Engineering the Impact of Phonon Dephasing on the Coherence of a WSe_{2} Single-Photon Source via Cavity Quantum Electrodynamics.

Emitter dephasing is one of the key issues in the performance of solid-state single-photon sources. Among the various sources of dephasing, acoustic phonons play a central role in adding decoherence to the single-photon emission. Here, we demonstrate that it is possible to tune and engineer the coherence of photons emitted from a single WSe_{2} monolayer quantum dot via selectively coupling it to a spectral cavity resonance. We utilize an open cavity to demonstrate spectral enhancement, leveling, and suppression of the highly asymmetric phonon sideband, finding excellent agreement with a microscopic description of the exciton-phonon dephasing in a truly two-dimensional system. Moreover, the impact of cavity tuning on the dephasing is directly assessed via optical interferometry, which points out the capability to utilize light-matter coupling to steer and design dephasing and coherence of quantum emitters in atomically thin crystals.

Bioactive compounds from Dichloromethane extract of Artemisia rupestris L. alleviates CCl4/ConA-induced acute liver injury by inhibiting PI3K-AKT pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia rupestris L. (AR) is a traditional medicinal herb commonly used in the Uyghurs and Kazakhs; it was first documented in the Supplement to Compendium of Materia Medica written by Zhao Xuemin in the Qing Dynasty of China and is used clinically to treat colds, hepatitis, and allergic diseases. AIM OF THE STUDY: The material basis and mechanisms of AR in acute liver injury (ALI) remain unclear. The purpose of this study was to reveal the possible active components involved in liver protection in AR and to preliminarily explore their pharmacological mechanisms. MATERIALS AND METHODS: The chemical composition of the ethanolic extract (ARA) was identified by UPLC-Q-Exactive-MS/MS and confirmed by 32 reference standards. The pharmacodynamic results were utilized to screen the active part within the ARA that contribute to the amelioration of CCl4/ConA-induced ALI. The main active components and core targets were predicted by network pharmacology and verified by molecular docking combined with qPCR and Western blotting. RESULTS: A total of 131 chemical components were identified in the ARA. The extraction parts of ARA had different therapeutic effects on ALI, among which the dichloromethane extract (ARA-D), which might constitute the main effective fraction of ARA, had significant anti-ALI effects. The network pharmacology results showed that targets including PIK3R1, AKT1, and EGFR, as well as 7 compounds, such as artemetin, vitexicarpin and rupestonic acid may play pivotal roles in treating CCl4/ConA-induced ALI. GO and KEGG pathway enrichment analyses revealed that the PI3K-AKT signaling pathway was the main pathway involved. In each model, ARA-D dose-dependently reduced the increase in ALT levels. High-dose ARA-D markedly decreased ALT activity from 196.79 ± 24.82 to 66.37 ± 16.19 U/L in the CCl4 model group and from 178.00 ± 28.39 to 50.67 ± 7.39 U/L in the ConA model group. Further studies revealed that ARA-D significantly inhibited TNF-α, IL-1ß, and IL-6 expression and inhibited the protein expression of PI3K, p-PI3K, and p-AKT in CCl4/ConA-induced ALI. CONCLUSION: ARA-D exhibits protective effects against ALI induced by CCl4/ConA, potentially through inhibition of the PI3K-AKT signaling pathway. These findings may help to determine the material basis and mechanisms of action of ARA-D for liver protection and provide ideas for future comprehensive studies.

Design, synthesis and neuroprotective biological evaluation of novel HDAC6 inhibitors incorporating benzothiadiazinyl systems as cap groups.

Histone deacetylase 6 (HDAC6), as the key regulatory enzyme, plays an important role in the development of the nervous system. More and more studies indicate that HDAC6 has become a promising therapeutic target for CNS diseases. Herein we designed and synthesized a series of novel HDAC6 inhibitors with benzothiadiazinyl systems as cap groups and evaluated their activity in vitro and in vivo. Among them, compound 3 exhibited superior selective inhibitory activity against HDAC6 (IC50 = 5.1 nM, about 30-fold selectivity over HDAC1). The results of docking showed that compound 3 can interact well with the key amino acid residues of HDAC6. Compound 3 showed lower cytotoxicity (20 µM to SH-SY5Y cells, inhibition rate = 25.75%) and better neuroprotective activity against L-glutamate-induced SH-SY5Y cell injury model in vitro. Meanwhile, compound 3 exhibited weak cardiotoxicity (10 µM hERG inhibition rate = 17.35%) and possess good druggability properties. Especially, compound 3 could significantly reduce cerebral infarction from 49.87% to 32.18%, and similar with butylphthalide in MCAO model, indicating potential clinical application prospects for alleviating ischemic stroke-induced brain infarction.

