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Yu-Yan Qin,1,* Hui Yu,1,2,* Yong Huang,1,* Xiaoyi Yang,1 Songpei Li,1 Ao Shen,1 Yinshan Lin,1 Mei Zhang,1 Qiulian Zhu,1 Jingwei Zhang,1 Lingmin Zhang,1 Xi-Yong Yu1 1Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, People’s Republic of China; 2Hutchison Whampoa Guangzhou Baiyunshan Chinese Medicine Co., Ltd, Guangzhou, Guangdong, 510515, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xi-Yong Yu; Lingmin Zhang, School of Pharmaceutical Sciences, Guangzhou Medical University, Xinzao Road, Panyu District, Guangzhou, 511436, People’s Republic of China, Email yuxycn@gzhmu.edu.cn; zhanglm@gzhmu.edu.cnBackground: Acute lung injury (ALI) leads to diffuse pulmonary interstitial and alveolar edema, further developing into acute respiratory distress syndrome (ARDS). The present therapeutic approaches showed limited effects with poor clinical efficacy or severe side effects. This study aims to develop novel pharmaceutical agents to reduce lung damage with acceptable side effects for ALI.Methods: Naked gene delivery system based on epigallocatechin 3-gallate (EGCG) was synthesized to deliver plasmid expressing DNA damage regulated autophagy modulator 1 (DRAM1), designated as EGCG/DRAM1 (ED). ED was characterized by dynamic light scattering analysis and transmission electron microscope. The biodistribution of ED in mice was measured by an in vivo small animal imaging system. The therapeutic potentials of ED were evaluated in MLE12 cells and LPS-induced ALI mice.Results: Our results showed that ED was nearly spherical with a diameter of ~100 nm and increased the stability of DRAM1 plasmid that encapsulated. The synthesized ED showed negligible toxicity at the selected experimental concentration in MLE12 cells. ED could be taken up by MLE12 cells with high efficiency and escape from the lysosome. In ALI mice, ED facilitated the accumulation and retention of DRAM1 plasmid in lung, and attenuated pulmonary edema and pulmonary vascular permeability. The therapeutic effects of ED on ALI were associated with increased autophagy and reduced oxidative stress in lung.Conclusion: In summary, ED attenuated pulmonary edema and pulmonary vascular permeability, and improved pulmonary dysfunction in ALI mice. This naked gene delivery system for autophagy enhancement may serve as a potential therapeutic strategy to attenuate ALI. Keywords: acute lung injury, EGCG, DRAM1, autophagy, oxidative stress

Guanlie Li,1,* Haiqing He,1,* Guodong Zheng,1,* Wenjing Jiang,1 Shuwen Du,1 Hua Tao,1 Tao Xiao,1 Dazhi Zhou,2 Shangwei Ding,2 Xi-Yong Yu,1 Yu Zhang,1 Ao Shen1 1Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Ultrasound, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ao Shen; Yu Zhang Tel +86 20 3110 0902; +86 20 3710 3275Email shenao@gzhmu.edu.cn; qianedyzy@163.comBackground: Pulmonary fibrosis (PF) is a fatal lung disease and affects over 5 million patients worldwide. Precise and early detection of PF is of pivotal importance to slow the disease progression. However, there are currently no effective tools to detect PF directly.Purpose: This study aimed to develop an imaging modality to detect PF directly. Excessive collagen deposition is the hallmark of PF. Herein, we developed a novel PF diagnostic agent, namely PVD (platelets-derived nanovesicles labeled with dye), by utilizing near-infrared (NIR)-responsive biomimetic platelets that specifically recognize collagen.Methods: In brief, platelets membrane was extracted from purified platelets by freeze/thaw and formed to PVD nanovesicles via sonication and extrusion, when loaded with DiR dye. Red blood cells membrane loaded with DiR was prepared in the same way as PVD to form RVD as control. Collagen self-assembled on microplates was used as an in vitro collagen fibrils model and monocrotaline-induced rats were used as an in vivo PF model.Results: We demonstrated that PVD, but not RVD nor other controls, could bind collagen both in vitro and in vivo, and directly detect pulmonary fibrosis in vivo and ex vivo at the early PF stage.Conclusion: Collectively, PVD is a versatile NIR-responsive probe for the direct visualization of collagen, and can be particularly helpful in direct detecting PF. To the best of our knowledge, PVD is the first report of a NIR probe for the direct detection of pulmonary fibrosis.Keywords: pulmonary fibrosis, collagen, platelets, imaging diagnosis, near-infrared

