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Glycosylphosphatidylinositol (GPI) anchoring is one of the conserved posttranslational modifications in eukaryotes that attach proteins to the plasma membrane. In fungi, in addition to plasma membrane GPI-anchored proteins (GPI-APs), some GPI-APs are specifically released from the cell membrane, secreted into the cell wall, and covalently linked to cell wall glucans as GPI-anchored cell wall proteins (GPI-CWPs). However, it remains unclear how fungal cells specifically release GPI-CWPs from their membranes. In this study, phospholipase PlcH was identified and confirmed as a phospholipase C that hydrolyzes phosphate ester bonds to release GPI-APs from the membrane of the opportunistic fungal pathogen Aspergillus fumigatus . Deletion of the plcH gene led to abnormal conidiation, polar abnormality, and increased sensitivity to antifungal drugs. In an immunocompromised mouse model, the Δ plcH mutant showed an attenuated inflammatory response and increased macrophage killing compared with the wild type. Biochemical and proteomic analyses revealed that PlcH was involved in the localization of various cell wall GPI-APs and contributed to the cell wall integrity. Our results demonstrate that PlcH can specifically recognize and release GPI-CWPs from the cell membrane, which represents a newly discovered secretory pathway of GPI-CWPs in A. fumigatus ., Competing Interests: The authors declare no conflict of interests., (© 2024 The Author(s). mLife published by John Wiley & Sons Australia, Ltd on behalf of Institute of Microbiology, Chinese Academy of Sciences.)

As one of the key components of supercapacitors (SCs), separators can directly affect the energy density, output power, and safety stability of SCs. However, it is still a challenge to prepare separators that simultaneously combine large pore size, ultrathin thickness, and excellent mechanical properties. Herein, a 5 μm ultrathin separator with a three-dimensional (3D) porous nanofiber skeleton dotted by fumed Al 2 O 3 nanoparticles has been developed using biaxial stretching. The unique structure of the 3D porous nanofiber skeleton ensures a mechanical strength up to 40 MPa, while the fumed Al 2 O 3 nanoparticles dotted on the 3D skeleton and the incorporation of the annealing process achieve a large average pore size of 130.8 nm, thus harmoniously resolving the contradiction between strength and large average pore size for ultrathin composite separators. The ultrathin thickness greatly shortens the ion transmission channel and effectively reduces ion transmission resistance. Moreover, the fumed Al 2 O 3 nanoparticles exposed on the surface of the 3D porous nanofiber skeleton enhance the wettability of the electrolyte as well as the thermal stability of the separator, achieving a low bulk resistance of 0.3 Ω and zero shrinkage at 130 °C. Due to the unique structure, UAPFS7 offers a better overall performance compared to commercial separators. These findings indicate that the developed separators exhibit excellent comprehensive performance and have the potential to promote the large-scale application of next-generation energy storage devices.

Bangia fusco-purpurea polysaccharide (UBFP) with ultra-high pressure assisted extraction has good in vitro hypolipidemic activity. To be explored as a natural hypolipidemic agent, the alleviation effect of UBFP on in vivo dyslipidemia in high-fat diet (HFD) induced mice was further investigated. Compared with native polysaccharide (BFP), UBFP was better to reduce weight gain, fat accumulation, serum and hepatic lipid abnormalities for HFD induced mice. This might be caused by the factor that UBFP was more effective to improve the diversity and structure of gut microbiota especially with SCFAs-producing bacteria (e.g., Allprevotella and Akkermansia) increased. Moreover, UBFP could up-regulate tryptophan, 5-hydroxyindoleacetic acid, leptin and N-arachidonic acid glutamate levels, and exhibited significant differential enrichment in the pathways of lysine biosynthesis, arginine biosynthesis, and tryptophan metabolism. In addition, UBFP could regulate energy metabolism and enhance fatty acid oxidation by inhibiting PPARγ protein expression and activating AMPK and ACC signaling pathways. Overall, with ultra-high pressure assisted extraction, UBFP possessed better function of regulating lipid homeostasis, which resulted from the altered structure of polysaccharides, improved intestinal flora and metabolites. The findings can lay the theoretical foundation for the design and development of desirable polysaccharides on regulating lipid homeostasis through ultra-high pressure modification., 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.)

Prolyl Hydroxylase Domain protein 2 (PHD2) targets Hypoxia Inducible Factor alpha subunits (HIFα) for oxygen-dependent proline hydroxylation that leads to subsequent ubiquitination and degradation of HIFα. In addition to HIF proteins, growing evidence suggested that PHD2 may exert its multifaceted function through hydroxylase-dependent or independent activities. Given the critical role of PHD2 in diverse biological processes, it is important to comprehensively identify potential PHD2 interacting proteins. In this study, we engineered HeLa cells that stably express HTBH-tagged PHD2 to facilitate the identification of PHD2 interactome. Using DSSO-based cross-linking mass spectrometry (XL-MS) technology and LC-MS n analysis, we mapped PHD2-HIF1α interaction hotspots and identified over 300 PHD2 interacting proteins. Furthermore, we validated the COP9 Signalosome (CSN) complex, a major deneddylase complex, as a novel PHD2 interactor. DMOG treatment promoted interaction between PHD2 and CSN complex and enhanced the deneddylase activity of the CSN complex, resulting in increased level of free Cullin and reduced target protein ubiquitination. This mechanism may serve as a negative feedback regulation of the HIF transcription pathway.

Facile chiral discrimination without relying on chromatographic techniques has long been a huge challenge due to the minimal differences in the physicochemical properties of enantiomers. Polysaccharide hydrogels with natural chiral selectivity can be promising materials for constructing chiral discrimination platforms. In this study, l-cysteine-induced cobalt nanoclusters (LC-CoNCs) were prepared and utilized as chiral nanozymes for promoting the chemiluminescent (CL) signal of a luminol-H 2 O 2 system. Based on the competitive affinity of LC-CoNCs and carnitine enantiomers on a Ca 2+ crosslinked sodium alginate (SA) hydrogel interface, a CL method was established for the effective discrimination of carnitine enantiomers. With this strategy, d-carnitine led to a significantly inhibited CL signal, whereas l-carnitine did not exhibit an inhibition effect on the CL signal. According to the results of density functional theory calculations and contact angle measurements, the hydrogel shows an affinity sequence of d-carnitine > LC-CoNCs > l-carnitine due to the synergistic effect of SA and Ca 2+ , which is the foundation for achieving effective discrimination. This approach demonstrated acceptable accuracy for assaying d-carnitine in complex matrices such as drug preparation and milk. This work pioneers the combination of a polysaccharide hydrogel as a chiral selector with a nanozyme as the CL indicator for the effective discrimination of enantiomers, offering an innovative tool for the development and production of chiral drugs.

