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Radical prostatectomy with pelvic lymph node dissection is the best treatment for intermediate- to high-risk localized prostate cancer (PCa). However, conventional white light surgery has difficulties in identifying tumor boundary and micrometastases intraoperatively. Fluorescence guided surgery (FGS) can solve the above difficulties, but lacks tumor-specific near-infrared fluorescent (NIRF) probes in PCa. STEAP1 was an ideal target in PCa treatment and imaging. Here, we constructed a PCa specific fluorescent probe based on extracellular vesicles targeting STEAP1 (AS-EVs) loaded with NIRF dye S0456 and evaluated its preclinical profiles. In vitro and in vivo studies both showed S0456@AS-EVs was safe and showed strong targeting ability to PCa in various mice xenograft models. S0456@AS-EVs could clear rapidly from blood (half-time of 4.29 h) and retain in the STEAP1 positive tumor tissues for more than 72 h with the highest tumor background ratio (TBR) of 3:1, which was superior to ICG, free S0456, ICG@Ctrl-EVs and S0456@Ctrl-EVs (p < 0.01). Finally, S0456@AS-EVs was applied in FGS on intramuscular model, and the tumors were resected under white light and fluorescence respectively. Compared with white light surgery, mice undergoing FGS had lower positive margin rate and better postoperative survival (p = 0.0342)., 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 © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Synthetic CB2 receptor agonists exhibit great potential in the treatment of neurodegenerative diseases, chronic and neuropathic pain, cancer, and inflammation-associated pathologies while avoiding adverse psychoactive effects caused by interactions with CB1 receptors. Herein, a class of 5-aryl-pyrazole-3-carboxamide derivatives was thus designed, synthesized, and biologically evaluated. Among the compounds tested, compound 33, one of the most potent leads, showed a remarkably high potency and selectivity at the CB2 receptor (EC 50, CB2  = 16.2 nM, EC 50, CB1  > 10 5  nM). Furthermore, 33 treatment significantly attenuate colon inflammation in a dextran sodium sulfate (DSS)-induced mouse model of colitis, supporting that CB2 receptor agonists might serve as potential therapeutics for treating colitis., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Graft-versus-host disease (GVHD) is a major concern for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Ruxolitinib has been proven effective in treating adult steroid-refractory GVHD; however, studies on pediatric patients are relatively scarce. Thus, this single-center study evaluated the efficacy and safety of ruxolitinib in pediatric patients with steroid-refractory GVHD. We retrospectively reviewed the data of patients aged < 18 years who underwent allogeneic HSCT and received ruxolitinib treatment for either acute GVHD (aGVHD) or chronic GVHD (cGVHD) between 2018 and 2023. Data on the clinical response, concomitant and subsequent medications, adverse events, and outcomes were obtained through medical chart review. Sixteen patients were analyzed in this study: seven with aGVHD and nine with cGVHD. The overall response rate for the 16 patients was 81% (aGVHD, 86%; cGVHD, 77%). The overall survival rate was 56%: (aGVHD, 57%; cGVHD, 55%). For 11 patients with at least stable disease, steroid dosage could be reduced by at least 75%; however, corticosteroids were successfully tapered off in only six patients at the last follow-up. Among four patients with documented lung cGVHD, none experienced lung cGVHD progression at 1-year follow-up. Further, 50% of the patients experienced grade 3 or 4 neutropenia and/or thrombocytopenia, and 56% had viral reactivation. Two patients discontinued ruxolitinib owing to adverse events. Ruxolitinib treatment for pediatric patients with aGVHD and cGVHD is associated with a high overall response rate, significant steroid-sparing effect, acceptable toxicity, and manageable adverse events. However, blood count and viral reactivation should be closely monitored during ruxolitinib use., Competing Interests: Declarations. Ethical approval: This study was performed in line with the principles of the Declaration of Helsinki. This study has been approved by the Institutional Review Board of National Taiwan University Hospital. Informed consent: The patient’s consent was waived for retrospective study. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (mC) in DNA, contributing to the regulation of gene transcription. Diverse mutations of TET2 are frequently found in various blood cancers, yet the full scope of their functional consequences has been unexplored. Here, we report that a subset of TET2 mutations identified in leukemia patients alter the substrate specificity of TET2 from acting on mC to thymine. This neomorphic activity results from substitutions at key residues involved in the interactions with the mC base, including Asn1387 and His1904. Recombinant human TET2 proteins harboring the mutation of these residues can catalyze the oxidation of thymine to 5-hydroxymethyluracil (hmU) and 5-formyluracil (fU). Exogenous expression of the mutant TET2 Asn1387Thr (N1387T) in HEK293T cells leads to hmU accumulation, with levels further increased in cells lacking the glycosylase SMUG1. Endogenous knock-in of N1300T, the murine equivalent of N1387T, in mouse embryonic stem cells induces hmU production, causing DNA lesions and transcriptional activation of DNA damage response genes. N1300T cells accumulate more additional mutations with extended culture and exhibit heightened sensitivity to ATR inhibition compared to Tet2 knockout cells. Our study reveals that certain patient-derived TET2 mutations can acquire unexpected gain-of-function activities beyond impairing mC oxidation, offering a fresh perspective on the diverse molecular etiology of mutant TET2-related leukemogenesis., Competing Interests: Competing interests statement:The authors declare no competing interest.

A Ru-catalyzed defluorinative cyclization of polyfluoroalkyl tetralones has been developed under visible-light irradiation for the precise assembly of γ-pyrones featuring α-perfluoroalkyl and β-fluorine substituents. Selective functionalization of five C(sp 3 )-F bonds at three carbon sites on the perfluoroalkyl chain provides a new mode for utilizing polyfluorides as versatile synthons to access difficult-to-obtain heterocyclic scaffolds. Moreover, the sulfinate salt serves dual roles as an oxygen source for creating the carbonyl group and as a defluorinating promoter.

FMS-like tyrosine kinase-3 (FLT3), a class 3 receptor tyrosine kinase, can be activated by mutations of internal tandem duplication (FLT3-ITD) or point mutations in the tyrosine kinase domain (FLT3-TKD), leading to constitutive activation of downstream signaling cascades, including the JAK/STAT5, PI3K/AKT/mTOR and RAS/MAPK pathways, which promote the progression of leukemic cells. Despite the initial promise of FLT3 inhibitors, the discouraging outcomes in the treatment of FLT3-ITD-positive acute myeloid leukemia (AML) promote the pursuit of more potent and enduring therapeutic approaches. The histone acetyltransferase complex comprising the E1A binding protein P300 and its paralog CREB-binding protein (p300/CBP) is a promising therapeutic target, but the development of effective p300/CBP inhibitors faces challenges due to inherent resistance and low efficacy, often exacerbated by the absence of reliable clinical biomarkers for patient stratification. In this study we investigated the role of p300/CBP in FLT3-ITD AML and evaluated the therapeutic potential of targeting p300/CBP alone or in combination with FLT3 inhibitors. We showed that high expression of p300 was significantly associated with poor prognosis in AML patients and positively correlated with FLT3 expression. We unveiled that the p300/CBP inhibitors A485 or CCS1477 dose-dependently downregulated FLT3 transcription via abrogation of histone acetylation in FLT3-ITD AML cells; in contrast, the FLT3 inhibitor quizartinib reduced the level of H3K27Ac. Concurrent inhibition of p300/CBP and FLT3 enhanced the suppression of FLT3 signaling and H3K27 acetylation, concomitantly reducing the phosphorylation of STAT5, AKT, ERK and the expression of c-Myc, thereby leading to synergistic antileukemic effects both in vitro and in vivo. Moreover, we found that p300/CBP-associated transcripts were highly expressed in quizartinib-resistant AML cells with FLT3-TKD mutation. Targeting p300/CBP with A485 or CCS1477 retained the efficacy of quizartinib, suggesting marked synergy when combined with p300/CBP inhibitors in quizartinib-resistant AML models, as well as primary FLT3-ITD + AML samples. These results demonstrate a potential therapeutic strategy of combining p300/CBP and FLT3 inhibitors to treat FLT3-ITD and FLT3-TKD AML., Competing Interests: Competing interests: The authors declare no competing interests. Ethics:: Animal experiments were conducted in accordance with the guidelines of the Institutional Animal Care and Use Committee of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Lingang Laboratory (Shanghai, China). Written informed consent was acquired for the utilization of clinical data, and the study was approved by the Ethics Committee of Shanghai Jiao Tong University School of Medicine Affiliated Shanghai General Hospital. The procedure was performed in accordance with the provisions of the Declaration of Helsinki of 1975., (© 2025. The Author(s).)

