MAP2K1 DAMPENS CIGARETTE SMOKE-INDUCED LUNG INFLAMMATION VIA SUPPRESSION OF TYPE I INTERFERON PATHWAY ACTIVATION.

Chronic Obstructive Pulmonary Disease (COPD), comprised of chronic bronchitis and emphysema, is a leading cause of morbidity and mortality worldwide. MAP2K (mitogen-activated protein 2 kinase) pathway activation is present in COPD lung tissue and a genetic polymorphism in Map2k1 associates with FEV1 decline in COPD, suggesting it may contribute to disease pathogenesis. To test the functional contribution of Map2k1 in cigarette smoke (CS)-induced lung inflammation, we used a short-term CS exposure model in mice deficient in myeloid Map2k1 (LysmCre+Mek1fl) and wild-type mice (Mek1fl). Mice deficient in myeloid Map2k1 had enhanced CS-induced lung inflammation characterized by increased neutrophil recruitment, augmented expression of elastolytic matrix metalloproteinases, and increased type I interferon-stimulated gene expression. The augmented neutrophilic inflammatory response could be abrogated by IFNAR1 blockade. These findings indicate that myeloid Map2k1 regulates the immune response to CS via inhibition of the type I interferon pathway. Overall, these results suggest that Map2k1 is a critical determinant in modulating the severity of CS-induced lung inflammation and its expression is protective.

The Role of 3' Regulatory Region Flanking Kinectin 1 Gene in Schizophrenia.

Objective: Schizophrenia is often associated with volumetric reductions in cortices and expansions in basal ganglia, particularly the putamen. Recent genome-wide association studies have highlighted the significance of variants in the 3' regulatory region adjacent to the kinectin 1 gene (KTN1) in regulating gray matter volume (GMV) of the putamen. This study aimed to comprehensively investigate the involvement of this region in schizophrenia. Methods: We analyzed 1136 single-nucleotide polymorphisms (SNPs) covering the entire 3' regulatory region in 4 independent dbGaP samples (4604 schizophrenia patients vs. 4884 healthy subjects) and 3 independent Psychiatric Genomics Consortium samples (107 240 cases vs. 210 203 controls) to identify consistent associations. Additionally, we examined the regulatory effects of schizophrenia-associated alleles on KTN1 mRNA expression in 16 brain areas among 348 subjects, as well as GMVs of 7 subcortical nuclei in 38 258 subjects, and surface areas (SA) and thickness (TH) of the entire cortex and 34 cortical areas in 36 936 subjects. Results: The major alleles (f > 0.5) of 25 variants increased (ß > 0) the risk of schizophrenia across 2 to 5 independent samples (8.4 × 10-4 ≤ P ≤ .049). These schizophrenia-associated alleles significantly elevated (ß > 0) GMVs of basal ganglia, including the putamen (6.0 × 10-11 ≤ P ≤ 1.1 × 10-4), caudate (8.7 × 10-4 ≤ P ≤ 9.4 × 10-3), pallidum (P = 6.0 × 10-4), and nucleus accumbens (P = 2.7 × 10-5). Moreover, they potentially augmented (ß > 0) the SA of posterior cingulate and insular cortices, as well as the TH of frontal (pars triangularis and medial orbitofrontal), parietal (superior, precuneus, and inferior), and temporal (transverse) cortices, but potentially reduced (ß < 0) the SA of the whole, frontal (medial orbitofrontal), and temporal (pole, superior, middle, and entorhinal) cortices, as well as the TH of rostral middle frontal and superior frontal cortices (8.9 × 10-4 ≤ P ≤ .050). Conclusion: Our findings identify significant and functionally relevant risk alleles in the 3' regulatory region adjacent to KTN1, implicating their crucial roles in the development of schizophrenia.

A framework for extending co-creative communication models to sustainability research.

