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Current antiviral therapy can not cure chronic hepatitis B virus (HBV) infection or eliminate the risk of hepatocellular carcinoma. The licensed epidermal growth factor receptor (EGFR) inhibitors have found to inhibit hepatitis C virus replication via downregulation of signal transducers and activators of transcription 3 (STAT3) phosphorylation. Since STAT3 is also involved in HBV replication, we further studied the anti-HBV efficacy of the EGFR inhibitors in this study. HBV-transfected HepG2.2.15 cells and HBV-infected HepG2-NTCP cells were used as cell models, and HBV replication, the syntheses of viral antigens and the magnitude of the covalently closed circular DNA (cccDNA) reservoir were used as indictors to test the anti-HBV effects of EGFR inhibitors erlotinib and gefitinib. Erlotinib inhibited HBV replication with a half-maximal inhibitory concentration of 1.05 μM. It also reduced the syntheses of viral antigens at concentrations of 2.5 μM or higher. The underlying mechanism was possibly correlated with its inhibition on STAT3 phosphorylation via up-regulation of suppressor of cytokine signaling 3. Gefitinib also inhibited HBV replication and antigen syntheses. Compared with the commonest antiviral drug entecavir, these EGFR inhibitors additionally reduced hepatitis B e antigen and erlotinib also marginally affected the cccDNA reservoir in HBV-infected HepG2-NTCP cells. Interestingly, these promising anti-HBV effects were significantly enhanced by extension of treatment duration. In conclusion, EGFR inhibitors demonstrated a comprehensive anti-HBV potential, highlighting a new strategy to cure HBV infection and suggesting animal model-related studies or clinical try in the future.

The regulation of aircraft engine NO x emissions was introduced to improve local air quality and reduce NO x emissions at altitude. Here, the authors find that greater fuel efficiency of aircrafts, and therefore lower CO2 emissions, could be preferable to reducing NO x emissions in terms of the aviation industries future climate impacts.

Abstract This study explored relationships between students’ attitudes toward science and their preferred versus actual experience of cooperative, constructivist-oriented, or direct instruction. The sample consisted of 1334 Chinese middle school students in physics and chemistry classrooms. Results showed that students report experiencing more direct instruction, very little constructivist-oriented instruction, and a moderate amount of cooperative instruction. Attitudes toward science were positively related to cooperative teaching strategies like group work in class or developing small-group projects. There was no significant effect of constructivist-oriented instruction or of direct instruction on students’ attitudes. Whereas previous studies demonstrated positive impacts of constructivist teaching on student understanding of science concepts, student attitude toward school science appears to be more related to social interaction or cooperation. Lack of any statistically significant differential effect from constructivist-oriented instruction might also be related to the overall low incidence of such instruction experienced by our sample.

Three global chemistry-transport models (CTM) are used to quantify the radiative forcing (RF) from aviation NOx emissions, and the resultant reductions in RF from coupling NOx to aerosols via heterogeneous chemistry. One of the models calculates the changes due to aviation black carbon (BC) and sulphate aerosols and their direct RF, as well as the BC indirect effect on cirrus cloudiness. The surface area density of sulphate aerosols is then passed to the other models to compare the resulting photochemical perturbations on NOx through heterogeneous chemical reactions. The perturbation on O3 and CH4 (via OH) is finally evaluated, considering both short- and long-term O3 responses. Ozone RF is calculated using the monthly averaged output of the three CTMs in two independent radiative transfer codes. According to the models, column ozone and CH4 lifetime changes due to coupled NOx/aerosol emissions are, on average, +0.56 Dobson Units (DU) and −1.1 months, respectively, for atmospheric conditions and aviation emissions representative of the year 2006, with an RF of +16.4 and −10.2 mW/m2 for O3 and CH4, respectively. Sulphate aerosol induced changes on ozone column and CH4 lifetime account for −0.028 DU and +0.04 months, respectively, with corresponding RFs of −0.63 and +0.36 mW/m2. Soot-cirrus forcing is calculated to be 4.9 mW/m2.

The role of B-cell lymphoma 2 (BCL2)-associated X (BAX) macropores in the leakage of mitochondrial DNA (mtDNA) and their impact on acute kidney injury (AKI) has recently been brought to the focus of researchers. This study aimed to explore the relationship between mtDNA leakage and BAX macropores during wasp sting-induced AKI. BAX mitochondrial translocation and macropores opening increased in both in vivo and in vitro models of wasp sting-induced AKI. In a mouse model, BAX inhibition dramatically attenuated mitochondrial impairment, cytoplasmic release of mtDNA, and suppressed activation of the mtDNA-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. This attenuation improved kidney function, reduced inflammatory response, and decreased apoptosis in mouse models. Furthermore, in cultured human proximal tubular epithelial cells (HK-2) treated with myoglobin and subjected to BAX knockdown, quantitative real-time polymerase chain reaction (PCR) directly demonstrated decreased mtDNA release into the cytoplasm. Consistent with in vivo results, downregulation of BAX expression in vitro ameliorated mitochondrial damage and attenuated subsequent inflammation and apoptosis caused by the activation of the mtDNA-cGAS-STING signaling pathway. Our findings revealed that mtDNA is released into the cytoplasm through BAX macropores in wasp sting-induced AKI, which provided an important novel perspective for understanding wasp sting-induced AKI and is conducive for identifying novel therapeutic targets and 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 © 2024 Elsevier B.V. All rights reserved.)

Plastic pollution poses a serious threat to marine ecosystems; yet quantifying the mass concentrations of nano- and microplastics (NMPs) in saltmarsh sediments at the ocean-land interface remains a critical research gap. Here, the study employed reliable and efficient analytical techniques, namely pressurized liquid extraction and the double-shot model of thermal desorption/pyrolysis-gas chromatography-mass spectrometry, to quantify six different types of NMPs in the sediment of a multi-species saltmarsh, providing the first comprehensive assessment of NMP mass concentration and burial in this saltmarsh environment. The results demonstrate that polyethylene, polyvinyl chloride, and polypropylene dominated the NMP composition in sediments, constituting 72.6%, 17.3%, and 4.5% of the total NMPs, respectively. The measured NMPs represent an anthropogenic intrusion, constituting 0.10%-0.23% of the carbon storage in the saltmarsh. By examining the vertical concentration profiles, this study unveiled the influence of saltmarsh vegetation on NMP deposition in sediments, establishing a connection with local sedimentation patterns and the historical zonation of plant species such as Scirpus mariqueter, Phragmites australis and Spartina alterniflora. These findings underscore the crucial role of saltmarsh vegetation in facilitating NMP settling and retention, highlighting the necessity of considering vegetation dynamics in examining the emerging NMP pollution in coastal wetlands., 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.)

Clarifying reactive oxygen species (ROS) variation in the presence of co-existing anions is significant for understanding the catalytic effect of magnetite (Fe 3 O 4 )-induced advanced oxidation processes (AOPs) in natural environment, yet this remains controversial. Herein, we compare the specific impacts of NO 3 - , SO 4 2- , and Cl - on ROS ( • OH, SO 4 •- , O 2 •- , and 1 O 2 ) exposure concentration in H 2 O 2 and peroxydisulfate (PDS) systems catalyzed by Fe 3 O 4 , as well as how these variations affect the catalytic efficiency by developing kinetic model. In both two systems, NO 3 - demonstrates no discernible effect on ROS, whereas SO 4 2- inhibits the exposure of all ROS and thus micropollutants degradation. Through theoretical calculation, it is proposed that SO 4 2- primarily exerts its influence through affecting the electronic structure over catalyst surface. Regarding Cl - , it affects ROS exposure mainly by reacting with ROS. It shows inhibitory effect on 1 O 2 in both systems, but its suppressive impact on • OH is markedly more pronounced in H 2 O 2 system compared to PDS system, which may be related to its rapid reactivity with SO 4 •- . Besides, the chlorine radicals (mainly ClO • ) generated through the reaction of Cl - may exert a selective influence on micropollutants degradation. This study can help to re-understand the influence behavior of co-existing anions during AOPs., 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. Published by Elsevier B.V.)