Optical computing, renowned for its light-speed processing and low power consumption, typically relies on the coherent control of two light sources. However, there are challenges in stabilizing and maintaining high optical spatiotemporal coherence, especially for large-scale computing systems. The coherence requires rigorous feedback circuits and numerous phase shifters, introducing system instability and complexity. Here we propose an innovative logic gate using a single light source, with frequency and polarization serving as two virtual inputs. Our design leverages frequency-polarization multiplexed metasurfaces to achieve all basic logic operations by selectively routing surface plasmon polaritons. This single-channel logic gate maintains inherent coherence between frequency and polarization, thereby considerably eliminating stringent light-source specifications and numerous rigid phase controls and resulting in higher stability. Our device showcases unique application potentials in on-chip readout of encryption information by using random sequences as a one-time pad, unlocking fresh prospects for information protection and optical computing with other simple light sources.

Sterols target sterol-sensing domain (SSD) proteins to lower cholesterol and circulating and hepatic triglyceride levels, but the mechanism remains unclear. In this study, we identify acyl-coenzyme A (CoA) synthetase long-chain family member 1 (ACSL1) as a direct target of ergosterol (ES). The C-terminal domain of ACSL1 undergoes conformational changes from closed to open, and ES may target the drug-binding pocket in the acetyl-CoA synthetase-like domain 1 (ASLD1) of ACSL1 to stabilize the closed conformation and maintain its activity. Moreover, ES is mainly enriched in the mitochondria and promotes fatty acid β-oxidation through ACSL1 allosteric activation. Structure-activity relationship analysis reveals how different structural sterols interact with the sterol-sensing domain-containing protein (SCAP) and ACSL1, explaining their regulatory effects on lipid metabolism. Moreover, our findings reveal that the combination of SCAP inhibitor 25-hydroxycholesterol (25-HC) and ES has a stronger lipid-lowering effect than alone., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Acoustic prosodic analysis is a novel approach that can be used to identify patients with mild cognitive impairment (MCI) and dementia in Alzheimer's disease (AD). We hypothesize that acoustic analysis can also differentiate cognitive impairment in Parkinson's disease (PD)., Methods: We investigated acoustic parameters in 90 subjects including 30 PD with normal cognition (PD-NC), 30 PD with mild cognitive impairment (PD-MCI) and 30 PD with dementia (PDD). The reading task "Supermarket Passage" and the picture description task "Cookie Theft" were used. Feature selection and modelling were then performed to systematically evaluate the importance and clinical implications of the acoustic parameters in identifying PD with cognitive impairment., Results: Analysis of covariance (ANCOVA) and mediation analysis revealed that acoustic parameters were independently associated with cognitive impairment including PDD and PD-MCI. These Acoustic parameters enabled the detection of PD with cognitive impairment with an area under the receiver operating characteristic curve (AUC) of 0.826. Compared with PD-NC, speech rate, pre-verb pause (≥1s), between-utterance pause (≥2s) in the "Cookie Theft" task were the two key cognitive impairment detection factors, which were frequently identified by LASSO model in both PDD and PD-MCI. F 0 SD of interrogative sentence was often selected in PDD. In feature selection, AUC was 0.944 in discriminating PDD from PD-NC and AUC was 0.753 in discriminating PD-MCI from PD-NC., Conclusion: We demonstrated that acoustic parameters are useful in differentiating PD patients with cognitive impairment from patients with normal cognition after adjusting variables such as age, which was also a significant contributor to cognitive decline. Acoustic parameters may be valuable for automated screening the risk of cognitive decline in PD patients. It deserves further investigation., Competing Interests: Declaration of competing Interest The authors have no potential conflicts of interest to disclose., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Background: A direct aspiration first pass technique (ADAPT) has emerged as a fast, safe, and efficacious method for treating acute large vessel occlusion. However, successful clot aspiration is not guaranteed in every ADAPT procedure. We have observed that when the catheter effectively ingested the clot, the catheter tip displayed a distinct fluttering motion, referred to herein as tip flutter. Thus this study aimed to assess whether this catheter tip flutter can be used as a sign of successful clot aspiration., Methods: This retrospective study included 231 consecutive patients admitted to our institution due to acute ischemic stroke and treated with ADAPT between October 2018 and November 2023. We obtained baseline and procedural data from all patients. Additionally, we assessed the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of the tip flutter in predicting clot aspiration., Results: The incidence of embolus translocation was significantly higher in the tip flutter positive group than in the tip flutter negative group (P < 0.001). Also, hyperdense artery presentation was more prevalent in the positive group (P<0.001), whereas the clot burden score was higher in the negative group (P=0.002). Clot aspiration in the first pass occurred in 83 (96.5%) and 37 (25.5%) patients in the positive and negative groups, respectively (P<0.001). Multivariable logistic regression analysis showed the tip flutter sign (OR 1.09, 95% CI 0.16 to 1.29; P<0.001) was an independent predictor of successful clot aspiration. Sensitivity, specificity, PPV, NPV, and accuracy of the tip flutter for predicting clot aspiration were 69.2%, 97.3%, 96.5 %, 74.5%, and 82.7%, respectively., Conclusions: In this study, we found that tip flutter was a reliable indicator of successful clot aspiration during ADAPT., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: There is limited epidemiological data regarding the association of blood lipids with thyroid hormones. Thus, the present article aims to explore whether there is an association between non-high-density to high-density lipoprotein cholesterol ratio (NHHR) and thyroid hormones., Methods: We analyzed samples from 3,881 adults aged 20 years and above who took part in the National Health and Nutrition Examination Survey (NHANES) spanning 2007 to 2012. The study tested for thyroid hormones, including total triiodothyronine (TT3), free triiodothyronine (FT3), total thyroxine (TT4), free thyroxine (FT4), as well as thyroid-stimulating hormone (TSH). Survey-weighted linear regression and restricted cubic spline (RCS) models were employed to investigate the relationship between NHHR and thyroid hormones. Subsequently, subgroup analyses were conducted. In Mendelian randomization (MR), the inverse variance weighting method (IVW) is used as the primary analytical approach., Results: This study finally comprised 3,881 adults aged 20 years and older. After extensive adjustments for covariables, the regression analysis revealed significant negative associations between NHHR and FT4 (β: -0.11, 95% confidence interval [CI]: -0.18, -0.04), FT4/FT3 (β: -0.06, 95% CI: -0.08, -0.04), and TT4/TT3 (β: -0.001, 95% CI: -0.001, 0.000). Both observational and Mendelian randomization studies suggest that high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol may not significantly influence the risk of hyperthyroidism or hypothyroidism., Conclusions: The study indicates negative associations between NHHR and FT4, as well as the ratios of FT4/FT3 and TT4/TT3. This suggests that NHHR may reflect changes in thyroid function, highlighting its potential clinical significance in assessing thyroid function and metabolic health., Competing Interests: 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 © 2025 Tan, Zhang, Wu, Zhu and Gao.)