Polymorphisms of CYP7A1 and HADHB Genes and Their Effects on Milk Production Traits in Chinese Holstein Cows.

Our preliminary research proposed the cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and hydroxyacyl-coenzyme A dehydrogenase trifunctional multienzyme complex beta subunit (HADHB) genes as candidates for association with milk-production traits in dairy cattle because of their differential expression across different lactation stages in the liver tissues of Chinese Holstein cows and their potential roles in lipid metabolism. Hence, we identified single-nucleotide polymorphisms (SNPs) of the CYP7A1 and HADHB genes and validated their genetic effects on milk-production traits in a Chinese Holstein population with the goal of providing valuable genetic markers for genomic selection (GS) in dairy cattle, This study identified five SNPs, 14:g.24676921A>G, 14:g.24676224G>A, 14:g.24675708G>T, 14:g.24665961C>T, and 14:g.24664026A>G, in the CYP7A1 gene and three SNPs, 11:g.73256269T>C, 11:g.73256227A>C, and 11:g.73242290C>T, in HADHB. The single-SNP association analysis revealed significant associations (p value ≤ 0.0461) between the eight SNPs of CYP7A1 and HADHB genes and 305-day milk, fat and protein yields. Additionally, using Haploview 4.2, we found that the five SNPs of CYP7A1 formed two haplotype blocks and that the two SNPs of HADHB formed one haplotype block; notably, all three haplotype blocks were also significantly associated with milk, fat and protein yields (p value ≤ 0.0315). Further prediction of transcription factor binding sites (TFBSs) based on Jaspar software (version 2023) showed that the 14:g.24676921A>G, 14:g.24675708G>T, 11:g.73256269T>C, and 11:g.73256227A>C SNPs could alter the 5' terminal TFBS of the CYP7A1 and HADHB genes. The 14:g.24665961C>T SNP caused changes in the structural stability of the mRNA for the CYP7A1 gene. These alterations have the potential to influence gene expression and, consequently, the phenotype associated with milk-production traits. In summary, we have confirmed the genetic effects of CYP7A1 and HADHB genes on milk-production traits in dairy cattle and identified potential functional mutations that we suggest could be used for GS of dairy cattle and in-depth mechanistic studies of animals.

Prognostic value of a nomogram model for postoperative liver metastasis of colon cancer.

BACKGROUND: Colon cancer is one of the most common malignant tumors of the digestive system. Liver metastasis after colon cancer surgery is the primary cause of death in patients with colon cancer. AIM: To construct a novel nomogram model including various factors to predict liver metastasis after colon cancer surgery. METHODS: We retrospectively analyzed 242 patients with colon cancer who were admitted and underwent radical resection for colon cancer in Zhejiang Provincial People's Hospital from December 2019 to December 2022. Patients were divided into liver metastasis and non-liver metastasis groups. Sex, age, and other general and clinicopathological data (preoperative blood routine and biochemical test indexes) were compared. The risk factors for liver metastasis were analyzed using single-factor and multifactorial logistic regression. A predictive model was then constructed and evaluated for efficacy. RESULTS: Systemic inflammatory index (SII), C-reactive protein/albumin ratio (CAR), red blood cell distribution width (RDW), alanine aminotransferase, preoperative carcinoembryonic antigen level, and lymphatic metastasis were different between groups (P < 0.05). SII, CAR, and RDW were risk factors for liver metastasis after colon cancer surgery (P < 0.05). The area under the curve was 0.93 for the column-line diagram prediction model constructed based on these risk factors to distinguish whether liver metastasis occurred postoperatively. The actual curve of the column-line diagram predicting the risk of postoperative liver metastasis was close to the ideal curve, with good agreement. The prediction model curves in the decision curve analysis showed higher net benefits for a larger threshold range than those in extreme cases, indicating that the model is safer. CONCLUSION: Liver metastases after colorectal cancer surgery could be well predicted by a nomogram based on the SII, CAR, and RDW.