The eliminate of antibiotic resistance genes (ARGs) is pivotal in mitigating the proliferation of antibiotic resistance. In this study, a PMS/CM-UV system was engineered, combining a Co 3 O 4 -modified carbon nanotubes catalytic membrane with LED-UV lamps, to effectively eliminate intracellular ARGs (iARGs). Leveraging the synergistic effect of singlet oxygen ( 1 O 2 ) and UV irradiation, this process requires only a brief hydraulic retention time of a few minutes and standard UV disinfection irradiation intensity. The cellular physiological function and transcriptomic analysis indicated that reactive oxygen species (ROS) and UV irradiation compromised the cell membrane integrity of E. coli MG1655-SD, as indicated by the down-regulation of the feoB gene, leading to an increased concentration of 1 O 2 within the intracellular environment. The synergistic effect of 1 O 2 and UV irradiation resulted in the down-regulation of btuE, thereby curtailing the SOS and oxidative stress responses. Additionally, UV irradiation down-regulated ftsK, uvrB, and uvrA genes, involved in DNA replication, damage site recognition, and self-repair. These processes collectively contribute to the oxidative damage of iARGs by 1 O 2 before their release into the extracellular environment. This work provided a strategy to develop advanced oxidation disinfection technology aimed at ARGs removal., 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.)

Abnormal fat accumulation can lead to metabolic syndrome (MetS), increasing the risk of diabetes and cardiovascular disease in MetS patients. Early identification of MetS risk is essential for effective disease prevention. Using bioinformatics methods, we sought biomarkers for MetS. After analyzing the GSE9624 and GSE15524 datasets, we identified three commonly differentially expressed genes: COX7A1, PRR12, and HHIP. Subsequently, we validated the expression of these DEGs using the GSE65540 dataset. Quantitative PCR and immunoblotting confirmed significantly elevated HHIP expression in the adipose tissue of HFD-fed and ob/ob mice. Furthermore, a population-based cohort study demonstrated that serum HHIP levels were significantly greater in MetS patients than in healthy controls and were correlated with all MetS components. Receiver operating characteristic (ROC) curve analysis confirmed the robust predictive capacity of HHIP levels for metabolic syndrome, with an area under the curve (AUC) of 0.72 (95 % confidence interval: 0.68-0.78, P < 0.001). Binary logistic regression showed that the serum HHIP concentration was significantly associated with MetS even after adjusting for anthropometric and lipid profile variables. In conclusion, our findings demonstrate that changes in HHIP expression are significantly associated with adverse MetS indicators, indicating that HHIP can serve as a new biomarker for the diagnosis of MetS., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ling Li reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they 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 Inc. All rights reserved.)

Fibrosis is characterized by excessive extracellular matrix (ECM) deposition resulting from dysregulated wound healing and connective tissue repair mechanisms. Excessive accumulation of ECM leads to fibrous tissue formation, impairing organ function and driving the progression of various fibrotic diseases. Recently, the role of small ubiquitin-like modifiers (SUMO) in fibrotic diseases has attracted significant attention. SUMO-mediated SUMOylation, a highly conserved posttranslational modification, participates in a variety of biological processes, including nuclear-cytosolic transport, cell cycle progression, DNA damage repair, and cellular metabolism. Conversely, SUMO-specific proteases cleave the isopeptide bond of SUMO conjugates, thereby regulating the deSUMOylation process. Mounting evidence indicates that SUMOylation and deSUMOylation regulate the functions of several proteins, such as Smad3, NF-κB, and promyelocytic leukemia protein, which are implicated in fibrotic diseases like liver fibrosis, myocardial fibrosis, and pulmonary fibrosis. This review summarizes the role of SUMO in fibrosis-related pathways and explores its pathological relevance in various fibrotic diseases. All evidence suggest that the SUMO pathway is important targets for the development of treatments for fibrotic diseases., (© 2024 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Background and Purpose: Activation of AMP-activated protein kinase (AMPK) is essential in maintaining the epithelial tight junction (TJ) barrier. Berberine, a phytochemical AMPK agonist, has been widely reported to ameliorate colitis. Berberine or AMPK activation inhibits cytoskeletal contraction induced by myosin light chain kinase (MLCK), thereby ameliorating TJ barrier defects. We previously found that swiprosin-1, an actin-binding protein, affects MLCK expression. Here, we aimed to reveal the role of swiprosin-1 in the regulation of AMPK/MLCK by berberine., Methods: Caco-2 monolayer transfected with AMPKα1 (or swiprosin-1) siRNA was treated with berberine after being stimulated with TNFα/IFNγ to assess the effect on the TJ barrier. Intestinal epithelial conditional knockout mice for AMPKα1 (or swiprosin-1) were treated with berberine after experimental colitis to evaluate the effect on the TJ barrier. TJ integrity was evaluated by immunoblotting and immunofluorescence for ZO-1 and Occludin., Results: The protection of berberine against TJ barrier damage was blocked by AMPK inhibitor or knockout of AMPKα1 in epithelial cells. Swiprosin-1 was distributed in colonic epithelial cells and upregulated in colitis. Knockout of swiprosin-1 in intestinal epithelial cells ameliorated TJ barrier damage and abolished the protective effect of berberine. Impaired assembly of TJ caused by overexpression of swiprosin-1 was alleviated by MLCK inhibitor, and inhibition of the MLCK pathway by berberine also required the presence of swiprosin-1. In addition, berberine downregulated swiprosin-1 expression in an AMPK-dependent manner., Conclusion: Swiprosin-1 may be a key intermediate molecule in the regulation of the AMPK/MLCK pathway by berberine to attenuate colitis-induced TJ barrier damage., 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 GmbH. All rights reserved.)

The use of agricultural biomass-based fertilizers, and the release of feces into the environment leads to last-lasting pollution of antibiotic resistance genes that cannot be removed from waters via traditional methods, resulting in significant health threats. To solve this issue, an antibiotic resistance gene removal method was proposed and tested that used sequence-specific DNA-binding designer zinc finger proteins, which target an 18-bp DNA sequence for specific antibiotic resistance gene binding and removal. Targeting the sulfonamide-resistant sul1 gene, sul1-binding zinc-finger protein was designed, overexpressed, and purified. This protein showed specific binding with sul1 over tetA that do not have the targeted sequence. This protein was further immobilized on agarose-based resins to prepare a sul1-removal column. When loaded with 10 mg protein, this column can remove over 99 % sul1 in water, suggesting high efficiency. This work presents a new method attempting to eliminate environmental and health threats posed by antibiotic resistance genes., 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.)

APE1, an essential enzyme for DNA repair, is overexpressed in various cancers and has been identified as a potential biomarker for cancer diagnosis. However, detecting APE1 at low expression levels in the early stage of cancer presents a significant obstacle. Here, we introduced a novel localized Cas12a-based cascade amplification (LCas12a-CA) method. This method confined both the terminal deoxynucleotidyl transferase and the crRNA/Cas12a complex onto the surfaces of gold nanoparticles (AuNPs). This confinement not only boosts the stability of the multiple enzymes but also induces a substrate channeling effect. As a result, it significantly accelerates the reaction rate and enhances the sensitivity of APE1 detection. Upon the addition of APE1, the AP sites within the APE1 primer can be recognized and cleaved by APE1, exposing the 3'-OH ends. In the presence of LCas12a-CA, polyA sequences are generated at 3'-OH ends with the help of TdT and dATP. The sequences directly enter the Cas12a system, activating the trans-cleavage activity of Cas12a, thereby cutting the reporters on the surface of AuNPs and releasing fluorescence. Our platform demonstrates a detection limit (LOD) as low as 2.51 × 10 -6 U/mL, which is more than 60 times lower than that of free Cas12a-CA. Furthermore, the LCas12a-CA exhibits enhanced resistance ability in extreme environments and has been proven effective for the detection of APE1 in clinical samples. Overall, this work offers a promising platform for robust biosensing in cancer diagnosis and prognosis., 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. 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.)

