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Jing Liang,1 Yu Wang,2 He Wang,3 Yu-Hsin Chen,3 Yu-Wei Wu,4 Wen-Jing Yan5 1College of Education, Hebei Normal University, Shijiazhuang, 050024, People’s Republic of China; 2Department of Education and Psychology, Tianjin University of Sport, Tianjin, 301617, People’s Republic of China; 3School of Mental Health, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China; 4Student Affairs Division, Wenzhou Business College, Wenzhou, 325035, People’s Republic of China; 5Zhejiang Provincial Clinical Research Centre for Mental Illness, Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, People’s Republic of ChinaCorrespondence: Yu-Wei Wu, Student Affairs Division, Wenzhou Business College, Wenzhou, 325035, People’s Republic of China, Email wyw@wzbc.edu.cn Wen-Jing Yan, Zhejiang Provincial Clinical Research Centre for Mental Illness, Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, People’s Republic of China, Email yanwj@wmu.edu.cnBackground: Shame-proneness, particularly in adolescence, is a critical psychological construct linked to aggressive behavior. This study addresses the gap in understanding the specific mechanisms of this relationship within the cultural context of Chinese adolescents.Aim: The study aims to explore the mediating roles of hostility and externalization of blame in the connection between shame-proneness and aggression among Chinese adolescents.Methods: A comprehensive sample of 1489 Chinese adolescents participated in the study. They completed the Test of Self-Conscious Affect for Adolescents to assess shame-proneness and an aggression questionnaire to measure aggressive behaviors. The study utilized network analysis and mediational analysis, to unravel the complex interactions between shame-proneness, externalization of blame, hostility, anger, and aggression.Results: The results identified two distinct pathways linking shame-proneness to aggression: one mediated by hostility and the other by externalization of blame. The pathway via hostility was particularly pronounced, marking it as a central node in the shame-aggression relationship. Interestingly, the study also revealed a direct, though less pronounced, inhibitory effect of shame-proneness on aggression, indicating a dualistic role of shame in adolescent behavior. These findings were consistent across different demographic subgroups, suggesting a generalizable pattern in the studied population.Conclusion: The dual nature of shame-proneness, as both an inhibitor and a facilitator of aggression, underscores the need for culturally sensitive approaches in psychological interventions and future research. The central role of hostility in this relationship points to potential targets for therapeutic interventions aimed at mitigating aggression in adolescents.Keywords: shame-proneness, aggression, network analysis, hostility, externalization of blame

Objectives: To elucidate the relationship between the auricular point stimulation and the activity of glutamatergic neurons in the anterior cingulate cortex (ACC) from the perspective of intrinsic excitability plasticity of neurons in mice with posttraumatic stress disorder (PTSD), so as to explore the underlying mechanisms of acupuncture at auricular points in improving emotional diseases induced by PTSD., Methods: C57BL/6J male mice were randomly divided into control, PTSD model, sham electroacupuncture (EA), and EA groups, with 5 mice in each group. The glutamatergic neurons were labelled by injection of AAV2/9-CaMKⅡα-EGFP viral fluid into the bilateral ACC. Fourteen days after the injection, the PTSD model was established by single prolonged stress (restraint stress, forced swimming, ether exposure) and plantar electrical shock. EA (2 Hz/15 Hz, 1 mA) was applied to bilateral "Xin" points and the center of auriculae of auricular concha area for 30 min, once daily for 7 days. Mice of the sham EA group were anesthetized for 30 min per day for 7 days, but no EA treatments were given. The anxiety-like behavior of mice was evaluated by open field (OF) and elevated plus maze (EPM) tests after 2 weeks of modeling. The whole-cell patch-clamp method was used to record the intrinsic excitability level of ACC glutamatergic neurons., Results: Compared with the control group, the dwell time and locomotor distance in the central area of the OF, the dwell time and entry times percentage in the open arms of the EPM in the model group were significantly reduced ( P <0.001, P <0.01). At the same time, the intrinsic excitability of ACC glutamatergic neurons in model mice was suppressed, presenting as enhanced rheobase currents ( P <0.01) and decreased spike number ( P <0.05, P <0.01, P <0.001). Compared with the model group, the dwell time and locomotor distance in the central area of the OF, the dwell time and entry times percentage in the open arms of the elevated plus maze were significantly increased ( P <0.001, P <0.01), and the intrinsic excitability of ACC glutamatergic neurons was significantly improved, presenting as reduced rheobase currents ( P <0.05) and an increased spike number ( P <0.05) in the EA group. Compared with the sham EA group, the dwell time and locomotor distance in the central area of the OF, the dwell time and entry times percentage in the open arms of the EPM were significantly increased ( P <0.001, P <0.01) in the EA group, and the intrinsic excitability of ACC glutamatergic neurons was significantly improved, presenting as reduced rheobase currents ( P <0.01) and an increased spike number ( P <0.05)., Conclusions: EA of auricular points can effectively alleviate the anxiety-like behavior of PTSD mice and increase the intrinsic excitability level of glutamatergic neurons in ACC, which may be one of the neural mechanisms of auricular point stimulation in the treatment of emotional diseases.

Objective: To assess the relationship between the Sarnat exam, early electroencephalogram (EEG) background, and death or neurodevelopmental impairment (NDI) at age two years among neonates with moderate to severe hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia., Study Design: Neonates enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial with EEG (n=463) or aEEG (n=15) reports available on the first day after birth were included in this cohort study. A Sarnat exam was performed between one and six hours after birth, and neonates were classified into three groups of increasing severity based on the number of severe features (none, 1 to 2, or 3+). EEG background continuity was extracted from reports and categorized as normal, excessively discontinuous, or severely abnormal. The primary outcome was severe NDI or death at age two., Results: Among 478 neonates with HIE, EEG background continuity was normal in 186 (39%), excessively discontinuous in 171 (36%), and severely abnormal in 121 (25%). For each additional severe feature on the Sarnat exam, the risk of abnormal EEG background increased by 16% (RR 1.16 [95% CI 1.09-1.23]). Both the Sarnat exam and EEG background severity were associated with an increased risk of severe NDI or death. After adjusting for Sarnat exam severity, severe EEG background remained associated with severe NDI and death (RR 5.7 [95% CI 3.7-8.9])., Conclusion: The early EEG background provides additional information beyond the Sarnat exam and could be an additional early marker when assessing the severity of HIE., (Copyright © 2024. Published by Elsevier Inc.)

Photonic heterostructures with codable properties have shown great values as versatile information carriers at the micro- and nanoscale. These heterostructures are typically prepared by a step-by-step growth or post-functionalization method to achieve varied emission colors with different building blocks. In order to realize high-throughput and multivariate information loading, we report here a strategy to integrate polarization signals into photonic heterojunctions. A U-shaped di-Pt(II) complex has been assembled into highly polarized yellow-phosphorescent crystalline microrods (Y-rod) by strong intermolecular Pt⋅⋅⋅Pt interaction. Upon end-initiated desorption of the incorporated CH 2 Cl 2 solvents, the Y-rod is transformed in a domino fashion into tri-block polarized photonic heterojunctions (PPHs) with alternate red-yellow-red emissions or red-phosphorescent microrods (R-rods). The red emissions of these structures are also highly polarized; however, their polarization directions are just orthogonal to those of the yellow phosphorescence of the Y-rod. With the aid of a patterned mask, the R-rod can be further programmed into multi-block PPHs with precisely controlled block sizes by side-allowed adsorption of CH 2 Cl 2 vapor. X-ray diffraction analysis and theoretical calculations suggest that the solvent-regulated modulation of the crystal packing and excited-state property is critical for the construction of these PPHs., (© 2024 Wiley-VCH GmbH.)