Hepatic arterial infusion chemotherapy (HAIC) has emerged as a promising treatment strategy for hepatocellular carcinoma (HCC), but a detailed understanding of the multicellular ecosystem after HAIC treatment is lacking. Here, we collected tumor samples from treatment-naïve primary and post-HAIC HCC, and integrated single-nucleus RNA sequencing with spatial transcriptomics to characterize the tumor ecosystem in the post-HAIC HCC. Increased fractions and enhanced cellular communication of CD4 + T, CD20 + B, and dendritic cell subtypes were identified in post-HAIC tumors. Moreover, it is substantiated that HAIC promoted tertiary lymphoid structures (TLS) formation, and addressed the roles of TLSs as spatial niches of cellular communication. Specifically, intermediate exhausted CD8 + T cells expressing Granzyme-K and PD-1 (PD-1 + CD8 + Tex-int) expanded following HAIC and exhibited a functionally antitumor phenotype. PD-1 + CD8 + Tex-int accumulated in the TLS vicinity and disseminated throughout the tumor microenvironment, demonstrating potential as an effective biomarker for HAIC-based treatment in HCC. This study provides valuable resources and biological insights in the cellular underpinnings of HAIC treatment., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

In traditional Chinese medicinal practices, Gegen (GG) and Tianma (TM) are widely utilized for headache relief, but their material basis has not been comprehensively characterized. This research utilized ultra performance liquid chromatography-quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF-MS) for precise determination of Gegen-Tianma's (GGTM) material composition, and employed desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) to pinpoint the brain-absorbed components and various metabolites post oral administration to rats. A total of 80 chemical constituents were identified from GGTM, 11 prototypes and 18 metabolites were identified from plasma. The brain tissue was identified in total 4 prototypes and 5 metabolites, these constituents were basically located in the prefrontal cortex and thalamus. The absorption patterns of components in the rat brain aligned with the varied distribution of metabolites within the brain. This study provides a solid theoretical basis for in-depth exploration of potential drug targets and elucidation of the specific mechanism of action of GGTM in the treatment of migraine., 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.)

Neutrophil extracellular traps (NETs) are released by neutrophils to modulate the immune response. Aluminum (Al) poisoning is linked to immunotoxicity, and selenium (Se) can maintain immune homeostasis. In this study, we investigated the toxic effects of Al on the release of NETs, the antagonistic effect of Se on Al-induced toxicity, and the potential molecular mechanisms underlying these processes. We assessed the cytotoxicity of aluminum on neutrophils using CCK-8 assay, visualized the structure of selenium/aluminum-induced NETs through immunofluorescence and scanning electron microscope, quantified ROS release during NETs formation using fluorescence microplate analysis, and employed the selenoprotein levels to dissect the mechanisms underlying selenium and aluminum-induced NETs release. Peripheral blood neutrophils were exposed to zymosan for a duration of 3 h to induce the formation of NETs. Microscopic analysis indicated that NETs formation was inhibited in the presence of aluminum. Furthermore, assessments using a multifunctional microplate reader demonstrated that aluminum suppressed both the production of extracellular DNA and the reactive oxygen species burst in neutrophils. Western blot analysis revealed that aluminum altered the levels of cellular selenoproteins. In contrast, Se reduced the Al-induced toxic reaction including restored NETs production, ROS burst, and selenoprotein levels. These results indicate that Al decreases the formation of NETs induced by Zym, while Se inhibits the Al toxicity, promoting the formation of NETs by modulating the expression of selenoprotein., Competing Interests: Declarations. Ethics Approval: All animal studies were approved by the institutional animal care and use committee of Foshan University. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The biocompatibility of carborane was a difficult problem that had drawn a lot of study interest. Using multi-ion inlay binding, water-soluble polymers were created by encapsulating nido-carborane in diazaspirodecaniums such as para-poly-nido-carboanylazaspirodecanium [5,4] (p-PNC54), para-poly-nido-carboanylazaspirodecanium [6,5] (p-PNC65), meta-poly-nido-carboanylazaspirodecanium [5,4] (m-PNC54), and meta-poly-nido-carboanylazaspirodecanium [6,5] (m-PNC65). First, the active control 5-fluorouracil demonstrated strong activity against HeLa and HCT-116 cells but minimal cytotoxicity at 19.22±2.85 μM and 21.47±5.99 μM, respectively. Second, the four carborane polymers that specifically penetrated the cells were imaged using HeLa cells. TEM was used to assess the dynamic self-assembling effect of these water-soluble polymers in order to gain a better understanding of their internal microphenomenon. All four derivatives' combined impacts on self-assembly in water were identified. Different degrees of selective entrance into targeted cells under different architectures were discovered by in vitro cell imaging., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ouyang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Tumor heterogeneity plays a pivotal role in tumor progression and resistance to clinical treatment. Single-cell RNA sequencing (scRNA-seq) enables us to explore heterogeneity within a cell population and identify rare cell types, thereby improving our design of targeted therapeutic strategies. Here, we use a pan-cancer and pan-tissue single-cell transcriptional landscape to reveal heterogeneous expression patterns within malignant cells, precancerous cells, as well as cancer-associated stromal and endothelial cells. We introduce a deep learning framework named Shennong for in silico screening of anticancer drugs for targeting each of the landscape cell clusters. Utilizing Shennong, we could predict individual cell responses to pharmacologic compounds, evaluate drug candidates' tissue damaging effects, and investigate their corresponding action mechanisms. Prioritized compounds in Shennong's prediction results include FDA-approved drugs currently undergoing clinical trials for new indications, as well as drug candidates reporting anti-tumor activity. Furthermore, the tissue damaging effect prediction aligns with documented injuries and terminated discovery events. This robust and explainable framework has the potential to accelerate the drug discovery process and enhance the accuracy and efficiency of drug screening., (© The Author(s) 2024. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.)

Serious adverse drug reactions of gentamicin (GM) significantly limit its clinical use, thus there is an urgent demand to develop reliable strategies to detect its concentration. In this study, we have developed a novel highly sensitive and portable lateral flow immunoassay (LFIA) based on CoFe PBAs/WS 2 nanozyme mediated chemiluminescence (CL) and photothermal (PT) dual-mode POCT biosensor for the detection of GM, which successfully combines sensitive laboratory analyses with portable in situ analyses in the field. In this proof-of-principle work, the dynamic detection ranges of CL-LFIA and PT-LFIA mode were 1 pg mL -1 to 100 ng mL -1 and 50 pg mL -1 to 100 ng mL -1 with the limits of detection of 0.33 and 16.67 pg mL -1 , respectively. The whole detection of CL-LFIA and PT-LFIA could be completed within 15 min and 30 min, respectively. The recoveries of GM spiked into complex matrices including milk, urine, and serum for CL-LFIA and PT-LFIA were 90.94%-109.74% and 94.49%-109.31%, respectively, indicating the reliability and applicability of the dual-mode LFIA in real samples. The dual-mode POCT biosensor could effectively overcome the false problems with improving accuracy and sensitivity, enabling user to precisely detect GM by laboratory analysis or on-site analysis depending on the source condition. Due to the complementary properties of CL-LFIA and PT-LFIA, the developed POCT biosensor can effectively ensure high-performance detection, showing the potential application of accurately detecting drug concentration in clinical practice., 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.)