Introduction and Aims: As an experimental teaching method, emerging learning methods including problem-based learning (PBL), case-based learning, team-based learning and flipped classroom (FC) have been widely applied in dental education. This study aims to evaluate the effect of these teaching methods on dental education performance compared to traditional lecture-based learning (LBL)., Methods: The search was carried out in April 2024 in PubMed, EMBASE, Web of Science, and Cochrane Library. All randomized controlled trials were included and the methodological quality assessment was based on the guidelines described in the Cochrane Handbook for Systematic Reviews, followed by a meta-analysis using Stata 14.0 software. Using standard mean deviation (SMD) and 95% confidence interval (95% CI) to determine the effectiveness of emerging teaching methods and LBL in all dental disciplines. Meta-regression was used to analyse sources of heterogeneity. Sensitivity analysis was performed to determine the stability, and Begg's analysis was used to determine whether there is publication bias., Results: A total of 29 randomized controlled trials including 3502 students were included. The results indicate that emerging educational methods have a significantly positive effect on achieving higher scores (SMD = 0.48, 95% CI = 0.34-0.62, P < .001), whether it was theoretical scores (SMD = 0.52, 95% CI = 0.32-0.72, P < .001) or skill scores (SMD = 0.45, 95% CI = 0.15-0.76, P < .001). Compared to LBL, PBL (SMD = 0.33, 95% CI = 0.01-0.65, P = .045) and FC (SMD = 0.50, 95% CI = 0.31-0.69, P < .001) can both significantly improve students' academic performance., Conclusion: Compared to LBL, emerging educational methods (PBL, case-based learning, and FC) have significantly improved the learning effectiveness of dental students. These emerging educational methods can be advocated and popularized as routine teaching methods., Clinical Relevance: This study is the first meta-analysis of the effects of emerging teaching methods in dental education which shows great impact of emerging teaching methods on students' development., Competing Interests: Conflict of 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 article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Lipid oxidation in air-fried seafood poses a risk to human health. However, the effect of a prooxidant environment on lipid oxidation in seafood at different air frying (AF) temperatures remains unknown. An integrated machine learning (ML) - guided REIMS and lipidomics method was applied to explore lipid profiles, lipid oxidation, and lipid metabolic pathways of salmons under different AF temperatures (140, 160, 180, and 200 °C). A significant difference in the lipidomic fingerprinting of air-dried salmon at different temperatures was shown by the main ML methods (neural networks, support vector machines, ensemble learning, and naïve bayes). In total, 773 differential expression metabolites (DEMs) were identified, including glycerophospholipids (GPs), glycerides (GLs), and sphingolipids. A total of 34 DEMs with p values <0.05 and variable importance of projection values >1.0 were analyzed, belonging to linoleic acid metabolism, GL metabolism, and GP metabolism pathways. Correlation network analysis revealed that some characteristic DEMs (phosphatidylcholine, lyso-phosphatidylcholine, triglycerides, fatty acids, and phosphatidylethanolamine) were highly correlated with lipid oxidation. In addition, variations of volatile compounds, color values, texture characteristics, and thiobarbituric acid-reactive substance values were analyzed to corroborate the oxidation characteristics., 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.)

Objective: Effective postoperative pain management is critical for pediatric craniotomies. Scalp nerve block (SNB) interventions present a potential solution, yet their comparative benefits in preoperative and postoperative settings remain unclear. This study investigated the analgesic effects of SNB in pediatric craniotomy patients by comparing preoperative versus postoperative administration., Methods: This randomized trial included 180 children (1-12 years) who underwent elective craniotomy and were assigned to the preoperative, postoperative, or nonblocking control group. The outcomes included cumulative sufentanil use, pain scores (1, 2, 4, 24, 48 h postoperation), rescue medicine utilization, postoperative complications (24, 48 h), and hospitalization length. The primary outcome was total sufentanil use within 24 h postsurgery., Results: Total sufentanil use (µg·kg - 1 ) in the postoperative block group was significantly lower than that in the nonblocking control group at 1 h (P < 0.001, 95% CI [-0.024 to -0.006]), 2 h (P < 0.001, 95% CI [-0.054 to -0.020]), 4 h (P < 0.001, 95% CI [-0.089 to -0.032]), 24 h (P < 0.001, 95% CI [-0.192 to -0.047]), and 48 h (P = 0.010, 95% CI [-0.208 to -0.022]) postoperation. Additionally, sufentanil use in the preoperative block group was significantly lower than that in the nonblocking control group at 1 h (P = 0.004, 95% CI [-0.021 to -0.003]), 2 h (P < 0.001, 95% CI [-0.043 to -0.010]), and 4 h (P = 0.002, 95% CI [-0.069 to -0.013]). Within 24 h postoperation, the use of sufentanil in the postoperative block group was significantly lower than that in the preoperative block group (P = 0.014, 95% CI [-0.157 to -0.013])., Conclusion: Compared with preoperative SNB or nonblocking, postoperative SNB significantly reduces postoperative sufentanil use within 24 h for pediatric patients undergoing craniotomy, highlighting its potential as an effective analgesic intervention in this population., Trial Registration: The trial was registered at the Chinese Clinical Trial Registry (ChiCTR1800017386) on 27/07/2018, under the title "A study of scalp nerve block for neurosurgical analgesia in children with craniotomy.", Competing Interests: Declarations. Ethics approval and consent to participate: This single-center, prospective, double-blinded, randomized controlled trial received approval from the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University (IRB No. KY 2018-078-02; August 23, 2018). The study period spanned from September 2018 to October 2020, with the first patient recruited on September 13, 2018. All children obtained written informed consent from their guardians, and school-aged children aged 7 years and older also provided their own informed consent. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Cancer stemness plays a crucial role in promoting the progression of colorectal cancer (CRC). Forkhead box N3 (FOXN3) is a tumor suppressor protein. Herein, we investigated the role of FOXN3 in the regulation of CRC cell stemness. Cell viability, proliferation, migration, and invasion were assessed utilizing cell counting kit-8 assay, 5-ethynyl-20-deoxyuridine assay, and Transwell assay, respectively. Cell-sphere formation was assessed using a sphere-forming assay. The enrichment of H3K27ac modifications at the SRY-related HMG-box 12 (SOX12) promoter, interactions among FOXN3, SOX12, and E1A binding protein p300 (EP300) were analyzed using chromatin immunoprecipitation or dual luciferase reporter assays. We found that FOXN3 overexpression inhibited CRC cell proliferation, migration, invasion, stemness, and tumor formation in mice by inactivating the Wnt/β-catenin signaling, while these effects of FOXN3 overexpression were reversed by the overexpression of SOX12. Mechanistically, EP300 increased SOX12 expression in CRC cells by promoting H3K27ac enrichment in the SOX12 promoter. In addition, FOXN3 transcriptionally inhibited EP300 expression in CRC cells by binding to the EP300 promoter. As expected, EP300 overexpression weakened the inhibitory effect of FOXN3 overexpression on CRC cell stemness. Collectively, FOXN3 upregulation inhibited CRC cell stemness by suppressing EP300-mediated epigenetic upregulation of SOX12., (© 2024 Wiley Periodicals LLC.)