Biological and genomic characterization of 4 novel bacteriophages isolated from sewage or the environment using non-aureus Staphylococci strains.

Non-aureus staphylococci (NAS) are an essential group of bacteria causing antimicrobial resistant intramammary infections in livestock, particularly dairy cows. Therefore, bacteriophages emerge as a potent bactericidal agent for NAS mastitis. This study aimed to obtain NAS-specific bacteriophages using bacterial strains isolated from cows with mastitis, subsequently evaluating their morphological, genomic, and lytic characteristics. Four distinct NAS bacteriophages were recovered from sewage or the environment of Chinese dairy farms; PT1-1, PT94, and PT1-9 were isolated using Staphylococcus chromogenes and PT1-4 using Staphylococcus gallinarum. Both PT1-1 (24/54, 44 %) and PT94 (28/54, 52 %) had broader lysis than PT1-4 (3/54, 6 %) and PT1-9 (10/54, 19 %), but PT1-4 and PT1-9 achieved cross-species lysis. All bacteriophages had a short latency period and good environmental tolerance, including surviving at pH=4-10 and at 30-60℃. Except for PT1-9, all bacteriophages had excellent bactericidal efficacy within 5 h of co-culture with host bacteria in vitro at various multiplicity of infection (MOIs). Based on whole genome sequencing, average nucleotide identity (ANI) analysis of PT1-1 and PT94 can be classified as the same species, consistent with whole-genome synteny analysis. Although motifs shared by the 4 bacteriophages differed little from those of other bacteriophages, a phylogenetic tree based on functional proteins indicated their novelty. Moreover, based on whole genome comparisons, we inferred that cross-species lysis of bacteriophage may be related to the presence of "phage tail fiber." In conclusion 4 novel NAS bacteriophages were isolated; they had good biological properties and unique genomes, with potential for NAS mastitis therapy.

Fibroblast growth factor pathway promotes glycolysis by activating LDHA and suppressing LDHB in a STAT1-dependent manner in prostate cancer.

BACKGROUND: The initiation of fibroblast growth factor 1 (FGF1) expression coincident with the decrease of FGF2 expression is a well-documented event in prostate cancer (PCa) progression. Lactate dehydrogenase A (LDHA) and LDHB are essential metabolic products that promote tumor growth. However, the relationship between FGF1/FGF2 and LDHA/B-mediated glycolysis in PCa progression is not reported. Thus, we aimed to explore whether FGF1/2 could regulate LDHA and LDHB to promote glycolysis and explored the involved signaling pathway in PCa progression. METHODS: In vitro studies used RT‒qPCR, Western blot, CCK-8 assays, and flow cytometry to analyze gene and protein expression, cell viability, apoptosis, and cell cycle in PCa cell lines. Glycolysis was assessed by measuring glucose consumption, lactate production, and extracellular acidification rate (ECAR). For in vivo studies, a xenograft mouse model of PCa was established and treated with an FGF pathway inhibitor, and tumor growth was monitored. RESULTS: FGF1, FGF2, and LDHA were expressed at high levels in PCa cells, while LDHB expression was low. FGF1/2 positively modulated LDHA and negatively modulated LDHB in PCa cells. The depletion of FGF1, FGF2, or LDHA reduced cell proliferation, induced cell cycle arrest, and inhibited glycolysis. LDHB overexpression showed similar inhibitory effect on PCa cells. Mechanistically, we found that FGF1/2 positively regulated STAT1 and STAT1 transcriptionally activated LDHA expression while suppressed LDHB expression. Furthermore, the treatment of an FGF pathway inhibitor suppressed PCa tumor growth in mice. CONCLUSION: The FGF pathway facilitates glycolysis by activating LDHA and suppressing LDHB in a STAT1-dependent manner in PCa.