Jijun Fu,1,* Qianni Wu,1,* Yuanye Dang,1,* Xueping Lei,1 Guining Feng,1 Mingyue Chen,2 Xi-Yong Yu1 1The Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, The First Affiliated Hospital of Guangzhou Medical University, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 511436, People’s Republic of China; 2Foshan Nanhai Vocational School of Health, Foshan, 528211, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jijun Fu Email fujj@gzhmu.edu.cnIntroduction: Traditional antitumor chemotherapy faces great challenges, such as multi-drug resistance (MDR) and poor penetration into tumor tissues. The newly emerging nitric oxide (NO)-based gas therapy has been recognized to reduce MDR and has improved permeation into tumor tissue.Methods: In this study, NO-generating prodrug sodium nitroprusside (SNP) was doped to hollow mesoporous Prussian blue (PB) nanoparticles to fabricate NO-generating nanoparticles (NO-PB), which was further loaded with doxorubicin (DOX).Results: DOX loaded NO-PB (DOX-NO-PB) was released quicker at pH 6 compared with neutral pH, suggesting NO-PB may facilitate the release of loaded drug in acidic tumor tissue. The capacity of NO production by NO-PB was measured, and the results showed the presence of NO in the culture medium from 4T1 cells incubated with NO-PB and inside the cells. NP-PB could be detected by photoacoustic imaging (PAI) in tumor tissue in 4T1 tumor bearing mice, suggesting this nanoparticle may serve as contrast agent for the noninvasive diagnosis of tumor tissues. NO-PB suppressed the growth of tissues in 4T1 tumor bearing mice. DOX-NO-PB showed more potent anti-tumor effects in 4T1 cells and tumor bearing mice compared with free DOX and NO-PB alone, indicating that the combination of DOX and NO-PB exhibited synergistic effects on tumor suppression.Conclusion: This study provides a novel nanocarrier for gas therapy with additional PAI imaging capacity. This nanocarrier can be utilized for combination therapy of NO and chemotherapeutics which may serve as theranostic agents.Keywords: gas therapy, nitric oxide, NO, photoacoustic imaging, PAI, sodium nitroprusside, SNP, hollow mesoporous Prussian blue (PB) nanoparticles

Yueheng Wu,1,2,* Lin jiang,2,* Zixuan Dong,1 Shaoxian Chen,2 Xi-Yong Yu,2 Shunqing Tang1 1National Engineering Research Center for Healthcare Devices, Guangdong Institute of Medical Instruments, Biomedical Engineering Institute, Jinan University, Guangzhou, 510632, People’s Republic of China; 2Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, 510080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shunqing TangNational Engineering Research Center for Healthcare Devices, Guangdong Institute of Medical Instruments, Biomedical Engineering Institute, Jinan University, Guangzhou, 510632, People’s Republic of ChinaEmail tshunqt@jnu.edu.cnIntroduction: Intracellular protein delivery is emerging as a potential strategy to revolutionize therapeutics in the field of biomedicine, aiming at treating a wide range of diseases including cancer, inflammatory diseases and other oxidative stress-related disorders with high specificity. However, the current challenges and limitations are addressed to either synthetically or biologically through multipotency of engineering, such as protein modification, insufficient delivery of large-size proteins, deficiency or mutation of proteins, and high cytotoxicity.Methods: We prepared the nanocomposites by mixing protein with PEI1200 at a certain molar ratio and demonstrated that it can deliver proteins into living cells in high efficiency and safety through the following experiments, such as dynamic light scattering, fluorescent detection, agarose gel electrophoresis, ß-Galactosidase activity detection, immunofluorescence staining, digital fluorescent detection, cell viability assay and flow cytometry.Results: The self-assembly of PEI1200/protein nanocomposites with appropriate molar ratio (4:1 and 8:1) could provide efficiently delivery of active proteins to a variety of cell types in the presence of serum. The nanocomposites could continuously release protein up to 96 h in their desired intracellular locations. In addition, these nanocomposites were able to preserve protein activity while maintain low cytotoxicity (when final concentration < 1 μg/mL).Conclusion: Collectively, PEI1200-based delivery system provided an alternative strategy to direct protein delivery in high efficiency and safety, offering increased potential applications in clinical biomedicine.Keywords: polyethyleneimine, protein delivery, nanocomposites, low-molecular-weight, cytotoxicity

Tita Alissa Listyowardojo,1 Xiaoling Yan,2,3 Stephen Leyshon,1 Bobbie Ray-Sannerud,1 Xin Yan Yu,4 Kai Zheng,4 Tao Duan2,3 1Life Sciences Program, Group Technology and Research, DNV GL, Hovik, Norway; 2Quality and Safety Department, Shanghai First Maternity and Infant Hospital, 3Tongji University School of Medicine, Shanghai, 4Healthcare Department, Business Assurance, DNV GL, Beijing, China Objective: To assess safety culture at a public maternity hospital in Shanghai, China, using a sequential mixed methods approach. The study was part of a bigger study looking at the application of the mixed methods approach to assess safety culture in health care in different organizations and countries.Methodology: A mixed methods approach was utilized by first distributing the Safety Attitudes Questionnaire measuring six safety culture dimensions and five independent items to all hospital staff (n=1482) working in 18 departments at a single hospital. Afterward, semistructured interviews were conducted using convenience sampling, where 48 hospital staff from nine departments at the same hospital were individually interviewed.Results: The survey received a response rate of 96%. The survey findings show significant differences between the hospital departments in almost all safety culture dimensions and independent items. Similarly, the interview findings revealed that there were different, competing priorities between departments perceived to result in a reduced quality of collaboration and bottlenecks in care delivery. Another major finding was that staff who worked more hours per week would perceive working conditions significantly more negatively. Issues related to working conditions were also the most common concerns discussed in the interviews, especially the issue on high workload. High workload was also reflected in the fact that 91.45% of survey respondents reported that they worked 40 hours or longer per week. Finally, interview findings complemented survey findings, thus providing a more complete and accurate picture of safety culture.Conclusion: Hospital leaders need to prioritize interventions focused on improving the quality of cross-department collaboration and reducing workload. A mixed methods assessment of safety culture provides more meaningful, targeted results, enabling leaders to prioritize and tailor improvement efforts to increase the impact of an intervention. Keywords: semi-structured interview, survey, one child policy, the safety attitudes questionnaire, safety climate