The UN Sustainable Development Goals (SDGs) present a challenge due to their potential for conflicting objectives, which hinders their effective implementation. In order to address the complexity of sustainability issues, a framework capable of capturing the specificity of diverse sustainability issues while offering a common methodology applicable across contexts is required. Co-creative communication can be regarded as a key source of uncertainty within functional systems, as it can be instrumental in realizing and sustaining sustainability. In this regard, the studies in Constructive approaches to Co-creative Communication (CCC), particularly those employing artificial intelligence (AI) methodologies such as computational social science and innovation studies, hold significant value for both theoretical and applied sustainability research. However, existing CCC frameworks cannot be directly applied to sustainability research. This work bridges this gap by proposing a framework that outlines a general approach to establishing formalized definitions of sustainability from the lens of communication. This approach enables the direct application of CCC models to sustainability studies. The framework is based on systems theory and the methodologies of artificial intelligence, including computational/symbolic modeling and formal methods. This framework emphasizes the social function of co-creative communication and the interaction between the innovation process and the sustainability of the system. It can be concluded that the application of our framework enables the achievements of CCC to be directly applied to sustainability research. Researchers from different disciplines are therefore able to establish their own specific definitions of sustainability, which are tailored to their particular concerns. Our framework lays the groundwork for future sustainability studies that employs CCC, facilitating the integration of CCC insights into sustainability research and application. The outcomes of computational creativity research based on AI technologies, such as distributed artificial intelligence and self-organizing networks, can deepen the understanding of sustainability mechanisms and drive their practical applications. Furthermore, the functional role of co-creative communication in societal sustainability proposed in this work offers a novel perspective for future discussions on the evolutionary adaptation of co-creative communication.

Does Electroencephalography Seizure Duration Account for an Adequate Treatment of Magnetic Seizure Therapy for Schizophrenia?

OBJECTIVES: A seizure lasting >15 s has been considered to indicate treatment for magnetic seizure therapy (MST), a modification of electroconvulsive therapy (ECT), without much validation. This study aimed to investigate whether this seizure duration was suitable for the treatment of schizophrenia. METHODS: Altogether, 34 and 33 in-patients with schizophrenia received 10 sessions of MST and ECT, respectively. Clinical symptoms were assessed using the Positive and Negative Symptom Scale at baseline and at the 4-week follow-up. Electroencephalogram (EEG) was monitored during each MST or ECT treatment using bifrontal electrodes. RESULTS: The proportion of participants who achieved the 15-second threshold was only 28.6% in the MST group, with a significant difference between responders and nonresponders. For patients receiving MST, the average EEG seizure duration correlated with the percentage of Positive and Negative Symptom Scale reduction (t(32) = 2.51, P = 0.017, uncorrected; t(32) = 2.00, P = 0.055, corrected with clinical characteristics). The average EEG seizure duration predicted the clinical response at a trend level (Z = 1.76, P = 0.078) with an optimal cutoff of 11.3 seconds. All patients in the ECT group achieved the 15-second threshold. However, their average EEG seizure duration was uncorrelated with clinical improvement. CONCLUSIONS: The duration of EEG seizures may be associated with the antipsychotic effects of MST. This association may have been influenced by various clinical and technical factors. More research is needed to define the specific criteria for adequate MST in schizophrenia in order to achieve personalized dosing.

Laminarin-modulated osmium nanozymes with high substrate-affinity and selective peroxidase-like behavior engineered colorimetric assay for hydroxyl radical scavenging capacity estimation.