Background: The High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia demonstrated no neurodevelopmental benefit but was associated with a higher rate of serious adverse events (SAEs). Understanding if targeted Epo plasma exposures were achieved in the HEAL trial and if SAEs were associated with higher exposures would help future therapeutic programs of Epo as a candidate neuroprotective treatment., Methods: Ancillary study of a subset of HEAL neonates who received Epo (1000 U/kg IV on days 1, 2, 3, 4, and 7) and had plasma drug concentrations measured. Within a Bayesian pharmacokinetic framework, the area under the curve during the first 48 h (AUC 48h ) and 7 days (AUC 7d ) of treatment was estimated. The % of neonates who achieved animal model neuroprotective targets of AUC 48h >140,000 mU*h/ml and AUC 7d >420,000 mU*h/ml was calculated. The relationship between AUC 7d and SAEs after study drug was evaluated using logistic regression., Results: Among n = 89 neonates, variation in Epo exposure was low, and over 95% of neonates achieved the target AUC 48h and AUC 7d . No meaningful relationship was seen between AUC 7d and risk of SAE., Conclusions: The Epo dosing strategy in the HEAL trial consistently achieved target plasma exposures. Higher exposures were not associated with SAEs., Impact: In the HEAL randomized, placebo-controlled trial of high-dose erythropoietin (Epo) for neonates with hypoxic-ischemic encephalopathy (HIE) receiving therapeutic hypothermia, the Epo dosing strategy achieved animal model neuroprotective plasma exposure targets in >95% of neonates. This understanding further strengthens the HEAL trial's primary conclusion that Epo provides no additional benefit in neonates with HIE also receiving therapeutic hypothermia. While Epo treatment was associated with a higher rate of serious adverse events (SAEs) compared to placebo in the primary HEAL trial, higher plasma exposures of Epo were not associated with the risk of SAEs., Competing Interests: Competing interests A.F. is a scientific advisor and holds a financial interest in Halo Biosciences unrelated to the current work. The other authors have no conflicts of interest relevant to this article to disclose. Informed consent Informed consent was obtained from parents of all neonates in the current study., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Organic optical heterostructures have emerged as promising candidates for applications in organic photonics. In this study, we demonstrate a facile strategy to integrate different emission and polarization properties into the sub-blocks of luminescent organic heterostructures, by a mask-assisted vapor treatment method on the microcrystals of a pyridine-functionalized tetraphenylethylene chromophore.

Inflammation is one of exacerbating factors of diabetic kidney disease (DKD). Upregulated CXCL5 is found in clinical and experimental diabetes studies. This study aimed to investigate the impact and mechanism of CXCL5 on DKD. DKD patients with different levels of urine albumin-to-creatinine ratio were enrolled. Lepr db/db mice and CXCL5-knockout diabetic mice were used as mouse models for DKD. Human renal tubular epithelial cells were used for in vitro experiments. Circulating CXCL5 were increased in DKD patients compared to the non-DKD subjects. CXCL5 inhibition through CXCL5-neutralizing antibodies or genetic knockout improved kidney function and ameliorated tubular injury and renal fibrosis. In high-glucose-stimulated tubular epithelial cells, administration of CXCL5-neutralizing antibodies or siRNA resulted in reduced phospho-JNK/c-JUN/p65 and the downstream inflammatory, fibrotic, and apoptotic protein expressions. Administration of CXCR2 and JNK inhibitors impeded the CXCL5-induced tubular epithelial cell damages. In conclusion, these findings indicated that anti-CXCL5 strategies may be potential treatments for DKD., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Background: Colorectal cancer (CRC) is a major global health challenge with a need for new biomarkers and therapeutic targets. This work investigated the biological mechanisms and clinical value of Ly1 antibody reactive (LYAR) in CRC. Methods: We analyzed LYAR mRNA expression across multiple public databases, including genotype-tissue expression, gene expression omnibus, Oncomine, and the cancer genome atlas, alongside in-house immunohistochemical data to evaluate LYAR protein expression in CRC and non-CRC colorectal tissues. Gene set enrichment analysis (GSEA) was used to elucidate LYAR's biological functions, and its impact on the tumor immune microenvironment was assessed using CIBERSORT, ESTIMATE, and single-cell RNA sequencing techniques. In addition, LYAR's association with clinicopathological features and patient prognosis was explored, and its influence on drug sensitivity was investigated using the Connectivity Map database. Results: LYAR was significantly upregulated in CRC tissues compared with non-CRC colorectal counterparts, associated with altered immune cell composition and enhanced RNA processing, splicing, and cell cycle regulation. High LYAR expression correlated with poor disease-free and overall survival, underscoring its prognostic value. GSEA revealed LYAR's involvement in critical cellular processes and pathways, including DNA repair, cell cycle, and mTORC1 signaling. Correlation analysis identified genes positively and negatively associated with LYAR, leading to the discovery of temsirolimus and WYE-354, mTOR inhibitors, as potential therapeutic agents for CRC. Furthermore, LYAR expression predicted increased sensitivity to cetuximab in RAS wild-type metastatic CRC, indicating its utility as a biomarker for treatment responsiveness. Conclusions: LYAR's upregulation in CRC highlights its potential as a biomarker for prognosis and therapeutic targeting, offering insights into CRC pathology and suggesting new avenues for treatment optimization.

NUS1 encodes the Nogo-B receptor, a critical regulator for unfolded protein reaction (UPR) signaling. Although several loss-of-function variants of NUS1 have been identified in patients with developmental and epileptic encephalopathy (DEE), the role of the NUS1 variant in Lennox-Gastaut syndrome (LGS), a severe child-onset DEE, remains unknown. In this study, we identified two de novo variants of NUS1, a missense variant (c.868 C > T/p.R290C) and a splice site variant (c.792-2 A > G), in two unrelated LGS patients using trio-based whole-exome sequencing performed in a cohort of 165 LGS patients. Both variants were absent in the gnomAD population and showed a significantly higher observed number of variants than expected genome-wide. The R290C variant was predicted to damage NUS1 and decrease its protein stability. The c.792-2 A > G variant caused premature termination of the protein. Knockdown of NUS1 activated the UPR pathway, resulting in apoptosis of HEK293T cells. Supplementing cells with expression of wild-type NUS1, but not the mutant (R290C), rescued UPR activation and apoptosis in NUS1 knockdown cells. Compared to wild-type Drosophila, seizure-like behaviors and excitability in projection neurons were significantly increased in Tango14 (homolog of human NUS1) knockdown and Tango14 R290C/+ knock-in Drosophila. Additionally, abnormal development and a small body size were observed in both mutants. Activated UPR signaling was also detected in both mutants. Thus, NUS1 is a causative gene for LGS with dominant inheritance. The pathogenicity of these variants is related to the UPR signaling activation, which may be a common pathogenic mechanism of DEE., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A Mn-based nanozyme, Mn-uNF/Si, with excellent alkali phosphatase-like activity was designed by in-situ growth of ultrathin Mn-MOF on the surface of silicon spheres, and implemented as an effective solid Lewis-Brønsted acid catalyst for broad-spectrum dephosphorylation. H 2 18 O-mediated GC-MS studies confirmed the cleavage sites and the involvement of H 2 O in the new bonds. DRIFT NH 3 -IR and in-situ ATR-FTIR confirmed the coexistence of Lewis-Brønsted acid sites and the adjustment of adsorption configurations at the interfacial sites. In addition, a green transformation route of "turning waste into treasure" was proposed for the first time ("OPs→PO 4 3- →P food additive") using edible C. reinhardtii as a transfer station. By alkali etching of Mn-uNF/Si, a nanozyme Mn-uNF with laccase-like activity was obtained. Intriguingly, glyphosate exhibits a laccase-like fingerprint-like response (+,-) of Mn-uNF, and a non-enzyme amplified sensor was thus designed, which shows a good linear relationship with Glyp in a wide range of 0.49-750 μM, with a low LOD of 0.61 μM, as well as high selectivity and anti-interference ability under the co-application of phosphate fertilizers and multiple pesticides. This work provides a controllable methodology for the design of bifunctional nanozymes, which sheds light on the highly efficient green transformation of OPs, and paves the way for the selective recognition and quantification of glyphosate. Mechanistically, we also provided deeper insights into the structure-activity relationship at the atomic scale., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This paper is new, neither the entire paper nor any part of its content has been published or has been accepted elsewhere. It is not being submitted to any other journal. We declare that all the authors are aware of the submission and agree to its publication in this journal., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Flavin-dependent halogenase (FDH) is highly prized in pharmaceutical and chemical industries for its exceptional capacity to produce halogenated aromatic compounds with precise regioselectivity. This study has devised a multi-enzyme self-assembly strategy to construct an effective and reliable in vitro coenzyme cycling system tailored for FDHs. Initially, tri-enzyme self-assembling nanoclusters (TESNCs) were developed, comprising glucose dehydrogenase (GDH), flavin reductase (FR) and FDH. The TESNCs exhibited enhanced thermal stability and conversion efficiency compared to free triple enzyme mixtures during the conversion of L-Trp to 6-Cl-L-Trp, resulting in a 2.1-fold increase in yield. Subsequently, an ordered co-immobilization of GDH, FR, and FDH was established, further amplifying the stability and catalytic efficiency of the FDH coenzyme cycle system. Compared to the free TESNCs, the immobilized TESNCs demonstrated a 4.2-fold increase in catalytic efficiency in a 5 mL reaction system. This research provides an effective strategy for developing a robust and efficient coenzyme recycling system for FDHs., (© 2024 Wiley Periodicals LLC.)