Aqueous secondary organic aerosol (aqSOA) formation from volatile and semivolatile organic compounds at the air-liquid interface is considered as an important source of fine particles in the atmosphere. However, due to the lack of in situ detecting techniques, the detailed interfacial reaction mechanism and dynamics still remain uncertain. In this study, synchrotron-based vacuum ultraviolet single-photon ionization mass spectrometry (VUV SPI-MS) was coupled with the System for Analysis at the Liquid Vacuum Interface (SALVI) to investigate glyoxal dark oxidation products at the aqueous surface. Mass spectral analysis and determination of appearance energies (AEs) suggest that the main products of glyoxal dark interfacial aging are carboxylic acid related oligomers. Furthermore, the VUV SPI-MS results were compared and validated against those of in situ liquid time-of-flight secondary ion mass spectrometry (ToF-SIMS). The reaction mechanisms of the dark glyoxal interfacial oxidation, obtained using two different approaches, indicate that differences in ionization and instrument operation principles could contribute to their abilities to detect different oligomers. Therefore, the mechanistic differences revealed between the VUV SPI-MS and ToF-SIMS indicate that more in situ and real-time techniques are needed to investigate the contribution of the air-liquid interfacial reactions leading to aqSOA formation.

Vacuum ultraviolet (VUV) single photon ionization mass spectrometry (SPI-MS) is a vacuum-based technique typically used for the analysis of gas phase and solid samples, but not for liquids due to the challenge in introducing volatile liquids in a vacuum. Here we present the first demonstration of in situ liquid analysis by integrating the System for Analysis at the Liquid Vacuum Interface (SALVI) microfluidic reactor into VUV SPI-MS. Four representative volatile organic compound (VOC) solutions were used to illustrate the feasibility of liquid analysis. Our results show the accurate mass identification of the VOC molecules and the reliable determination of appearance energy that is consistent with ionization energy for gaseous species in the literature as reported. This work validates that the vacuum-compatible SALVI microfluidic interface can be utilized at the synchrotron beamline and enable the in situ study of gas-phase molecules evaporating off the surface of a liquid, which holds importance in the study of condensed matter chemistry.

Early metastases of hepatocellular carcinoma (HCC) may be detected by the isolation of circulating tumor cells (CTCs) in the bloodstream. During the course of therapeutic attempts, monitoring CTC changes in patients with HCC is helpful for the efficacy assessment. Nevertheless, the markers used for the detection, such as α-feto protein, asialoglycoprotein receptor or epithelial cell adhesion molecule, CD133 or CD90, are not specific for HCC CTCs. In spite of these limitations, a timely determination of the existence of CTCs will be beneficial for the monitoring of distant metastases, the evaluation of therapeutic attempts, and the prediction of prognosis.

Objectives: To observe the effect of electroacupuncture (EA) of "Jiaji" (EX-B2) on expression of high mobility group box 1 (HMGB1)/Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) related proteins and inflammation-related factors in spinal cord injury (SCI) rats, so as to explore the dynamic process of inhibiting inflammatory response in rats with SCI, and to provide a new idea and theoretical basis of molecular biology for the treatment of SCI., Methods: Fifty-four SD rats were randomly divided into sham operation, model, and EA groups ( n =18 in each group), which were further divided into 3 d, 7 d and 14 d subgroups, with 6 rats at each time point. The SCI model was established according to the Allen's method. Rats in EA group received EA (1 mA, 100 Hz) intervention at EX-B2 of T9 and T11 24 hours after modeling for 30 min, once a day for 3 d, 7 d, or 14 d, respectively. The motor function of rats' hind limbs was evaluated using BBB scale, the morphological structure of rats' spinal cord tissue was observed by H.E. staining. The contents of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in spinal cord tissue were detected by ELISA. Western blot and immunofluorescence staining were used to detect the relative protein expression and fluorescence positive expression of HMGB1, TLR4 and NF-κB p65 in spinal cord tissue, respectively., Results: Compared with the sham operation group, the BBB scores after modeling and on day 3, 7 and 14 were all decreased ( P <0.05), while the contents of iNOS and COX-2 in spinal cord tissue, the protein expression and fluorescence positive expression of HMGB1, TLR4, and NF-κB p65 were increased ( P <0.05) in the model group. In comparison with the model group, the BBB scores on day 3, 7 and 14 were obviously increased ( P <0.05), while the contents of iNOS and COX-2, the protein expression and fluorescence positive expression of HMGB1, TLR4, and NF-κB p65 were significantly down-regulated in the EA group ( P <0.05)., Conclusions: EA of "Jiaji" can promote the recovery of SCI neurological function, which may be related to its function in regulating the HMGB1/TLR4/NF-κB signaling pathway, down-regulating the expression of iNOS and COX-2, and inhibiting the neuroinflammatory response after SCI.