Association between serum galectin-3 and chronic obstructive pulmonary disease: A meta-analysis.

Chronic obstructive pulmonary disease (COPD) is a significant public health issue characterized by progressive and irreversible airflow limitation. The aim of this meta-analysis was to determine the association between changes in serum galectin-3 levels and COPD and to assess the relationship between serum galectin-3 levels and acute exacerbations of COPD (AECOPD). Relevant observational studies were retrieved from electronic databases, including PubMed, Web of Science, Embase, Wanfang, and China National Knowledge Infrastructure (CNKI). A random-effects model was used to combine the data, incorporating the influence of between-study heterogeneity. Twelve case-control studies were included. The pooled results showed a significantly higher serum level of galectin-3 in patients with COPD compared to controls (standardized mean difference [SMD] 0.60; 95% confidence interval [CI] 0.40 - 0.80; P < 0.001; I2 = 68%). Further meta-analysis suggested higher levels of serum galectin-3 in patients with AECOPD compared to those with stable COPD (SMD 0.33; 95% CI 0.20 - 0.46; P < 0.001; I2 = 0%). Subgroup analyses according to the mean age of the participants, the proportion of males, and study quality scores did not significantly change the results (P for subgroup differences all > 0.05). In conclusion, patients with COPD were found to have higher serum levels of galectin-3, with levels further elevated in patients with AECOPD compared to those with stable COPD.

Tumor-neutrophil cross talk orchestrates the tumor microenvironment to determine the bladder cancer progression.

The immune landscape of bladder cancer progression is not fully understood, and effective therapies are lacking in advanced bladder cancer. Here, we visualized that bladder cancer cells recruited neutrophils by secreting interleukin-8 (IL-8); in turn, neutrophils played dual functions in bladder cancer, including hepatocyte growth factor (HGF) release and CCL3highPD-L1high super-immunosuppressive subset formation. Mechanistically, c-Fos was identified as the mediator of HGF up-regulating IL-8 transcription in bladder cancer cells, which was central to the positive feedback of neutrophil recruitment. Clinically, compared with serum IL-8, urine IL-8 was a better biomarker for bladder cancer prognosis and clinical benefit of immune checkpoint blockade (ICB). Additionally, targeting neutrophils or hepatocyte growth factor receptor (MET) signaling combined with ICB inhibited bladder cancer progression and boosted the antitumor effect of CD8+ T cells in mice. These findings reveal the mechanism by which tumor-neutrophil cross talk orchestrates the bladder cancer microenvironment and provide combination strategies, which may have broad impacts on patients suffering from malignancies enriched with neutrophils.

2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis.

Sirtuin 3 (SIRT3) is well known as a conserved nicotinamide adenine dinucleotide+ (NAD+)-dependent deacetylase located in the mitochondria that may regulate oxidative stress, catabolism and ATP production. Accumulating evidence has recently revealed that SIRT3 plays its critical roles in cardiac fibrosis, myocardial fibrosis and even heart failure (HF), through its deacetylation modifications. Accordingly, discovery of SIRT3 activators and elucidating their underlying mechanisms of HF should be urgently needed. Herein, we identified a new small-molecule activator of SIRT3 (named 2-APQC) by the structure-based drug designing strategy. 2-APQC was shown to alleviate isoproterenol (ISO)-induced cardiac hypertrophy and myocardial fibrosis in vitro and in vivo rat models. Importantly, in SIRT3 knockout mice, 2-APQC could not relieve HF, suggesting that 2-APQC is dependent on SIRT3 for its protective role. Mechanically, 2-APQC was found to inhibit the mammalian target of rapamycin (mTOR)-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal kinase (JNK) and transforming growth factor-ß (TGF-ß)/ small mother against decapentaplegic 3 (Smad3) pathways to improve ISO-induced cardiac hypertrophy and myocardial fibrosis. Based upon RNA-seq analyses, we demonstrated that SIRT3-pyrroline-5-carboxylate reductase 1 (PYCR1) axis was closely assoiated with HF. By activating PYCR1, 2-APQC was shown to enhance mitochondrial proline metabolism, inhibited reactive oxygen species (ROS)-p38 mitogen activated protein kinase (p38MAPK) pathway and thereby protecting against ISO-induced mitochondrialoxidative damage. Moreover, activation of SIRT3 by 2-APQC could facilitate AMP-activated protein kinase (AMPK)-Parkin axis to inhibit ISO-induced necrosis. Together, our results demonstrate that 2-APQC is a targeted SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis, which may provide a new clue on exploiting a promising drug candidate for the future HF therapeutics.