Objective: This study aimd to assess recent trends in the control of low-density lipoprotein cholesterol (LDL-C) and the utilization of lipid-lowering drugs (LLD) among patients with atherosclerotic cardiovascular disease (ASCVD) in Taiwan., Methods: Patients with ASCVD and without a history of hemorrhagic stroke were identified from the Taiwanese Secondary Prevention for patients with AtheRosCLErotic disease (T-SPARCLE) Registry. ASCVD patients were stratified into four categories: those who ever had acute coronary syndrome (ACS), those who underwent percutaneous coronary intervention or coronary artery bypass grafting (PCI/CABG) without ACS, those who ever had an ischemic stroke (IS) without ACS or PCI/CABG, and other ASCVD cases. We assessed their latest recorded LDL-C levels for the periods 2015-16, 2017-18, and 2019-20. LLD therapy patterns were presented as monotherapy, dual therapy, or combination therapy of three or more drugs, with statin use classified by intensity., Results: We identified 3831 ASCVD patients in 2015-16, 3531 in 2017-18, and 1231 in 2019-20. LLD utilization rose from 58.4% in 2015-16 to 73.2% in 2019-20. The proportions of patients achieving LDL-C goals in 2015-16, 2017-18, and 2019-20 were 21.5%, 25.8%, and 33.3% in the ACS cohort (goal <70 mg/dL); 20.4%, 26.1%, and 39.0% in the PCI/CABG cohort (goal <70 mg/dL); 54.4%, 58.5%, and 58.9% in the IS cohort (goal <100 mg/dL); and 60.0%, 65.5%, and 67.0% in the other ASCVD cohort (goal <100 mg/dL), respectively. Over half of the patients were prescribed moderate-intensity statins. Statin use, age, history of diabetes mellitus, and hypertension were important factors for attaining LDL-C goal in ACS patients., Conclusion: Despite improvements in LDL-C management observed over recent years, significant gaps remain in guideline adherence, especially for patients with ACS or PCI/CABG in Taiwan, with over 60% not meeting LDL-C targets. Intensifying efforts to align clinical practice with guidelines are imperative., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Photoinduced intramolecular charge separation in a pyrene- and triarylamine-based donor-acceptor dyad was studied by polarization-dependent femtosecond time-resolved transient absorption (TA) spectroscopy in polar solvents. Photoexcitation forms an excited state with charge transfer (CT) character due to the intrinsic electronic coupling between the triarylamine and pyrene groups, resulting in ultrafast charge separation (CS) in polar solvents. TA measurements reveal a correlation between the rate of CS and solvation dynamics, which implies that solvation is involved in the CS reaction. In addition, polarization-dependent TA spectroscopy was devoted to tracking the ultrafast anisotropy evolution of the cationic absorption band, which is attributed to intramolecular torsional motion and is proposed to be coupled to diffusive orientational solvent modes. The results therefore reveal that the evolution of the CT state in the condensed phase is driven by solvation-coupled excited-state structural relaxation. In other words, intramolecular torsional motion is directly confirmed to be involved in the reaction coordinate of the CS reaction in a strongly coupled donor-acceptor dyad.

A general and practical K 2 CO 3 -promoted [3+2] annulation between trifluoroacetaldehyde N -triftosylhydrazone (TFHZ-Tfs) and 4-nitroisoxazoles has been developed to access structurally diverse trifluoromethylpyrazolo[3,4- d ]isoxazoles. Mechanistically, CF 3 CHN 2 is formed in situ by TFHZ-Tfs decomposition and involves a formal [3+2] dearomative cycloaddition with 4-nitroisoxazoles, followed by aromatization via the elimination of the nitro group. Furthermore, this protocol is metal-free, scalable, mild, and operationally safe, with a broad substrate scope and high functional group compatibility.

Organoborons have recently received much attention, while a biocatalytic platform for the synthesis of chiral organoborons is limited only to Rma cytochrome c . In this study, we exploited the other heme protein, neuroglobin (Ngb), and engineered a quadruple mutant, A15C/H64G/V68F/F28M Ngb, by redesigning the heme active site using the structural information on A15C Ngb and molecular docking studies. The enzyme was shown to be efficient in catalyzing carbene transfer B-H insertion reactions between pyridine/quinoline boranes and benzyl 2-diazopropanoates and their derivatives (29 examples). The designed cavity in the heme distal site favors the binding of large volume substrates such as those containing a quinoline, naphthyl, or biphenyl group. As further determined by the X-ray crystallography of 6c , the chiral products are in the R -configuration, with up to 98:2 e.r. Furthermore, both the whole cell and cell lysate containing the enzyme are reactive toward the B-H insertion reactions. This study presents a convenient biocatalytic platform that may be generally applicable for the synthesis of functional chiral organoborons.

Background: The pathophysiology and molecular mechanisms of schizophrenia (SCZ) remain unclear, and the effective treatment resources are still limited. The goal of this study is to identify the expression of AQP4 in SCZ patients and explore whether AQP4 inhibition could ameliorate schizophrenia-like behaviors and its mechanisms., Methods: Microarray datasets of PFC compared with healthy control were searched in the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were analyzed with the GEO2R online tool. The Venny online tool and metascape online software were used to identify common abnormally expressed genes and conduct cell type signature enrichment analysis. SCZ mouse models were induced with MK-801, an NMDA receptor antagonist (intraperitoneal injection, 0.1 mg/kg/day for 7 days), and C6 cell models were treated with 100 μM MK-801. RT-qPCR, Western Blotting, and immunofluorescence were employed to determine the expression of AQP4, proinflammatory cytokines, and GFAP. Open field tests and social interaction tests were performed to evaluate the schizophrenia-like behaviors., Results: Bioinformatics analysis identified upregulation of AQP4 in the PFC of SCZ patients compared with healthy controls. Cell type signature enrichment analysis showed that all three DEGs lists were strongly enriched in the FAN EMBRYONIC CTX ASTROCYTE 2 category. Upregulation of AQP4 was also observed in MK-801-treated C6 cells and the PFC of MK-801-induced SCZ mouse model. Moreover, AQP4 inhibition with TGN-020 (an inhibitor of AQP4) improved anxiety-like behavior and social novelty preference defects in MK-801-treated mice. AQP4 inhibition also reduced the expression of IL-1β, IL-6, and TNF-α in MK-801-treated C6 cells and mouse model., Conclusions: AQP4 is upregulated in the PFC of SCZ patients compared with healthy controls. AQP4 inhibition could alleviate the anxiety-like behavior and social novelty defects in MK-801-treated mice, this may be due to the role of AQP4 in the regulation of the expression of proinflammatory cytokines., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lysine β-hydroxybutyrylation (Kbhb) is a post-translational modification that has recently been found to regulate protein functions. However, whether and how protein Kbhb modification participates in Alzheimer's disease (AD) remains unknown. Herein, we carried out 4D label-free β-hydroxybutylation quantitative proteomics using brain samples of 8-month-old and 2-month-old APP/PS1 AD model mice and wild-type (WT) controls. We identified a series of tricarboxylic acid (TCA) cycle-associated enzymes including citrate synthase (CS) and succinate-CoA ligase subunit alpha (SUCLG1), whose Kbhb modifications were decreased in APP/PS1 mice at pathological stages. Sodium β-hydroxybutyrate (Na-β-OHB) treatment markedly increased Kbhb modifications of CS and SUCLG1 and their enzymatic activities, leading to elevated ATP production. We further found that Kbhb modifications at lysine 393 site in CS and at lysine 81 site in SUCLG1 were crucial for their enzymatic activities. Finally, we found that β-OHB levels were decreased in the brain of APP/PS1 mice at pathological stages. While ketogenic diet not only significantly increased β-OHB levels, Kbhb modifications and enzymatic activities of CS and SUCLG1, and ATP production, but also dramatically attenuated β-amyloid plaque pathologies and microgliosis in APP/PS1 mice. Together, our findings indicate the importance of protein Kbhb modification for maintaining normal TCA cycle and ATP production and provide a novel molecular mechanism underlying the beneficial effects of ketogenic diet on energy metabolism and AD intervention., (© 2024 The Author(s). Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Background: Epilepsy is a common neurological disorder with complex pathogenic mechanisms, and refractory epilepsy often lacks effective treatments. Gene therapy is a promising therapeutic option, with various preclinical experiments achieving positive results, some of which have progressed to clinical studies., Data Sources: This narrative review was conducted by searching for papers published in PubMed/MEDLINE with the following single and/or combination keywords: epilepsy, children, neurodevelopmental disorders, genetics, gene therapy, vectors, transgenes, receptors, ion channels, micro RNAs (miRNAs), clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)9 (CRISPR/Cas9), expression regulation, optogenetics, chemical genetics, mitochondrial epilepsy, challenges, ethics, and disease models., Results: Currently, gene therapy research in epilepsy primarily focuses on symptoms attenuation mediated by viral vectors such as adeno-associated virus and other types. Advances in gene therapy technologies, such as CRISPR/Cas9, have provided a new direction for epilepsy treatment. However, the clinical application still faces several challenges, including issues related to vectors, models, expression controllability, and ethical considerations., Conclusions: Here, we summarize the relevant research and clinical advances in gene therapy for epilepsy and outline the challenges facing its clinical application. In addition to the shortcomings inherent in gene therapy components, the reconfiguration of excitatory and inhibitory properties in epilepsy treatment is a delicate process. On-demand, cell-autonomous treatments and multidisciplinary collaborations may be crucial in addressing these issues. Understanding gene therapy for epilepsy will help clinicians gain a clearer perception of the research progress and challenges, guiding the design of future clinical protocols and research decisions., (© 2024. Children's Hospital, Zhejiang University School of Medicine.)