In Xinjiang, previous reports of cystic echinococcosis (CE) in livestock have focused on West and Middle Tianshan Mountains. In contrast, there is an absence of research on CE in the East Tianshan Mountains. To determine the epidemiology and genetic diversity of Echinococcus granulosus sensu stricto (s.s.) in domestic animals in the East Tianshan Mountains, Xinjiang, China, the livers and lungs of 1773 domestic animals were examined, between January 2023 and March 2023, and 40 cysts were collected. Polymerase chain reaction was used for the molecular diagnosis of the cysts. Statistical results showed that the overall prevalence of echinococcosis in sheep was 6.92% (114/1646), which was significantly higher than that in cattle (1.57%, 2/127). A total of 40 cyst isolates were obtained, including 38 from sheep and 2 from cattle. Genomic DNA was extracted, and the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene was amplified by PCR to obtain the target 850 bp fragment. The results revealed that all the isolates had the G1 genotype, with similarities ranging from 98.88-100%. Haplotype network analysis revealed 32 haplotypes of the cox1 gene, among which Hap&#95;7 was the main haplotype. Furthermore, haplotype diversity (Hd = 0.313 ± 0.093) and nucleotide diversity (π = 0.00173 ± 0.00079) were lower in the East Tianshan Mountains than in other regions, indicating that the populations are genetically less differentiated. Tajima's D and Fu's Fs tests were negative (p ≤ 0.01), indicating an expansion of the population in the East Tianshan Mountains of Xinjiang, similar to the results previously reported for Xinjiang. The low fixation index (Fst) ranged from negative values (Gansu Province) to 0.30346 (Mongolia), indicating that the genetic differentiation between the East Tianshan Mountains and Gansu, and Tibet, Xinjiang was relatively low, with frequent gene flow. In this survey, two 'new' haplotypes were identified in the East Tianshan livestock. In addition, two different haplotypes of liver and lung infections were found in one cattle. This survey provides information on the epidemiology and genetic diversity of E. granulosus s.s. in the East Tianshan Mountains of Xinjiang, China., Competing Interests: Declarations. Ethics statement: Not applicable. Clinical trial number: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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).)

Background: Research has found that the amygdala plays a significant role in underlying pathology of major depressive disorder (MDD). However, few studies have explored machine learning-assisted diagnostic biomarkers based on amygdala functional connectivity (FC)., Aim: To investigate the analysis of neuroimaging biomarkers as a streamlined approach for the diagnosis of MDD in adolescents., Methods: Forty-four adolescents diagnosed with MDD and 43 healthy controls were enrolled in the study. Using resting-state functional magnetic resonance imaging, the FC was compared between the adolescents with MDD and the healthy controls, with the bilateral amygdala serving as the seed point, followed by statistical analysis of the results. The support vector machine (SVM) method was then applied to classify functional connections in various brain regions and to evaluate the neurophysiological characteristics associated with MDD., Results: Compared to the controls and using the bilateral amygdala as the region of interest, patients with MDD showed significantly lower FC values in the left inferior temporal gyrus, bilateral calcarine, right lingual gyrus, and left superior occipital gyrus. However, there was an increase in the FC value in Vermis-10. The SVM analysis revealed that the reduction in the FC value in the right lingual gyrus could effectively differentiate patients with MDD from healthy controls, achieving a diagnostic accuracy of 83.91%, sensitivity of 79.55%, specificity of 88.37%, and an area under the curve of 67.65%., Conclusion: The results showed that an abnormal FC value in the right lingual gyrus was effective as a neuroimaging biomarker to distinguish patients with MDD from healthy controls., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