Even though N6-methyladenosine (m6A) RNA modifications are increasingly being implicated in human disease, their mechanisms are not fully understood in smokers with coronary artery disease (CAD). Thirty m6A-related regulators' expression (MRRE) in CAD individuals (smokers and non-smokers) were analyzed from GEO. Support Vector Machine, random forest, and nomogram models were constructed to assess its clinical value. Consensus clustering, principal component analysis, and ssGSEA were used to construct a full picture of m6A-related regulators in smokers with CAD. Oxygen-glucose deprivation (OGD) and qRT-PCR were used to validate hypoxia's effect on MRRE. A comparison between smokers with CAD and controls revealed lower expression levels of RBM15B, YTHDC2, and ZC3H13. Based on three key MRREs, all models showed good clinical value, and smokers with CAD were divided into two distinct molecular subgroups. The correlations were found between key MRRE and the degree of immune infiltration. Three key MRREs in HUVECs and FMC84 mouse cardiomyocytes were reduced in the OGD group. Through hypoxia, smoking might reduce the expression levels of RBM15B, YTHDC2, and ZC3H13 in smokers with CAD. Our findings provide an important theoretical basis for the treatment of smokers with CAD.

Liver regeneration is a complex process that involves the recruitment of bone marrow (BM)-derived hematopoietic stem and progenitor cells (HSPCs). Pregnane X receptor (PXR), also known as NR1I2, is an important regulator for liver enlargement and regeneration. However, the role of PXR activation in hematopoiesis during liver regeneration remains unclear. This study investigates the effects of PXR activation on HSPCs and hematopoiesis during liver regeneration, as well as the underlying mechanisms involved. Using a 70 % partial hepatectomy (PHx) on C57BL/6 wild-type (WT) and Pxr-null mice, we observed a significant correlation between the changes in HSPCs numbers in BM and the process of liver regeneration. PXR activation significantly increased the population of Lineage - Sca-1 + c-Kit + (LSK) cells in the BM, which are key HSPCs involved in hematopoiesis. Additionally, PXR activation increased serum levels of thrombopoietin (TPO) and erythropoietin (EPO), factors known to support HSPCs proliferation and hematopoiesis in the process of liver regeneration. PXR activation does not affect the hematopoietic function of normal mice. Furthermore, mice subjected to irradiation or busulfan-induced hematopoietic dysfunction exhibited impaired liver regeneration, which was alleviated by PXR activation. Importantly, in Pxr-null mice, the promotive effects of PXR activation on liver regeneration and increase of HSPCs were markedly diminished. Moreover, liver-specific Pxr silencing using AAV-Pxr shRNA attenuated the PXR activation-mediated liver regeneration and increase in BM LSK cells, confirming the critical role of hepatic PXR in hematopoiesis during liver regeneration. Collectively, these findings reveal that PXR activation promotes HSPCs proliferation and hematopoiesis during liver regeneration, providing new insights into the molecular mechanisms underlying the role of PXR in liver regeneration and hematopoiesis., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Brucellosis remains a major public health challenge in China and globally. This study analyzed long-term trends in brucellosis incidence in China from 2006 to 2020, assessed the effects of age, period, and birth cohort, and projected future incidence up to 2030. Data on brucellosis were obtained from the Data-center of China Public Health Science, and temporal trends in incidence rates were analyzed using joinpoint regression, while an age-period-cohort model evaluated the effects of age, period, and cohort. A Bayesian age-period-cohort model was applied for future projections. From 2006 to 2020, 586,371 brucellosis cases were reported, with an upward trend in age-standardized incidence rates for both males and females, showing average annual percent changes of 3.37 % and 4.61 %, respectively. The age-period-cohort model revealed that age, period, and cohort all influenced incidence, with males facing higher rates. High-risk groups were identified among those aged 50-84, particularly in the 65-69 age range, where incidence was highest and showed the most significant annual increase. Period risk initially rose then declined, while later-born cohorts had higher risks. Projections indicate a continued rise in brucellosis incidence. Targeted prevention and control measures are recommended, especially for older adults and males., Competing Interests: Declaration of competing interest All authors declare that they have no known competing financial interests. The corresponding author of this manuscript serves as the editor-in-chief of this journal. To avoid any potential or actual conflict of interest, the manuscript will be handled and reviewed entirely by other editors or independent external experts. The corresponding author will not be involved in any part of the manuscript's processing, peer review, or decision-making., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Preoperative prediction of the acetabular cup press-fit stability in total hip arthroplasty is necessary for clinical decision-making. This study aims to establish and validate machine learning models to investigate the feasibility of predicting the intraoperative press-fit stability of the acetabular cup in total hip arthroplasty (THA)., Methods: 226 patients who underwent primary THA from 2018 to 2022 in our hospital were retrospectively enrolled. Patients were divided into press-fit stable or unstable groups according to the intraoperative pull-out test of the implanted cup. Then, they were randomly assigned to the training or test cohort in an 8:2 ratio. We used 3Dslicer software to segment the region of interest (ROI) of the patient's bilateral hip X-ray to extract radiomics features. The least absolute shrinkage and selection operator (LASSO) regression was used in our feature selection. Finally, four machine learning models were employed in this study, including support vector machine (SVM), random forest (RF), logistic regression (LR), and XGBoost (XGB). Decision curve analysis (DCA), and receiver operating characteristic (ROC) curves of the models were plotted. The area under the curve (AUC), diagnostic accuracy, sensitivity, and specificity were calculated as well. The AUCs of the four models were compared using the DeLong test., Results: Twenty-seven valuable radiomics features were determined by dimensionality reduction and selection. Regarding to the DeLong test, the AUC of the XGB model was significantly different from those of the other three models. (p < 0.05). Among all models, the XGB model exhibited the best performance with an AUC of 0.823 (95 % CI: 0.711-0.919) in the test cohort and showed optimal clinical efficacy according to the DCA., Conclusion: Machine learning models based on X-ray radiomics can accurately predict the intraoperative press-fit stability of implanted cups preoperatively, providing surgeons with valuable information to lower the complication risk in THA., 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.)

Phytophthora pathogens secrete numerous apoplastic effectors to manipulate host immunity. Herein, we identified a polysaccharide lyase 1 protein, PsPL1, which acts as an essential virulence factor of P. sojae infection in soybean. However, the overexpression of PsPL1 in P. sojae reduced infection and triggered enhanced immune responses in soybean. PsPL1 exhibited pectin lyase activity and degraded plant pectin to generate pectin oligosaccharides (POSs) with a polymerization degree of 3-14, exhibiting different levels of acetylation and methylation modifications. PsPL1 and the degraded pectin products triggered immune responses in soybean and different Solanaceous plants. The PsPL1-triggered immune responses required RSPL1, a membrane-localized leucine-rich repeat receptor-like protein, which is essential for Phytophthora resistance. Conversely, the PsPL1-degraded product-triggered immune responses depended on the membrane-localized lysin motif receptor-like kinase CERK1. This study reveals that the pectin lyase exhibits a dual immunogenic role during P. sojae infection, which activates plant resistance through different immune receptors and provides novel insights into the function of pectin lyase in host-pathogen interactions., Competing Interests: Compliance and ethics. A patent (application number: 202411277480.6) based on this study has been filed by Nanjing Agricultural University with Y.W., G.S., Y.W., Q.Z. and J.C. as inventors. The authors declare that they have no other conflict of interest., (© 2024. Science China Press.)