Hydroxyl radical (·OH) scavenging capacity (HOSC) estimation is essential for evaluating antioxidants, natural extracts, or drugs against clinical diseases. While nanozymes offer advantages in related applications, they still face limitations in activity and selectivity. In response, this work showcases the fabrication of laminarin-modulated osmium (laminarin-Os) nanoclusters (1.45 ± 0.05 nm), functioning as peroxidase-like nanozymes within a colorimetric assay tailored for rational HOSC estimation. This study validates both the characterization and remarkable stability of laminarin-Os. By leveraging the abundant surface negative charges of laminarin-Os and the surface hydroxyls of laminarin, oxidation reactions are facilitated, augmenting laminarin-Os's affinity for 3,3',5,5'-tetramethylbenzidine (TMB) (KM = 0.04 mM). This enables the laminarin-Os-based colorimetric assay to respond to ·OH more effectively than citrate-, albumin-, or other polysaccharides-based Os. In addition, experimental results also validate the selective peroxidase-like behavior of laminarin-Os under acidic conditions. Antioxidants like ascorbic acid, glutathione, tannic acid, and cysteine inhibit absorbance at 652 nm in the colorimetric platform using laminarin-Os's peroxidase-like activity. Compared with commercial kits, this assay demonstrates superior sensitivity (e.g., responds to ascorbic acid 0.01-0.075 mM, glutathione 1-15 µg/mL, tannic acid 0.5-5 µM, and monoammonium glycyrrhizinate cysteine 1.06-10.63 µM) and HOSC testing for glutathione, tannic acid, and monoammonium glycyrrhizinate cysteine. Overall, this study introduces a novel Os nanozyme with exceptional TMB affinity and ·OH selectivity, paving the way for HOSC estimation in biomedical research, pharmaceutical analysis, drug quality control, and beyond.

The impact of microplastics polystyrene on the microscopic structure of mouse intestine, tight junction genes and gut microbiota.

Microplastics, which are tiny plastic particles less than 5 mm in diameter, are widely present in the environment, have become a serious threat to aquatic life and human health, potentially causing ecosystem disorders and health problems. The present study aimed to investigate the effects of microplastics, specifically microplastics-polystyrene (MPs-PS), on the structural integrity, gene expression related to tight junctions, and gut microbiota in mice. A total of 24 Kunming mice aged 30 days were randomly assigned into four groups: control male (CM), control female (CF), PS-exposed male (PSM), and PS-exposed female (PSF)(n = 6). There were significant differences in villus height, width, intestinal surface area, and villus height to crypt depth ratio (V/C) between the PS group and the control group(C) (p <0.05). Gene expression analysis demonstrated the downregulation of Claudin-1, Claudin-2, Claudin-15, and Occludin, in both duodenum and jejunum of the PS group (p < 0.05). Analysis of microbial species using 16S rRNA sequencing indicated decreased diversity in the PSF group, as well as reduced diversity in the PSM group at various taxonomic levels. Beta diversity analysis showed a significant difference in gut microbiota distribution between the PS-exposed and C groups (R2 = 0.113, p<0.01), with this difference being more pronounced among females exposed to MPs-PS. KEGG analysis revealed enrichment of differential microbiota mainly involved in seven signaling pathways, such as nucleotide metabolism(p<0.05). The relative abundance ratio of transcriptional pathways was significantly increased for the PSF group (p<0.01), while excretory system pathways were for PSM group(p<0.05). Overall findings suggest that MPs-PS exhibit a notable sex-dependent impact on mouse gut microbiota, with a stronger effect observed among females; reduced expression of tight junction genes may be associated with dysbiosis, particularly elevated levels of Prevotellaceae.

Role of mitochondria-associated membranes in the hippocampus in the pathogenesis of depression.

BACKGROUND: Pathological changes, such as microglia activation in the hippocampus frequently occur in individuals with animal models of depression; however, they may share a common cellular mechanism, such as endoplasmic reticulum (ER) stress and mitochondrial dysfunction. Mitochondria associated membranes (MAMs) are communication platforms between ER and mitochondria. This study aimed to investigate the role of intracellular stress responses, especially structural and functional changes of MAMs in depression. METHODS: We used chronic social defeat stress (CSDS) to mimic depression in C57 mice to investigate the pathophysiological changes in the hippocampus associated with depression and assess the antidepressant effect of electroacupuncture (EA). Molecular, histological, and electron microscopic techniques were utilized to study intracellular stress responses, including the ER stress pathway reaction, mitochondrial damage, and structural and functional changes in MAMs in the hippocampus after CSDS. Proteomics technology was employed to explore protein-level changes in MAMs caused by CSDS. RESULTS: CSDS caused mitochondrial dysfunction, ER stress, closer contact between ER and mitochondria, and enrichment of functional protein clusters at MAMs in hippocampus along with depressive-like behaviors. Also, EA showed beneficial effects on intracellular stress responses and depressive-like behaviors in CSDS mice. LIMITATION: The cellular specificity of MAMs related protein changes in CSDS mice was not explored. CONCLUSIONS: In the hippocampus, ER stress and mitochondrial damage occur, along with enriched mitochondria-ER interactions and MAM-related protein enrichment, which may contribute to depression's pathophysiology. EA may improve depression by regulating intracellular stress responses.