Purpose: Knee osteoarthritis (KOA) is a prevalent degenerative bone and joint disease observed in clinical practice. While acupuncture has demonstrated efficacy in treating KOA, the central mechanisms underlying its effects remain ambiguous. Recently, functional magnetic resonance imaging (fMRI) has been extensively applied in studying the brain mechanisms of acupuncture analgesia. Currently, network analysis based on brain connectomics is a focal point in acupuncture imaging research. Therefore, this study uses KOA as the research vehicle, focuses on the abnormal connectivity patterns of brain functional networks, and integrates clinical pain assessments to thoroughly investigate the central mechanisms of acupuncture therapeutic effects on KOA., Patients and Methods: In this parallel, randomized, sham-controlled neuroimaging trial, 60 KOA patients will be randomly divided into the acupuncture group and sham acupuncture group in a 1:1 ratio, treated three times weekly for a total of 12 sessions. Patients will undergo clinical symptom assessments and cranial fMRI scans at baseline (-1-0 weeks), post-treatment (4 weeks), and at the follow-up (16 weeks). Forty healthy subjects will be recruited for observation, with a single MRI scan conducted only at baseline (-1-0 week). The primary efficacy indicator will be the change in NRS score after four weeks of treatment, with secondary outcomes including WOMAC, STAI, and safety assessments. fMRI observations will employ independent component analysis, brain network construction, and functional connectivity, complemented by Pearson correlation analysis to explore the relationship between brain responses and clinical improvements., Conclusion: This study will initially uncover how acupuncture intervention for chronic KOA pain centrally regulates and exerts therapeutic effects through the modulation of abnormal brain network functional connectivity patterns, with a demonstrated long-term effect., Ethics and Dissemination: This study has been approved by the ethics committee of Shandong University of Traditional Chinese Medicine Affiliated Hospital ((2024) Lunshen No. (028) - KY)., Clinical Trial Registration: This study has been approved by registered in the Chinese Clinical Trial Registry (ChiCTR2400083695)., Competing Interests: The authors report no conflicts of interest in this work., (© 2025 Sun et al.)

Background and Objective: Gastric cancer (GC) remains a prevalent and preventable disease, yet accurate early diagnostic methods are lacking. Exosome non-coding RNAs (ncRNAs), a type of liquid biopsy, have emerged as promising diagnostic biomarkers for various tumours. This study aimed to identify a serum exosome ncRNA feature for enhancing GC diagnosis., Designs: Serum exosomes from patients with GC (n=37) and healthy donors (n=20) were characterised using RNA sequencing, and potential biomarkers for GC were validated through quantitative reverse transcription PCR (qRT-PCR) in both serum exosomes and tissues. A combined diagnostic model was developed using LASSO-logistic regression based on a cohort of 518 GC patients and 460 healthy donors, and its diagnostic performance was evaluated via receiver operating characteristic curves., Results: RNA sequencing identified 182 candidate biomarkers for GC, of which 31 were validated as potential biomarkers by qRT-PCR. The combined diagnostic score (cd-score), derived from the expression levels of four long ncRNAs (RP11.443C10.1, CTD-2339L15.3, LINC00567 and DiGeorge syndrome critical region gene (DGCR9)), was found to surpass commonly used biomarkers, such as carcinoembryonic antigen, carbohydrate antigen 19-9 (CA19-9) and CA72-4, in distinguishing GC patients from healthy donors across training, testing and external validation cohorts, with AUC values of 0.959, 0.942 and 0.949, respectively. Additionally, the cd-score could effectively identify GC patients with negative gastrointestinal tumour biomarkers and those in early-stage. Furthermore, molecular biological assays revealed that knockdown of DGCR9 inhibited GC tumour growth., Conclusions: Our proposed serum exosome ncRNA feature provides a promising liquid biopsy approach for enhancing the early diagnosis of GC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

The patient-derived xenograft (PDX) model is a crucial in vivo model extensively employed in cancer research that has been shown to maintain the genomic characteristics and pathological structure of patients across various subtypes, metastatic, and diverse treatment histories. Various treatment strategies utilized in PDX models can offer valuable insights into the mechanisms of tumor progression, drug resistance, and the development of novel therapies. This review provides a comprehensive overview of the establishment and applications of PDX models. We present an overview of the history and current status of PDX models, elucidate the diverse construction methodologies employed for different tumors, and conduct a comparative analysis to highlight the distinct advantages and limitations of this model in relation to other in vivo models. The applications are elucidated in the domain of comprehending the mechanisms underlying tumor development and cancer therapy, which highlights broad applications in the fields of chemotherapy, targeted therapy, delivery systems, combination therapy, antibody-drug conjugates and radiotherapy. Furthermore, the combination of the PDX model with multiomics and single-cell analyses for cancer research has also been emphasized. The application of the PDX model in clinical treatment and personalized medicine is additionally emphasized., Competing Interests: The authors declare that they have no conflict of interest., (© 2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

Colorectal cancer (CRC) is closely linked to obesity, a condition that significantly impacts tumor progression and therapeutic resistance. Although cetuximab, an EGFR-targeting monoclonal antibody, is a cornerstone in metastatic CRC treatment, resistance often emerges, leading to poor outcomes. This study investigated the role of drug-tolerant persister (DTP) cells and their metabolic interactions within the tumor microenvironment (TME) in cetuximab resistance. Using patient-derived organoids and in vivo models, we identified the FABP4/UCP2 axis as a critical mediator of resistance. Organoids derived from cetuximab non-responders revealed upregulated FABP4 and UCP2 expression post-treatment. Coculture experiments with adipocytes showed that FABP4 and UCP2 promote lipid metabolic reprogramming, facilitating cancer cell survival in a dormant state. CRISPR/Cas9 mediated inhibition of FABP4 disrupted this metabolic interaction, sensitising resistant cells to cetuximab. In vivo, the FABP4 inhibitor BMS309403, either alone or in combination with cetuximab, significantly reduced tumor growth in resistant CRC models, highlighting its therapeutic potential. These findings establish the FABP4/UCP2 axis as a pivotal driver of cetuximab resistance in obesity-associated CRC and suggest that targeting this metabolic pathway could improve outcomes in DTP-resistant CRC patients., Competing Interests: Declaration of competing interest The authors declare no conflict of interest regarding the publication of this paper., (Copyright © 2025. Published by Elsevier Inc.)

Aims: Flavobacterium strains are widely distributed in various environments and generally exhibit specialized roles in the degradation of complex organic substrates. To obtain a deeper understanding of their enzyme profiles, patterns of action on natural carbohydrates degradation, and to mine gene resources for biomass conversion., Methods and Results: We sequenced the whole genome of a novel carbohydrate-degrading Flavobacterium sp. strain YJ01. The genome size of strain YJ01 was 5.48 Mb and encoded 4674 predicted genes. Comparative genomic analysis revealed Flavobacterium strains were characterized by the presence of abundant genes associated with catalytic activity and metabolic processes, especially carbohydrate metabolism. About 9% of genes of strain YJ01 encoded carbohydrate-active enzymes. These enzymes can act on various complex natural and cellular carbohydrates. The synergistic effect of the enzymes on the hydrolysis of complex natural polysaccharides was further experimentally evidenced by using starch and xylan as substrates, in which the degradation rate of an enzyme combination was ~10-fold higher than that of the single enzyme., Conclusions: Flavobacterium sp. strain YJ01 has a high degree of catalytic and metabolic activity toward carbohydrates, and it harbors abundant, complete, and efficient enzymes for mediating complex polysaccharide degradation. These enzymes, acting synergistically on complex substrates, greatly improved the efficiency of digestion, which may be associated with the extensive ecological adaptability of Flavobacterium, which genetically heterologous divergent from extremely environments origin Flavobacterium strains., (© The Author(s) 2025. Published by Oxford University Press on behalf of Applied Microbiology International.)