Aristolochic acids are one of the major compounds in aristolochia plants, which are nephrotoxic and carcinogenic. A method was established for the detection and identification of aristolochic acids and their DNA adducts in four different herbs using ultra-high performance liquid chromatography-ion mobility quadrupole time-of flight mass spectrometry. Solid phase extraction conditions were optimized to improve the sensitivity of the experiment by using 40 mg of C 18 as adsorbent and 100 μL ethanol as elution solvent. At a collision energy of 10-40 eV, these compounds and cleavage patterns were precisely identified and analyzed by secondary fragmentation and collision cross section values. The obtained mass spectrometry data were then analyzed by targeted metabolomics, including principal component analysis, partial least squares-discriminant analysis and hierarchical clustering analysis, and importing the samples in the established model, the confidence values can reach 0.61 and 0.76. All in all, this method can provide a useful tool for the detection of aristolochic acids and deoxyribonucleic acid adducts. In conclusion, this method was successfully used for the detection and identification of aristolochic acids and their DNA adducts., Competing Interests: Declaration of competing interest The authors (Ying Shi, Yi-Wen Wu, Qian-Xue Shen, Jun Cao) declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Precedential evidence ascertaining the overexpression of LSD1 and HDACs in colorectal cancer spurred us to design a series of dual LSD1-HDAC inhibitors. Capitalizing on the modular nature of the three-component HDAC inhibitory model, tranylcypromine as a surface recognition motif was appended to zinc-binding motifs via diverse linkers. A compendium of hydroxamic acids was generated and evaluated for in vitro cytotoxicity against HCT-116 cells (human colorectal cancer cell lines). The most potent cell growth inhibitor 2 (GI 50 = 0.495 μMm HCT-116 cells) shows promising anticancer effects by reducing colony formation and inducing cell cycle arrest in HCT-116 cells. It exhibits preferential inhibition of HDAC6, along with potent inhibition of LSD1 compared to standard inhibitors. Moreover, Compound 2 upregulates acetyl-tubulin, acetyl-histone H3, and H3K4me2, indicative of LSD1 and HDAC inhibition. In vivo , it demonstrates significant antitumor activity against colorectal cancer, better than irinotecan, and effectively inhibits growth in patient-derived CRC organoids.

Background: Knee osteoarthritis (KOA) was characterized by pain and limited joint function, which seriously affected the quality of life of patients. The vast majority of KOA was closely related to degeneration of the patellofemoral joint and abnormal patellar movement trajectory. Tissue-bone homeostasis manipulation (TBHM) could correct abnormal patellar movement trajectory on the basis of loosening soft tissue. However, there was little strong evidence to verify its efficacy on the patients with KOA. The study objective was to explore the efficacy of the TBHM on gait and knee function in the patients with KOA., Methods: Sixty KOA patients were randomly assigned to either the joint mobilization (n = 30) or TBHM (n = 30) group. The joint mobilization group received joint mobilization, while the TBHM group received TBHM. For two groups, the patients participated in 30 min rehabilitation sessions thrice per week for 12 weeks. The primary outcome was biomechanical gait outcomes during walking, including step length, step velocity, double support, knee range of motion (ROM), and knee adduction moment (KAM). The secondary outcomes were the Western Ontario and McMaster Index (WOMAC) and 36-Item short- form health survey (SF-36), which reflected improvements in knee function and quality of life, respectively. At baseline and 12 weeks, evaluations were conducted and compared between groups., Results: After a 12-week intervention, significant group differences were observed in KAM (p = 0.018), WOMAC-Pain (p = 0.043) and WOMAC-Stiffness (p = 0.026). A noteworthy finding was the presence of a significant interaction effect between group and time specifically observed in step velocity during gait (p = 0.046), WOMAC-Function (p = 0.013) and SF-36 (p = 0.027). Further analysis revealed a significant difference in step velocity (p = 0.034), WOMAC-Function (p = 0.025) and SF-36 (p = 0.042) during post-assessment between the two groups. Moreover, a significant time effect was observed across all outcomes of the two groups (p < 0.05)., Conclusion: The TBHM intervention has better improved the gait, knee function, and quality of life in the patients with KOA., Trial Registration: ITMCTR, ITMCTR2200005507. Registered 06/01/2022, http://itmctr.ccebtcm.org.cn/zh-CN/Home/ProjectView?pid=09cdadad-0aef-41ee-81bd-a8dceb63f7f5 ., (© 2024. The Author(s).)

In this study, we constructed a metal-binding site close to the heme cofactor in myoglobin (Mb) by covalently attaching a nonnative metal-binding ligand of bipyridine to Cys46 through the F46C mutation in the heme distal site. The X-ray structure of the designed enzyme, termed F46C-mBpy Mb, was solved in the Cu(II)-bound form, which revealed the formation of a heterodinuclear center of Cu-His-H 2 O-heme. Cu(II)-F46C-mBpy Mb exhibits not only nitrite reductase reactivity but also cascade reaction activity involving both hydrolysis and oxidation. Furthermore, F46C-mBpy Mb displays Mn-peroxidase activity by the oxidation of Mn 2+ to Mn 3+ using H 2 O 2 as an oxidant. This study shows that the construction of a nonnative metal-binding site close to the heme cofactor is a convenient approach to creating an artificial metalloenzyme with a heterodinuclear center that confers multiple functions.

Background: The effectiveness of Ranolazine on chronic angina had been proved and launched in the United States. This study aimed to determine whether add-on Ranolazine could also be effective in Taiwanese population with persisting angina symptoms despite taking conventional antianginal agents., Methods: This is a multi-center, randomized, parallel, double-blind comparative study. The endpoint is to compare the change from the baseline of the exercise treadmill test (ETT) performing duration between add-on ranolazine and placebo at week 12., Results: 46 patients were evaluable for the efficacy and safety endpoints. The mean change from baseline in ETT duration at week 12 was increased in the treatment and control group, and their mean difference was 20.8 s. All data in the Taiwanese population was like those in the CARISA study (24.0 s). The safety evaluation revealed that patients were tolerable to the add-on ranolazine therapy. The AE incidence for both ranolazine and placebo was 34.8%. The data were comparable to the past studies despite the limited statistical power., Conclusion: The add-on ranolazine therapy shows the potential to raise the exercise performance and tolerance of patients with chronic angina., Competing Interests: Declaration of Competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Oocytes are the largest cell type in multicellular animals. Here, we show that mRNA transporter 4 (MTR4) is indispensable for oocyte growth and functions as part of the RNA surveillance mechanism, which is responsible for nuclear waste RNA clearance. MTR4 ensures the normal post-transcriptional processing of maternal RNAs, their nuclear export to the cytoplasm, and the accumulation of properly processed transcripts. Oocytes with Mtr4 knockout fail to accumulate sufficient and normal transcripts in the cytoplasm and cannot grow to normal sizes. MTR4-dependent RNA surveillance has a previously unrecognized function in maintaining a stable nuclear environment for the establishment of non-canonical histone H3 lysine-4 trimethylation and chromatin reorganization, which is necessary to form a nucleolus-like structure in oocytes. In conclusion, MTR4-dependent RNA surveillance activity is a checkpoint that allows oocytes to grow to a normal size, undergo nuclear and cytoplasmic maturation, and acquire developmental competence., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