Background: Massive rotator cuff defects represent an important source of shoulder pain and functional debilitation, substantially diminishing patients' quality of life. The primary treatment of massive rotator cuff defects includes complete or partial repair and patch augmentation. However, because of the tendon's limited regenerative ability, the tendon retear risk after rotator cuff defect repair is still high. Thus, a new therapy is needed to promote tendon regeneration for repair of massive rotator cuff defects., Questions/purposes: Using an in vitro analysis, we first asked: (1) What is the biocompatibility and collagen synthesis ability of fibrin glue, and what is the cell growth of tissue-engineered bicipital tendon patches, which is comprised of fibrin glue and biceps tendon tissue particles? Then, using an in vivo animal model of full-thickness defects in the infraspinatus tendon in New Zealand White rabbits, we asked: (2) What is the potential of the tissue-engineered bicipital autologous tendon patch to promote tendon regeneration?, Methods: In vitro experiments were conducted to assess the survival, proliferation, and collagen synthesis ability of tendon stem/progenitor cells cultured in fibrin glue. This was achieved through an assay of live/dead cell viability, cell counting kit-8 (CCK-8) assay, and Sirius red staining, respectively. The in vivo animal study was conducted using 8- to 12-week-old New Zealand White rabbits. The left shoulder of each animal was operated on, with equal numbers of males and females. There were 12 rabbits in the control group and 15 rabbits each in the gel and patch groups. Six rabbits were allocated to each of the three groups at the 1- and 3-month time points and three rabbits each were in the gel and patch groups at 2-month time point. Through an infraspinatus tendon defect model, the effectiveness of tissue-engineered bicipital autologous tendon patches (patch group) in tendon repair was assessed compared with untreated (control group) and fibrin glue (gel group) treatments in vivo. This assessment included histological evaluation of repaired tissue morphology, transmission electron microscopy (TEM) evaluation of regenerated collagen fibrils, and RNA sequencing to explore the potential mechanisms of tissue-engineered bicipital autologous tendon patches in tendon regeneration., Results: In vitro experiments demonstrated that fibrin glue enhanced the collagen synthesis ability of tendon stem/progenitor cells (0.38 ± 0.02) compared with standard cell culture alone (0.27 ± 0.02, mean difference 0.11 [95% CI 0.07 to 0.14]; p < 0.001). With prolonged cultivation, the cell growth area of tissue-engineered bicipital tendon patches showed a notable increase after culturing for 14 days (78.13% ± 3.68%) compared with 11 days (13.05% ± 8.78%, mean difference -65.08% [95% CI -77.99% to -52.15%]; p󿇀001), 7 days (2.67% ± 2.62%, mean difference -75.46% [95% CI -88.37% to -62.53%]; p󿇀001), and 1 day (0.33% ± 0.30%, mean difference -77.80% [95% CI -90.71% to -64.87%]; p＜0.001). At 3 months after transplantation, in vivo experiments revealed that compared with the control and gel groups, the patch group displayed improved repair outcomes. This was evidenced by better histological scores in the patch group (3.83 ± 2.01) compared with the gel group (10.67 ± 0.58, mean difference 6.84 [95% CI 3.67 to 10.00]; p = 0.001) and control group (10.75 ± 0.66, mean difference 6.92 [95% CI 3.75 to 10.08]; p = 0.001), and by regular alignment and larger diameters of newly formed collagen fibrils in the patch group (77.52 ± 44.41 nm) compared with the control group (53.34 ± 6.64 nm, mean difference 24.18 [95% CI 22.24 to 26.11]; p < 0.001). RNA sequencing analysis revealed that a tissue-engineered bicipital autologous tendon patch facilitated tendon regeneration by modulating the immune response, promoting collagen fibril organization, and alleviating vasoconstriction., Conclusion: This animal study demonstrates that the tissue-engineered bicipital autologous tendon patch effectively modulates an immune response and collagen fibril organization, leading to the promotion of tendon regeneration., Clinical Relevance: The tissue-engineered bicipital autologous tendon patch represents a promising strategy for tendon regeneration, offering potential in the repair of massive rotator cuff defects during clinical rotator cuff surgery. Subsequent research could focus on large animal experiments using a tissue-engineered bicipital autologous tendon patch to explore their feasibility for clinical translation., Competing Interests: Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Association of Bone and Joint Surgeons.)

Walnut (Juglans regia L.) meal, being the primary by-product of walnut oil processing, is rich in high-quality proteins and of significant potential for development and utilization. The study used multi-stage gradient purification, liquid-quantity chromatography, and computerized virtual screening to isolate and characterize antioxidant peptides from walnut meal. Active sites and mechanism actions of antioxidant peptides were examined using oxidative damage model of HepG2 cells. Five novel peptides exhibiting high antioxidant activity were identified, among which YR-10 significantly increased the cell viability of HepG2 oxidatively damaged cells to 20.64 %. Meanwhile, YR-10 significantly reduced the ROS content to 42.54 % and apoptosis level to 11.80 % in HepG2 oxidatively damaged cells. In addition, YR-10 competed with Nrf2 for Keap1 binding site, inhibited Keap1 (13.83 %) expression, and promoted Nrf2 (27.15 %), HO-1 (34.59 %), and SOD1 (42.67 %) expression, which ultimately activated the Keap1/Nrf2/HO-1 pathway and alleviated oxidative damage., Competing Interests: Declaration of competing interest These 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.)

The medicinal fungus Phellinus Igniarius (P. igniarius) has been demonstrated to possess a variety of pharmacological effects, including anti-oxidant, anti-tumor, blood circulation promotion, anti-diarrheal and sedative properties, etc. In order to gain a deeper understanding of the components in P. igniarius extract and its dynamic process in vivo, an ultra-performance liquid chromatography-triple quadrupole mass spectrometry method was developed and validated for the simultaneous determination of 12 major components (nobiletin tangeretin, narirutin, 3,4-dihydroxybenzaldehyde, hesperidin, hispidin, caffeic acid, hispolon, osmundacetone, amygdalin, salvianolic acid B and protocatechuic acid) of P. igniarius extract in rat plasma. The analyses were conducted using an ACQUITY UPLC BEH C18 column with acetonitrile and 0.1 % formic acid (v/v) in aqueous solution as the mobile phases. The intra-day and inter-day precision was less than 12.61 % for all 12 experiments, with a precision range of -11.28-12.25 %. Extraction recovery exhibited a range of 74.03-114.33 %, while the matrix effect demonstrated a range of 83.95-119.28 %. The stability tests demonstrated that the analytes remained stable, with relative standard deviations below 11.65 %. The pharmacokinetic parameters of the 12 compounds in rat plasma after oral administration of P. igniarius extract were successfully determined by the established UPLC-MS/MS method. The findings presented a pivotal foundation for advancing future research on the in vivo processes and mechanisms underlying the effects of P. igniarius extracts., Competing Interests: Declaration of Competing Interest The authors declare that they have no 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.)