Ag-Catalyzed Switchable Synthesis of Site-Specifically Functionalized Pyrroles via Azafulvenium Intermediates.

Here, we present a versatile, silver-catalyzed multi-auto-tandem reaction involving enamines, alkynals, and nucleophiles, utilizing the highly reactive intermediate azafulvenium. This method allows for flexible and switchable regiodivergent reactions through either intermolecular or intramolecular nucleophilic attacks, which can be controlled by adjusting the catalytic conditions. A range of site-specific functionalized or polycyclic fused pyrrole products were efficiently produced with a high level of chemocontrol.

Pathway-based stratification of gliomas uncovers four subtypes with different TME characteristics and prognosis.

Increasing evidences have found that the interactions between hypoxia, immune response and metabolism status in tumour microenvironment (TME) have clinical importance of predicting clinical outcomes and therapeutic efficacy. This study aimed to develop a reliable molecular stratification based on these key components of TME. The TCGA data set (training cohort) and two independent cohorts from CGGA database (validation cohort) were enrolled in this study. First, the enrichment score of 277 TME-related signalling pathways was calculated by gene set variation analysis (GSVA). Then, consensus clustering identified four stable and reproducible subtypes (AFM, CSS, HIS and GLU) based on TME-related signalling pathways, which were characterized by differences in hypoxia and immune responses, metabolism status, somatic alterations and clinical outcomes. Among the four subtypes, HIS subtype had features of immunosuppression, oxygen deprivation and active energy metabolism, resulting in a worst prognosis. Thus, for better clinical application of this acquired stratification, we constructed a risk signature by using the LASSO regression model to identify patients in HIS subtype accurately. We found that the risk signature could accurately screen out the patients in HIS subtype and had important reference value for individualized treatment of glioma patients. In brief, the definition of the TME-related subtypes was a valuable tool for risk stratification in gliomas. It might serve as a reliable prognostic classifier and provide rational design of individualized treatment, and follow-up scheduling for patients with gliomas.

Atomic-scale observation of localized phonons at FeSe/SrTiO3 interface.

In single unit-cell FeSe grown on SrTiO3, the superconductivity transition temperature features a significant enhancement. Local phonon modes at the interface associated with electron-phonon coupling may play an important role in the interface-induced enhancement. However, such phonon modes have eluded direct experimental observations. The complicated atomic structure of the interface brings challenges to obtain the accurate structure-phonon relation knowledge. Here, we achieve direct characterizations of atomic structure and phonon modes at the FeSe/SrTiO3 interface with atomically resolved imaging and electron energy loss spectroscopy in an electron microscope. We find several phonon modes highly localized (~1.3 nm) at the unique double layer Ti-O terminated interface, one of which (~ 83 meV) engages in strong interactions with the electrons in FeSe based on ab initio calculations. This finding of the localized interfacial phonon associated with strong electron-phonon coupling provides new insights into understanding the origin of superconductivity enhancement at the FeSe/SrTiO3 interface.

Evaluation of the preoperative neutrophil-to-lymphocyte ratio as a predictor of the micropapillary component of stage IA lung adenocarcinoma.