USP25 encodes ubiquitin-specific protease 25, a key member of the deubiquitinating enzyme family that is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown aetiology. Five heterozygous USP25 variants, including two de novo and three co-segregated variants, were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared with the East Asian population and all populations in the gnomAD database. The mean age at onset of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom, except that one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was expressed ubiquitously in mouse brain with two peaks, on embryonic Days 14-16 and postnatal Day 21, respectively. In human brain, likewise, USP25 is expressed in the fetus/early childhood stage and with a second peak at ∼12-20 years old, consistent with the seizure onset age in patients during infancy and in juveniles. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knockout mice, which showed increased seizure susceptibility compared with wild-type mice in a pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we used multiple functional detections. In HEK293 T cells, the variant associated with a severe phenotype (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed stable truncated dimers with an increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del variants increased neuronal excitability in mouse brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating that USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play an epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have a profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Endocervical adenocarcinoma (ECA) is reported increasingly often in young women, and this aggressive disease lacks effective methods of targeted therapy. Since mismatch repair deficiency (dMMR) is an important biomarker for predicting response to immune checkpoint inhibitors, it is important to investigate the clinicopathological features and immune microenvironment of dMMR ECAs. We assessed 617 ECAs from representative tissue microarray sections, gathered clinicopathologic information, reviewed histological characteristics, and performed immunohistochemical staining for MMR, programmed cell death 1 (PD-L1), and other immune markers. Of 617 ECA samples, 20 (3.2%) cases had dMMR. Among them, loss of MMR-related proteins expression was observed in 17/562 (3.0%) human papilloma virus-associated (HPVA) adenocarcinoma and 3/55 (5.5%) non-HPV-associated (NHPVA) adenocarcinoma. In NHPVA cohort, dMMR status was observed in 3 (3/14, 15.0%) patients with clear cells. dMMR ECAs had a higher tendency to have a family history of cancer, larger tumor size, p16 negative, HPV E6/E7 mRNA in situ hybridization (HPV E6/E7 RNAscope) negative, and lower ki-67 index. Among the morphological variables evaluated, poor differentiation, necrosis, stromal tumor-infiltrating lymphocytes, peritumoral lymphocytes, and lymphoid follicles were easily recognized in the dMMR ECAs. In addition, dMMR ECAs had higher CD3+, CD8+, CD38+, CD68+ and PD-1+ immune cells. A relatively high prevalence of PD-L1 expression was observed in dMMR ECAs. dMMR ECAs were significantly more likely to present with a tumor-infiltrating lymphocytes -high/PD-L1-positive status. In conclusion, dMMR ECAs have some specific morphological features and a critical impact on the immune microenvironment, which may provide insights into improving responses to immunotherapy-included comprehensive treatment for ECAs in the future., (© The Author(s) 2024. Published by Oxford University Press.)

Gesture sensors are essential to collect human movements for human-computer interfaces, but their application is normally hampered by the difficulties in achieving high sensitivity and an ultrawide response range simultaneously. In this article, inspired by the spider silk structure in nature, a novel gesture sensor with a core-shell structure is proposed. The sensor offers a high gauge factor of up to 340 and a wide response range of 60%. Moreover, the sensor combining with a deep learning technique creates a system for precise gesture recognition. The system demonstrated an impressive 99% accuracy in single gesture recognition tests. Meanwhile, by using the sliding window technology and large language model, a high performance of 97% accuracy is achieved in continuous sentence recognition. In summary, the proposed high-performance sensor significantly improves the sensitivity and response range of the gesture recognition sensor. Meanwhile, the neural network technology is combined to further improve the way of daily communication by sign language users.

CD2-associated protein (CD2AP) is a scaffolding/adaptive protein that regulates intercellular adhesion and multiple signaling pathways. Although emerging evidence suggests that CD2AP is associated with several malignant tumors, there is no study investigating the expression and biological significance of CD2AP in glioblastoma multiforme (GBM). Here by studying public datasets, we found that CD2AP expression was significantly elevated in GBM and that glioma patients with increased CD2AP expression had a worse prognosis. We also confirmed the increase of CD2AP expression in clinical GBM samples and GBM cell lines. CD2AP overexpression in GBM cells promoted their proliferation, colony formation, migration, and invasion in vitro and their tumorigenesis in vivo, and reduced cell apoptosis both at basal levels and in response to temozolomide. While CD2AP knockdown had the opposite effects. Mechanistically, we revealed that CD2AP interacted with TRIM5, an NF-κB modulator. CD2AP overexpression and knockdown increased and decreased TRIM5 levels as well as the NF-κB activity, respectively. Moreover, downregulation of TRIM5 reversed elevated NF-κB activity in GBM cells with CD2AP overexpression; and inhibition of the NF-κB activity attenuated malignant features of GBM cells with CD2AP overexpression. Our findings demonstrate that CD2AP promotes GBM progression through activating TRIM5-mediated NF-κB signaling and that downregulation of CD2AP can attenuate GBM malignancy, suggesting that CD2AP may become a biomarker and the CD2AP-TRIM5-NF-κB axis may become a therapeutic target for GBM., (© 2024. The Author(s).)

Objective: This study aims to assess the expansive effects of pterygomaxillary disjunction (PMD) in surgically assisted rapid maxillary expansion (SARME) surgery using a meta-analysis approach., Materials and Methods: The study conducted a comprehensive literature search across five databases: PubMed, Scopus, Medline, Embase, and Cochrane, adhering to the PRISMA 2020 guidelines. Dental alterations were assessed using either cone-beam computed tomography (CBCT) or dental casts, while skeletal changes were exclusively measured from CBCT scans. We analysed the dentoskeletal changes between PMD +/- groups and conducted a within-group comparison. The primary focus of the results was on the mean differences observed in pre- and post-operative measurements., Results: Dental expansion was larger in the PMD+ group but not statistically significant. Skeletal expansion showed a significantly larger expansion in the posterior region in the PMD+ group (P = .033). Without PMD, anterior palatal expansion was significantly larger (P = .03), and the buccal tipping of posterior teeth was also significantly larger (P = .011) to achieve acceptable dental expansion outcomes., Conclusions: Both PMD +/- groups of SARME surgery can achieve satisfactory dental expansion outcomes. However, bone expansion and tooth inclination are also important factors that influence orthodontic treatment and post-expansion stability. By reducing the bony resistance with PMD, larger posterior palatal expansion and more parallel bony expansion are observed. In contrast, without PMD, there is smaller palatal expansion and greater tooth inclination in the posterior region. This could potentially lead to compromised periodontal conditions following expansion., (© 2024 The Authors. Orthodontics & Craniofacial Research published by John Wiley & Sons Ltd.)

Integrin beta 4 (ITGB4) is a vital factor for numerous cancers. However, no reports regarding ITGB4 in small cell lung carcinoma (SCLC) have been found in the existing literature. This study systematically investigated the expression and clinical value of ITGB4 in SCLC using multi-center and large-sample (n = 963) data. The ITGB4 expression levels between SCLC and control tissues were compared using standardized mean difference and Wilcoxon rank-sum test. The clinical significance of the gene in SCLC was observed using Cox regression and Kaplan-Meier curves. ITGB4 is overexpressed in multiple cancers and represents significant value in distinguishing among cancer samples (AUC = 0.91) and predicting the prognoses (p < 0.05) of patients with different cancers. In contrast, decreased ITGB4 mRNA expression was determined in SCLC (SMD < 0), and this finding was further confirmed at protein levels using in-house specimens (p < 0.05). This decrease in expression may be attributed to the regulatory role of estrogen receptor 1. ITGB4 may participate in the progression of SCLC by affecting several signaling pathways (e.g., tumor necrosis factor signaling pathway) and a series of immune cells (e.g., dendritic cells) (p < 0.05). The gene may serve as a potential marker for predicting the disease status (AUC = 0.97) and prognoses (p < 0.05) of patients with SCLC. Collectively, ITGB4 was identified as an identification and prognosis marker associated with immune infiltration in SCLC., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Two dual fluorescent/phosphorescent tris-heteroleptic mononuclear Ru(ΙΙ) complexes ( 2 and 3 ) were designed and applied in amyloid-β (Aβ) sensing. These complexes have a general formula of [Ru(phen)(dppz)( L )](PF 6 ) 2 , where L is (2-pyrazinyl)(2-pyridyl)(methyl)amine (H- L ) with different substituents (-OMe for 2 , -H for 3 ), phen is 1,10-phenanthroline, and dppz is dipyridophenazine, respectively. Compared with the previously reported ratiometric probe 1 with a di(pyrid-2-yl)(methyl)amine ligand, complex 2 can be employed for not only ratiometric emissive detection of Aβ aggregation but also ratiometric imaging detection of Aβ fibrils. In ratiometric emissive detection, as the incubation time of the Aβ sample (Aβ 40 and Aβ 42 ) was prolonged, a new phosphorescence emission band appeared with gradual enhancement of the emission intensity, while the fluorescence emission was basically unchanged, which could be treated as an intrinsic internal reference signal. In comparison, a larger ratiometric photoluminescence enhancement ( I 640 / I 440 ) was observed for Aβ 40 aggregation with respect to Aβ 42 . In ratiometric imaging detection, the imaging signals obtained from the phosphorescence emission are much brighter than the fluorescence emission in both Aβ 40 and Aβ 42 fibrils. As indicated by molecular docking results, stronger interactions were found between complex 2 with Aβ 40 fibrils, which included π/π, π/C-H, and π/H interactions between bidentate ligands dppz and phen with amino acid residues. Moreover, computational calculations were carried out to assist the interpretation of these experimental findings.