AMPK (Adenosine 5'-Monophosphate activated Protein Kinase) functions as a fundamental regulator of glycolipid metabolism by regulating the rate-limiting enzyme activity of ACC (Acetyl-CoA Carboxylase, essential for fatty acid biosynthesis) and CPT-1 (Carnitine palmitoyltransferase-1, essential for mitochondrial fatty acid oxidation, FAO) in cells, which is crucial for maintaining energy homeostasis in the human body. Coptisine (COP) is a natural berberine and isoquinoline alkaloid in Coptis chinensis that has been used as a traditional Chinese herb to treat diabetes for thousands of years, but its mechanism of action is still unclear. In this study, we investigated the anti-lipid accumulation effect and mechanism of COP in high glucose and palmitic acid-induced HK-2 cells. Compared with the control HK-2 cells, the model HK-2 cells exhibited markedly greater lipid deposition, after treatment with high glucose (HG, 30 mM) and palmitic acid (PA, 250 µM) for 24 h. However, COP significantly decreased the TC and TG levels in a dose dependent manner (2.5, 5, and 10 µM). Moreover, COP dramatically enhanced the effect of the positive control (AICAR, Acadesine, an AMPK activator) in alleviating lipid deposition, which was reversed by the negative control (Compound C, an AMPK inhibitor). Furthermore, COP also increased p-AMPK, p-ACC and CPT-1 protein expression. Our results indicate that COP can effectively protects HK-2 cells against HG- and PA-induced lipid accumulation by affecting the AMPK/ACC/CPT-1 signaling pathway, inhibiting de novo lipogenesis and enhancing the FAO processes, which offers novel insights for the application of COP in the clinic., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The RON receptor tyrosine kinase is critical in the pathogenesis of various cancer types, however, its role in bladder cancer invasive growth is still largely unknown. Here, we found that over 90% of bladder cancer samples exhibit elevated levels of RON expression, with significantly higher expression levels observed in invasive bladder cancer compared to non-invasive bladder cancer. In vitro, RON activation resulted in increased bladder cancer cell migration and invasiveness. Results from mRNA sequencing and transcriptome analysis further demonstrated that MMP12, a downstream molecule of RON, is functionally involved in regulating RON-mediated bladder cancer cell migration and invasiveness. The underlying mechanism appeared to be the RON-mediated inhibition of HIF-2α ubiquitination, which is channeled through the activation of the JNK signaling pathway. Consequently, the activated JNK pathway increased MMP12 expression, ultimately driving bladder cancer cell migration and invasion. As evident in bioinformatics and dual-luciferase reporter assays, the RON mRNA at its 3'-untranslated regions specifically interacted with hsa-miR-659-3p. The binding of hsa-miR-659-3p downregulated the RON gene expression, attenuating the receptor-mediated tumorigenic activities of bladder cancer cells in vitro and in vivo. In conclusion, aberrant RON expression in bladder cancer cells and MMP12 and HIF-2α activities form a functional axis that causes increased bladder cancer cell migration and invasion. The fact that hsa-miR-659-3p downregulates RON expression indicates its critical role in attenuating RON-mediated tumorigenic effect on bladder cancer cells. These findings highlight the importance of RON targeting as a therapeutic means for potential bladder cancer therapy., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate This study involving humans was conducted in compliance with the principles of the Declaration of Helsinki. Informed consent was obtained from all the subjects. Ethics approval for human subjects was provided by the Ethical Committee of the First Affiliated Hospital of Ningbo University, with the approval number: 2022-065A. All animal experiments complied with the National Research Council’s Guide for the Care and Use of Laboratory Animals. Ethics approval for animal work was provided by the Institutional Animal Care and Use Committee (IACUC), ZJCLA, with the approval number: ZJCLA-IACUC-20010178. Consent for publication All authors agree to the content of the manuscript and to publish the paper as co-authors., (© 2024. The Author(s).)

The acidity and high GSH level in the tumor microenvironment (TME) greatly limit the antitumor activity of nanozymes. Thus, enhancing nanozymes' activity is fundamentally challenging in tumor therapy. Although the combination of photothermal therapy (PTT) and nanozymes can enhance the catalytic activity, cancer cells will overexpress heat shock proteins (HSPs) at high temperature, aggravating the heat resistance of tumor cells, which in turn compromises the outcome of chemodynamic therapy. Herein, we propose an iron-doped metal-organic framework nanozyme (IB@Fe-ZIF8@PDFA) that can be activated under the weak acidity and high level of GSH, demonstrating the activities of GSH oxidation (GSH-OXD), peroxidase (POD), and NADH oxidase (NADH-OXD). Under laser irradiation, it displays photothermal-enhanced multienzyme activities to simultaneously eliminate tumors and inhibit tumor metastasis. While consuming endogenous GSH, IB@Fe-ZIF8@PDFA promotes the decomposition of H 2 O 2 into ·OH, enhancing ferroptosis in tumor cells. Surprisingly, IB@Fe-ZIF8@PDFA nanozyme can oxide NADH and subsequently limit the ATP supply, reducing the expression of HSPs and significantly weakening the heat resistance of tumor cells during PTT. Meanwhile, H 2 O 2 is generated during this procedure, which can endogenously replenish the consumed H 2 O 2 . Thus, this IB@Fe-ZIF8@PDFA nanozyme constitutes a self-cascading platform to consume GSH and NADH, endogenously replenish the H 2 O 2 and continuously generate ·OH to facilitate ferroptosis by disrupting the redox and metabolic homeostasis in tumor cells, achieving tumor elimination and tumor metastasis inhibition.

Superatoms are special clusters with similar physicochemical properties to individual atoms in the periodic table, which open up new avenues for exploring inexpensive catalysts. Given that the ZrO superatom possesses the same number of valence electrons as a Pd atom, the mechanisms of the Suzuki-Miyaura reaction catalyzed by (ZrO) n ( n = 1-4) clusters have been investigated and compared with the corresponding Pd n ( n = 1-4) species to explore superatom-based catalysts for the formation of C-C bonds via a density functional theory (DFT) study. It was interesting to find that the catalytic activities of (ZrO) n ( n = 1-4) towards the Suzuki-Miyaura reaction gradually improved as the cluster size increased. Therefore, to obtain more efficient catalysts, the catalytic activity of a well-designed (ZrO) 12 nanocage towards this cross-coupling reaction has been further evaluated. Gratifyingly, this nanocage shows excellent catalytic performance for the considered coupling reaction, which is even comparable to that of the commonly used Pd catalyst and outperforms the corresponding Pd 12 cluster. We hope this study can not only provide valuable guidance for the development of noble metal-like catalysts for C-C bond formation, but also expand the application of superatoms in the catalysis of organic reactions.