High-precision geophones play crucial roles in terrestrial applications such as oil and gas exploration as well as seismic monitoring. The development of optomechanical precision measurements provides a new design method for geophones, offering higher sensitivity and smaller dimensions compared to traditional geophones. In this work, we introduce an optomechanical microelectromechanical system (MEMS) geophone based on a plano-concave Fabry‒Perot (F-P) microcavity, which has a high sensitivity of 146 V/g. The F‒P microcavity consists of a movable mirror on the sensing element and a fixed hemispherical micromirror fabricated from silicon-on-insulator (SOI) and monocrystalline silicon wafers, respectively. The experimental results show that the geophone has a low noise floor of 2.5 ng/Hz 1/2 (with a displacement noise floor of 6.2 fm/Hz 1/2 ) within the frequency range of 100~200 Hz, a broad bandwidth of 500 Hz (-3 dB), and a measurement range of ±4 mg. To mitigate common-mode noise originating from the laser source and environmental factors such as temperature and air fluctuations, a balanced detection method is employed. This method substantially reduces the noise floor, nearly reaching the thermal noise limit (2.5 ng/Hz 1/2 ). Furthermore, a compactly packaged optomechanical MEMS geophone with a diameter of 40 mm is demonstrated. The high performance and robust features hold great potential for applications in oil and gas exploration., Competing Interests: Competing interests: H.L. is an editor for the journal. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Background: A deep learning (DL) model that can automatically detect and classify cervical canal and neural foraminal stenosis using cervical spine magnetic resonance imaging (MRI) can improve diagnostic accuracy and efficiency., Methods: A method comprising region-of-interest (ROI) detection and cascade prediction was formulated for diagnosing cervical spinal stenosis based on a DL model. First, three part-specific convolutional neural networks were employed to detect the ROIs in different parts of the cervical MR images. Cascade prediction of the stenosis categories was subsequently performed to record the stenosis level and position on each patient slice. Finally, the results were combined to obtain a patient-level diagnostic report. Performance was evaluated based on the accuracy (ACC), area under the curve (AUC), sensitivity, specificity, F1 Score, diagnosis time of the DL model, and recall rate for ROI detection localization., Results: The average recall rate of the ROI localization was 89.3% (neural foramen) and 99.7% (central canal) under the five-fold cross-validation of the DL model. In the dichotomous classification (normal or mild vs. moderate or severe), the ACC and AUC of the DL model were comparable to those of the radiologists, and the F1 score (84.8%) of the DL model was slightly higher than that of the radiologists (83.8%) for the central canal. Diagnosing whether the central canal or neural foramen of a slice is narrowed in the cervical MRI scan required an average of 15 and 0.098 s for the radiologists and DL model, respectively., Conclusions: The DL model demonstrated comparable performance with subspecialist radiologists for the detection and classification of central canal and neural foraminal stenosis on cervical spine MRI. Moreover, the DL model demonstrated significant timesaving ability., Competing Interests: Declarations. Ethics approval and consent to participate: The methods were performed in accordance with relevant guidelines and regulations and approved by Peking University Third Hospital Medical Science Research Ethic Committee, which waived the requirement of informed consent due to the retrospective nature of the study. Consent for publication: Not Applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Cells have evolved intricate mechanisms for recognizing and responding to changes in oxygen (O 2 ) concentrations. Here, we have reprogrammed cellular hypoxia (low O 2 ) signaling via gas tunnel engineering of prolyl hydroxylase 2 (PHD2), a non-heme iron dependent O 2 sensor. Using computational modeling and protein engineering techniques, we identify a gas tunnel and critical residues therein that limit the flow of O 2 to PHD2's catalytic core. We show that systematic modification of these residues can open the constriction topology of PHD2's gas tunnel. Using kinetic stopped-flow measurements with NO as a surrogate diatomic gas, we demonstrate up to 3.5-fold enhancement in its association rate to the iron center of tunnel-engineered mutants. Our most effectively designed mutant displays 9-fold enhanced catalytic efficiency (k cat /K M =830±40 M -1  s -1 ) in hydroxylating a peptide mimic of hypoxia inducible transcription factor HIF-1α, as compared to WT PHD2 (k cat /K M =90±9 M -1  s -1 ). Furthermore, transfection of plasmids that express designed PHD2 mutants in HEK-293T mammalian cells reveal significant reduction of HIF-1α and downstream hypoxia response transcripts under hypoxic conditions of 1 % O 2 . Overall, these studies highlight activation of PHD2 as a new pathway to reprogram hypoxia responses and HIF signaling in cells., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Preventing the progression of acute pancreatitis (AP) to severe acute pancreatitis (SAP) is crucial for AP patients. The use of clinical parameters in laboratory facilities for predicting SAP can be rapid, efficient, and cost-effective. This study aimed to investigate the predictive and prognostic value of collected clinical detection parameters, such as serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) levels, and their ratios, such as ALP-to-hemoglobin (Hb) and LDH-to-Hb ratios, for the prediction of SAP occurrence, complications, and mortality. In all, 50 healthy controls (CON), 455 patients with mild acute pancreatitis (MAP), 127 patients with moderately severe acute pancreatitis (MSAP), and 93 patients with SAP were included in the study. Thirty clinical parameters were collected, measured, compared, and analyzed. The ratios of ALP/Hb and LDH/Hb were subsequently calculated and evaluated with respect to gender and age and whether they could predict SAP occurrence, complications, and mortality. The results revealed that 15 parameters were significant for the prediction of AP. Furthermore, the following 6 indicators are associated with the occurrence of SAP: ALP, ALP/Hb, LDH, LDH/Hb, CRP, and blood glucose. Among these parameters, the predictive abilities of ALP/Hb and LDH/Hb for SAP were most effective. However, they fail to differentiate between MAP and MSAP or gender in SAP patients. Positive correlations were only observed between the levels of these indicators and age at onset of SAP. In addition, receiver operating characteristic (ROC) curves were generated to predict SAP incidence rates, complications, and mortality. The area under the curve (AUC) values for the ALP/Hb ratio ranged from 0.7097 to 0.7837, whereas those for the LDH/Hb ratio ranged from 0.5043 to 0.7778. These findings suggest that ALP and LDH alone or in combination with Hb possess unique predictive characteristics that may serve as independent factors for predicting SAP occurrence, complications, and mortality; of these, the ALP/Hb ratio is especially predictive of SAP mortality., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Chondroblastoma (CBL) of the femoral head is a rare disease, typically encountered in the epiphysis of long bones, with its occurrence in the femoral head being particularly uncommon. The unique location and aggressive nature of this tumor pose substantial challenges in its treatment, leading to ongoing controversies regarding the therapeutic approaches. In this study, we introduce a technique of curettage without surgical dislocation as a treatment option for CBL in this challenging location., Methods: A total of 6 children diagnosed with chondroblastoma of the femoral head underwent a surgical procedure consisting of curettage, the application of anhydrous alcohol as an adjuvant therapy, followed by bone grafting. The epiphyseal plate status of the femoral head was classified as open, closing, or closed. To evaluate the children's postoperative functional outcome, the Musculoskeletal Tumour Society (MSTS) scoring system was utilized. Additionally, the Lodwick classification was employed to assess the extent of bone destruction. Furthermore, the kappa coefficient was calculated to quantify the level of inter-observers agreement in assessing the status of the epiphyseal plate., Results: The epiphyseal plate status was closing in two patients and closed in four patients. According to the Lodwick classification, one patient was classified as IA, one as IB, and four as IC. The mean MSTS score was 28. Notably, one patient developed a femoral neck fracture three months post-curettage., Conclusions: Curettage without surgical dislocation, combined with the use of anhydrous alcohol as an adjuvant therapy, followed by bone grafting, constitutes an effective treatment technique for femoral head chondroblastoma., Competing Interests: Declarations Ethics approval and consent to participate The research had been approved by the Ethics Committee of Children's Hospital affiliated to Chongqing Medical University. Informed consent was obtained from all of their legal guardians. Consent for publication Written informed consent for publishing identification images or other personal or clinical details was obtained from the legal guardians of all participants. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Cnidii Fructus (CF) is a herbal medicine with pharmacological activities such as antitumor, antiviral, antiallergic, antipruritic effects, and so on., Objective: In this study, an ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC- MS/MS) method was prepared and verified to measure the concentrations of seven analytes (bergapten, xanthotoxol, xanthotoxin, imperatorin, osthole, isopimpinellin, isoimperatorin) in HepG2 cells., Methods: The separation of seven analytes was performed on an ACQUITY UPLC® BEH C18 column (2.1×100 mm, 1.7 μm) with a gradient mobile phase system of 0.1% formic acid/water and acetonitrile., Results: The CV of analytes was within 7.77%, and the bias was in the range of -5.43%-3.84%. The matrix effects of analytes ranged from 92.95% to 104.58%, and the extraction recoveries ranged from 76.45% to 104.69%. The relative standard deviation of stability results was less than 8.21%, indicating that seven analytes were stable., Conclusion: The method was successfully applied to the determination of the content of seven analytes of CF extracts by UPLC-MS/MS, and the results will provide a reference for the cellular pharmacokinetics of CF., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Chemical-intensive agriculture challenges environmental sustainability and biodiversity and must be changed. Minimizing the use of agrochemicals based on renewable resources can reduce or eliminate ecosystems and biodiversity threats. Nanochitosan as a sustainable alternative offers promising solutions for sustainable agricultural practices that work at multiple spatial and temporal scales throughout the plant growth cycle. This review focuses on the potential of nanochitosan in sustainable agricultural production and provides insights into the mechanisms of action and application options of nanochitosan throughout the plant growth cycle. We emphasize the role of nanochitosan in increasing crop yields, mitigating plant diseases, and reducing agrochemical accumulation. The paper discusses the sources of nanochitosan and its plant growth promotion, antimicrobial properties, and delivery capacity. Furthermore, we outline the challenges and prospects of research trends of nanochitosan in sustainable agricultural production practices and highlight the potential of nanochitosan as a sustainable alternative to traditional agrochemicals.