Background: The genomic landscape of esophageal squamous cell carcinoma (ESCC) has been characterized extensively, but there remains a significant need for actionable targets and effective therapies., Methods: Here, we perform integrative analysis of genome-wide loss of heterozygosity and expression to identify potential tumor suppressor genes. The functions and mechanisms of one of the candidates, TACC2, are then explored both in vitro and in vivo, leading to the proposal of a therapeutic strategy based on the concept of synthetic lethality., Findings: We reveal that the inactivation of TACC2, due to copy number loss and promoter hypermethylation, is associated with poor prognosis in ESCC patients. TACC2 depletion enhances ESCC tumorigenesis and progression, as demonstrated in Tacc2 knockout mouse models and by increased growth abilities of ESCC cells. Mechanistically, TACC2 interacts with components of the NuRD and CoREST co-repressor complexes, including MTA1, MBD3, and HMG20B, in the cytoplasm. TACC2 loss leads to the translocation of these proteins into the nucleus, facilitating the formation of functional NuRD and CoREST complexes and the epigenetic repression of CDKN1A. This repression results in elevated CDK1/2 activation. Furthermore, TACC2-deficient cells and ESCC patient-derived organoids with reduced TACC2 expression show increased sensitivity to CDK inhibitors, particularly dinaciclib, which is currently in a phase III trial. Notably, the combination of TACC2-specific RNAi and dinaciclib in subcutaneous ESCC models significantly impairs tumor growth., Conclusions: The findings suggest a strategy for cancer treatment based on synthetic lethality., Funding: Funded by NKRDP, NSFC, GDIIET, GDBABRF, GDECISTP, and SYSUTP., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: Erythropoiesis is controlled by several factors, including oxygen level under different circumstances. However, the role of hypoxia in erythroid differentiation and the underlying mechanisms are poorly understood. We studied the effect and mechanism of hypoxia on erythroid differentiation of K562 cells and observed the effect of hypoxia on early erythropoiesis of zebrafish. Results: Compared with normal oxygen culture, both hemin-induced erythroid differentiation of K562 cells and the early erythropoiesis of zebrafish were inhibited under hypoxic treatment conditions. Hypoxia-inducible factor 1 alpha (HIF1α) plays a major role in the response to hypoxia. Here, we obtained a stable HIF1α knockout K562 cell line using the CRISPR-Cas9 technology and further demonstrated that HIF1α knockout promoted hemin-induced erythroid differentiation of K562 cells under hypoxia. We demonstrated an HIF1-mediated induction of the nuclear factor interleukin-3 (NFIL3) regulated in K562 cells under hypoxia. Interestingly, a gradual decrease in NFIL3 expression was detected during erythroid differentiation of erythropoietin-induced CD34 + hematopoietic stem/progenitor cells (HSPCs) and hemin-induced K562 cells. Notably, erythroid differentiation was inhibited by enforced expression of NFIL3 under normoxia and was promoted by the knockdown of NFIL3 under hypoxia in hemin-treated K562 cells. In addition, a target of NFIL3, pim-1 proto-oncogene, serine/threonine kinase (PIM1), was obtained by RNA microarray after NFIL3 knockdown. PIM1 can rescue the inhibitory effect of NFIL3 on hemin-induced erythroid differentiation of K562 cells. Innovation and Conclusion: Our findings demonstrate that the HIF1α-NFIL3-PIM1 signaling axis plays an important role in erythroid differentiation under hypoxia. These results will provide useful clues for preventing the damage of acute hypoxia to erythropoiesis. Antioxid. Redox Signal. 42, 36-52.

Global warming and extremely high temperatures affect insect survival and distribution. In this study, we characterized the gene expression profiles of red (PAR) and green (PAG) morphs of the pea aphid (Acyrthosiphon pisum) at three high temperatures (30 °C, 36 °C, and 38 °C) and three treatment durations (6 h, 12 h, and 24 h) by high-throughput sequencing. Both PARs and PAGs increased the number of significantly differentially expressed genes as temperature and treatment duration increased, particularly for genes associated with stress resistance, lipid metabolism, cuticular protein expression, and the initiation of various regulatory mechanisms. However, the response mechanisms and their intensities varied between the morphs. More cuticular protein genes were down-regulated in PAGs, while more stress resistance genes up-regulated in PARs. JAK-STAT, MAPK, Estrogen, Insulin signaling, and Longevity-regulating pathways were enriched in PARs, whereas AMPK, Insulin signaling, and Circadian rhythm pathways were enriched in PAGs. These results suggested that PARs possesses greater adaptability than PAGs under extreme high temperatures. The different temperature adaptability between morphs may represent an ecological strategy developed by A. pisum to adapt to global warming. This research enhances our understanding of the mechanisms underlying insect survival in high-temperatures environments and provides guidance for the development of control strategies., 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 © 2025 Elsevier B.V. All rights reserved.)

Eremopyrum triticeum is a typical spring ephemeral species, which in China mainly distributed in the desert regions of northern Xinjiang, and play an important role in the desert ecosystems. E. triticeum has several adaptive characteristics such as short growth rhythms, high photosynthetic efficiency, high seed production, drought and salt resistance. However, the molecular regulatory mechanism of E. triticeum in responses to abiotic stress resistance is still unknown. In this study, two NAC-like transcription factor-encoding genes, EtNAC1 and EtNAC2, were isolated from E. triticeum. The predicted EtNAC1 and EtNAC2 proteins possess a typical NAC DNA-binding domain at the N-terminal region. The qRT-PCR analysis showed that EtNAC1 and EtNAC2 were highly expressed in mature roots of E. triticeum, and were significantly up-regulated under drought, high salt and abscisic acid (ABA) stresses. Subcellular localization analysis in onion epidermal cells revealed that EtNAC1 and EtNAC2 were located in the nucleus. Expression of EtNAC1 and EtNAC2 in yeast cells improved the survival rate of yeast under low temperature, H 2 O 2 , high drought and salt stresses. Overexpression of EtNAC1 and EtNAC2 in Arabidopsis thaliana conferred enhanced tolerance to drought and salt stresses, increased ABA sensitivity, and transgenic plants showed higher proline (Pro) content, but lower malondialdehyde content, lower chlorophyll leaching, lower water loss rate and stomatal aperture (width/length) than WT plants. In conclusion, EtNAC1 and EtNAC2 play important roles in abiotic stress responses of E. triticeum, which might have significant potential in crop molecular breeding for abiotic stress tolerance., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: No Ethical statement was reported., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The optimal imaging modality for selecting the device size in patients with atrial fibrillation undergoing one-stop left atrial appendage occlusion (LAAO) with concomitant pulmonary vein isolation (PVi) remains undefined. We compared preprocedural 3-dimensional computed tomography (3D CT) with intra-procedural transesophageal echocardiography (TEE) and left atrial appendage (LAA) angiography in guiding one-stage PVi and LAAO., Methods: We measured the LAA ostium diameter using an interactive 3D CT system with a central line-based approach and compared these measurements with those from intra-procedural TEE and angiography, and the actual device size. The optimal compression ratio was used to assess the attainment rates of the three imaging modalities., Results: Twenty-two patients (median age: 68.5 years, 21.8 % female) underwent the one-stage procedure. The median LAA ostium diameter measured by 3D CT (24.3 mm, interquartile range [IQR] = 22.0-27.0 mm) was closer to the Watchman device size (27.0 mm, IQR = 24.0-31.0 mm, P = 0.127) compared to TEE (21.2 mm, IQR = 18.4-22.7 mm, P < 0.001) and angiography (22.5 mm, IQR = 17.9-25.1 mm, P < 0.001). 3D CT had a better attainment rate for the optimal compression ratio than TEE (10.8 %, IQR = 7.4-16.5 % vs. 22.7 %, IQR = 19.2-29.3 %, P < 0.001) and angiography (19.7 %, IQR = 15.1-24.1 %, P = 0.001). All patients underwent successful device implantation without peri-device leak or complications during the periprocedural period and follow-up., Conclusions: In this pilot study, a preprocedural central line-based 3D CT planning system appeared to be more effective than intraoperative TEE and angiography in measuring the LAA ostium diameter to guide device size selection in patients with atrial fibrillation undergoing one-stop LAAO with concomitant PVi., Competing Interests: 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., (© 2024 The Authors.)

