way analysis of variance was used to compare the objective and subjective indicators among the five groups. The task-based transfer function was derived for three distinct contrasts representing anatomical structures, lower-contrast lesion, and higher-contrast lesion. RESULTS: The results of the study demonstrated significant differences in image noise, SNR, and CNR among the five groups (P < 0.001). The FBP images exhibited the highest levels of noise and the lowest SNR and CNR among the five groups (P < 0.001). When compared to the FBP and HIR groups, the noise was lower in the FIRST-LUNG-MILD/STANDARD/STRONG group, while the SNR and CNR were higher (P < 0.001). The subjective overall image quality score of FIRST-LUNG-MILD/STANDARD was significantly better than FBP and FIRST-LUNG-STRONG (P < 0.001). FIRST-LUNG-MILD was superior to FBP, HIR, FIRST-LUNG-STANDARD, and FIRST-LUNG-STRONG in visualizing proximal and peripheral bronchovascular and subpleural vessels (P < 0.05). Additionally, FIRST-LUNG-MILD achieved the best scores in evaluating abnormal lung structure (P < 0.001). The overall interobserver agreement was substantial (intraclass correlation coefficient = 0.891). The task-based transfer function 50% values of FIRST reconstructions are consistently higher compared to FBP and HIR. CONCLUSIONS: The FIRST-LUNG-MILD/STANDARD algorithm can enhance the image quality of chest CT in patients with COVID-19 pneumonia, while preserving important details of the lesions, better than the FBP and HIR algorithms. After evaluating various COVID-19 pneumonia lesions and considering the improvement in image quality, we recommend using the FIRST-LUNG-MILD reconstruction for diagnosing COVID-19 pneumonia.

Health effect of multiple air pollutant mixture on sarcopenia among middle-aged and older adults in China.

BACKGROUND: As the global aging process accelerates, the health challenges posed by sarcopenia among middle-aged and older adults are becoming increasingly prominent. However, the available evidence on the adverse effects of air pollution on sarcopenia is limited, particularly in the Western Pacific region. This study aimed to explore relationships of multiple air pollutants with sarcopenia and related biomarkers using the nationally representative database. METHODS: Totally, 6585 participants aged over 45 years were enrolled from the China Health and Retirement Longitudinal Study (CHARLS) in 2011 and 3443 of them were followed up until 2015. Air pollutants were estimated from high-resolution satellite-based spatial-temporal models. In the cross-sectional analysis, we used generalized linear regression, unconditional logistic regression analytical and restricted cubic spline (RCS) methods to assess the single-exposure and non-linear effects of multiple air pollutants on sarcopenia and related surrogate biomarkers (serum creatinine and cystatin C). Several popular mixture analysis techniques such as Bayesian kernel machine regression (BKMR), weighted quantile sum (WQS) regression, and quantile-based g-computation (Qgcomp) were further used to examinate the combined effects of multiple air pollutants. Logistic regression was used to further analyze the longitudinal association between air pollution and sarcopenia. RESULTS: Each interquartile range increase in PM2.5, PM10 and NO2 was significantly associated with an increased risk of sarcopenia, with adjusted odds ratios (aORs) of 1.09 [95 % confidence interval (CI): 1.01, 1.20], 1.24 (95 % CI: 1.14, 1.35) and 1.18 (95 % CI: 1.08, 1.28), respectively. Our findings also showed that five air pollutants were significantly associated with the sarcopenia index. In addition, employing a mixture analysis approach, we confirmed significant combined effects of air pollution mixtures on sarcopenia risk and associated biomarkers, with PM10 and PM2.5 identified as major contributors to the combined effect. The results of the exposure-response (E-R) relationships, subgroup analysis, longitudinal analysis and sensitivity analysis all showed the unfavorable impact of air pollution on sarcopenia risk and related vulnerable populations. CONCLUSIONS: Single-exposure and co-exposure to multiple air pollutants were positively associated with sarcopenia among middle-aged and older adults in China. Our study provided new evidence that air pollution mixture was significantly associated with sarcopenia related biomarkers.