Pulmonary fibrosis (PF) is an interstitial lung disease tightly associated with the disruption of mitochondrial pool homeostasis, a delicate balance influenced by functional and dysfunctional mitochondria within lung cells. Mitochondrial transfer is an emerging technology to increase functional mitochondria via exogenous mitochondrial delivery; however, the therapeutic effect on mitochondrial transfer is hampered during the PF process by the persistence of dysfunctional mitochondria, which is attributed to impaired mitophagy. Herein, we reported engineering mito chondria mediated by m itophagy- e nhanced n anoparticle (Mito-MEN), which promoted synchronal regulation of functional and dysfunctional mitochondria for treating PF. Mitophagy-enhanced nanoparticles (MENs) were fabricated through the encapsulation of Parkin mRNA , and the electrostatic interaction favored MENs to anchor isolated healthy mitochondria for the construction of Mito-MEN. Mito-MEN increased the load of functional exogenous mitochondria by enhancing mitochondrial delivery efficiency and promoted mitophagy of dysfunctional endogenous mitochondria. In a bleomycin (BLM)-induced PF mouse model, Mito-MEN repaired mitochondrial function and efficiently relieved PF-related phenotypes. This study provides a powerful tool for synchronal adjustment of mitochondrial pool homeostasis and offers a translational approach for pan-mitochondrial disease therapies.

Background and Objectives: Gemcitabine plus cisplatin (GP) and docetaxel plus cisplatin plus fluorouracil (TPF) are induction chemotherapy (IC) regimens for locally advanced nasopharyngeal carcinoma (LA-NPC). The oral convenience of capecitabine presents its potential as a fluorouracil substitute in the TPF regimen, which has yet to be thoroughly investigated. This study aims to compare the efficacy and safety of the docetaxel, cisplatin, and capecitabine (TPC) with GP and TPF in LA-NPC., Methods: A retrospective analysis was conducted on newly diagnosed stage III-IVa nasopharyngeal carcinoma patients who received GP, TPC, or TPF induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) between February 2019 and December 2021. A comparison of the prognostic outcomes and associated adverse reactions among patients receiving different IC regimens. Multivariate Cox regression was applied to analyze independent prognostic factors, and subgroup survival analyses were conducted based on these factors., Results: A total of 291 LA-NPC patients were included, with 70 receiving TPC, 119 receiving GP, and 102 receiving TPF. Kaplan-Meier survival analysis indicated no significant differences in OS, PFS, LRFS, and DMFS among the 3 groups. Multivariate Cox regression identified T classification and clinical stage as independent prognostic factors. Subgroup analyses revealed no significant differences in OS and PFS between the 3 groups across T1-2 and T3-4 classifications or III and IVa stages.The TPC group exhibited lower incidence rates of treatment-related acute toxicity reactions, including grade 3-4 toxicities., Conclusion: The TPC induction chemotherapy regimen demonstrates comparable efficacy to GP and TPF, while maintaining a favorable safety profile., 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. Published by Elsevier Ltd.)

Background: The coronavirus disease 2019 (COVID-19) has exhibited escalating contagion and resistance to immunity, resulting in a surge in infections and severe cases. This study endeavors to formulate two nomogram predictive models aimed at discerning patients at heightened risk of severe and fatal outcomes upon hospital admission. The primary objective is to enhance clinical management protocols and mitigate the incidence of severe illness and mortality associated with COVID-19., Methods: 1600 patients diagnosed with COVID-19 and discharged from Fujian Provincial Hospital were chosen as the subjects of this study. These patients were categorized into three groups: mild group (n = 940), severe group (n = 433), and fatal group (n = 227). The patients were randomly divided into training and validation cohorts in a 7:3 ratio. COVID-19 symptoms were treated as dependent variables, and univariate regression analysis was conducted for the laboratory indicators. Risk factors with p-values greater than 0.05 in the univariate regression analysis were eliminated. The remaining risk factors were then analyzed using direct multiple regression analysis to establish an unadjusted model. Subsequently, risk factors with p-values greater than 0.05 were further removed. Clinical characteristics were added to the model as adjustment factors, and the method of multiple stepwise regression analysis was employed to derive the final fully adjusted model. The severe and fatal COVID-19 models were converted into nomograms, respectively. Receiver operating characteristic (ROC) curves were utilized to evaluate the discrimination of the nomogram models. Calibration was assessed using the Hosmer-Lemeshow test and calibration curves. Clinical benefit was evaluated by decision curve analysis., Results: Compared to the mild group, individuals in the severe COVID-19 group exhibited significant increases in age, neutrophil (NEU), and lactate dehydrogenase (LDH) levels, alongside notable decreases in lymphocyte (LYM) and albumin (ALB) levels. Nomogram model incorporating age, NEU, LDH, LYM, and ALB demonstrated efficacy in predicting the onset of severe COVID-19 (AUC = 0.771). Furthermore, history of cerebral infarction and cancer, LDH and ALB as risk factors for fatal COVID-19 cases compared to the severe group. The nomogram model comprising these factors was capable of early identification of COVID-19 fatalities (AUC = 0.748)., Conclusions: Elevated age, NEU, and LDH levels, along with decreased LYM and albumin (ALB) levels, are risk factors for severe illness in hospitalized patients with COVID-19. A history of cerebral infarction and tumors, along with elevated LDH and decreased ALB levels, are risk factors for death in critically ill patients. The nomogram model based on these factors can effectively predict the risk of severe or fatal illness from COVID-19, thereby assisting clinicians in timely interventions to reduce the rates of severe illness and mortality among hospitalized patients. However, the model faces challenges in processing longitudinal data and specific points in time, indicating that there is room for improvement., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Fujian Provincial Hospital. The data used in this study were anonymized before use. Informed consent: was obtained from all individual participants included in the study., (© 2024. The Author(s).)

With the advancement of synthetic biology, recombinant proteins are poised to play a significant role in medical applications. The scaled manufacturing is a pillar for the extensive application and development of recombinant proteins across various fields. In the large-scale production process of recombinant proteins, the removal and detection of endotoxins are essential to reduce their levels to safe thresholds in the final products. Currently, establishing stringent endotoxin limits for different recombinant protein products is a crucial aspect of safety assessment. This review begins by shedding light on the pathogenicity of endotoxins and discusses the methods for the removal and determination of endotoxins during the production processes of recombinant proteins. Subsequently, this review summarizes the endotoxin limits in industries such as biologics, medical devices, and human recombinant DNA products, particularly those in recombinant protein injection products. It is highlighted that regardless of whether the hosts for recombinant protein expression are bacteria or not, endotoxin testing is required for the final products of injectable recombinant proteins, and compliance with relevant industry standards is necessary. This review aims to provide a reference for the research on endotoxins in the large-scale production process of recombinant proteins.