Plants frequently encounter phosphate (Pi) starvation due to its scarce availability in soil, necessitating an adaptive phosphate starvation response (PSR). This study explores this adaptation in pepper (Capsicum annuum L.) under low-Pi stress, focusing on the PHOSPHATE STARVATION RESPONSE (PHR) gene family. We observably halted shoot growth but promoted root elongation in pepper seedlings under low-Pi conditions, significantly impacting regulatory networks. Our research identified 13 PHR transcription factors in pepper, particularly noting that CaPHR3 rapidly up-regulates in response to low-Pi stress. Overexpressing CaPHR3 in Arabidopsis thaliana enhanced Pi starvation tolerance by modulating PSR-related genes and mitigated hypersensitivity in the Atphr1phl1 double mutant. Furthermore, CaPHR3 binds to the P1BS motif in the pepper PHOSPHATE TRANSPORTER 1;4 (PHT1;4) promoter to boost its expression under Pi deficiency. This activation increased Pi uptake and starvation tolerance when overexpressed. Overall, we pinpointed key players in the PSR mechanism through the CaPHR3-CaPHT1;4 pathway, contributing significantly to our understanding of Pi homeostasis and adaptive strategies in pepper under Pi-deficient conditions., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The ability to recognize antigen epitope is crucial for generating an effective immune response. By engineering these epitopes, researchers can reduce on-target/off-tumor toxicity associated with targeted immunotherapy. Recent studies indicate that employing various gene editing tools to modify the epitopes of healthy hematopoietic stem and progenitor cells (HSPCs) can protect these cells from toxicity during tumor eradication, all while preserving their differentiation and function. This advancement greatly enhances the safety and efficacy of tumor immunotherapy., Competing Interests: Given her role as the Associate Editor, Y.Z. had no involvement in the peer-review of this article and has no access to information regarding its peer-review. The rest authors declare no competing interests., (© 2024 The Author(s).)

Aim: To describe tyrosine kinase inhibitor (TKI) treatment patterns and analyze co-variates of TKI switch for chronic myeloid leukemia (CML) patients in a center from China., Methods: A retrospectively study was designed to analyze TKI switching patterns, reasons and associated covariates in patients with CP-CML., Results: 1766 patients receiving initial imatinib (n = 1374), nilotinib (n = 254), dasatinib (n = 63) and flumatinib (n = 75) therapy were retrospectively interrogated. Median follow-up was 48 (IQR, 24-77) months. TKI switch proportions were 32% (570/1766) for first-line, 36% (208/570) for second-line and 34% (71/208) for third-line. Common therapy sequences included imatinib-dasatinib (37%) or nilotinib (35%) in those with 1 switch, imatinib-nilotinib-dasatinib (25%) with 2 switches and imatinib-nilotinib-dasatinib-olverembatinib (18%) with 3 switches. TKI switches were mainly due to resistance (64%, 76%, 88% across lines) and intolerance (19%, 14%, 7%). Multivariable analyses revealed ELTS intermediate/high-risk group (vs. low-risk), male, and lower hemoglobin were significantly associated with a higher probability of TKI switch. Compared to imatinib, initial nilotinib or dasatinib had lower switch rates. Male and ELTS high-risk (vs. low/intermediate) were associated with resistance-related switches, while lower hemoglobin, older age and initial dasatinib or flumatinib (vs. imatinib) were associated with intolerance-related switches to second-line therapy. Second-line imatinib/flumatinib (vs. nilotinib/dasatinib) and no/nonspecific ABL mutation were associated with resistance-related switches to third-line therapy., Conclusion: These findings emphasized the complexities involved in the management of patients with CP-CML and highlighted the importance of personalized treatment strategies., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A conformal Mg(OH) 2 nanoshell was constructed through a wet-chemical process, where a gradual release of OH - as the precipitating agent was designed to ensure the heterogeneous growth of the coating species. Such a coating treatment was found to be efficient in improving the structural stability and electrochemical stability of a 5 V LiNi 0.5 Mn 1.5 O 4 cathode.

Background: Cholesterol metabolism is essential for the development and progression of prostate cancer (PCa). Our previous study provided a new insight of cholesterol metabolism in the systematic management of PCa. However, the comprehensive role of cholesterol metabolism in PCa remains unclear., Methods: Using the cholesterol metabolism related genes (CMRGs) downloaded from the MSigDB database, and gene expression data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we constructed a cholesterol risk index by the least absolute shrinkage and selection operator (LASSO) model, and correlated the risk index with prognosis, tumor mutation burden (TMB), tumor microenvironment (TME) infiltration and response to chemotherapy and immunotherapy. RT-qPCR, western blot, immunohistochemistry, cell proliferation assays by CCK-8 and EdU assays, and cell apoptosis assays by flow cytometry analysis were also performed., Results: We found PCa was tightly correlated with the cholesterol metabolism pathways. The cholesterol risk index was an excellent and independent predictor of prognosis for PCa. A nomogram involving the risk index and other clinical factors (age, T stage) was established to explore the clinical value of risk index. We found high-risk index group was associated with worse prognosis, higher TMB, lower infiltration level of CD8 + T cells and a worse response to chemotherapy and immunotherapy. RT-qPCR, western blot and immunohistochemical staining validated the expression level of important CMRGs in PCa. In vitro experiments revealed downregulation of cholesterol metabolism could inhibit the proliferation of PCa cells and promoted their apoptosis., Conclusions: We demonstrated the comprehensive role of cholesterol metabolism in PCa. Using the risk index, we could predict the prognosis, TME infiltration and response to chemotherapy/immunotherapy of PCa. Better understanding and evaluating the cholesterol metabolism could aid in precision medicine and promoting prognosis of PCa., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Studies have shown that circRNAs play an important regulatory role in trophoblast function and embryonic development. Based on sequencing and functional experiments, we found that hsa&#95;circ&#95;0069443 can regulate the function of trophoblast cells, and its presence is found in the exosomes secreted by trophoblast cells. It is known that exosomes mediate the interaction between the uterus and embryo, which is crucial for successful pregnancy. We found that trophoblast cell-derived exosomes overexpressing hsa&#95;circ&#95;0069443 promoted the migration and invasion of endometrial stromal cells as well as the EMT process of endometrial glandular epithelial cells, and this process promotes embryo implantation and adhesion, thus proving that a decrease in hsa&#95;circ&#95;0069443 may be the key factor leading to early pregnancy loss. This study also found that hsa&#95;circ&#95;0069443 can bind to the RNA-binding protein demethylase ALKBH5, affecting the overall m6A level of trophoblast cells, and hsa&#95;circ&#95;0069443 and ALKBH5 can regulate the expression level of FN1, verifying the role of the 0069443/ALKBH5/FN1 axis in trophoblast cells and endometrial stromal cells. In summary, this study demonstrates that hsa&#95;circ&#95;0069443 may be a key factor leading to early pregnancy loss, and the regulation of the hsa&#95;circ&#95;0069443/ALKBH5/FN1 axis may provide new insights into early diagnostic markers for early pregnancy loss., Competing Interests: All authors declare no competing interests., (© 2024 The Authors.)

The Topological Hall effect (THE) is a fascinating physical phenomenon related to topological spin textures, serving as a powerful electrical probe for detecting and understanding these unconventional magnetic orders and skyrmions. Recently, the THE has been observed in strontium ruthenate (SrRuO 3 , SRO) thin films and its heterostructures, which originates from the disruption of interfacial inversion symmetry and Dzyaloshinskii-Moriya interaction (DMI). Here, we demonstrate a practically pure proton doping effect for controlling the DMI and THE in the SRO epitaxial films using the Pt electrode-assisted hydrogenation method. The hydrogenation process can realize approximately 0.8 protons per unit cell incorporating into the SRO films (thickness >10 nm) without causing significant lattice expansion and oxygen vacancies. Consistent with first-principles calculations, atomic-scale observations confirm that the proton doping induces a vertical displacement of Ru and O atoms in hydrogenated SRO (H-SRO), which remarkably enhances the DMI and leads to the emergence of the THE. More importantly, the proton doping drives two distinct topological signals in the ferromagnetic H-SRO, exhibiting greater THE values but no occurrence of structural transition. Our study has demonstrated that catalysis-assisted hydrogenation is an efficient strategy for manipulating the emerging THE and magnetic textures in correlated oxide thin films.