Risk factors of post-operative diarrhoea in patients with pancreatic cancer after neoadjuvant chemotherapy: A retrospective cohort study.

BACKGROUND: Post-operative diarrhoea is a common adverse event after pancreatic surgery. While the risk factors for this condition have been identified, the increasing trend of administering chemotherapy before surgery might change these factors. This study aimed to identify the risk factors of post-operative diarrhoea in patients with pancreatic ductal adenocarcinoma (PDAC) who underwent neoadjuvant chemotherapy. DESIGN: A retrospective cohort study. METHODS: Patients who underwent neoadjuvant chemotherapy and pancreatectomy because of PDAC between 2021 and 2023 were included. The preoperative characteristics of, operative details of and post-operative outcomes in patients with and without post-operative diarrhoea were collected and compared. The independent risk factors of post-operative diarrhoea were identified using logistic regression analysis. STROBE checklist was used. RESULTS: Post-operative diarrhoea occurred in 65 out of 145 (44.8%) patients during hospitalization. Elevated white blood cell count, advanced tumour stage, and late abdominal drain removal were independent risk factors for post-operative diarrhoea (p < .001, p = .006 and p = .009, respectively). CONCLUSIONS: Some perioperative factors influence post-operative diarrhoea in patients who undergo neoadjuvant chemotherapy. More attention should be paid to patients at a higher risk of post-operative diarrhoea, with an emphasis on high-quality management for these patients.

DNA Methylation and Chromatin Accessibility Impact Subgenome Expression Dominance in the Common Carp (Cyprinus carpio).

DNA methylation and chromatin accessibility play important roles in gene expression, but their function in subgenome expression dominance remains largely unknown. We conducted comprehensive analyses of the transcriptome, DNA methylation, and chromatin accessibility in liver and muscle tissues of allotetraploid common carp, aiming to reveal the function of epigenetic modifications in subgenome expression dominance. A noteworthy overlap in differential expressed genes (DEGs) as well as their functions was observed across the two subgenomes. In the promoter and gene body, the DNA methylation level of the B subgenome was significantly different than that of the A subgenome. Nevertheless, differences in DNA methylation did not align with changes in homoeologous biased expression across liver and muscle tissues. Moreover, the B subgenome exhibited a higher prevalence of open chromatin regions and greater chromatin accessibility, in comparison to the A subgenome. The expression levels of genes located proximally to open chromatin regions were significantly higher than others. Genes with higher chromatin accessibility in the B subgenome exhibited significantly elevated expression levels compared to the A subgenome. Contrastingly, genes without accessibility exhibited similar expression levels in both subgenomes. This study contributes to understanding the regulation of subgenome expression dominance in allotetraploid common carp.

Gas chromatography-ion mobility spectrometry (GC-IMS) technique and its recent applications in grain research.

Grains are the primary source of food for most people worldwide and constitute a major source of carbohydrates. Many novel technologies are being employed to ensure the safety and reliability of grain supply and production. Gas chromatography-ion mobility spectrometry (GC-IMS) can effectively separate and sensitively detect volatile organic compounds. It possesses advantages such as speed, convenience, high sensitivity, no pretreatment, and wide applicability. In recent years, many studies have shown that the application of GC-IMS technology for grain flavor analysis can play a crucial role in grains. This article elucidates the working principle of GC-IMS technology, reviews the application of GC-IMS in grains in the past 5 years. GC-IMS technology is mainly applied in four aspects in grains. In grain classification, it distinguishes varieties, quality, origin, production year, and processing methods based on the trace differences in volatile organic compounds, thereby fulfilling various grain classification requirements such as origin tracing, geographical indication product recognition, variety identification, production year identification, and detection of counterfeit and inferior grain samples. In optimizing the processing technology of grains and their products, it can improve food flavor, reduce undesirable flavors, and identify better processing parameters. In grain storage, it can determine the storage time, detect spoilage phenomena such as mold and discoloration during storage, eliminate pests affecting storage, and predict the vitality of seeds after storage. In aroma evaluation of grains and their processed products, it can assess the impact of new raw materials, new technologies, fermentation processes, and even oral processing on the quality of grain products. This article also summarizes the characteristics of GC-IMS technology, compiles typical grain flavor compounds, and provides prospects for the future application of GC-IMS. © 2024 Society of Chemical Industry.