Anisotropic composite aerogel with thermal insulation and flame retardancy from cellulose nanofibers, calcium alginate and boric acid.

With the increasing severity of energy shortages and environmental pollution, there is an urgent need for advanced thermal insulation materials with excellent comprehensive performance, including low thermal conductivity, high flame resistance, and strong compressive strength. Herein, an anisotropic composite aerogel based on cellulose nanofibers (CNF), calcium alginate (CA), and boric acid (BA) is fabricated using a directional freeze-drying strategy. The CA and BA, as double cross-linking agents, associated with oriented porous structure provide the resultant aerogel with good mechanical strength. Additionally, self-flame retardant CA and BA act as synergistic flame retardants that endow the aerogel with excellent flame retardance properties such as a limiting oxygen index value of 44.2 %, UL-94 V-0 rating, and low heat release. Furthermore, this composite aerogel exhibits outstanding thermal insulation performance with a low thermal conductivity of approximately 30 mW m-1 K-1. Therefore, the composite aerogel is expected to have a wide potential application in areas such as construction, automotive industry, batteries, petrochemical pipelines, and high-temperature reaction devices.

Environmental Controls on Evapotranspiration and Its Components in a Qinghai Spruce Forest in the Qilian Mountains.

Qinghai spruce forests, found in the Qilian mountains, are a typical type of water conservation forest and play an important role in regulating the regional water balance and quantifying the changes and controlling factors for evapotranspiration (ET) and its components, namely, transpiration (T), evaporation (Es) and canopy interceptions (Ei), of the Qinghai spruce, which may provide rich information for improving water resource management. In this study, we partitioned ET based on the assumption that total ET equals the sum of T, Es and Ei, and then we analyzed the environmental controls on ET, T and Es. The results show that, during the main growing seasons of the Qinghai spruce (from May to September) in the Qilian mountains, the total ET values were 353.7 and 325.1 mm in 2019 and 2020, respectively. The monthly dynamics in the daily variations in T/ET and Es/ET showed that T/ET increased until July and gradually decreased afterwards, while Es/ET showed opposite trends and was mainly controlled by the amount of precipitation. Among all the ET components, T always occupied the largest part, while the contribution of Es to ET was minimal. Meanwhile, Ei must be considered when partitioning ET, as it accounts for a certain percentage (greater than one-third) of the total ET values. Combining Pearson's correlation analysis and the boosted regression trees method, we concluded that net radiation (Rn), soil temperature (Ts) and soil water content (SWC) were the main controlling factors for ET. T was mainly determined by the radiation and soil hydrothermic factors (Rn, photosynthetic active radiation (PAR) and TS30), while Es was mostly controlled by the vapor pressure deficit (VPD), atmospheric precipitation (Pa), throughfall (Pt) and air temperature (Ta). Our study may provide further theoretical support to improve our understanding of the responses of ET and its components to surrounding environments.

[Retracted] LncRNA GAS6 antisense RNA 1 facilitates the tumorigenesis of clear cell renal cell carcinoma by regulating the AMP­activated protein kinase/mTOR signaling pathway.

[This retracts the article DOI: 10.3892/ol.2021.12988.].

Leritrelvir for the treatment of mild or moderate COVID-19 without co-administered ritonavir: a multicentre randomised, double-blind, placebo-controlled phase 3 trial.