Background: Electroacupuncture (EA) has been demonstrated to be efficacious and safe in patients with knee osteoarthritis (KOA), yet the optimal current intensity for pain control in KOA remains unspecified. The present meta-analysis aimed to compare the effects of high-intensity and low-intensity EA in terms of pain relief and functional improvement in KOA., Methods: A thorough and comprehensive literature search for randomized controlled trials (RCTs), all looking at the intensity of EA for KOA, was carried out in PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Science Journal Citation Report (VIP) and Wanfang database, as well as ClinicalTrials.gov. All databases were searched from their inception until April 2022. Study quality was assessed using the Cochrane risk of bias (RoB)2 tool. Finally, a meta-analysis of all eligible RCTs was performed using Review Manager 5.3., Results: Three studies with 472 individuals were included in the meta-analysis. The pain intensity reductions were significantly different between the high-intensity EA group and low-intensity EA group (mean difference (MD) = -0.22, 95% confidence interval (CI) = -0.26 to -0.18, p  < 0.00001). There was no significant difference between the two groups in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores (MD = -3.62, 95% CI = -12.22 to 4.98, p  = 0.41). High-intensity EA significantly improved emotional scale (ES) scores compared to low-intensity EA (MD = -0.72, 95% CI = -0.76 to -0.67, p  < 0.00001)., Conclusion: The findings of this systematic review and meta-analysis indicated that high-intensity EA provides superior pain relief and has a bigger impact on emotional scale scores in patients with KOA., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Zinc ions (Zn 2 ⁺) is actively involved in diverse biological processes. Therefore, the precise detection of Zn 2 ⁺ ion is an important object of increasing investigation. Although numerous fluorescent zinc ion detection probes have been developed, simple, biocompatible, and sensitive probes are still urgently needed. Herein, we reported two novel fluorescent probes, ZnTP1 and ZnTP2, by incorporating a quinoline fluorophore into a membrane-permeable zinc chelator tris(2-pyridylmethyl)amine. ZnTP1 exhibited a significant fluorescence enhancement in the presence of zinc ions through chelation-enhanced fluorescence (CHEF) processes, whereas probe ZnTP2 did not show any significant change in fluorescence due to the insertion of the carbonyl group. Further investigations revealed that ZnTP1 can effectively penetrate cell membranes and detect Zn 2+ with high sensitivity in diverse biological samples, including living cells, plant tissues, and animal model zebrafish. This work suggests that ZnTP1 as a simple and efficient chemical probe has great potential for zinc ions detection in various biological contexts, thus providing a new tool for probing zinc ions in biosystems., 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.)

Purpose: Both Ku80 and Ku70 are promising drug targets for hepatocellular carcinoma (HCC) and crucial for immune regulation. However, their correlation with HCC immune signatures has not yet been investigated. Therefore, we aimed to investigate the relationship between Ku80, Ku70, and immune signatures in HCC and validate their significance in cytotoxic lymphocyte (CTL) immunotherapy., Patients and Methods: Analyses of Ku70, Ku80, and immune signatures in public datasets was performed using R software, an online Kaplan-Meier plotter, g:Profiler, GeneTrail, and Metascape. Uniform manifold approximation and projection, correlation chord diagrams, Pearson's correlation tests, and Spearman correlation tests were used to describe various correlation levels. HCC mRNA sequencing data (n=373 tumor samples and n=50 para-tumor samples) were drawn from The Cancer Genome Atlas (TCGA) public database. Immunofluorescent staining was used to validate Ku70/Ku80 and CD8 + CTL expression in 120 HCC patients from our center. Survival analysis was performed using the Kaplan-Meier survival analysis with the Log rank test and was adopted to analyze immunotherapy outcomes correlated with Ku70/Ku80 expression in various solid tumors. Multivariate analysis of HCC patient data from our center was performed using a Cox proportional hazards model., Results: Increased Ku70/Ku80 expression positively correlated with more enriched immune microenvironment signatures, indicating increased immune infiltration in HCC. Upregulation of Ku70/Ku80 indicated better anti-PD1 and anti-PDL1 treatment outcomes in various solid tumors. Higher Ku70/Ku80 expression with lower CD8 + CTL signatures indicated worse survival outcomes, whereas lower Ku70/Ku80 expression with higher CD8 + CTL signatures indicated the best prognosis., Conclusion: Higher Ku70/Ku80 expression indicated an immune-hot infiltration signature in HCC. Patients with increased Ku70/Ku80 expression and high CD8 + CTL signatures may potentially benefit from CTL-centered immunotherapies., Competing Interests: All authors declare no conflicts of interests., (© 2024 Yang et al.)

Background: Multiple brands of immune checkpoint inhibitors (ICIs), including domestic and imported agents, have been approved as front-line therapy in China. However, little is known about the difference in efficacy and safety of these agents of different origins. This study aims to systematically compare the difference between National Medical Products Administration (NMPA) approved domestic and imported ICIs regarding their efficacy, safety, and price., Methods: We systematically searched PubMed, Embase, and Cochrane Central, from inception to July 1st, 2023, for phase III trials evaluating ICIs as first- or second-line settings that have available hazard ratio (HR) for Asians or non-Asians. Studies of domestic and imported ICIs were screened and paired by the matching clinical characteristics as mirror groups. The primary endpoint was to assess the difference in efficacy between domestic and imported ICIs regarding overall survival. An effect size was derived from each mirror group and then pooled across all groups using a random-effects model. Heterogeneity was assessed by I 2 statistics. Monthly treatment costs for each drug were calculated based on dosing information on National Medical Products Administration (NMPA) label and prices extracted from INSIGHT database. The difference in monthly treatment costs was compared by unpaired T-test. The protocol is registered on PROSPERO, CRD42024580753., Results: Overall, domestic ICIs exhibited better efficacy regarding overall survival (HR, 0.87; 95 % CI, 0.79-0.97; P < 0.05; I 2 = 0) compared with imported agents. No difference was observed regarding benefits in progression free survival (HR, 0.95; 95 % CI, 0.82-1.09; P > 0.05; I 2 = 0). Consistent results were obtained through frequentists and Bayesian approaches. The differences in safety; measured by relative risk of treatment-related adverse events (TARE) of any grade, TARE of grade 3 or higher, immune-related adverse events(irAE) of any grade, irAE of grade 3 or higher, discontinuation due to treatment, and death due to treatment; were also similar between domestic and imported ICIs. Moreover, in current Chinese market, the monthly treatment prices of domestic ICIs was statistically lower than that of imported ICIs (P < 0.01)., Conclusions: Our research provides an essential reference of cost-effectiveness of ICIs manufactured in China for clinicians in routine practice of cancer care as well as public health authorities for decision making process., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The ability to lubricate and resist wear at temperatures above 600 °C in an oxidative environment remains a significant challenge for metals due to their high-temperature softening, oxidation, and rapid degradation of traditional solid lubricants. Herein, we demonstrate that high-temperature lubricity can be achieved with coefficients of friction (COF) as low as 0.10-0.32 at 600-900 °C by tailoring surface oxidation in additively-manufactured Inconel superalloy. By integrating high-temperature tribological testing, advanced materials characterization, and computations, we show that the formation of spinel-based oxide layers on superalloy promotes sustained self-lubrication due to their lower shear strength and more negative formation and cohesive energy compared to other surface oxides. A reversible phase transformation between the cubic and tetragonal/monoclinic spinel was driven by stress and temperature during high temperature wear. To span Ni- and Cr-based ternary oxide compositional spaces for which little high-temperature COF data exist, we develop a computational design method to predict the lubricity of oxides, incorporating thermodynamics and density functional theory computations. Our finding demonstrates that spinel oxide can exhibit low COF values at temperatures much higher than conventional solid lubricants with 2D layered or Magnéli structures, suggesting a promising design strategy for self-lubricating high-temperature alloys., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: The current evidence regarding the association between long-term exposure to ozone (O 3 ) and hypertension incidence is limited and inconclusive, particularly at low O 3 concentrations. Therefore, our research aims to investigate the potential link between long-term O 3 exposure and hypertension in a region with low pollution levels., Methods: From 2010 to 2012, we conducted a cohort prospective study by recruiting nearly 10,000 attendees through multistage cluster random sampling in Guizhou Province, China. These individuals were followed up from 2016 to 2020, and 5563 cases were finally included in the analysis. We employed a high-resolution model with both temporal and spatial accuracy to estimate the maximum daily 8-h average O 3 and utilized annual average O 3 concentrations for three exposure periods (2009&#95;10, 2007&#95;10, 2005&#95;10) as the exposure indicator. Time-dependent covariates Cox regression model was exerted to estimate the hazard ratios (HRs) of hypertension incidence. Generalized linear model was employed to assess the association between O 3 and systolic, diastolic, pulse, and mean arterial pressure. The dose-response curve was explored using a restricted cubic spline function., Results: 1213 hypertension incidents occurred during 39,001.80 person-years, with an incidence density of 31.10/1000 Person Years (PYs). The average O 3 concentrations during the three exposure periods were 66.76 μg/m 3 , 67.85 μg/m 3 , and 67.21 μg/m 3 , respectively. Per 1 μg/m 3 increase in O 3 exposure was associated with 11 % increase in the incidence of hypertension in the single-pollution model, and the association was more pronounced in Han, urban, and higher altitude areas. SBP, PP, and MAP were increased by 0.619 (95 % CI, 0.361-0.877) mm Hg, 0.477 (95 % CI, 0.275-0.679) mm Hg, 0.301 (95 % CI, 0.127-0.475) mm Hg, respectively. Furthermore, we observed a nonlinear exposure-response relationship between O 3 and hypertension incidence., Conclusions: Long-term exposure to low-level O 3 exposure is associated with an increased risk of hypertension., 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.)