Trans-Himalayan winters are projected to become milder, with shifting precipitation patterns and freeze-thaw cycles; changing stressors for their lichen communities. Lichens from Antarctica and high latitudes are cryoresistant when dry, but susceptible to cell damage if frozen when wet, or subjected to repeated freeze-thaw events. Little is known regarding cryoresistance in high-elevation, mid-latitude lichens. We collected thalli of nine species of epiphytic lichenized fungi, from three regions of the trans-Himalayas; at ≈ 4000 m, 3400 m and 2400 m elevation. We subjected thalli to differing freezing (continuous - 18 °C and - 36 °C or freeze-thaw cycles in natural daylight) and moisture conditions. Even dry thalli suffered some damage. Frozen wet thalli had greater chlorophyll degradation and reduced chlorophyll content. There were no clear elevational trends in freeze-thaw susceptibility: it caused more damage than continuous freezing. The most freeze-thaw resilient lichens were Dolichousnea longissima (from 4000 m) and Usnea florida (from 2400 m). However, species from coldest sites were most resilient to extreme freezing. Under predicted climate change conditions these sites would experience fewer annual freeze-thaw cycles, annual sub-zero days and frost days. Reduced freezing constraints might allow range expansion of mid-elevation lichens, but increase competitive pressures and temperature stressors impacting high-elevation lichens., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Once considered unconventional cellular structures, membraneless organelles (MLOs), cellular substructures involved in biological processes or pathways under physiological conditions, have emerged as central players in cellular dynamics and function. MLOs can be formed through liquid-liquid phase separation (LLPS), resulting in the creation of condensates. From neurodegenerative disorders, cardiovascular diseases, aging, and metabolism to cancer, the influence of MLOs on human health and disease extends widely. This review discusses the underlying mechanisms of LLPS, the biophysical properties that drive MLO formation, and their implications for cellular function. We highlight recent advances in understanding how the physicochemical environment, molecular interactions, and post-translational modifications regulate LLPS and MLO dynamics. This review offers an overview of the discovery and current understanding of MLOs and biomolecular condensate in physiological conditions and diseases. This article aims to deliver the latest insights on MLOs and LLPS by analyzing current research, highlighting their critical role in cellular organization. The discussion also covers the role of membrane-associated condensates in cell signaling, including those involving T-cell receptors, stress granules linked to lysosomes, and biomolecular condensates within the Golgi apparatus. Additionally, the potential of targeting LLPS in clinical settings is explored, highlighting promising avenues for future research and therapeutic interventions., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: To investigate the effects of hepatic enzyme activity variations and CYP2B6 gene polymorphisms on the in vivo and in vitro metabolism of efavirenz., Main Methods: In vitro enzyme systems using rat and human liver microsomes (RLM/HLM) were established, with in vivo studies conducted on Sprague-Dawley rats. Metabolite detection was performed via LC-MS/MS. Human recombinant CYP2B6 microsomes were prepared using a baculovirus-insect cell system and ultracentrifugation, with efavirenz serving as the substrate to study enzyme kinetics., Results: Isavuconazole exhibited an IC 50 of 21.14 ± 0.57 μM in RLM, indicating a mixed competitive and noncompetitive mechanism, and an IC 50 of 40.44 ± 4.23 μM in HLM, suggesting an anticompetitive mechanism. In rats, coadministration of efavirenz and isavuconazole significantly increased the AUC, T max , and C max of efavirenz. Co-administration of efavirenz and rifampicin significantly elevated the AUC, T max , and C max of 8-OH-efavirenz. The activity of CYP2B6.4, 6, and 7 increased significantly compared to CYP2B6.1, with relative clearance ranging from 158.34% to 212.72%. Conversely, the activity of CYP2B6.3, 8, 10, 11, 13-15, 18-21, 23-27, 31-33, and 37 was markedly reduced, ranging from 4.30% to 79.89%., Conclusion: Variations in liver enzyme activity and CYP2B6 genetic polymorphisms can significantly alter the metabolism of efavirenz. It provides laboratory-based data for the precise application of efavirenz and other CYP2B6 substrate drugs.

High-altitude and marine mammals inhabit distinct ecosystems but share a common challenge: hypoxia. To survive in low-oxygen environments, these species have evolved similar phenotypic pulmonary adaptations, characterized by a high density of elastic fibers. In this study, we explored the molecular mechanisms underlying these adaptations, focusing on pulmonary fibrosis and hypoxia tolerance through comparative genomics and convergent evolution analyses. We observed significant expansions and contractions in certain gene families across both high-altitude and marine mammals, closely associated with processes involved in pulmonary fibrosis. Notably, members of the keratin gene family, such as KRT17 and KRT14 , appear to be associated with the development of the dense elastic fiber phenotype observed in the lungs of hypoxia-tolerant mammals. Through selection pressure and amino acid substitution analyses, we identified multiple genes exhibiting convergent accelerated evolution, positive selection, and amino acid substitution in these species, associated with adaptation to hypoxic environments. Specifically, the convergent evolution of ZFP36L1 , FN1 , and NEDD9 was found to contribute to the high density of elastic fibers in the lungs of both high-altitude and marine mammals, facilitating their hypoxia tolerance. Additionally, we identified convergent amino acid substitutions and gene loss events associated with sperm development, differentiation, and spermatogenesis, such as amino acid substitutions in SLC26A3 and pseudogenization of CFAP47 , as confirmed by PCR. These genetic alterations may be linked to changes in the reproductive capabilities of these animals. Overall, this study offers novel perspectives on the genetic and molecular adaptations of high-altitude and marine mammals to hypoxic environments, with a particular emphasis on pulmonary fibrosis.