Terrestrial runoff is a key pathway for the transmission of the terrestrial pathogen Toxoplasma gondii from land to sea, posing a significant threat to marine ecosystems. Understanding the mechanisms by which T. gondii is transported from terrestrial to marine environment is crucial for developing effective prevention and control strategies for toxoplasmosis in marine organisms. This study investigates the transport of T. gondii through terrestrial runoff in the Sow River, a representative watershed in Weihai, China. Surface water, bottom water and sediment samples were collected and analyzed for T. gondii DNA using PCR methods. Out of 5328 samples, the prevalence of T. gondii was found to be 8.61 % in surface water, 9.80 % in bottom water and 16.61 % in sediment, with sediment identified as a significant reservoir. Additionally, estuarine zones showed a higher prevalence of T. gondii (16.80 %) compared to riverine areas (9.00 %). The study further revealed that seasonal climate variations, such as temperature and precipitation, had no significant impact on the distribution of T. gondii. However, there was significant spatial variability, with estuarine conditions facilitating increased pathogen transmission. These findings highlight the importance of estuaries and sediments as key conduits for T. gondii entry in marine food webs. The results provide a theoretical basis for designing infection prevention and control strategies aimed at protecting marine ecosystems., 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 Elsevier B.V. All rights reserved.)

To enhance the capacity for early and effective management of genital tract infections at primary and secondary levels of the healthcare system, we developed a prediction model, validated internally to help predict individual risk of self-reported genital tract infections (sGTIs) at the community level in Ghana. The study involved 32973 men and women aged 15-49 years from three rounds of the Ghana Demographic Health Survey, from 2003 to 2014. The outcomes were sGTIs. We applied the least absolute shrinkage and selection operator (LASSO) penalized regression with a 10-fold cross-validation model to 11 predictors based on prior review of the literature. The bootstrapping technique was also employed as a sensitivity analysis to produce a robust model. We further employed discriminant and calibration analyses to evaluate the performance of the model. Statistical significance was set at P -value <0.05. The mean±standard deviation age was 29.1±9.7 years with female preponderance (60.7%). The prevalence of sGTIs within the period was 11.2% (95% CI = 4.5-17.8) and it ranged from 5.4% (95% CI = 4.8-5.86) in 2003 to 17.5% (95% CI = 16.4-18.7) in 2014. The LASSO regression model retained all 11 predictors. The model's ability to discriminate between those with sGTIs and those without sGTIs was approximately 73.50% (95% CI = 72.50-74.26) from the area under the curve with bootstrapping technique. There was no evidence of miscalibration from the calibration belt plot with bootstrapping (test statistic = 17.30; P -value = 0.060). The model performance was judged to be good and acceptable. In the absence of clinical measurement, this prediction tool can be used to identify individuals aged 15-49 years with a high risk of sGTIs at the community level in Ghana. Frontline healthcare staff can use this tool for screening and early detection. We, therefore, propose external validation of the model to confirm its generalizability and reliability in different population.

Chlorophyll is an important nutrient in celery and one of the main indexes of quality evaluation. RNA editing in chloroplasts is an important factor affecting chloroplast development and chlorophyll biosynthesis. Multisite organelle RNA editing factor (MORF) protein is a necessary regulator of chloroplast RNA editing. In this study, a total of 8 MORF genes in celery were identified, which were named AgMORF1a, AgMORF1b, AgMORF2a, AgMORF2b, AgMORF3, AgMORF7, AgMORF8 and AgMORF9 according to their subfamily classification. The physicochemical property, conserved motifs, cis-acting elements and protein interaction were predicted according to the sequences. The phylogenetic relationships and evolutionary selective pressure between MORF genes in celery and other Apiaceae plants were further analyzed. The results showed that AgMORF1b, AgMORF2a, AgMORF2b and AgMORF9 were predicted to be localized in chloroplasts. The evolution of MORF genes in 4 Apiaceae plants including celery, carrot, coriander and water dropwort was influenced by purify selection. Transcriptome data showed that the transcriptional levels of AgMORF2a, AgMORF2b, AgMORF8 and AgMORF9 were relatively higher among all MORF genes in petioles of celery, indicating their major role. RT-qPCR data showed that the expression levels of the above 4 genes were significantly higher in petioles of green celery than those of white celery. This study provided a basis for analyzing the effects of MORF proteins on chloroplast development of celery with different chlorophyll accumulation., 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 The Author(s). Published by Elsevier Inc. All rights reserved.)

Prostate cancer (PCa) is a prevalent malignant tumor affecting the male reproductive system and there are mainly three widely accepted PCa surgery types in current clinical treatment: open radical prostatectomy (ORP), laparoscopic radical prostatectomy (LRP) and robot-assisted radical prostatectomy (RARP). Here, we aimed to evaluate the clinical effect of RARP for PCa patients compared with ORP and LRP based on the context of PCa encompass two dimensions: oncological outcomes (biochemical recurrence (BCR) and positive surgical margin (PSM)) and functional outcomes (urinary continence and recovery of erectile function) in this network meta-analysis (NMA). PubMed, Embase and Cochrane databases were systematically searched in January 7, 2024. 4 randomized controlled trials (RCTs) and 72 non-RCTs were included. RARP displayed significant positive effect on lower BCR and better recovery of erectile function but no significant differences existed among three surgery types for PSM and urinary continence., Competing Interests: Declaration of Competing Interest All authors declare no financial and personal relationships., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The purpose of this study was to understand whether acupuncture can decrease the risk of dementia in patients with rheumatoid arthritis (RA)., Methods: Using the registry from the National Health Insurance Research Database of Taiwan, we carried out a 1:1 propensity-score matched cohort study to analyze patients with RA diagnosed between 2000 and 2010. The patients who received acupuncture therapy were grouped as acupuncture users ( n = 9,919), while the others were grouped as non-acupuncture users ( n = 19,331). After propensity-score matching, the final sample included 9,218 matched participants in both groups, and these participants were followed up until the end of 2011. We used a Cox regression model to adjust for age, sex, comorbidiy, and conventional drugs and compared the hazard ratios (HRs) of developing dementia in the acupuncture and non-acupuncture groups., Results: Acupuncture users tended to be more female-dominant and younger than non-acupuncture users. After propensity-score matching, both groups have comparable demographic characteristics. Acupuncture users had a lower risk of dementia than non-acupuncture users (adjusted HR: 0.55, 95% CI: 0.46-0.66). The cumulative incidence of dementia in the acupuncture group was significantly lower than that in the non-acupuncture group (log-rank test, p < 0.001). Patients who received the combinational treatment of conventional drugs and acupuncture had a significantly lower risk of developing dementia (adjusted HR: 0.64, 95% CI: 0.56-0.73) compared to those who only received conventional drugs., Conclusion: Acupuncture therapy is associated with a reduced risk of dementia in patients with RA. Further clinical and mechanistic studies are needed., (© 2024 Korea Institute of Oriental Medicine. Published by Elsevier B.V.)

Objectives: Cancer cells undergo metabolic reprogramming to adapt to high oxidative stress, but little is known about how metabolic remodeling enables gastric cancer cells to survive stress associated with aberrant reactive oxygen species (ROS) production. Here, we aimed to identify the key metabolic enzymes that protect gastric cancer (GC) cells from oxidative stress., Methods: ROS level was detected by DCFH-DA probes. Multiple cell biological studies were performed to identify the underlying mechanisms. Furthermore, cell-based xenograft and patient-derived xenograft (PDX) model were performed to evaluate the role of MTHFD2 in vivo., Results: We found that overexpression of MTHFD2, but not MTHFD1, is associated with reduced overall and disease-free survival in gastric cancer. In addition, MTHFD2 knockdown reduces the cellular NADPH/NADP+ ratio, colony formation and mitochondrial function, increases cellular ROS and cleaved PARP levels and induces in cell death under hypoxia, a hallmark of solid cancers and a common inducer of oxidative stress. Moreover, genetic or pharmacological inhibition of MTHFD2 reduces tumor burden in both tumor cell lines and patient-derived xenograft-based models., Discussion: our study highlights the crucial role of MTHFD2 in redox regulation and tumor progression, demonstrating the therapeutic potential of targeting MTHFD2.