Industrial effluents and N-nitrosamines in karst aquatic systems: a study on distribution and ecological implications.

The discharge of electroplating wastewater, containing high concentrations of N-nitrosamines, poses significant risks to human health and aquatic ecosystems. Karst aquatic environment is easily impacted by N-nitrosamines due to the fragile surface ecosystem. However, it's still unclear in understanding N-nitrosamine transformation in karst water systems. To explore the response and transport of nine N-nitrosamines in electroplating effluent within both karst surface water and groundwater, different river and groundwater samples were collected from both the upper and lower reaches of the effluent discharge areas in a typical karst industrial catchment in Southwest China. Results showed that the total average concentrations of N-nitrosamines (∑NAs) in electroplating effluent (1800 ng/L) was significantly higher than that in the receiving river water (130 ng/L) and groundwater (70 ng/L). The dynamic nature of karst aquifers resulted in comparable average concentrations of ∑NAs in groundwater (70 ng/L) and river water (79 ng/L) at this catchment. Based on the principal component analysis and multiple linear regression analysis, the electroplating effluent contributed 89% and 53% of N-nitrosamines to the river water and groundwater, respectively. The results based on the species sensitivity distribution model revealed N-nitrosodibutylamine as a particularly toxic compound to aquatic organisms. Furthermore, the average N-nitrosamine carcinogenic risk was significantly higher in lower groundwater reaches compared to upper reaches. This study represents a pioneering effort in considering specific N-nitrosamine properties in evaluating their toxicity and constructing species sensitivity curves. It underscores the significance of electroplating effluent as a primary N-nitrosamine source in aquatic environments, emphasizing their swift dissemination and significant accumulation in karst groundwater.

Analysing N-nitrosamine occurrence and sources in karst reservoirs, Southwest China.

N-nitrosamines in reservoir water have drawn significant attention because of their carcinogenic properties. Karst reservoirs containing dissolved organic matter (DOM) are important drinking water sources and are susceptible to contamination because of the fast flow of various contaminants. However, it remains unclear whether N-nitrosamines and their precursor, DOM, spread in karst reservoirs. Therefore, this study quantitatively investigated the occurrence and sources of N-nitrosamines based on DOM properties in three typical karst reservoirs and their corresponding tap water. The results showed that N-nitrosamines were widely spread, with detection frequencies > 85%. Similar dominant compounds, including N-nitrosodimethylamine, N-nitrosomethylethylamine, N-nitrosopyrrolidine, and N-nitrosodibutylamine, were observed in reservoirs and tap water, with average concentrations of 4.7-8.9 and 2.8-6.7 ng/L, respectively. The average carcinogenic risks caused by these N-nitrosamines were higher than the risk level of 10-6. Three-dimensional fluorescence excitation-emission matrix modeling revealed that DOM was composed of humus-like component 1 (C1) and protein-like component 2 (C2). Fluorescence indicators showed that DOM in reservoir water was mainly affected by exogenous pollution and algal growth, whereas in tap water, DOM was mainly affected by microbial growth with strong autopoietic properties. In the reservoir water, N-nitrosodiethylamine and N-nitrosopiperidine were significantly correlated with C2 and biological indicators, indicating their endogenously generated sources. Based on the principal component analysis and multiple linear regression methods, five sources of N-nitrosamines were identified: agricultural pollution, microbial sources, humus sources, degradation processes, and other factors, accounting for 46.8%, 36.1%, 7.82%, 8.26%, and 0.96%, respectively. For tap water, two sources, biological reaction processes, and water distribution systems, were identified, accounting for 75.7% and 24.3%, respectively. Overall, this study presents quantitative information on N-nitrosamines' sources based on DOM properties in typical karst reservoirs and tap water, providing a basis for the safety of drinking water for consumers.