Background: The bHLH genes play a crucial role in plant growth, development, and stress responses. However, there is currently limited research on bHLH genes in the important horticultural plant Rhododendron delavayi Franch., Methods: In this study, we conducted a comprehensive genome-wide identification and in-depth analysis of the bHLH gene family in R. delavayi using bioinformatics approaches., Results: A total of 145 bHLH family members were identified, encoding proteins ranging from 98 to 3300 amino acids in length, with molecular weights ranging from 11.44 to 370.51 kDa and isoelectric points ranging from 4.22 to 10.80. These 145 bHLH genes were unevenly distributed across 13 chromosomes, with three bHLH genes located on contig 52. Chromosome 8 contained the highest number of bHLH family members with 19 genes, while chromosomes 9 and 13 had the lowest, with 7 genes each. Phylogenetic analysis revealed a close evolutionary relationship between bHLH genes in R. delavayi and Arabidopsis thaliana . Subcellular localization analysis indicated that most bHLH genes were located in the nucleus. Promoter analysis of R. delavayi bHLH genes revealed the presence of various cis-regulatory elements associated with light responses, methyl jasmonate responses, low-temperature responses, and coenzyme responses, suggesting that bHLH genes are involved in multiple biological processes in R. delavayi . Through transcriptome analysis, we identified three key functional genes- Rhdel02G0041700 , Rhdel03G0013600 , and Rhdel03G0341200 -that may regulate flower color in R. delavayi ., Conclusions: In conclusion, our study comprehensively identified and analyzed the bHLH gene family in R. delavayi and identified three bHLH genes related to flower color, providing a foundation for molecular biology research and breeding in R. delavayi .

The incidence of Mycobacterium marinum infection is on the rise; however, the existing drug treatment cycle is lengthy and often requires multi-drug combination. Therefore, there is a need to develop new and effective anti- M. marinum drugs. Cochliomycin A, a 14-membered resorcylic acid lactone with an acetonide group at C-5' and C-6', exhibits a wide range of antimicrobial, antimalarial, and antifouling activities. To further explore the effect of this structural change at C-5' and C-6' on this compound's activity, we synthesized a series of compounds with a structure similar to that of cochliomycin A, bearing ketal groups at C-5' and C-6'. The R / S configuration of the diastereoisomer at C-13' was further determined through an NOE correlation analysis of CH 3 or CH 2 at the derivative C-13' position and the H-5' and H-6' by means of a 1D NOE experiment. Further comparative 1 H NMR analysis of diastereoisomers showed the difference in the chemical shift ( δ ) value of the diastereoisomers. The synthetic compounds were screened for their anti-microbial activities in vitro. Compounds 15 - 24 and 28 - 35 demonstrated promising activity against M. marinum , with MIC 90 values ranging from 70 to 90 μM, closely approaching the MIC 90 of isoniazid. The preliminary structure-activity relationships showed that the ketal groups with aromatic rings at C-5' and C-6' could enhance the inhibition of M. marinum . Further study demonstrated that compounds 23 , 24 , 29 , and 30 had significant inhibitory effects on M. marinum and addictive effects with isoniazid and rifampicin. Its effective properties make it an important clue for future drug development toward combatting M. marinum resistance.

Objectives: To explore the relationship between sensitization points of the body surface and the expression of pituitary adenylate cyclase activating polypeptides (PACAP) in myocardial ischemia (MI) mice, so as to reveal the underlying mechanisms of acupoint sensitization from the perspective of molecular biology., Methods: Male C57BL/6J mice were randomly divided into control and model groups (28 mice/group). The MI-induced visceral pain model was established by intraperitoneal injection of isoprenaline (ISO, 160 mg/kg). The mice of the control group received intraperitoneal injection of the same dose of normal saline. Six days after modeling, the Evans blue (EB) dye was injected into the tail vein of mice to observe the distribution and quantity of the plasma extravasated EB points at the body surface. Meanwhile, the mechanical pain threshold (MPT) was measured to evaluate the level of pain sensitivity in the activated area on their body surface and left forelimb and hindlimb, respectively. Hematoxylin-eosin (H.E.) staining was used to evaluate the morphologic and pathological changes of the heart tissue in the two groups. Then, the expressions of PACAP in the thoracic (T)1-T5 dorsal root ganglia (DRGs), spinal cord and skin in the dominant area of body surface were detected by Western blot and immunofluorescence staining, respectively., Results: Compared with the control group, the heart tissue of the model group was hypertrophic and the myocardial tissue showed obvious inflammatory cell infiltration and fibrosis. In addition to these pathologic changes, the number of EB exudation points on the body surface was significantly increased ( P <0.01), and was mainly distributed in the innervated region of T1-T5 segments of the spinal cord, and the MPT of these EB exudation points was lower than that of non-exudation points ( P <0.01). At the same time, the MPTs of left forelimb and hindlimb were significantly decreased in the model group ( P <0.001). More importantly, the level of protein and positive expression of PACAP were significantly higher in the model group than those in the control group, which was observed in the innervated body surface, spinal cord and its DRG neurons of T1-T5 segments ( P <0.01, P <0.001, P <0.05)., Conclusions: ISO injection resulted in histological lesions and cardiogenic referred pain on the body surface after the formation of MI in mice. The expression of PACAP in the body surface of the sensitization points, the corresponding T1-T5 segments of spinal cord and DRG neurons were significantly increased, which may partly explain the reason for acupoint sensitization in the animal model of visceral pain.

Circularly polarized phosphorescent (CPP) materials, especially chiral platinum(II) complexes, which combine the advantages of both circularly polarized luminescence (CPL) and phosphorescence, show broad potential applications in chiral optoelectronic devices. Developing CPP emitters with both excellent chiroptical properties and high yield is urgently needed. Here, a chiral cation strategy is employed to construct the CPP Pt(II) complexes R / S -ABA·[Pt(ppy)Cl 2 ] and R / S -MBA·[Pt(ppy)Cl 2 ] through a simple one-step reaction with almost 100% yield. The circular dichroism and CPL spectra confirm that the chirality was successfully transferred to the [Pt(ppy)Cl 2 ] - anion. The luminescence asymmetry factors ( g lum ) are +1.4/-1.8 × 10 -3 for R / S -ABA·[Pt(ppy)Cl 2 ] and +4.4/-2.8 × 10 -3 for R / S -MBA·[Pt(ppy)Cl 2 ]. The stronger chiroptical property of R / S -MBA·[Pt(ppy)Cl 2 ] is attributed to the enhanced chiral structural deformation and better matched electric and magnetic transition dipole moments. This chiral cation strategy is confirmed to efficiently construct CPP Pt(II) complexes, which will accelerate the development of CPP emitters towards commercialization.