Communication of gut hormones with the central nervous system is important to regulate systemic glucose homeostasis, but the precise underlying mechanism involved remain little understood. Nesfatin-1, encoded by nucleobindin-2 (NUCB2), a potent anorexigenic peptide hormone, was found to be released from the gastrointestinal tract, but its specific function in this context remains unclear. Herein, we found that gut nesfatin-1 can sense nutrients such as glucose and lipids and subsequently decreases hepatic glucose production. Nesfatin-1 infusion in the small intestine of NUCB2-knockout rats reduced hepatic glucose production via a gut - brain - liver circuit. Mechanistically, NUCB2/nesfatin-1 interacted directly with melanocortin 4 receptor (MC4R) through its H-F-R domain and increased cyclic adenosine monophosphate (cAMP) levels and glucagon-like peptide 1 (GLP-1) secretion in the intestinal epithelium, thus inhibiting hepatic glucose production. The intestinal nesfatin-1 -MC4R-cAMP-GLP-1 pathway and systemic gut-brain communication are required for nesfatin-1 - mediated regulation of liver energy metabolism. These findings reveal a novel mechanism of hepatic glucose production control by gut hormones through the central nervous system., Competing Interests: Disclosure and competing interests statement The authors declare no competing interests., (© 2024. The Author(s).)

Amyloid β (A β ) deposition and neurofibrillary tangles are widely considered the primary pathological hallmarks of familial and sporadic forms of Alzheimer disease (AD). However, cerebrovascular inflammation, which is prevalent in 70% of AD patients, is emerging as another core feature of AD pathology. In our current work, we investigated the hypothesis that A β 42 exposure drives an increase in vascular cell adhesion molecule-1 (VCAM-1) expression, a cerebrovascular inflammatory marker expressed on the blood-brain barrier (BBB) endothelium in humans and murine models. We have demonstrated that the inflammation signaling pathway is upregulated in AD patient brains, and VCAM-1 expression is increased in AD patients compared with healthy controls. Furthermore, dynamic SPEC/CT imaging in APP,PS1 transgenic mice (a mouse model that overexpresses A β 42) demonstrated VCAM-1 upregulation at the BBB. Although there is a strong association between A β 42 exposure and an increase in VCAM-1 expression, the underlying mechanisms remain partially understood. Molecular mechanisms driving VCAM-1 expression at the BBB were investigated in polarized human cerebral microvascular endothelial cell monolayers. Moreover, by employing reverse-phase protein array assays and immunocytochemistry we demonstrated that A β 42 increases VCAM-1 expression via the Src/p38/MEK signaling pathway. Therefore, targeting the Src/p38/MEK pathway may help modulate VCAM-1 expression at the BBB and help mitigate cerebrovascular inflammation in Alzheimer disease. SIGNIFICANCE STATEMENT: Although considered a core pathological feature of Alzheimer disease, molecular pathways leading to cerebrovascular inflammation remain only partially understood. Moreover, clinical diagnostic methods for detecting cerebrovascular inflammation are underdeveloped. This study demonstrated the detection of VCAM-1 using radio-iodinated VCAM-1 antibody and single-photon emission computed tomography/computed tomography imaging. Additionally, exposure to A β 42 increases VCAM-1 expression on the blood-brain barrier endothelium via the Src/p38/MEK pathway. These findings are expected to aid in the development of diagnostic and therapeutic approaches for addressing cerebrovascular inflammation in AD., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Melanoma, recognized as the most aggressive type of skin cancer, has experienced a notable increase in cases, especially within populations with fair skin. This highly aggressive cancer is largely driven by UV radiation exposure, resulting in the uncontrolled growth and malignant transformation of melanocytes. The cGAS-STING pathway, an immune signaling mechanism responsible for detecting double-stranded DNA in the cytoplasm, is essential for mediating the immune response against melanoma. This pathway serves a dual purpose: it enhances antitumor immunity by activating immune cells, but it can also promote tumor growth when chronically activated by creating an immunosuppressive environment. This review comprehensively examines the multifaceted implication of the cGAS-STING pathway in melanoma pathogenesis and treatment. We explore its molecular mechanisms, including epigenetic regulation, interaction with signaling pathways such as AR signaling, and modulation by various cellular effectors like TG2 and activin-A. The therapeutic potential of modulating the cGAS-STING pathway is highlighted, with promising results from STING agonists, combination therapies with immune checkpoint inhibitors, and novel drug delivery systems, including nanoparticles and synthetic drugs. Our findings underscore the importance of the cGAS-STING pathway in melanoma, presenting it as a critical target for enhancing anti-tumor immunity. By leveraging this pathway, future therapeutic strategies can potentially convert 'cold' tumors into 'hot' tumors, making them more susceptible to immune responses., Competing Interests: Declarations Ethics approval and consent to participate Not applicable (Review Study). Informed consent to consent for publication Not applicable (Review Study). Declaration of generative AI and AI-assisted technologies in the writing process During the preparation of this work, the authors used ChatGPT by OpenAI to improve paper readability. After using this tool/service, the authors reviewed and edited the content as needed and took full responsibility for the publication’s content. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Cervical cancer (CC), a significant global health threat, necessitates comprehensive understanding for improved therapeutic interventions. Many research indicates that dysregulation of the Hippo-YAP1 pathway leads to uncontrolled proliferation and invasion of tumor cells, promoting the progression of various cancers. This article aims to elucidate the role of RNF6 in CC and its regulation of the Hippo-YAP1 signaling pathway., Methods: The public tumor dataset analyses, immunohistochemistry, and western blotting were used to explore the expression of RNF6 in CC. Gain- and loss-of-function assays were conducted to elucidate the role of RNF6 in the proliferation and invasion of CC cells. Transcriptome sequencing was used to explore RNF6's role in cervical cancer, with validation of its regulation of the Hippo-YAP1 pathway through western blotting and RT-qPCR. Co-transfection of YAP overexpression plasmids into RNF6-silenced CC cells were preformed to confirm YAP1's pivotal role in RNF6-mediated CC progression. Animal experiments were preformed to further validate RNF6 interference's inhibitory effect on CC proliferation in vivo., Results: Clinical samples and bioinformatics analysis revealed high expression of RNF6 in CC, and closely associated with advanced FIGO (International Federation of Gynecology and Obstetrics) stage, larger tumor size, and poor prognosis. Cellular functional experiments demonstrate that RNF6 promotes the proliferation, invasion, and migration of CC cells, while knockdown of RNF6 yields the opposite effect. Transcriptome sequencing further reveals that RNF6 may promote CC progression through the Hippo-YAP signaling pathway. Western blotting and RT-qPCR further unveil that RNF6 enhances the upregulation of YAP1 protein levels, thereby activating downstream oncogenes CTGF and CYR61 transcription. Additionally, exogenous overexpression of YAP1 reverses the inhibitory effect of RNF6 silencing on CC proliferation and invasion. Furthermore, RNF6 interference significantly attenuates tumor growth in vivo experiments., Conclusion: Our research reveals that RNF6 is highly expressed in CC, driving malignant progression by upregulating YAP1 protein expression and enhancing the transcription of downstream target genes CTGF and CYR61, offering potential therapeutic targets for CC treatment., Competing Interests: Declarations Ethics statement Our study was approved by Ethics Review Board of the First Affiliated Hospital of the Nanchang University and Jiangxi Maternal and Child Health Hospital. Competing interests The authors declare no competing interests. Conflict of interest The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s).)