Legumain Is an Endogenous Modulator of Integrin αvß3 Triggering Vascular Degeneration, Dissection, and Rupture.

BACKGROUND: The development of thoracic aortic dissection (TAD) is closely related to extracellular matrix degradation and vascular smooth muscle cell (VSMC) transformation from contractile to synthetic type. LGMN (legumain) degrades extracellular matrix components directly or by activating downstream signals. The role of LGMN in VSMC differentiation and the occurrence of TAD remains elusive. METHODS: Microarray datasets concerning vascular dissection or aneurysm were downloaded from the Gene Expression Omnibus database to screen differentially expressed genes. Four-week-old male Lgmn knockout mice (Lgmn-/-), macrophage-specific Lgmn knockout mice (LgmnF/F;LysMCre), and RR-11a-treated C57BL/6 mice were given BAPN (ß-aminopropionitrile monofumarate; 1 g/kg/d) in drinking water for 4 weeks for TAD modeling. RNA sequencing analysis was performed to recapitulate transcriptome profile changes. Cell interaction was examined in macrophage and VSMC coculture system. The reciprocity of macrophage-derived LGMN with integrin αvß3 in VSMCs was tested by coimmunoprecipitation assay and colocalization analyses. RESULTS: Microarray datasets from the Gene Expression Omnibus database indicated upregulated LGMN in aorta from patients with TAD and mice with angiotensin II-induced AAA. Elevated LGMN was evidenced in aorta and sera from patients with TAD and mice with BAPN-induced TAD. BAPN-induced TAD progression was significantly ameliorated in Lgmn-deficient or inhibited mice. Macrophage-specific deletion of Lgmn alleviated BAPN-induced extracellular matrix degradation. Unbiased profiler polymerase chain reaction array and Gene Ontology analysis displayed that LGMN regulated VSMC phenotype transformation. Macrophage-specific deletion of Lgmn ameliorated VSMC phenotypic switch in BAPN-treated mice. Macrophage-derived LGMN inhibited VSMC differentiation in vitro as assessed by macrophages and the VSMC coculture system. Macrophage-derived LGMN bound to integrin αvß3 in VSMCs and blocked integrin αvß3, thereby attenuating Rho GTPase activation, downregulating VSMC differentiation markers and eventually exacerbating TAD development. ROCK (Rho kinase) inhibitor Y-27632 reversed the protective role of LGMN depletion in vascular dissection. CONCLUSIONS: LGMN signaling may be a novel target for the prevention and treatment of TAD.

Knock-out of the critical nitric oxide synthase regulator DDAH1 in mice impacts amphetamine sensitivity and dopamine metabolism.

The enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1) plays a pivotal role in the regulation of nitric oxide levels by degrading the main endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). Growing evidence highlight the potential implication of DDAH/ADMA axis in the etiopathogenesis of several neuropsychiatric and neurological disorders, yet the underlying molecular mechanisms remain elusive. In this study, we sought to investigate the role of DDAH1 in behavioral endophenotypes with neuropsychiatric relevance. To achieve this, a global DDAH1 knock-out (DDAH1-ko) mouse strain was employed. Behavioral testing and brain region-specific neurotransmitter profiling have been conducted to assess the effect of both genotype and sex. DDAH1-ko mice exhibited increased exploratory behavior toward novel objects, altered amphetamine response kinetics and decreased dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) level in the piriform cortex and striatum. Females of both genotypes showed the most robust amphetamine response. These results support the potential implication of the DDAH/ADMA pathway in central nervous system processes shaping the behavioral outcome. Yet, further experiments are required to complement the picture and define the specific brain-regions and mechanisms involved.