Background: Okanin, a flavonoid compound derived from Bidens pilosa L., has garnered attention for its anti-inflammatory properties. Although Bidens pilosa is commonly used in healthcare products and functional foods, the anticancer potential of okanin, particularly in oral cancer, remains underexplored. This study aims to investigate the effects of okanin on oral cancer cell lines and its potential as a therapeutic agent., Methods: The study involved assessing the cytotoxic effects of okanin on oral cancer cell lines SAS, SCC25, HSC3, and OEC-M1. The IC50 values were determined using methylene blue assays, and the clonogenic capacity was evaluated through colony formation assays. Flow cytometry was used to analyze cell cycle progression and apoptosis. Caspase-3/7 activity assays and annexin V/7-AAD staining confirmed the induction of apoptosis and pyroptosis. In vivo efficacy was assessed using a SAS xenograft model, and immunohistochemical analysis of xenograft tissue was performed to examine pyroptosis-related markers., Results: Okanin exhibited potent cytotoxic effects with IC50 values of 12.0 ± 0.8, 58.9 ± 18.7, 18.1 ± 5.3, and 43.2 ± 6.2 μM in SAS, SCC25, HSC3, and OEC-M1 cells, respectively. It caused dose- and time-dependent reductions in cell viability and significantly impaired clonogenic capacity. Flow cytometry revealed G2/M cell cycle arrest and increased sub-G1 population, indicating cell cycle disruption and death. Okanin induced both apoptosis and pyroptosis, as confirmed by caspase-3/7 activity and annexin V/7-AAD staining. In vivo, okanin reduced tumor growth and involved pyroptosis-related markers such as CASP1, GSDMC, GSDMD, and GSDME., Conclusions: Okanin demonstrates significant anticancer potential, particularly in oral cancer, by inducing both apoptosis and pyroptosis. Its efficacy in reducing tumor growth in vivo further supports its potential as a novel therapeutic option. Further mechanistic studies are needed to elucidate the pathways involved in okanin-mediated cell death and to explore its clinical applications.

Background: Nontyphoidal Salmonella (NTS) outbreaks of invasive diseases are increasing. Whether the genetic diversity of invasive NTS correlates with the clinical characteristics and bacteremia development in NTS infections remains unclear. In this study, we compared the global transcriptomes between bacteremic and nonbacteremic NTS strains after their interaction with human intestinal epithelial cells in vitro., Methods: We selected clinical isolates obtained from stool and blood samples of patients with or without bacteremia and patients with high and low C-reactive protein (CRP) levels. The bacterial RNA samples were isolated after coculturing with Caco-2 cells for RNA sequencing and subsequent analyses., Results: CRP is an unreliable predictive maker for NTS bacteremia with a median CRP level of 1.6 mg/dL. Certain Salmonella Pathogenicity Island (SPI)-1 genes (sipC, sipA, sicA, sipD, and sipB), SPI-2 genes (ssaP, ssrA, and ssaS), and six SPI-4 genes (siiA, siiB, siiC, siiD, siiE, and siiF) remained upregulated in the bacteremic blood-derived strains but significantly downregulated in the nonbacteremic strains after their interaction with Caco-2 cells. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis identified that arginine biosynthesis, ascorbate and aldarate metabolism, and phosphotransferase system pathways were activated in bacteremic NTS strains after Caco-2 cell priming., Conclusion: CRP levels were not correlated with bacteremia development. Significant regulation of certain SPI genes in bacteremic NTS strains after Caco-2 cell priming; bacteremia development might be influenced by the host immune response and the extent to which specific metabolism pathways in NTS strains can be prevented from invading the bloodstream., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Covalent organic framework (COF) film with electrofluorochromic (EFC) and electrochromic (EC) properties has been synthesized by using triphenylamine-based monomers. The film exhibited a high maximum fluorescence contrast of 151 when subjected to a drive voltage of 0.75 V vs the Ag/AgCl electrode, causing the fluorescence to be quenched, which resulted in the EFC process's "fluorescence off" state. The switching times for the fluorescence on and off states were 0.51 and 7.79 s, respectively. Over the same voltage range, the COF film also displayed EC properties, achieving a contrast of 50.23% and a coloration efficiency of 297.4 cm 2 C -1 at 532 nm, with switching times of 18.6 s for coloration and 0.7 s for bleaching. Notably, the quenched fluorescence of the COF film could be restored by adding dopamine as a reductant. This phenomenon enabled the implementation of a NAND logic gate using the applied potential as a physical input and dopamine addition as a chemical input. This study demonstrates the successful development of COF films with bifunctional EFC and EC properties, showcasing their potential for use in constructing advanced optoelectronic devices.

Chronic kidney disease (CKD) is a clinical syndrome characterized by persistent renal function decline. Renal fibrosis is the main pathological process in CKD, but an effective treatment does not exist. Stratifin (SFN) is a highly-conserved, multi-function soluble acidic protein. Therefore, this study explored the effects of SFN on renal fibrosis. First, we found that SFN was highly expressed in patients with CKD, as well as in renal fibrosis animal and cell models. Next, transforming growth factor-beta 1 (TGF-β 1 ) induced injury and fibrosis in human renal tubule epithelial cells, and SFN knockdown reversed these effects. Furthermore, SFN knockdown mitigated unilateral ureteral obstruction (UUO)-induced renal tubular dilatation and renal interstitial fibrosis in mice. Liquid chromatography-tandem mass spectrometry/mass spectrometry (LC-MS/MS), co-immunoprecipitation (Co-IP), and immunofluorescence co-localization assays demonstrated that SFN bound the non-muscle myosin-encoding gene, myosin heavy chain 9 (MYH9), in the cytoplasm of renal tubular epithelial cells. MYH9 knockdown also reduced Col-1 and α-SMA expression, which are fibrosis markers. Finally, silencing SFN decreased MYH9 expression, alleviating renal fibrosis. These results suggest that SFN promotes renal fibrosis in CKD by interacting with MYH9. This study may provide potential strategies for the treatment of CKD., Competing Interests: Declaration of competing interest We declare that we do not have any commercial or associative interest that represents., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A novel artificial peroxidase has been developed for the efficient degradation of the non-steroidal anti-inflammatory drug meloxicam by combining computer simulation and genetic engineering techniques. The results showed that the artificial peroxidase was able to completely degrade meloxicam within 90 s, with a degradation rate of 100 %, which was much higher than that of natural lacquer (46 %). The reaction time of the artificial enzyme was significantly shorter than that of natural peroxidase (10 min) and laccase (48 h). Further studies showed that the amino acid arrangement of the active site of the protein plays an important role in the catalytic performance. The degradation pathway of meloxicam was revealed using UPLC-MS analysis. In vitro toxicity assay showed complete disappearance of toxicity after meloxicam degradation. Therefore, the biocatalytic system proved to be an effective route for the green degradation of meloxicam with important application potential., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Dermal white adipose tissue may participate in the wound-healing process. Obesity-mediated chronic low-grade inflammation impairs wound healing by suppressing vascularity. Given that FABP4 is upregulated in the skin tissue of animals with obesity, this study aimed to investigate the effects of FABP4 inhibition on wound healing in mice with high-fat diet-induced metabolic dysfunction in vivo. The interaction between adipocyte-derived FABP4 and vascular endothelial cell function was also investigated. In mice with high-fat diet-induced metabolic dysfunction, FABP4 inhibition increased angiogenesis and facilitated wound healing with reduced wound inflammation. FABP4 inhibition not only attenuated systemic inflammation, decreased body weight, and reduced insulin resistance but also improved the sizes of adipocytes and hypoxic conditions in dermal white adipose tissue. In vitro hypoxia was used to induce adipocyte inflammation, and the supernatants from hypoxia-stimulated adipocytes impaired the function and angiogenetic capability of human dermal microvascular endothelial cells (HDMECs). Both of them were improved by FABP4 inhibition. Altogether, FABP4 inhibition reduced systemic and adipocyte inflammation, improved vascular endothelial cell function, and facilitated wound healing in metabolic dysfunctions. Given the complex involvement of wound healing, future studies may be required to validate FABP4 as a potential therapeutic target for wound repair in metabolic dysfunctions., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Exploiting a photocatalyst with high stability and excellent activity for Cr(VI) reduction under mild conditions is crucial yet challenging. Herein, the rigid aromatic multicarboxylate ligand with chromophore anthracene was selected to coordinate with multivalent metal ion manganese and to obtain a stable two-dimensional (2D) Mn-based metal-organic framework (MOF), LCUH-120 , which can efficiently and quickly convert Cr(VI) into Cr(III) under light without the need for any additional photosensitizer. The efficient photosensitive anthracene group serves as a photosensitizer center and multivalent Mn(II) ion as a photocatalyst center in LCUH-120 , and the conversion of Cr(VI) to Cr(III) can be realized completely in just 40 min. Specifically, the rate constant ( k ) and reduction rate of the Cr(VI) photocatalytic reaction can be high up to 0.134 min -1 and 2.50 mg Cr(VI) g -1 cata min -1 in an acidic environment (pH = 2), respectively. Compared to our previously reported three-dimensional (3D) Sm-MOF , LCUH-120 exhibits a significantly higher catalytic reaction rate, which might be ascribed to the fact that the photocatalyst center Mn node can improve the rate of electron transfer and promote the separation of holes and photogenerated electrons. In an acidic environment, the reaction mechanism can be verified through various contrast experiments and theoretical simulations.