Predicting the bioconcentration of chemical compounds plays a crucial role in assessing environmental risks and toxicological impacts. This study presents a robust multitask deep learning model for predicting the bioconcentration potential. The model can predict the bioconcentration of compounds in multiple categories, including non-bioconcentrative (non-BC), weakly bioconcentrative (weak-BC), and strongly bioconcentrative (strong-BC). We also employed the SHapley Additive exPlanations (SHAP) technology for the model interpretation. The binary classification models (non-BC vs BC and weak-BC vs strong-BC) showed good predictive performance, which achieved accuracy values over 90% and area under the curve (AUC) values with 0.95. The final ternary classification model provided an overall accuracy with 91.11%. Comparative analysis of molecular physicochemical properties showed that the importance of molecular weight, polar surface area, solubility, and hydrogen bonding are important for chemical bioconcentration. Besides, we identified eight structural alerts responsible for chemical bioconcentration. We made the model available as an online tool named BCdpi-predictor, which is accessible at http://bcdpi.sapredictor.cn/. Users can predict the bioconcentration potential of chemical compounds freely. The model has significant implications for environmental policy and regulatory frameworks, such as REACH, by providing a more accurate and interpretable method for assessing chemical risks. We hope that the results of this study can provide helpful tools and meaningful information for chemical bioconcentration prediction in environmental risk assessment., 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 Inc. All rights reserved.)

Background: Cephalanthera nanchuanica is a terrestrial orchid species and has been red listed as a second-grade protected plant due to its limited distributions in China. Initially classified within a monotypic genus Tangtsinia, this species was later reassigned to Cephalanthera based on morphological and molecular data. However, previous phylogenetic analyses of Cephalanthera using several segment sequences exhibited a low discriminatory power in delineating its relationships., Results: In this study, we characterized and comparatively analyzed the complete chloroplast (cp) genome of C. nanchuanica with those of six previously reported Cephalanthera species. Our findings revealed that the cp genome of C. nanchuanica had the typical quadripartite structure, with a size of 161,365 bp and a GC content of 37.27%. A total of 113 unique genes were annotated, among which nearly half of protein-encoding genes (RSCU > 1) showed a preference in codon usage. No structural rearrangements were observed among the cp genomes of Cephalanthera species, except for C. humilis, which displayed structural alterations due to gene loss, relocation, and inverted repeat (IR) expansion/contraction. The cp genomes of Cephalanthera species were highly conserved, with only a small number of SSRs detected, most of which preferred A/T bases. Comparative analysis of cp genomes indicated that IR and coding regions were less divergent than single copy and non-coding regions and eight mutational hotspots were identified. Phylogenetic analysis suggested that the tribe Neottieae was a monophyletic group, divided into five clades. Palmorchis was the earliest-diverging lineage, followed by Cephalanthera. Diplandrorchis was deeply nested within Neottia, forming a clade. Aphyllorchis and Limodorum formed another clade, sister to Epipactis. Within the Cephalanthera clade, C. nanchuanica was sister to C. falcata with a strong support., Conclusions: This study demonstrated that the cp genome characters of C. nanchuanica are highly similar to those of other Cephalanthera species, except for the mycoheterotrophic species C. humilis. Although the cp genomes of Cephalanthera species (excluding C. humilis) exhibited conservation in genome structure and sequence, SSR repeats and mutational hotspots were identified, which could potentially serve as as molecular markers for distinguishing Cephalanthera species. The phylogenetic analysis based on the protein-coding genes provided high-resolution support for the infrageneric classification. Therefore, cp genome data will be instrumental in resolving the phylogeny of the genus Cephalanthera., 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: Keratoconus (KC) is an asymmetrical bilateral corneal ectasia, of which the pathogenesis is unknown. Moreover, genetic factors play an important role. We reported ophthalmic findings in a Chinese family with monozygotic twins with KC to describe the clinical features and identify genetic variants., Methods: Comprehensive ophthalmic clinical assessments and examinations, including history, slit-lamp biomicroscopy, best-corrected visual acuity, corneal topography, anterior segment optical coherence tomography, and corneal biomechanics, were carried out on the twins and their parents. Whole-genome sequencing (WGS) was performed to identify variants in this family. SIFT, PolyPhen2, MutationTaster, and CADD were used to predict the effect of amino acid substitutions on the affected protein., Results: The twins presented typical KC features. However, their mother did not meet the criteria for a KC diagnosis but exhibited KC subclinical manifestations. After screening, 12 potentially pathogenic variants in 10 genes were identified in both twins and emerged as candidate variants for this family. These genes included 1 previously reported KC-associated variant (ZNF469, c.4384 G>A); 8 variants in 6 KC-associated genes (GRHPR, c.337 G>A, c.862&#95;863del; COL6A1, c.920 G>A; FLG, c.8753C>G; HSPG2, c.9503C>T; KRT82, c.1306 G>A; SCN9A, c.5702&#95;5706del, c.641 G>A); and 3 variants in 3 non-KC-associated genes (PDE6G, c.6C>A; HAL, c.1724C>T; AGBL1, c.2381 G>A)., Conclusions: The accumulation of these potentially pathogenic variants in twins may have caused KC in these twins. These results expand the spectrum of KC candidate variants and provide a basis for further studies on KC.

Currently, as the largest family of E3 ubiquitin ligases, Skp1-Cullin 1-F-box (SCF) E3 ligase complexes have attracted extensive attention. Among SCF complexes, Skp2, β-TrCP, and FBXW7 have undergone extensive research on their structures and functions. Previous studies suggest Skp2, β-TrCP, and FBXW7 are overexpressed in numerous cancers. Thus, the SCF E3 ligase complex has become a significant target for the development of anti-cancer drugs. Over the past few decades, a variety of anti-tumor inhibitors targeting the SCF E3 ligase complex have been attempted. However, since almost none of the SCF E3 ligase inhibitors passed clinical trials, the design and synthesis of the new inhibitors are needed. Here, we will introduce the structure and function of Skp2, β-TrCP, and FBXW7, their connections with cancer development, the relevant in vitro and in vivo activities, selectivity, structure-activity relationships, and the therapeutic or preventive application of small molecule inhibitors targeting these three F-box proteins reported in the patent (2010-present). This information will help develop drugs targeting the SCF E3 ubiquitin ligase, providing new strategies for future cancer treatments., Competing Interests: Declaration of competing interest This paper has not been published elsewhere in whole or in part. All authors have read and approved the content, and agree to submit it for consideration for publication in your journal. This paper does not address ethical/legal conflicts., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Effective pathogen inactivation is highly desired in public health but limited by existing methods each capable of assessing pathogen inactivation effectiveness (PIE) only in a specific condition. We therefore developed a novel method maxPIE designed to identify maximal PIEs across inactivation conditions by leveraging the power of massive array technologies. maxPIE implements a three-step algorithm to quickly identify maximal PIEs of inactivation treatments: (1) dilute pathogens into different initial titers each stored in an array well, (2) submit one sorted array to one treatment, (3) scan the treated array to find the maximum. maxPIE outperformed the conventional methods in (a) inactivating S. aureus using ultraviolet light of different wavelengths with different durations; (b) antibiotic treatment of S. aureus, E. coli, and multidrug-resistant E. coli; (c) inactivating S. aureus in plasma using ultraviolet light in different wavelengths with and without riboflavin. maxPIE was easy to understand and interpret and was robust in situations where conventional PIE methods would suffer. Hence, maxPIE can serve as an innovative and high throughput approach that can be widely used to enhance pathogen inactivation practices., 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.)