Covered stent treatment for arterial complications after pancreatic surgery: risk assessment for recurrence and peri-stent implantation management.

OBJECTIVES: To explore the risk factors for recurrence of arterial complications after pancreatectomy during the period of covered stent implantation and to provide some opinions on peri-stent implantation management. METHODS: Data on patients implanted with covered stents due to arterial complications after pancreatectomy between January 2017 and December 2021 were analyzed retrospectively. Technical success, clinical success, recurrence, and survival were evaluated to elucidate the practicability of covered stents. Wilson score, Random Forest, logistic regression, and Pearson's chi-square test with bootstrap aggregation were performed for determining the perioperative risk factors for recurrence. RESULTS: Among all fifty-five patients, success stent implantation (technical success) was achieved 100%. Patients who were hemodynamically stabilized without further treatment for artery complications in situ (clinical success) accounted for 89.1%. Based on statistical analysis, pre-stent implantation pancreatic fistula was identified as a robust recurrence-related risk factor for preoperative assessment (p = 0.02, OR = 4.5, 95% CI [1.2, 16.9]; pbootstrap = 0.02). Post-stent implantation pancreatic fistula (p = 0.01, OR 4.5, 95% CI [1.4, 14.6]; pbootstrap < 0.05) and SMA branches or GDA stumps (p = 0.02, OR 3.4, 95% CI [1.1, 10.3]) were relevant to recurrence. The survival rate during hospitalization was 87.3%. All survivors were free from recurrence during the subsequent follow-up. Vasospasm and stent occlusion were observed as short-term and long-term complications, respectively. CONCLUSION: A covered stent implantation is a feasible and effective treatment option for post-pancreatectomy arterial complications. Rigorous management of pancreatic fistula, timely detection of problems, sensible strategies during stent implantation, and reasonable anticoagulation therapy are necessary for a better prognosis. KEY POINTS: • A covered stent is feasible for various artery-related complications after pancreatectomy and has an ideal therapeutic effect. • Pancreatic fistula during the perioperative period of the covered stent is an independent risk factor for recurrent arterial complications and SMA branches or GDA stumps are prone to be recurrent offending arteries. • Rigorous management of pancreatic fistula, timely detection of problems, sensible strategies during stent implantation, and reasonable anticoagulation therapy are necessary for a better prognosis.

Superconductivity of monolayer functionalized biphenylene with Dirac cones.

Monolayer biphenylene is a new two-dimensional (2D) carbon allotrope, which has been experimentally synthesized and theoretically predicted to show superconductivity. In this work, we investigate functionalized biphenylene with the adsorption of Li. The superconducting critical temperature (Tc) can be pushed from 0.59 K up to 3.91 K after Li adsorption. Our calculations confirm that the adsorption pushes the peak showing a high electronic density of states closer to the Fermi level, which usually leads to a larger Tc. Furthermore, the application of biaxial tensile strain can soften phonons and further enhance the Tc up to 15.86 K in Li-deposited biphenylene. Interestingly, a pair of type-II Dirac cones below the Fermi level has been observed, expanding the range of Dirac materials. It suggests that monolayer biphenylene deposited with Li may be a material with potential applications and improves the understanding of Dirac-type superconductors.

Urolithin A ameliorates obesity-induced metabolic cardiomyopathy in mice via mitophagy activation.