Direct electrochemical seawater splitting is a renewable, scalable, and potentially economic approach for green hydrogen production in environments where ultra-pure water is not readily available. However, issues related to low durability caused by complex ions in seawater pose great challenges for its industrialization. In this review, a mechanistic analysis of durability issues of electrolytic seawater splitting is discussed. We critically analyze the development of seawater electrolysis and identify the durability challenges at both the anode and cathode. Particular emphasis is given to elucidating rational strategies for designing electrocatalysts/electrodes/interfaces with long lifetimes in realistic seawater including inducing passivating anion layers, preferential OH - adsorption, employing anti-corrosion materials, fabricating protective layers, immobilizing Cl - on the surface of electrocatalysts, tailoring Cl - adsorption sites, inhibition of OH - binding to Mg 2+ and Ca 2+ , inhibition of Mg and Ca hydroxide precipitation adherence, and co-electrosynthesis of nano-sized Mg hydroxides. Synthesis methods of electrocatalysts/electrodes and innovations in electrolyzer are also discussed. Furthermore, the prospects for developing seawater splitting technologies for clean hydrogen generation are summarized. We found that researchers have rethought the role of Cl - ions, as well as more attention to cathodic reaction and electrolyzers, which is conducive to accelerate the commercialization of seawater electrolysis., (© 2024 Wiley-VCH GmbH.)

Breast cancer (BC) is the most common malignant tumor in women, and the majority of BC-related deaths are due to tumor metastasis. There is emerging evidence for the role of long noncoding RNAs (lncRNAs) in tumor progression. Nevertheless, lncRNAs that drive metastasis in patients with BC and the underlying mechanisms of lncRNAs are still largely elusive. In this study, we showed that LINC00882 was highly expressed in metastatic BC tissues, and a receiver operating characteristic (ROC) curve was able to distinguish well between BC cases with lymph node metastasis (LNM) and those without LNM. Functionally, LINC00882 promoted BC invasion and metastasis in vitro and in vivo. Mechanistically, at the transcriptional level, CEBP-β could bind directly to the LINC00882 promoter region and activate its transcription. Moreover, at the posttranscriptional level, m 6 A modification of LINC00882 mediated by methyltransferase-like 14 (METTL14) promoted its expression via an IGF2BP2-dependent pathway. Furthermore, 514-615 nucleotides of LINC00882 could directly interact with poly (A) binding protein cytoplasmic 1 (PABPC1) and promote the interaction between PABPC1 and ELK3 mRNA, thereby stabilizing ELK3 mRNA and enhancing the ELK3 protein level. E-cadherin expression was suppressed via ELK3-mediated transcription inhibition, subsequently activating epithelial-mesenchymal transition to promote BC metastasis. These results highlight the role of LINC00882 in BC, and LINC00882 may be a diagnostic and therapeutic target for BC., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate Fresh BC tissues were obtained with informed patient consent and approval from the Qilu Hospital of Shandong University, and the Research Ethics Committee of Shandong University. Patients’ privacy has been fully protected. Animal experiments were conducted according to the Guidelines for Animal Health and Use (Ministry of Science and Technology, China, 2006), and were approved by the Committee for Animal Protection of Shandong University. Consent for publication Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Notch signaling activation drives an endothelial-to-mesenchymal transition (EndMT) critical for heart development, although evidence suggests that the reprogramming of endothelial cell metabolism can regulate endothelial function independent of canonical cell signaling. Herein, we investigated the crosstalk between Notch signaling and metabolic reprogramming in the EndMT process. Biochemically, we find that the NOTCH1 intracellular domain (NICD1) localizes to endothelial cell mitochondria, where it interacts with and activates the complex to enhance mitochondrial metabolism. Targeting NICD1 to mitochondria induces more EndMT compared with wild-type NICD1, and small molecule activation of PDH during pregnancy improves the phenotype in a mouse model of congenital heart defect. A NOTCH1 mutation observed in non-syndromic tetralogy of Fallot patients decreases NICD1 mitochondrial localization and subsequent PDH activity in heart tissues. Altogether, our findings demonstrate NICD1 enrichment in mitochondria of the developing mouse heart, which induces EndMT by activating PDH and subsequently improving mitochondrial metabolism., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Mn-based layered oxide cathodes have attracted widespread attention due to high capacity and low cost, however, poor air stability, irreversible phase transitions, and slow kinetics inhibit their practical application. Here, we propose a universal interfacial reconstruction strategy based on converting residual alkali to tunnel phase Na 0.44 MnO 2 for addressing the above mentioned issue simultaneously, using O3 NaNi 0.4 Fe 0.2 Mn 0.4 O 2 @2 mol % Na 0.44 MnO 2 (NaNFM@NMO) as the prototype material. The optimized material exhibits an initial capacity and energy density comparable with lithium-ion batteries. The reversible anionic redox behavior and charge compensation mechanism of NaNFM@NMO were analyzed and verified by soft X-ray absorption spectrum and in situ X-ray absorption spectrum. Due to the intrinsic stability of the tunnel structure, excellent air stability and highly reversible structure evolution of the NaNFM@NMO cathode material are achieved, which are confirmed by contact angle test, rigorous aging test, and in situ X-ray diffraction. More importantly, the NaNFM@NMO cathode demonstrates a great match with the nonpresodiated hard carbon anode and shows excellent electrochemical performance of the full cell. Additionally, such a strategy could be also applied to modify P2-type cathodes, showing superior universality and good prospects in industrialized production. Overall, the proposed strategy could improve air stability while remaining interfacial and bulk stable simultaneously and will open up a whole new field for the optimization of other electrode materials.