Background: Leritrelvir is a novel α-ketoamide based peptidomimetic inhibitor of SARS-CoV-2 main protease. A preclinical study has demonstrated leritrelvir poses similar antiviral activities towards different SARS-CoV-2 variants compared with nirmatrelvir. A phase 2 clinical trial has shown a comparable antiviral efficacy and safety between leritrelvir with and without ritonavir co-administration. This trial aims to test efficacy and safety of leritrelvir monotherapy in adults with mild-to-moderate COVID-19. Methods: This was a randomised, double-blind, placebo-controlled, multicentre phase 3 trial at 29 clinical sites in China. Enrolled patients were from 18 to 75 years old, diagnosed with mild or moderate COVID-19 and not requiring hospitalization. Patients had a positive SARS-CoV-2 nucleic acid test (NAT) and at least one of the COVID-19 symptoms within 48 h before randomization, and the interval between the first positive SARS-CoV-2 NAT and randomization was ≤120 h (5 days). Patients were randomly assigned in a 1:1 ratio to receive a 5-day course of either oral leritrelvir 400 mg TID or placebo. The primary efficacy endpoint was the time from the first dose to sustained clinical recovery of all 11 symptoms (stuffy or runny nose, sore throat, shortness of breath or dyspnea, cough, muscle or body aches, headache, chills, fever ≥37 °C, nausea, vomiting, and diarrhea). The safety endpoint was the incidence of adverse events (AE). Primary and safety analyses were performed in the intention-to-treat (ITT) population. This study is registered with ClinicalTrials.gov, NCT05620160. Findings: Between Nov 12 and Dec 30, 2022 when the zero COVID policy was abolished nationwide, a total of 1359 patients underwent randomization, 680 were assigned to leritrelvir group and 679 to placebo group. The median time to sustained clinical recovery in leritrelvir group was significantly shorter (251.02 h [IQR 188.95-428.68 h]) than that of Placebo (271.33 h [IQR 219.00-529.63 h], P = 0.0022, hazard ratio [HR] 1.20, 95% confidence interval [CI], 1.07-1.35). Further analysis of subgroups for the median time to sustained clinical recovery revealed that (1) subgroup with positive viral nucleic acid tested ≤72 h had a 33.9 h difference in leritrelvir group than that of placebo; (2) the subgroup with baseline viral load >8 log 10 Copies/mL in leritrelvir group had 51.3 h difference than that of placebo. Leritrelvir reduced viral load by 0.82 log10 on day 4 compared to placebo. No participants in either group progressed to severe COVID-19 by day 29. Adverse events were reported in two groups: leritrelvir 315 (46.46%) compared with placebo 292 (43.52%). Treatment-relevant AEs were similar 218 (32.15%) in the leritrelvir group and 186 (27.72%) in placebo. Two cases of COVID-19 pneumonia were reported in placebo group, and one case in leritrelvir group, none of them were considered by the investigators to be leritrelvir related. The most frequently reported AEs (occurring in ≥5% of participants in at least one group) were laboratory finding: hypertriglyceridemia (leritrelvir 79 [11.7%] vs. placebo 70 [10.4%]) and hyperlipidemia (60 [8.8%] vs. 52 [7.7%]); all of them were nonserious. Interpretation: Leritrelvir monotherapy has good efficacy for mild-to-moderate COVID-19 and without serious safety concerns. Funding: This study was funded by the National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine, Guangdong Science and Technology Foundation, Guangzhou Science and Technology Planning Project and R&D Program of Guangzhou Laboratory.

Intracranial infection accompanied sweet's syndrome in a patient with anti-interferon-γ autoantibodies: A case report.