Metabolic cardiomyopathy (MC) is characterized by intracellular lipid accumulation and utilizing fatty acids as a foremost energy source, thereby leading to excess oxidative stress and mitochondrial dysfunction. There is no effective therapy available yet. In this study we investigated whether defective mitophagy contributed to MC and whether urolithin A (UA), a naturally occurring microflora-derived metabolite, could protect against MC in experimental obese mice. Mice were fed high fat diet for 20 weeks to establish a diet-induced obese model. We showed that mitochondrial autophagy or mitophagy was significantly downregulated in the heart of experimental obese mice. UA (50 mg·kg-1·d-1, for 4 weeks) markedly activated mitophagy and ameliorated MC in obese mice by gavage. In PA-challenged H9C2 cardiomyocytes, UA (5 µM) significantly increased autophagosomes and decreased autolysosomes. Furthermore, UA administration rescued PINK1/Parkin-dependent mitophagy and relieved mitochondrial defects in the heart of obese mice, which led to improving cardiac diastolic function and ameliorating cardiac remodelling. In PA-challenged primarily isolated cardiomyocytes, both application of mitophagy inhibitor Mdivi-1 (15 µM) and silencing of mitophagy gene Parkin blunted the myocardial protective effect of UA. In summary, our data suggest that restoration of mitophagy with UA ameliorates symptoms of MC, which highlights a therapeutic potential of UA in the treatment of MC.

Inhibiting von Hippel‒Lindau protein-mediated Dishevelled ubiquitination protects against experimental parkinsonism.

Dopaminergic neuron degeneration is a hallmark of Parkinson's disease (PD). We previously reported that the inactivation of von Hippel‒Lindau (VHL) alleviated dopaminergic neuron degeneration in a C. elegans model. In this study, we investigated the specific effects of VHL loss and the underlying mechanisms in mammalian PD models. For in vivo genetic inhibition of VHL, AAV-Vhl-shRNA was injected into mouse lateral ventricles. Thirty days later, the mice received MPTP for 5 days to induce PD. Behavioral experiments were conducted on D1, D3, D7, D14 and D21 after the last injection, and the mice were sacrificed on D22. We showed that knockdown of VHL in mice significantly alleviated PD-like syndromes detected in behavioral and biochemical assays. Inhibiting VHL exerted similar protective effects in MPP+-treated differentiated SH-SY5Y cells and the MPP+-induced C. elegans PD model. We further demonstrated that VHL loss-induced protection against experimental parkinsonism was independent of hypoxia-inducible factor and identified the Dishevelled-2 (DVL-2)/ß-catenin axis as the target of VHL, which was evolutionarily conserved in both C. elegans and mammals. Inhibiting the function of VHL promoted the stability of ß-catenin by reducing the ubiquitination and degradation of DVL-2. Thus, in vivo overexpression of DVL-2, mimicking VHL inactivation, protected against PD. We designed a competing peptide, Tat-DDF-2, to inhibit the interaction between VHL and DVL-2, which exhibited pharmacological potential for protection against PD in vitro and in vivo. We propose the therapeutic potential of targeting the interaction between VHL and DVL-2, which may represent a strategy to alleviate neurodegeneration associated with PD.

Controlled synthesis of Fe3O4/MnO2 (3 1 0)/ZIF-67 composite with enhanced synergetic effects for the highly selective and efficient adsorption of Cu (II) from simulated copperplating effluents.

This study designed a composite material with internal synergistic effects among multiple components to achieve highly selective adsorption of Cu (II). Through controlled synthesis, the Fe3O4/MnO2(3 1 0)/ZIF-67 composite was successfully fabricated, leading to significant improvement in adsorption selectivity, capacity, and adsorption rate. The experimental results showed that the composite is of outstanding selectivity in the adsorption of Cu (II), with a partition coefficient K of Cu (II) that was 2.2-5.3 times higher than that of other coexisting ions. Moreover, the composite exhibited a remarkable adsorption capacity of 1261.0 mg g-1 and a fast adsorption rate of 840.7 mg g-1 h-1 at 298 K. Additionally, its magnetic property facilitated easy separation from wastewater, thereby enhancing its potential for commercial applications. The synergetic effect mechanism was analyzed through characterizations and DFT calculations. Furthermore, the recyclability of the composite was investigated, which showed that after seven cycles, the adsorption efficiency remained at 85% of its initial efficiency. It can be concluded that Fe3O4/MnO2(3 1 0)/ZIF-67 has potential to address challenges posed by heavy metal pollution in copperplating effluents.