As a prominent complication of diabetes mellitus (DM) affecting microvasculature, diabetic retinopathy (DR) originates from blood-retinal barrier (BRB) damage. Natural polyphenolic compound chlorogenic acid (CGA) has already been reported to alleviate DR. This study delves into the concrete mechanism of the CGA-supplied protection against DR and elucidates its key target in retinal endothelial cells. DM in mice was induced using streptozotocin (STZ). CGA mitigated BRB dysfunction, leukocytes adhesion and the formation of acellular vessels in vivo. CGA suppressed retinal inflammation and the release of tumor necrosis factor-α (TNFα) by inhibiting nuclear factor kappa-B (NFκB). Furthermore, CGA reduced the TNFα-initiated adhesion of peripheral blood mononuclear cell (PBMC) to human retinal endothelial cell (HREC). CGA obviously decreased the TNFα-upregulated expression of vascular cell adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1), and abrogated the TNFα-induced NFκB activation in HRECs. All these phenomena were reversed by overexpressing type 1 TNF receptor (TNFR1) in HRECs. The CGA-provided improvement on leukocytes adhesion and retinal inflammation was disappeared in mice injected with an endothelial-specific TNFR1 overexpression adeno-associated virus (AAV). CGA reduced the interaction between TNFα and TNFR1 through binding to TNFR1 in retinal endothelial cells. In summary, excepting reducing TNFα expression via inhibiting retinal inflammation, CGA also reduced the adhesion of leukocytes to retinal vessels through decreasing VCAM1 and ICAM1 expression via blocking the TNFα-initiated NFκB activation by targeting TNFR1 in retinal endothelial cells. All of those mitigated retinal inflammation, ultimately alleviating BRB breakdown in DR., 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.)

Triboelectric nanogenerators (TENGs) are highly promising as implantable, degradable energy sources and self-powered sensors. However, the degradable triboelectric materials are often limited in terms of contact electrification and mechanical properties. Here, a bio-macromolecule-assisted toughening strategy for PVA aerogel-based triboelectric materials is proposed. By introducing β-lactoglobulin fibrils (BF) into the PVA aerogel network, the material's mechanical properties while preserving its swelling resistance is significantly enhanced. Compared to pure PVA porous film, the BF-PVA porous film exhibits an eightfold increase in fracture strength (from 1.92 to 15.48 J) and a fourfold increase in flexibility (from 10.956 to 39.36 MPa). Additionally, the electrical output of BF-PVA in triboelectric performance tests increased nearly fivefold (from 45 to 203 V). Leveraging these enhanced properties, a biodegradable TENG (bi-TENG) for implantable muscle activity sensing is developed, achieving real-time monitoring of neuromuscular processes. This innovation holds significant potential for advancing implantable medical devices and promoting new applications in bio-integrated electronics., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The effectiveness of imagery rescripting (IR) in reducing psychological symptoms associated with aversive memories has been confirmed across various disorders. To better understand the neural mechanisms underlying IR, we assessed the immediate and lasting effects and their associations with imagery tendency by using unpleasant pictures depicting child maltreatment within a population with childhood maltreatment (CM) history. Participants (n = 68) were instructed to engage in two experimental phases while electroencephalogram was recorded. In the rescripting phase, participants viewed neutral or unpleasant pictures and then either imagined the same pictures or rescripted unpleasant ones to assess immediate effect. In the re-exposure phase, participants passively viewed all pictures without instruction to assess lasting effect. Participants rated their subjective valence and imagery vividness in the rescripting phase or intensity of negative feelings in the re-exposure phase. IR led to an attenuation of the late positive potential (LPP) amplitude in the late time window (2000-6000 ms at parietal-occipital electrodes) and a decrease in self-reported unpleasantness during the rescripting phase. After 5-min interval, unpleasant pictures with rescripted history elicited smaller LPP (400-1500 ms at centro-parietal electrodes) and negative feelings than those with imagery history in the re-exposure phase. The higher habitual use of imagery was associated with a greater reduction in late LPP during the rescripting phase and full-time range LPP during the re-exposure phase. The current findings suggest that IR has an immediate effect and a lasting effect on subjective and neural response in the CM population. Individuals with higher imagery tendency are likely to profit more from IR., (© 2024 Society for Psychophysiological Research.)

Rotator cuff tendinopathy is the most common tendinopathy type with the worst prognosis. Conventional treatments often elicit heterogeneous drug responses due to the diversity of tendinopathy. Hence, this study attempted a classification of 126 diseased tendons into three distinct subtypes with opposite pathogenic mechanisms based on transcriptomic and clinical features. The hypoxic atrophic subtype with white appearance (Hw) exhibits downregulated neovascularization pathways. The inflammatory proliferative subtype with white appearance (Iw) shows a moderate upregulation of inflammatory characteristics. The inflammatory proliferative subtype with red appearance (Ir) exhibits the highest levels of upregulated neovascularization and inflammatory pathways, along with severe joint dysfunction. We then established research models, including subtype-specific simulations in animal models and clinical data analysis. These revealed that glucocorticoid, a controversial commonly used drug, was only effective in treating the Ir subtype. Hence, the tendinopathy subtypes elucidated in this study have significant implications for developing precision treatment of tendinopathy., (© 2024. The Author(s).)