We aimed to prospectively explore the risk factors for measurable residual disease (MRD) positivity after allogeneic stem cell transplantation (allo-SCT) in AML patients (n = 478). The cumulative incidences (CIs) of post-SCT MRD positivity at 100 days, 360 days and 3 years were 4.6%, 12.1% and 18.3%, respectively. Positive pre-SCT MRD and pre-SCT active disease were risk factors for post-SCT MRD positivity at both 360 days and 3 years (P < 0.001). European LeukemiaNet (ELN) 2017 risk stratification was a risk factor for positive post-SCT MRD at 360 days (P = 0.044). A scoring system for predicting post-SCT MRD positivity at 360 days was established by using pre-SCT MRD, pre-SCT active disease and ELN 2017 risk stratification. The CI of positive post-SCT MRD at 3 years was 13.2%, 23.7%, and 43.9% for patients with scores of 0, 1, and 2, respectively (P < 0.001). Multivariate analysis demonstrated that the scoring system was associated with a higher CI of post-SCT MRD positivity, leukemia relapse and inferior survival. Our data indicate that positive pre-SCT MRD status, pre-SCT active disease, and ELN 2017 risk stratification are risk factors for positive post-SCT MRD status in AML patients., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate Research was performed in compliance with all applicable guidelines and regulations. The study was performed in accordance with Declaration of Helsinki and was approved by Institutional Review Board of Peking University (Ethics Committee of Peking University People’s Hospital), the reference number was 2017PHB033-01. Informed consent All of the patients who were included in the study provided signed informed consent., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: The aim of this study was to investigate the association of macular microcirculation with renal function and the feasibility of using macular microcirculatory parameters to monitor renal function in Chinese non-diabetic patients with hypertension., Methods: This case-control study included 62 non-diabetic patients with hypertension, including 31 with renal dysfunction (estimated glomerular filtration rate [eGFR] <90 mL/min/1.73 m 2 ) and 31 with normal renal function (eGFR ≥90 mL/min/1.73 m 2 ). Age, sex and clinic blood pressure were matched between groups. Macular microcirculatory parameters of 124 eyes of the 62 patients were evaluated by optical coherence tomography (OCT) and OCT angiography (OCTA)., Results: In comparison with the patients with normal renal function, patients with renal dysfunction had lower macular superficial parafovea vessel density (18.6 vs. 19.4%, P = 0.029), macular cube average thickness (273.0 vs. 280.2 µm, P = 0.003), and average ganglion cell layer and inner plexiform layer (GCL-IPL) thickness (79.5 vs. 82.8 µm, P = 0.006), but similar macular central fovea vessel density and central fovea thickness (P ≥ 0.54). After adjustment for confounders, eGFR was significantly associated with macular superficial parafovea vessel density, cube average thickness and GCL-IPL thickness (P < 0.02). In detecting renal dysfunction, areas under the curve were 0.61, 0.66 and 0.65 for macular superficial parafovea vessel density, cube average thickness and GCL-IPL thickness., Conclusion: In non-diabetic patients with hypertension, macular superficial parafovea vessel density, cube average thickness and GCL-IPL thickness were significantly worse in patients with renal dysfunction than those with normal renal function. Using macular parameters to monitor renal function is feasible., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Inherently chiral calixarenes hold great potential for applications in chiral recognition, sensing, and asymmetric catalysis due to their unique structures. However, due to their special structures and relatively large sizes, the catalytic asymmetric synthesis of inherently chiral calixarenes is challenging with very limited examples available. Here, we present an efficient method for the enantioselective synthesis of inherently chiral sulfur-containing calix[4]arenes through the desymmetrizing electrophilic sulfenylation of calix[4]arenes. This catalytic asymmetric reaction is enabled by a chiral 1,1'-binaphthyl-2,2'-diamine-derived sulfide catalyst and hexafluoroisopropanol. Various inherently chiral sulfur-containing calix[4]arenes are obtained in moderate to excellent yields with high enantioselectivities. Control experiments indicate that the thermodynamically favored C-SAr product is formed from the kinetically favored N-SAr product and the combination of the chiral sulfide catalyst and hexafluoroisopropanol is crucially important for both enantioselectivity and reactivity., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)