Chitosan, as a kind of naturally occurring green and degradable material for the preservation of perishable foods, was investigated in this study with the objective of enhancing its preservation performances. Herein, lignin was modified using the solvent fractionation method (modified lignin, ML, including ML1-ML3), while natural clinoptilolite zeolite was modified using the alkali modification method (modified clinoptilolite zeolite, MCZ, including MCZ1-MCZ5). After optimizing the conditions, it was discovered that incorporating both ML3 and MCZ3 into pure chitosan-based membranes might be conducive to fabricate chitosan-based composite membranes for the preservation of perishable foods. As-prepared composite membranes possessed better visible light transmittance, antioxidant activity, and carbon dioxide/oxygen selectivity, resulting in improved preservation effects on the model perishable foods such as bananas, cherry tomatoes, and cheeses. These findings might indicate promising applications for chitosan-based composite membranes with modified lignin and zeolite in the field of eco-friendly degradable materials for the preservation of perishable foods., 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 Elsevier Ltd. All rights reserved.)

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome with cardiac dysfunction, fluid retention and reduced exercise tolerance as the main manifestations. Current treatment of HFpEF is using combined medications of related comorbidities, there is an urgent need for a modest drug to treat HFpEF. Geniposide (GE), an iridoid glycoside extracted from Gardenia Jasminoides, has shown significant efficacy in the treatment of cardiovascular, digestive and central nervous system disorders. In this study we investigated the therapeutic effects of GE on HFpEF experimental models in vivo and in vitro. HFpEF was induced in mice by feeding with HFD and L-NAME (0.5 g/L) in drinking water for 8 weeks, meanwhile the mice were treated with GE (25, 50 mg/kg) every other day. Cardiac echocardiography and exhaustive exercise were performed, blood pressure was measured at the end of treatment, and heart tissue specimens were collected after the mice were euthanized. We showed that GE administration significantly ameliorated cardiac oxidative stress, inflammation, apoptosis, fibrosis and metabolic disturbances in the hearts of HFpEF mice. We demonstrated that GE promoted the transcriptional activation of Nrf2 by targeting MMP2 to affect upstream SIRT1 and downstream GSK3β, which in turn alleviated the oxidative stress in the hearts of HFpEF mice. In H9c2 cells and HL-1 cells, we showed that treatment with GE (1 μM) significantly alleviated H 2 O 2 -induced oxidative stress through the MMP2/SIRT1/GSK3β pathway. In summary, GE regulates cardiac oxidative stress via MMP2/SIRT1/GSK3β pathway and reduces cardiac inflammation, apoptosis, fibrosis and metabolic disorders as well as cardiac dysfunction in HFpEF. GE exerts anti-oxidative stress properties by binding to MMP2, inhibiting ROS generation in HFpEF through the SIRT1/Nrf2 signaling pathway. In addition, GE can also affect the inhibition of the downstream MMP2 target GSK3β, thereby suppressing the inflammatory and apoptotic responses in HFpEF. Taken together, GE alleviates oxidative stress/apoptosis/fibrosis and metabolic disorders as well as HFpEF through the MMP2/SIRT1/GSK3β signaling pathway., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Since silver nanoparticles (AgNPs) and polystyrene microplastics (PS-MP) share common environmental niches, their interactions can modulate their hazard impacts. Herein, we assessed the developmental toxicity of 1 mg/L PS-MP, 0.5 mg/L AgNPs and the mixtures of AgNPs and PS-MP on embryo-larval zebrafish. We found that AgNPs co-exposure with PS-MP remarkably decreased mortality rates, malformation rates, heart rates and yolk sac area, while it increased hatching rates and eye size compared to the AgNPs group. These phenomena revealed that the cell cycle, oxidative stress, apoptosis, lipid metabolism, ferroptosis and p53 signalling pathway were obviously affected by single AgNPs exposure at 96 hpf (hours post fertilization). Interestingly, all these effects were effectively ameliorated by co-exposure with PS-MP. The combination of transcriptomic and metabolomic analyses showed that the imbalance of DEGs (differentially expressed genes) and DEMs (differentially expressed metabolites) (PI, phosphatidylinositol and TAG-FA, triacylglycerol-fatty acid) disturbed both the cell cycle and lipid metabolism following single AgNPs exposure and co-exposure with PS-MP. These findings suggest that PS-MP attenuates the developmental toxicity of AgNPs on embryo-larval zebrafish. Overall, this study provides important insight into understanding the transcriptional responses and mechanisms of AgNPs alone or in combination with PS-MPs on embryo-larval zebrafish, providing a reference for ecological risk assessment of combined exposure to PS-MP and metal nanoparticles., 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 Elsevier B.V. All rights reserved.)

Atherosclerosis (AS) is an inflammatory arterial disorder that occurs due to the deposition of the excessive lipoprotein under the artery intima, mainly including low-density lipoprotein and other apolipoprotein B-containing lipoproteins. G protein-coupled receptors (GPCRs) play a crucial role in transmitting signals in physiological and pathophysiological conditions. GPCRs recognize inflammatory mediators, thereby serving as important players during chronic inflammatory processes. It has been demonstrated that free fatty acids can function as ligands for various GPCRs, such as free fatty acid receptor (FFAR)1/GPR40, FFAR2/GPR43, FFAR3/GPR41, FFAR4/GPR120, and the lipid metabolite binding glucose-dependent insulinotropic receptor (GPR119). This review discusses GPR43 and its ligands in the pathogenesis of AS, especially focusing on its distinct role in regulating chronic vascular inflammation, inhibiting oxidative stress, ameliorating endothelial dysfunction and improving dyslipidemia. It is hoped that this review may provide guidance for further studies aimed at GPR43 as a promising target for drug development in the prevention and therapy of AS., Competing Interests: The authors declare there are no competing interests.

Background: Although optical coherence tomography (OCT) guidance with the 'MLDMAX' criteria is very useful for de-novo lesions during percutaneous coronary intervention (PCI), there are limited studies on its benefits in patients with in-stent restenosis (ISR). This study aimed to compare the clinical outcomes of patients with ISR who underwent repeat PCI (re-PCI) with OCT or angiographic guidance., Methods: This retrospective study enrolled 2142 patients with ISR who underwent re-PCI at Nanjing First Hospital from January 2016 to January 2023. The primary endpoint was the incidence of target vessel failure (TVF) post-re-PCI within 3 years. The secondary endpoints included each component of TVF., Results: After propensity score matching, 161 matched pairs were enrolled. OCT guidance of re-PCI was associated with a significantly lower risk of TVF compared with angiographic guidance alone [hazard ratio (HR), 0.51; 95% confidence interval (CI), 0.31-0.83; P  = 0.007] in patients with ISR. However, only 68.9% of patients with ISR met the final criteria of 'MLDMAX' post-re-PCI, which was associated with a lower risk of TVF compared with patients without meeting the OCT criteria (HR, 0.24; 95% CI, 0.11-0.54; P  < 0.001), and satisfied the angiographic criteria (HR, 0.40; 95% CI, 0.19-0.85; P  = 0.017)., Conclusion: Compared with angiographic guidance, OCT guidance significantly reduced TVF risk following re-PCI for ISR lesions, especially for patients who met the final criteria of 'MLDMAX'., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The dual inhibition of histone lysine-specific demethylase 1 (LSD1) and histone deacetylase (HDAC) has emerged as a promising strategy for cancer therapy. In this study, we report the discovery of novel 5-cyano-3-phenylindole-based LSD1/HDAC dual inhibitors, evaluated through both in vitro and in vivo assays. Among these inhibitors, compound 20c was identified as particularly potent, exhibiting high inhibitory activity against LSD1 (IC 50 = 39.0 nM) and HDAC1/2/3/6/8 (IC 50 = 1.4, 1.0, 1.3, 2.9, and 16.0 nM, respectively). Compound 20c effectively modulated the expression of biomarkers associated with LSD1 and HDAC inhibition and demonstrated superior antiproliferative activity compared to SAHA and 4SC-202 across multiple colorectal cancer cell lines. Following pharmacokinetic studies, 20c was further assessed in HCT-116 and HT-29 xenograft mouse models. It demonstrated significantly enhanced antitumor efficacy compared to SAHA, without causing observable toxicity. These findings highlight the potential of LSD1/HDAC dual inhibitors for the treatment of malignant cancers.