The structure and in vitro hypolipidemic activity of Bangia fusco-purpurea polysaccharide (BFP) assisted extracted with ultra-high pressure (UHP) at 100-600 MPa were studied. Compared to native BFP, UHP assisted extracted BFP had a more loose network structure with higher total sugar and uronic acid contents while less molecular weight (p < 0.05). Moreover, UHP assisted extraction significantly improved the in vitro hypolipidemic and antioxidant activity of BFP. Especially at 400 MPa UHP, the cholesterol adsorption and antioxidant capacities of BFP were increased by approximately 38.02 % and 11.69 %-32.29 %, respectively. BFP with UHP assisted extraction could alleviate oleic acid-induced lipid accumulation and lipid oxidation in HepG2 cells more effectively by activating the AMPK signaling pathway as well as inhibiting PPARγ expression, which was much related with its reduced molecular weight and loose network structure. The findings indicated that UHP assisted extracted BFP has better potential to develop natural hypolipidemic agent., 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.)

Background and Objective: The triglyceride-glucose (TyG) index, a surrogate marker for insulin resistance, has been proposed as a predictor of cardiovascular events. However, the combined impact of the TyG index and obesity indicators, such as body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR), on stroke risk was not fully understood. This study aimed to investigate the association between the TyG index combined with these obesity indicators and stroke risk in the Chinese population., Materials and Methods: Data on 17,708 participants aged 45 years or older for this study were collected from the China Health and Retirement Longitudinal Study (CHARLS) from baseline (2011) to the Wave 5 follow-up (2020). Cox proportional hazards model, restricted cubic spline (RCS) and receiver operating characteristic (ROC) analysis were employed to examine the association between the TyG index and its combined obesity-related indicators with stroke. Mediation analysis was conducted to explore the mutual potential mediating role of TyG and obesity indicators in the above relationships., Results: A total of 8,207 participants with an average age of 58.2 years were investigated, of which 11.0% were stroke individuals, 44.80% were men and 84.6% were from rural areas. TyG, TyG-BMI, TyG-WHtR, TyG-WC were significantly higher in stroke subjects than in the non-stroke subjects (P < 0.001), and were significantly and positively associated with stroke in all 3 models (P < 0.05). Restricted cubic spline models revealed nonlinear associations between TyG and TyG-BMI with stroke (P-overall < 0.001, P-nonlinear = 0.003 for TyG, and P-overall < 0.001, P-nonlinear = 0.028 for TyG-BMI), while TyG-WC and TyG-WHtR (P-overall < 0.001 and P-nonlinear > 0.05) demonstrated linear associations with stroke after adjusting for covariates. TyG-WHtR, TyG-BMI and TyG-WC had more robust predictive power than TyG for risk of stroke. TyG-WHtR or TyG-WC had the highest predictive power for stroke (AUC:0.696, 95% CI 0.677-0.715), slightly higher than the other indicators. Associations between TyG, TyG-WC, TyG-WHtR, and TyG-BMI with stroke were found to be stronger among individuals who were ≥ 55 years of age, male. The relationship between TyG and stroke was significantly mediated by BMI, WHtR and WC (15.79%, 21.72%, and 24.06% respectively), while the relationship between these obesity measures and stroke was significantly mediated by TyG (18.48%, 14.45%, and 14.70% respectively)., Conclusion: The combination of TyG and obesity-related indicators was significantly associated with stroke risk, and could improve predictive power for stroke compared to the single TyG. Obesity indicators and TyG mediated each other in their respective associations with stroke risk., (© 2024. The Author(s).)

Metabolic-associated steatotic liver disease (MASLD), known as non-alcoholic fatty liver disease (NAFLD) in the past, encompasses a range of liver pathological conditions marked by the excessive lipid accumulation. Consumption of coffee is closely associated with the reduced risk of MASLD. Caffeic acid (CA), a key active ingredient in coffee, exhibits notable hepatoprotective properties. This study aims to investigate the improvement of CA on MASLD and the engaged mechanism. Mice underwent a 12-week high-fat diet (HFD) regimen to induce MASLD, and liver pathology was assessed using hematoxylin-eosin (H&E) and oil red O (ORO) staining. Hepatic inflammation was evaluated by F4/80 and Ly6G immunohistochemistry (IHC) and myeloperoxidase (MPO) measurement. Pathways and transcription factors relevant to MASLD were analyzed by using microarray data from patients' livers. Oxidative damage was evaluated by detecting reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD). Co-immunoprecipitation (CoIP), cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) were used to validate the binding between CA and its target protein. CA significantly alleviated liver damage, steatosis and inflammatory injury, and reduced the elevated NAFLD activity score (NAS) in HFD-fed mice. Clinical data indicate that fatty acid metabolism and ROS generation are pivotal in MASLD progression. CA increased the expression of fibroblast growth factor 21 (FGF21), FGF receptor 1 (FGFR1) and β-Klotho (KLB), and promoted fatty acid consumption. Additionally, CA mitigated oxidative stress injury and activated nuclear factor erythroid 2-related factor-2 (Nrf2). In primary hepatocytes isolated from Nrf2 knockout mice, CA's promotion on FGF21 release and inhibition on oxidative stress and lipotoxicity was disappeared. CA could directly bind to kelch-like ECH-associated protein 1 (Keap1) that is an Nrf2 inhibitor protein. This study suggests that CA alleviates MASLD by reducing hepatic lipid accumulation, lipotoxicity and oxidative damage through activating Nrf2 via binding to Keap1., 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.)

Hepatocellular injury, a pivotal contributor to liver diseases, particularly hepatitis, lacks effective pharmacological treatments. Interleukin-22 (IL-22), crucial for liver cell survival, shows potential in treating liver diseases by regulating repair and regeneration through signal transducer and activator of transcription 3 (STAT3) activation. However, the short half-life and off-target effects limit its clinical applications. To address these issues, lipid nanoparticles are employed to deliver synthetic IL-22 mRNA (IL-22/NP) for in situ IL-22 expression in hepatocytes. The study reveals that IL-22/NP exhibits liver-targeted IL-22 expression, with increased IL-22 levels detected in the liver as early as 3 h postintravenous injection, lasting up to 96 h. Furthermore, IL-22/NP activates STAT3 signaling in an autocrine or paracrine manner to upregulate downstream factors Bcl-xL and CyclinD1, inhibiting hepatocyte apoptosis and promoting cell proliferation. The therapeutic efficacy of IL-22/NP is demonstrated in both chronic and acute liver injury models, suggesting IL-22 mRNA delivery as a promising treatment strategy for hepatitis and liver diseases involving hepatocellular injury., (© 2024 Wiley‐VCH GmbH.)