BACKGROUND: Several reports of adult-onset immunodeficiency syndrome have been associated with anti-interferon-gamma (IFN-γ) autoantibodies (AIGAs). However, it is rare to find AIGAs with intracranial infections. CASE SUMMARY: In this case study, we report a case of an AIGAs with intracranial infection and hand rashes considered Sweet's syndrome. The patient presented to our hospital with a persistent cough, a fever that had been going on for 6 mo, and a rash that had been going on for a week. The patient started losing consciousness gradually on the fourth day after admission, with neck stiffness and weakened limb muscles. The upper lobe of the left lung had a high-density mass with no atypia and a few inflammatory cells in the interstitium. Brain magnetic resonance imaging and cerebrospinal fluid suggest intracranial infection. The pathology of the skin damage on the right upper extremity revealed an infectious lesion that was susceptible to Sweet's disease. It has an anti-IFN-γ autoantibody titer of 1:2500. She was given empirical anti-non-tuberculous mycobacterial and antifungal treatments. The patient had no fever, obvious cough, headache, or rash on the hand. She got out of bed and took care of herself following hospitalization and discharge with medicine. CONCLUSION: Adults with severe and recurrent infections of several organs should be considered for AIGAs if no other known risk factors exist. AIGAs are susceptible to subsequent intracranial infections and Sweet's syndrome.

Program of algorithm for pharmacological treatment of major depressive disorder in China: Benefits or not?

Background: This research was designed to investigate Algorithm Guided Treatment (AGT) and clinical traits for the prediction of antidepressant treatment outcomes in Chinese patients with major depressive disorder (MDD). Methods: This study included 581 patients who had reached treatment response and 406 patients remained non-responded observed after three months of treatment. Sociodemographic factors, clinical traits, and psychiatric rating scales for evaluating therapeutic responses between the two groups were compared. Logistic regression analysis was adopted to determine the risk factors of unresponsive to antidepressant (URA) in MDD. Kaplan-Meier survival analysis was utilized to compare the therapeutic response between AGT and treatment as usual (TAU). Results: Compared to the MDD responsive to antidepressant (RA) group, the URA group had significantly lower rates of the following clinical traits: married status, anxious distress, moderate to severe depressive symptoms, and higher rates of comorbidity (p-value < 0.05). Logistic Regression Analysis showed that eight clinical traits from psychiatric rating scales, such as anxious characteristics, were correlated positively with URA, while the other eight symptoms, such as autonomic symptoms, were negatively correlated. Time to symptomatic remission was longer in TAU without statistically significant (p-value = 0.11) by log-rank testing. Conclusions: The factors may affect the therapeutic responses and compliance of patients, increasing the non-response risk for antidepressants. Therapeutic responses might be improved by increasing the clarification and elucidation of different symptom clusters of patients. Benefits on treatment response to AGT were not found in our study, indicating a one-size-fits-all approach may not work.Trial Registration: We registered as a clinical trial at the International Clinical Trials Registry Platform (No. NCT01764867) and obtained ethical approval 2012-42 from SMHC.

Design and testing of a humanized porcine donor for xenotransplantation.

Recent human decedent model studies1,2 and compassionate xenograft use3 have explored the promise of porcine organs for human transplantation. To proceed to human studies, a clinically ready porcine donor must be engineered and its xenograft successfully tested in nonhuman primates. Here we describe the design, creation and long-term life-supporting function of kidney grafts from a genetically engineered porcine donor transplanted into a cynomolgus monkey model. The porcine donor was engineered to carry 69 genomic edits, eliminating glycan antigens, overexpressing human transgenes and inactivating porcine endogenous retroviruses. In vitro functional analyses showed that the edited kidney endothelial cells modulated inflammation to an extent that was indistinguishable from that of human endothelial cells, suggesting that these edited cells acquired a high level of human immune compatibility. When transplanted into cynomolgus monkeys, the kidneys with three glycan antigen knockouts alone experienced poor graft survival, whereas those with glycan antigen knockouts and human transgene expression demonstrated significantly longer survival time, suggesting the benefit of human transgene expression in vivo. These results show that preclinical studies of renal xenotransplantation could be successfully conducted in nonhuman primates and bring us closer to clinical trials of genetically engineered porcine renal grafts.

A novel risk variant block across introns 36-45 of CACNA1C for schizophrenia: a cohort-wise replication and cerebral region-wide validation study.