Background/purpose: Shared decision-making (SDM) promotes patient awareness about medical conditions and treatments, facilitating patient involvement in care decisions. This two-stage multicenter study evaluated impacts of SDM in Taiwanese adults with atrial fibrillation (AF) eligible for novel oral anticoagulant (NOAC) therapy., Methods: Participants were NOAC-naïve (part I) or dabigatran-experienced (part II). During Stage I, part I participants (n = 124) completed a semi-structured survey (understanding evaluation sections only) before and after viewing SDM materials on stroke prevention for AF. Surveys collected data on anxiety about AF, confidence in healthcare professionals, usefulness of the SDM materials, and perception of different NOACs. During Stage II, part I participants after being prescribed NOACs, and part II participants completed another survey to compare impacts of SDM., Results: During Stage I, dabigatran was the preferred NOAC after viewing the SDM materials among 90% of part I participants. During Stage II, both part I (n = 87) and part II participants (n = 104) completed another survey. Fewer part I participants were anxious about AF (p < 0.01), and more had confidence in healthcare professionals (p < 0.01) after viewing SDM materials than before. Most part I participants (≥90%) rated the SDM materials as "very helpful". In Stage II, participants viewing SDM before initiating dabigatran had lower anxiety (part I, 43%; part II, 53%; p < 0.01) and a higher trust (part I, 92%; part II, 84%; p < 0.01)., Conclusion: In conclusion, SDM reduced anxiety and improved trust in healthcare professionals among NOAC-naïve participants with AF., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: The burgeoning field of regenerative medicine has significantly advanced with recent findings on biotherapies using human platelet lysates (HPLs), derived from clinical-grade platelet concentrates (PCs), for treating brain disorders. These developments have opened new translational research avenues to explore the neuroprotective effects of platelet-extracellular vesicles (PEVs). Their potential in managing neurodegenerative conditions like traumatic brain injury (TBI) and Parkinson's disease (PD) warrants further exploration. We aimed here to characterize the composition of a PEV preparation isolated from platelet concentrate (PC) supernatant, and determine its neuroprotective potential and neurorestorative effects in cellular and animal models of TBI and PD., Methods: We isolated PEVs from the supernatant of clinical-grade PC collected from healthy blood donors utilizing high-speed centrifugation. PEVs were characterized by biophysical, biochemical, microscopic, and LC-MS/MS proteomics methods to unveil biological functions. Their functionality was assessed in vitro using SH-SY5Y neuronal cells, LUHMES dopaminergic neurons, and BV-2 microglial cells, and in vivo by intranasal administration in a controlled cortical impact (CCI)-TBI model using 8-weeks-old male C57/BL6 mice, and in a PD model induced by MPTP in 5-month-old male C57/BL6 mice., Results: PEVs varied in size from 50 to 350 nm, predominantly around 200 nm, with concentrations ranging between 10 10 and 10 11 /mL. They expressed specific platelet membrane markers, exhibited a lipid bilayer by cryo-electron microscopy and, importantly, showed low expression of pro-coagulant phosphatidylserine. LC-MS/MS indicated a rich composition of trophic factors, including neurotrophins, anti-inflammatory agents, neurotransmitters, and antioxidants, unveiling their multifaceted biological functions. PEVs aided in the restoration of neuronal functions in SH-SY5Y cells and demonstrated remarkable neuroprotective capabilities against erastin-induced ferroptosis in dopaminergic neurons. In microglial cells, they promoted anti-inflammatory responses, particularly under inflammatory conditions. In vivo, intranasally delivered PEVs showed strong anti-inflammatory effects in a TBI mouse model and conserved tyrosine hydroxylase expression of dopaminergic neurons of the substantia nigra in a PD model, leading to improved motor function., Conclusions: The potential of PEV-based therapies in neuroprotection opens new therapeutic avenues for neurodegenerative disorders. The study advocates for clinical trials to establish the efficacy of PEV-based biotherapies in neuroregenerative medicine., (© 2024. The Author(s).)

Importance: Epidural analgesia is used by approximately 70% of birthing persons in the US to alleviate labor pain and is a common cause of elevated temperature in the birthing parent during labor, which, in turn, is associated with adverse neonatal outcomes such as hypoxic-ischemic encephalopathy (HIE)., Objective: To determine whether epidural analgesia is associated with increased risk of HIE after adjusting for the birthing person's maximal temperature before epidural placement and for the propensity to get an epidural., Design, Setting, and Participants: This retrospective, population-based cohort study was conducted at 15 Kaiser Permanente Northern California hospitals. Participants included singleton neonates born at 35 weeks' or later gestational age between 2012 and 2019. Elective cesarean deliveries and deliveries within 2 hours of hospital admission were excluded. Data analysis was performed from November 2022 to June 2024., Exposure: The primary exposure was epidural analgesia during labor., Main Outcomes and Measures: The primary outcome was HIE, defined as the presence of both neonatal acidosis (ie, pH <7 or base deficit ≥10) and encephalopathy. The presence and timing of epidural analgesia and demographic, pregnancy, and labor characteristics were extracted from electronic medical records. A propensity score for receiving epidural analgesia was created including demographic variables and comorbidities predating epidural placement. Logistic regression was used to evaluate the association between epidural analgesia and HIE, adjusting for maximal birthing parent's temperature before epidural placement and the propensity for receiving an epidural., Results: Among 233 056 infants born at 35 weeks' or later gestational age by vaginal or unplanned cesarean delivery after at least 2 hours of in-hospital labor, 177 603 (76%) were exposed to epidural analgesia and 439 (0.19%) had HIE. On unadjusted analysis, epidural analgesia was associated with an increased risk of maximal temperature greater than 38 °C during labor (risk ratio [RR], 8.58; 95% CI, 8.06-9.14). Each degree increase in maximal temperature during labor was associated with nearly triple the odds of HIE (odds ratio [OR], 2.82; 95% CI, 2.51-3.17). However, there was no significant association between epidural analgesia and the risk of HIE either on crude (RR, 1.21; 95% CI, 0.96-1.53) or adjusted (adjusted OR, 0.93; 95% CI, 0.73-1.17) analyses., Conclusions and Relevance: In this cohort study including more than 230 000 parent-infant dyads, epidural analgesia was associated with increased maximal temperature during labor, a known risk factor for HIE. However, epidural analgesia was not associated with increased odds of HIE.

We here report the multicolor electrochemiluminescence (ECL) of binary microcrystals prepared from a blue-emissive iridium complex 1 and an orange-emissive ruthenium complex 2. These materials display a plate-like morphology with high crystallinity, as demonstrated by microscopic and powder X-ray diffraction analyses. Under light excitation, these microcrystals exhibit gradient emission color changes as a result of the efficient energy transfer between two complexes. When modified on glass carbon electrodes, these microcrystals exhibit tunable ECLs with varied emission colors including sky-blue, white, orange, and red, depending on the doping ratio of complex 2 and the applied potential. Furthermore, organic amines with different molecular sizes are used as the co-reactant to examine their influences on the ECL efficiency of the porous microcrystals of 1. The analysis on the luminance and RGB values of ECL suggests the existence of energy transfer in the generation of multicolor ECLs in these binary crystals., (© 2024 Wiley-VCH GmbH.)

Functionalization of Si-bound methyl group provides an efficient access to diverse organosilanes. However, the asymmetric construction of silicon-stereogenic architectures by functionalization of Si-bound methyl group has not yet been described despite recent significant progress in producing chiral silicon. Herein, we disclosed the enantioselective silylmethyl functionalization involving the aryl to alkyl 1,5-palladium migration to access diverse naphthalenes possessing an enantioenriched stereogenic silicon center, which are inaccessible before. It is worthy to note that the realization of asymmetric induction at the step of metal migration itself remains challenging. Our study constitutes the first enantioselective aryl to alkyl 1,5-palladium migration reaction. The key to the success is the discovery and fine-tuning of the different substituents of α,α,α,α-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL)-based phosphoramidites, which ensure the enantioselectivity and desired reactivity., (© 2024 Wiley-VCH GmbH.)