Urea's transmembrane transport through urea transporters (UT) is a fundamental physiological behavior for life activities. Here, we present 11 cryo-EM structures of four UT members in resting states, urea transport states, or inactive states bound with synthetic competitive, uncompetitive or noncompetitive inhibitor. Our results indicate that the binding of urea via a conserved urea recognition motif (URM) and the urea transport via H-bond transfer along the Q Pb -T 5b -T 5a -Q Pa motif among different UT members. Moreover, distinct binding modes of the competitive inhibitors 25a and ATB3, the uncompetitive inhibitor CF11 and the noncompetitive inhibitor HQA2 provide different mechanisms for blocking urea transport and achieved selectivity through L-P pocket, UCBP region and SCG pocket, respectively. In summary, our study not only allows structural understanding of urea transport via UTs but also afforded a structural landscape of hUT-A2 inhibition by competitive, uncompetitive and noncompetitive inhibitors, which may facilitate developing selective human UT-A inhibitors as a new class of salt-sparing diuretics., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

This study developed a MgBi 2 O 6 -based photocatalyst via low-temperature hydrothermal synthesis. AgBr was co-precipitated onto MgBi 2 O 6 , and silver nanoparticles (AgNPs) were photo-reduced onto the surface. The photocatalytic performance, assessed by methylene blue (MB) degradation under white-light LED irradiation (2.5 W, power density = 0.38 W/cm 2 ), showed that Ag/AgBr/MgBi 2 O 6 achieved 98.6% degradation in 40 min, outperforming MgBi 2 O 6 (37.5%) and AgBr/MgBi 2 O 6 (85.5%). AgNPs boosted electron-hole separation via surface plasmon resonance, reducing recombination. A Z-scheme photocatalytic mechanism was suggested, where photogenerated carriers transferred across the p-n heterojunction between AgBr and MgBi 2 O 6 , producing reactive oxygen species like superoxide and hydroxyl radicals critical for dye degradation. Thus, the Ag/AgBr/MgBi 2 O 6 composites possessed excellent photocatalytic performance regarding dyestuff degradation (85.8-99.9% degradation within 40 min) under white-light LED irradiation.

Epilepsy remains a prevalent chronic neurological disease that is featured by aberrant, recurrent and hypersynchronous discharge of neurons and poses a great challenge to healthcare systems. Although several therapeutic interventions are successfully utilized for treating epilepsy, they can merely provide symptom relief but cannot exert disease-modifying effect. Therefore, it is of urgent need to explore other potential mechanism to develop a novel approach to delay the epileptic progression. Since approximately 30 years ago, histone deacetylases (HDACs), the versatile epigenetic regulators responsible for gene transcription via binding histones or non-histone substrates, have grabbed considerable attention in drug discovery. There are also substantial evidences supporting that aberrant expressions and/activities of HDAC isoforms are reported in epilepsy and HDAC inhibitors (HDACi) have been successfully utilized for therapeutic purposes in this condition. However, the specific mechanisms underlying the role of HDACs in epileptic progression have not been fully understood. Herein, we reviewed the basic information of HDACs, summarized the recent findings associated with the roles of diverse HDAC subunits in epilepsy and discussed the potential regulatory mechanisms by which HDACs affected the development of epilepsy. Additionally, we also provided a brief discussion on the potential of HDACs as promising therapeutic targets for epilepsy treatment, serving as a valuable reference for basic study and clinical translation in epilepsy field., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Aim: To investigate the proliferation regulatory effect of cone-rod homeobox (CRX) in retinal pigment epithelium (RPE) and retinoblastoma (RB) cells to explore the potential application and side effect (oncogenic potential) of CRX-based gene therapy in RPE-based retinopathies., Methods: Adult human retinal pigment epithelial (ARPE)-19 and human retinal pigment epithelial (RPE)-1 cells and Y79 RB cell were used in the study. Genetic manipulation was performed by lentivirus-based technology. The cell proliferation was determined by a CellTiter-Glo Reagent. The mRNA and protein levels were determined by quantitative real-time polymerase chain reaction (qPCR) and Western blot assay. The transcriptional activity of the promoter was determined by luciferase reporter gene assay. The bindings between CRX and transcription factor 7 (TCF7) promoter as well as TCF7 and the promoters of TCF7 target genes were examined by chromatin immunoprecipitation (ChIP) assay. The transcription of the TCF7 was determined by a modified nuclear run-on assay., Results: CRX overexpression and knockdown significantly increased ( n =3, P <0.05 in all the cells) and decreased ( n =3, P <0.01 in all the cells) the proliferation of RPE and RB cells. CRX overexpression and knockdown significantly increased and deceased the mRNA levels of Wnt signaling target genes [including MYC proto-oncogene ( MYC ), JUN , FOS like 1 ( FOSL1 ), CCND1 , cyclin D2 ( CCND2 ), cyclin D3 ( CCND3 ), cellular communication network factor 4 ( CCN4 ), peroxisome proliferator activated receptor delta ( PPARD ), and matrix metallopeptidase 7 ( MMP7 )] and the luciferase activity driven by the Wnt signaling transcription factor (TCF7). TCF7 overexpression and knockdown significantly increased and decreased the proliferation of RPE and RB cells and depletion of TCF7 significantly abolished the stimulatory effect of CRX on the proliferation of RPE and RB cells. CRX overexpression and knockdown significantly increased and decreased the mRNA level of TCF7 and the promoter of TCF7 was significantly immunoprecipitated by CRX antibody., Conclusion: CRX transcriptionally activates TCF7 to promote the proliferation of RPE and RB cells in vitro . CRX is a potential target for RPE-based regenerative medicine. The potential risk of this strategy, tumorigenic potential, should be considered., Competing Interests: Conflicts of Interest: Zhao N, None; Li YY, None; Xu JM, None; Yang MY, None; Li YZ, None; Lam TC, None; Zhou L, None; Tong QH, None; Zhang JT, None; Wang SZ, None; Hu XX, None; Wu YF, None; Lu QK, None; Lang TY, None., (International Journal of Ophthalmology Press.)

This study investigates the stability, electronic structure, and optical properties of the GaN/g-C 3 N 4 heterojunction using the plane wave super-soft pseudopotential method based on first principles. Additionally, an external electric field is employed to modulate the band structure and optical properties of GaN/g-C 3 N 4 . The computational results demonstrate that this heterojunction possesses a direct band gap and is classified as type II heterojunction, where the intrinsic electric field formed at the interface effectively suppresses carrier recombination. When the external electric field intensity (E) falls below -0.1 V/Å and includes -0.1 V/Å, or exceeds 0.2 V/Å, the heterojunction undergoes a transition from a type II structure to the superior Z-scheme, leading to a significant enhancement in the rate of separation of photogenerated carriers and an augmentation in its redox capability. Furthermore, the introduction of a positive electric field induces a redshift in the absorption spectrum, effectively broadening the light absorption range of the heterojunction. The aforementioned findings demonstrate that the optical properties of GaN/g-C 3 N 4 can be precisely tuned by applying an external electric field, thereby facilitating its highly efficient utilization in the field of photocatalysis.