OBJECTIVES: Numerous genome-wide association studies have identified CACNA1C as one of the top risk genes for schizophrenia. As a necessary post-genome-wide association study (GWAS) follow-up, here, we focused on this risk gene, carefully investigated its novel risk variants for schizophrenia, and explored their potential functions. METHODS: We analyzed four independent samples (including three European and one African-American) comprising 5648 cases and 6936 healthy subjects to identify replicable single nucleotide polymorphism-schizophrenia associations. The potential regulatory effects of schizophrenia-risk alleles on CACNA1C mRNA expression in 16 brain regions (n = 348), gray matter volumes (GMVs) of five subcortical structures (n = 34 431), and surface areas and thickness of 34 cortical regions (n = 36 936) were also examined. RESULTS: A novel 17-variant block across introns 36-45 of CACNA1C was significantly associated with schizophrenia in the same effect direction across at least two independent samples (1.8 × 10-4 ≤ P ≤ 0.049). Most risk variants within this block showed significant associations with CACNA1C mRNA expression (1.6 × 10-3 ≤ P ≤ 0.050), GMVs of subcortical structures (0.016 ≤ P ≤ 0.048), cortical surface areas (0.010 ≤ P ≤ 0.050), and thickness (0.004 ≤ P ≤ 0.050) in multiple brain regions. CONCLUSION: We have identified a novel and functional risk variant block at CACNA1C for schizophrenia, providing further evidence for the important role of this gene in the pathogenesis of schizophrenia.

Oxidative stress induces mitochondrial iron overload and ferroptotic cell death.

Oxidative stress has been shown to induce cell death in a wide range of human diseases including cardiac ischemia/reperfusion injury, drug induced cardiotoxicity, and heart failure. However, the mechanism of cell death induced by oxidative stress remains incompletely understood. Here we provide new evidence that oxidative stress primarily induces ferroptosis, but not apoptosis, necroptosis, or mitochondria-mediated necrosis, in cardiomyocytes. Intriguingly, oxidative stress induced by organic oxidants such as tert-butyl hydroperoxide (tBHP) and cumene hydroperoxide (CHP), but not hydrogen peroxide (H2O2), promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to increased lipid peroxidation. Moreover, elevated oxidative stress is also linked to labile iron overload through downregulation of the transcription suppressor BTB and CNC homology 1 (Bach1), upregulation of heme oxygenase 1 (HO-1) expression, and enhanced iron release via heme degradation. Strikingly, oxidative stress also promoted HO-1 translocation to mitochondria, leading to mitochondrial iron overload and lipid reactive oxygen species (ROS) accumulation. Targeted inhibition of mitochondrial iron overload or ROS accumulation, by overexpressing mitochondrial ferritin (FTMT) or mitochondrial catalase (mCAT), respectively, markedly inhibited oxidative stress-induced ferroptosis. The levels of mitochondrial iron and lipid peroxides were also markedly increased in cardiomyocytes subjected to simulated ischemia and reperfusion (sI/R) or the chemotherapeutic agent doxorubicin (DOX). Overexpressing FTMT or mCAT effectively prevented cardiomyocyte death induced by sI/R or DOX. Taken together, oxidative stress induced by organic oxidants but not H2O2 primarily triggers ferroptotic cell death in cardiomyocyte through GPX4 and Bach1/HO-1 dependent mechanisms. Our results also reveal mitochondrial iron overload via HO-1 mitochondrial translocation as a key mechanism as well as a potential molecular target for oxidative stress-induced ferroptosis in cardiomyocytes.

Estimating canopy stomatal conductance and photosynthesis in apple trees by upscaling parameters from the leaf scale to the canopy scale in Jinzhong Basin on Loess Plateau.

The estimations of stomatal conductance and photosynthesis performed by upscaling the parameters from the leaf scale to the canopy scale are key points in the fields of forest ecohydrology and physiology. The foundation for solving this scientific problem is determining the optimal models for calculating the leaf stomatal conductance (gl) and photosynthetic rate (Pl). In this study, we used the Jarvis model combined with modification factors, including leaf-air temperature (ΔT) and CO2 concentration inside and outside the stomata (ΔC), to estimate gl and the new Ye light-response model to estimate the Pl of apple trees in Jinzhong Basin on Loess Plateau. The results show that the modified Jarvis (JarvisΔT-ΔC) model and the new Ye light-response model could estimate gl and Pl, respectively, with very high accuracy, with R2 values of 0.926 and 0.959 for the former, and 0.987 and 0.983 for the latter in 2019 and 2021, respectively. Then, we estimated the canopy stomatal conductance (gc) and photosynthetic rate (Pc) by first dividing the apple tree canopy into sunlit and shaded leaves and then summing the contribution of sunlit and shaded gl, Pl and leaf area index. Our efforts will be a valid reference for estimating the gc and Pc of other tree or crop species in the future.