OBJECTIVE: To assess the ability of markers of inflammation to identify the solid or micropapillary components of stage IA lung adenocarcinoma and their effects on prognosis. METHODS: We performed a retrospective study of clinicopathologic data from 654 patients with stage IA lung adenocarcinoma collected between 2013 and 2019. Logistic regression analysis was used to identify independent predictors of these components, and we also evaluated the relationship between markers of inflammation and recurrence. RESULTS: Micropapillary-positive participants had high preoperative neutrophil-to-lymphocyte ratios. There were no significant differences in the levels of markers of systemic inflammation between the participants with or without a solid component. Multivariate analysis showed that preoperative neutrophil-to-lymphocyte ratio (odds ratio [OR] = 2.094; 95% confidence interval [CI], 1.668-2.628), tumor size (OR = 1.386; 95% CI, 1.044-1.842), and carcinoembryonic antigen concentration (OR = 1.067; 95% CI, 1.017-1.119) were independent predictors of a micropapillary component. There were no significant correlations between markers of systemic inflammation and the recurrence of stage IA lung adenocarcinoma. CONCLUSIONS: Preoperative neutrophil-to-lymphocyte ratio independently predicts a micropapillary component of stage IA lung adenocarcinoma. Therefore, the potential use of preoperative neutrophil-to-lymphocyte ratio in the optimization of surgical strategies for the treatment of stage IA lung adenocarcinoma should be further studied.

A promising future of metal-N-heterocyclic carbene complexes in medicinal chemistry: The emerging bioorganometallic antitumor agents.

Metal complexes based on N-heterocyclic carbene (NHC) ligands have emerged as promising broad-spectrum antitumor agents in bioorganometallic medicinal chemistry. In recent decades, studies on cytotoxic metal-NHC complexes have yielded numerous compounds exhibiting superior cytotoxicity compared to cisplatin. Although the molecular mechanisms of these anticancer complexes are not fully understood, some potential targets and modes of action have been identified. However, a comprehensive review of their biological mechanisms is currently absent. In general, apoptosis caused by metal-NHCs is common in tumor cells. They can cause a series of changes after entering cells, such as mitochondrial membrane potential (MMP) variation, reactive oxygen species (ROS) generation, cytochrome c (cyt c) release, endoplasmic reticulum (ER) stress, lysosome damage, and caspase activation, ultimately leading to apoptosis. Therefore, a detailed understanding of the influence of metal-NHCs on cancer cell apoptosis is crucial. In this review, we provide a comprehensive summary of recent advances in metal-NHC complexes that trigger apoptotic cell death via different apoptosis-related targets or signaling pathways, including B-cell lymphoma 2 (Bcl-2 family), p53, cyt c, ER stress, lysosome damage, thioredoxin reductase (TrxR) inhibition, and so forth. We also discuss the challenges, limitations, and future directions of metal-NHC complexes to elucidate their emerging application in medicinal chemistry.

Discovery of a novel small-molecule activator of SIRT3 that inhibits cell proliferation and migration by apoptosis and autophagy-dependent cell death pathways in colorectal cancer.

Colorectal cancer (CRC) is well known as a prevalent malignancy affecting the digestive tract, yet its precise etiological determinants remain to be elusive. Accordingly, identifying specific molecular targets for colorectal cancer and predicting potential malignant tumor behavior are potential strategies for therapeutic interventions. Of note, apoptosis (type I programmed cell death) has been widely reported to play a pivotal role in tumorigenesis by exerting a suppressive effect on cancer development. Moreover, autophagy-dependent cell death (type II programmed cell death) has been implicated in different types of human cancers. Thus, investigating the molecular mechanisms underlying apoptosis and autophagy-dependent cell death is paramount in treatment modalities of colorectal cancer. In this study, we uncovered that a new small-molecule activator of SIRT3, named MY-13, triggered both autophagy-dependent cell death and apoptosis by modulating the SIRT3/Hsp90/AKT signaling pathway. Consequently, this compound inhibited tumor cell proliferation and migration in RKO and HCT-116 cell lines. Moreover, we further demonstrated that the small-molecule activator significantly suppressed tumor growth in vivo. In conclusion, these findings demonstrate that the novel small-molecule activator of SIRT3 may hold a therapeutic potential as a drug candidate in colorectal cancer.

Searching to Exploit Memorization Effect in Deep Learning with Noisy Labels.