Introduction and Importance: Congenital iris and choroidal coloboma is a congenital ocular developmental anomaly, most occur in both eyes, which may exist in isolation or be accompanied by systemic developmental abnormalities. Herein, we report a case of congenital bilateral coloboma of iris and choroid accompanied by unilateral multiple primary pigmented iris cysts. The selection of treatment methods for iris cysts has always been a challenge for ophthalmologists. Especially for primary iris pigment epithelial cysts without clinical symptoms, no particular intervention measures are required. Which in turn helps ophthalmologists to make clinical decisions in real-world practice., Case Presentation: A 16-year-old boy presented to the ophthalmology clinic with a history of poor eyesight in both eyes since childhood. The pupils of both eyes were pear shaped, and there was a pigmented iris cyst about 1.5 mm × 2 mm at 6-7 o'clock pupillary margin of the left eye on slit-lamp examination. A large fan-shaped coloboma of choroid in both eyes respectively, involving the optic nerve and macular area on fundus examination. Ultrasound biomicroscopy revealed three cysts with hyperreflective walls and clear hyporeflective lumen in the left eye, one located on the anterior surface of the iris and the other two located on the posterior surface of the iris. Above all, he had no history of surgery, trauma, infection, tumor or medication. Therefore, primary pigmented iris epithelial cysts were diagnosed. Given that the patient was asymptomatic, with no impact on visual function, his cysts were monitored. After 2 years follow-up, the cysts remained stable., Clinical Discussion: Iris cysts, whether primary or secondary, are a diagnostic and a treatment challenge. Primary iris cysts are mostly present in the iridociliary sulcus and the ciliary crown, often asymptomatic, with a few located forward or larger, manifested as local protrusions around the iris. This patient had no history of ocular surgery or trauma, therefore, combining clinical manifestations and imaging examination results, primary pigmented iris epithelial cysts were diagnosed. For this patient, on the one hand, the surgical risk was high, and iris cysts probably recur after surgery, and there might be no improvement in postoperative visual acuity. On the other hand, the patient's fundus was poor and his family's economic conditions were not good. In addition, the iris cysts of this patient remained stable after 2 years of observation, therefore, no treatment was taken., Conclusion: Ophthalmologists should be aware of this rare but distinctive presentation, especially in patients without symptoms. Prompt diagnosis and treatment are pivotal in ensuring favorable outcomes and preventing further ocular complications in individuals affected by these uveal anomalies., Competing Interests: Conflict of interest statement The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We describe the design, synthesis, and structure-activity relationship (SAR) of heterobifunctional RET ligand-directed degraders (LDDs) derived from three different second-generation RET inhibitors. These LDDs are composed of a target binding motif (TBM) that binds to the RET protein, a linker, and a cereblon binding motif (CBM) as the E3 ligase recognition unit. This led to the identification of a series of pyrazolopyridine-based heterobifunctional LDDs, as exemplified by compound 39 . LDD 39 demonstrated high in vitro inhibitory and degradation potency against both RET wild-type and the two representative mutants, V804M and G810R. Importantly, in PK/PD studies, 39 exhibited a differentiated and favorable in vivo profile compared to the corresponding tyrosine kinase inhibitor (TKI), compound 3 . Robust and sustained degradation of total-RET (tRET) protein and inhibition of phospho-RET (pRET) signaling were observed in TPC-1 xenograft tumors driven by RET and the RET/G810R mutant following a single dose of LDD 39 at 15 and 75 mg/kg, respectively.

Coleoptile length, in wheat, is a significant agronomic trait impacting yield by facilitating the successful establishment of seedlings. In arid regions, varieties possessing longer coleoptile can evade harsh conditions by deep sowing, paving the way for improved yield. However, the study of genes involved in coleoptile development is insufficient. In this study, a high-density 660 K SNP array was used for genome-wide association study (GWAS) on coleoptile length in 150 wheat varieties. The findings revealed the detection of 353 significantly associated SNPs across all environments. The integration of linkage disequilibrium analysis and haplotype analysis mined 23 core QTLs capable responsible for the stable regulating coleoptile length in wheat. In wheat varieties characterized by extended coleoptile length, 6,600, 11,524, and 6,059 genes were found to be differentially expressed at three distinct developmental stages within the coleoptile, respectively. Through GWAS, gene expression levels, and functional annotation, we concluded the identification of two candidate genes ( TraesCS2B02G423500 , TraesCS2B02G449200 ) regulating wheat coleoptile length. By employing WGCNA and protein interactions prediction, discovered that the 19 genes were found to interact with candidate genes and participate in plant hormone metabolism and signaling, cell elongation or proliferation, which collectively contributing to coleoptile elongation. Additionally, two KASP markers were developed which can be used in breeding. These results offer a basis for understanding the genetic regulatory network responsible for wheat coleoptile length formation. The QTLs and candidate genes identified in this study can be further utilized for genetic improvement of wheat coleoptile length., Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01520-6., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer Nature B.V. 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

In recent years, organic electrochemical transistors (OECTs) have attracted widespread attention due to their significant advantages such as low-voltage operation, biocompatibility, and compatibility with flexible substrates. Organic photoelectrochemical transistors (OPECTs) are OECTs with photoresponse capabilities that achieve photoresponse and signal amplification in a single device, demonstrating tremendous potential in multifunctional optoelectronic devices. In this mini-review, we briefly introduce the channel materials and operation mechanisms of OECTs/OPECTs. Then different types of OPECTs are discussed depending on their device-architecture-related photoresponse generation. Following this, we summarize recent advances in OPECT applications across various fields including biomedical sciences, optoelectronics, and sensor technologies. Finally, we outline the current challenges and explore future research prospects, aiming at extending their further development and applications.

Background: The COVID-19 pandemic has led to long-term neurological and psychological effects, including sleep disturbances. While prior studies have identified altered brain function post-COVID-19, specific functional connectivity (FC) patterns predicting sleep quality after recovery remain unclear. This study aims to identify FC patterns associated with sleep quality two months after the first negative COVID-19 antigen test., Methods: Using a connectome-based predictive modeling (CPM) approach, we identified the functional connectome regulating sleep quality based on a 164-region parcellation. Significant connections were analyzed using mediation models to examine their role in the relationship between anxiety, depression, and sleep., Results: FC between the right cerebellar peduncle and the left VIII of the cerebellum, and between the left middle temporal pole (MTP) and left ventral tegmental area (VTA), significantly predicted Pittsburgh Sleep Quality Index (PSQI) scores for sleep disturbances two months post-recovery (q 2  = 0.059, MSE = 0.154, p = 0.017, r = 0.350). Mediation analysis showed a significant indirect effect of FC between the left MTP and VTA on the relationship between generalized anxiety and sleep disturbances (indirect effect = 0.013, 95% CI = [0.002, 0.03], pfdr <0.05). FC between the right dorsal raphe nucleus and ipsilateral regions-including occipital, parietal, and temporal areas-predicted PSQI scores for daytime dysfunction (q 2  = 0.092, MSE = 0.678, p = 0.025, r = 0.342)., Conclusion: Post-COVID-19 brain connectivity and anxiety predict sleep quality. These findings highlight the potential for targeted therapeutic strategies to improve sleep and identify patients at risk for prolonged disturbances through FC biomarkers., Competing Interests: Declaration of competing interest Authors have declared no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)