Ferroptosis contributes to catecholamine-induced cardiotoxicity and pathological remodeling.

High levels of circulating catecholamines cause cardiac injury, pathological remodeling, and heart failure, but the underlying mechanisms remain elusive. Here we provide both in vitro and in vivo evidence that excessive ß-adrenergic stimulation induces ferroptosis in cardiomyocytes, revealing a novel mechanism for catecholamine-induced cardiotoxicity and remodeling. We found that isoproterenol, a synthetic catecholamine, promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to GPX4 inactivation and enhanced lipid peroxidation. Isoproterenol also promoted heme oxygenase 1 (HO-1) expression by downregulating the transcription suppressor BTB and CNC homology 1 (Bach1), leading to increased labile iron accumulation through heme degradation. Moreover, isoproterenol markedly induced the accumulation of free iron and lipid reactive oxygen species (ROS) in the mitochondria, while targeted inhibition of iron overload and ROS accumulation within mitochondria effectively inhibited ferroptosis in cardiomyocytes. Importantly, isoproterenol administration markedly induced ferroptosis in the myocardium in vivo, associated with elevated non-heme iron accumulation driven by HO-1 upregulation. Strikingly, blockade of ferroptosis with ferrostatin-1 or inhibition of HO-1 activity with zinc protoporphyrin (ZnPP) effectively alleviated cardiac necrosis, pathological remodeling, and heart failure induced by isoproterenol administration. Taken together, our results reveal that catecholamine stimulation primarily induces ferroptotic cell death in cardiomyocyte through GPX4 and Bach1-HO-1 dependent signaling pathways. Targeting ferroptosis may represent a novel therapeutic strategy for catecholamine overload-induced myocardial injury and heart failure.

Pleiotropic Association of CACNA1C Variants With Neuropsychiatric Disorders.

BACKGROUND: Neuropsychiatric disorders are highly heritable and have overlapping genetic underpinnings. Single nucleotide polymorphisms (SNPs) in the gene CACNA1C have been associated with several neuropsychiatric disorders, across multiple genome-wide association studies. METHOD: A total of 70,711 subjects from 37 independent cohorts with 13 different neuropsychiatric disorders were meta-analyzed to identify overlap of disorder-associated SNPs within CACNA1C. The differential expression of CACNA1C mRNA in five independent postmortem brain cohorts was examined. Finally, the associations of disease-sharing risk alleles with total intracranial volume (ICV), gray matter volumes (GMVs) of subcortical structures, cortical surface area (SA), and average cortical thickness (TH) were tested. RESULTS: Eighteen SNPs within CACNA1C were nominally associated with more than one neuropsychiatric disorder (P < .05); the associations shared among schizophrenia, bipolar disorder, and alcohol use disorder survived false discovery rate correction (five SNPs with P < 7.3 × 10-4 and q < 0.05). CACNA1C mRNA was differentially expressed in brains from individuals with schizophrenia, bipolar disorder, and Parkinson's disease, relative to controls (three SNPs with P < .01). Risk alleles shared by schizophrenia, bipolar disorder, substance dependence, and Parkinson's disease were significantly associated with ICV, GMVs, SA, or TH (one SNP with P ≤ 7.1 × 10-3 and q < 0.05). CONCLUSION: Integrating multiple levels of analyses, we identified CACNA1C variants associated with multiple psychiatric disorders, and schizophrenia and bipolar disorder were most strongly implicated. CACNA1C variants may contribute to shared risk and pathophysiology in these conditions.