Sample selection approaches are popular in robust learning from noisy labels. However, how to control the selection process properly so that deep networks can benefit from the memorization effect is a hard problem. In this paper, motivated by the success of automated machine learning (AutoML), we propose to control the selection process by bi-level optimization. Specifically, we parameterize the selection process by exploiting the general patterns of the memorization effect in the upper-level, and then update these parameters using predicting accuracy obtained from model training in the lower-level. We further introduce semi-supervised learning algorithms to utiilize noisy-labeled data as unlabeled data. To solve the bi-level optimization problem efficiently, we consider more information from the validation curvature by the Newton method and cubic regularization method. We provide convergence analysis for both optimization methods. Results show that while both methods can converge to an (approximately) stationary point, the cubic regularization method can find better local optimal than the Newton method with less time. Experiments on both benchmark and real-world data sets demonstrate that the proposed searching method can lead to significant improvements upon existing methods. Compared with existing AutoML approaches, our method is much more efficient on finding a good selection schedule.

N6022 attenuates cerebral ischemia/reperfusion injury-induced microglia ferroptosis by promoting Nrf2 nuclear translocation and inhibiting the GSNOR/GSTP1 axis.

Stroke poses a significant risk of mortality, particularly among the elderly population. The pathophysiological process of ischemic stroke is complex, and it is crucial to elucidate its molecular mechanisms and explore potential protective drugs. Ferroptosis, a newly recognized form of programmed cell death distinct from necrosis, apoptosis, and autophagy, is closely associated with the pathophysiology of ischemic stroke. N6022, a selective inhibitor of S-nitrosoglutathione reductase (GSNOR), is a "first-in-class" drug for asthma with potential therapeutic applications. However, it remains unclear whether N6022 exerts protective effects in ischemic stroke, and the precise mechanisms of its action are unknown. This study aimed to investigate whether N6022 mitigates cerebral ischemia/reperfusion (I/R) injury by reducing ferroptosis and to elucidate the underlying mechanisms. Accordingly, we established an oxygen-glucose deprivation/reperfusion (OGD/R) cell model and a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to mimic cerebral I/R injury. Our data, both in vitro and in vivo, demonstrated that N6022 effectively protected against I/R-induced brain damage and neurological deficits in mice, as well as OGD/R-induced BV2 cell damage. Mechanistically, N6022 promoted Nrf2 nuclear translocation, enhancing intracellular antioxidant capacity of SLC7A11-GPX4 system. Furthermore, N6022 interfered with the interaction of GSNOR with GSTP1, thereby boosting the antioxidant capacity of GSTP1 and attenuating ferroptosis. These findings provide novel insights, showing that N6022 attenuates microglial ferroptosis induced by cerebral I/R injury through the promotion of Nrf2 nuclear translocation and inhibition of the GSNOR/GSTP1 axis.

Heme oxygenase activates calcium release from the endoplasmic reticulum of bovine mammary epithelial cells to promote TFEB entry into the nucleus to reduce the intracellular load of Mycoplasma bovis.

Heme oxygenase HO-1 (HMOX) regulates cellular inflammation and apoptosis, but its role in regulation of autophagy in Mycoplasma bovis infection is unknown. The objective was to determine how the HO-1/CO- Protein kinase RNA-like endoplasmic reticulum kinase (PERK)-Ca2+- transcription factor EB (TFEB) signaling axis induces autophagy and regulates clearance of M. bovis by bovine mammary epithelial cells (bMECs). M. bovis inhibited autophagy and lysosomal biogenesis in bMECs and suppressed HO-1 protein and expression of related proteins, namely nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (keap1). Activation of HO-1 and its production of carbon monoxide (CO) were required for induction of autophagy and clearance of intracellular M. bovis. Furthermore, when HO-1 was deficient, CO sustained cellular autophagy. HO-1 activation increased intracellular calcium (Ca2+) and cytosolic localization activity of TFEB via PERK. Knockdown of PERK or chelation of intracellular Ca2+ inhibited HO-1-induced M. bovis autophagy and clearance. M. bovis infection affected nuclear localization of lysosomal TFEB in the MiT/TFE transcription factor subfamily, whereas activation of HO-1 mediated dephosphorylation and intranuclear localization of TFEB, promoting autophagy, lysosomal biogenesis and autophagic clearance of M. bovis. Nuclear translocation of TFEB in HO-1 was critical to induce M. bovis transport and survival of infected bMECs. Furthermore, the HO-1/CO-PERK-Ca2+-TFEB signaling axis induced autophagy and M. bovis clearance, providing a viable approach to treat persistent M. bovis infections.