Soybean rust (SBR), caused by an obligate biotrophic pathogen Phakopsora pachyrhizi, is a devastating disease of soybean worldwide. However, the mechanisms underlying plant invasion by P. pachyrhizi are poorly understood, which hinders the development of effective control strategies for SBR. Here we performed detailed histological characterization on the infection cycle of P. pachyrhizi in soybean and conducted a high-resolution transcriptional dissection of P. pachyrhizi during infection. This revealed P. pachyrhizi infection leads to significant changes in gene expression with 10 co-expressed gene modules, representing dramatic transcriptional shifts in metabolism and signal transduction during different stages throughout the infection cycle. Numerous genes encoding secreted protein are biphasic expressed, and are capable of inhibiting programmed cell death triggered by microbial effectors. Notably, three co-expressed P. pachyrhizi apoplastic effectors (PpAE1, PpAE2, and PpAE3) were found to suppress plant immune responses and were essential for P. pachyrhizi infection. Double-stranded RNA coupled with nanomaterials significantly inhibited SBR infection by targeting PpAE1, PpAE2, and PpAE3, and provided long-lasting protection to soybean against P. pachyrhizi. Together, this study revealed prominent changes in gene expression associated with SBR and identified P. pachyrhizi virulence effectors as promising targets of RNA interference-based soybean protection strategy against SBR., (© 2024 Institute of Botany, Chinese Academy of Sciences.)

The anterior cruciate ligament is anchored to the femur and tibia via specialized interfaces known as entheses. These play a critical role in ligament homeostasis and joint stability by transferring forces, varying in magnitude and direction between structurally and functionally dissimilar tissues. However, the precise structural and mechanical characteristics underlying the femoral and tibial entheses and their intricate interplay remain elusive. In this study, two thin-graduated mineralization regions in the femoral enthesis (~21 μm) and tibial enthesis (~14 μm) are identified, both exhibiting distinct biomolecular compositions and mineral assembly patterns. Notably, the femoral enthesis interface exhibits progressively maturing hydroxyapatites, whereas the mineral at the tibial enthesis interface region transitions from amorphous calcium phosphate to hydroxyapatites with increasing crystallinity. Proteomics results reveal that Matrix Gla protein uniquely enriched at the tibial enthesis interface, may stabilize amorphous calcium phosphate, while C-type lectin domain containing 11 A, enriched at the femoral enthesis interface, could facilitate the interface mineralization. Moreover, the finite element analysis indicates that the femoral enthesis model exhibited higher resistance to shearing, whereas the tibial enthesis model contributes to tensile resistance, suggesting that the discrepancy in biomolecular expression and the corresponding mineral assembly heterogeneities collectively contribute to the superior mechanical properties of both the femoral enthesis and tibial enthesis models. These findings provide novel perspectives on the structure-function relationships of anterior cruciate ligament entheses, paving the way for improved management of anterior cruciate ligament injury and regeneration., (© 2024. The Author(s).)

Background/Objectives: Homeodomain-interacting protein kinase 2 (HIPK2) is critically involved in the progression of renal fibrosis. This study aims to identify and characterize a novel HIPK2 inhibitor, CHR-6494, and investigate its therapeutic potential. Methods: Using structure-based virtual screening and molecular dynamics simulations, we identified CHR-6494 as a potent HIPK2 inhibitor with an IC 50 of 0.97 μM. The effects of CHR-6494 on the phosphorylation of p53 in Normal Rattus norvegicus kidney cells (NRK-49F) induced by transforming growth factor-β (TGF-β) were assessed, along with its impact on TGF-β signaling and downstream profibrotic markers. Results: CHR-6494 significantly reduces p53 phosphorylation induced by TGF-β and enhances the interaction between HIPK2 and seven in absentia 2 (SIAH2), facilitating HIPK2 degradation via proteasomal pathways. Both CHR-6494 and Abemaciclib inhibit NRK-49F cell proliferation and migration induced by TGF-β, suppressing TGF-β/Smad3 signaling and decreasing profibrotic markers such as Fibronectin I (FN-I) Collagen I and α-smooth muscle actin (α-SMA). Additionally, these compounds inhibit nuclear factor kappa-B (NF-κB) signaling and reduce inflammatory cytokine expression. Conclusions: The study highlights the dual functionality of HIPK2 kinase inhibitors like CHR-6494 and Abemaciclib as promising therapeutic candidates for renal fibrosis and inflammation. The findings provide new insights into HIPK2 inhibition mechanisms and suggest pathways for the design of novel HIPK2 inhibitors in the future.

Background: Asthma is an inflammatory disease where the balance between Th1/Th2 and Th17/Treg plays a crucial role in its pathogenesis. Shikonin is used to treat a variety of autoimmune diseases due to its good anti-inflammatory activity. However, the effect and mechanism of shikonin on asthma remain unknown., Method: Mice were sensitized with ovalbumin (OVA)/house dust mite (HDM) and treated with shikonin. Lung inflammation was assessed histologically and via flow cytometry. Bronchoalveolar lavage fluid (BALF) was analyzed for cell counts and cytokines. Shikonin's impact on p-STAT3 was studied in vivo and in vitro., Results: Shikonin inhibited OVA or HDM-induced inflammation and airway hyperresponsiveness. Upon treatment, a restoration of the Th1/Th2 and Th17/Treg balance was observed, evidenced by a reduction in IL-4 and IL-17A levels in BALF, alongside an elevation in interferon-gamma and IL-10. Furthermore, shikonin impeded the infiltration of eosinophils, neutrophils, macrophages, and lymphocytes into lung tissue. The observed decrease in STAT3 phosphorylation and diminished nuclear translocation of p-STAT3 confirmed that shikonin promotes the balance of Th1/Th2 and Th17/Treg by regulating airway epithelial STAT3., Conclusion: Shikonin mitigates asthma symptoms through a STAT3-dependent mechanism, indicating its potential as an anti-asthmatic therapeutic agent., Competing Interests: Conflict of interest: No conflicts of interest are to be declared for all authors., (© 2024 the author(s), published by De Gruyter.)

With vigorous developments in nanotechnology, the elaborate regulation of microstructure shows attractive potential in the design of electromagnetic wave absorbers. Herein, a hierarchical porous structure and composite heterogeneous interface are constructed successfully to optimize the electromagnetic loss capacity. The macro-micro-synergistic graphene aerogel formed by the ice template‑assisted 3D printing strategy is cut by silicon carbide nanowires (SiC nws ) grown in situ, while boron nitride (BN) interfacial structure is introduced on graphene nanoplates. The unique composite structure forces multiple scattering of incident EMWs, ensuring the combined effects of interfacial polarization, conduction networks, and magnetic-dielectric synergy. Therefore, the as-prepared composites present a minimum reflection loss value of - 37.8 dB and a wide effective absorption bandwidth (EAB) of 9.2 GHz (from 8.8 to 18.0 GHz) at 2.5 mm. Besides, relying on the intrinsic high-temperature resistance of SiC nws and BN, the EAB also remains above 5.0 GHz after annealing in air environment at 600 °C for 10 h., (© 2024. The Author(s).)

The study investigated the lipid oxidation of pumpkin seed kernels (PSK) under different storage conditions (room temperature, vacuum-room temperature, refrigeration, and vacuum-refrigeration) using HPLC-MS and GC-MS. Experimental results found the vacuum-refrigeration group showed the lowest PV (0.24 g/100 g), diene (8.68), hexanal (356.64 ± 16.06 ng/g), and nonanal (132.05 ± 8.38 ng/g) after a 9-month storage. A total of 586 lipids, including 6 classes and 27 subclasses, were detected, 46 of which showed significant differences. Refrigeration samples had the highest diacylglycerol content, while room temperature samples demonstrated the highest triacylglycerol and phosphatidylcholine content. Differential lipid metabolite analyses indicated that storage conditions mainly affected glycerolipid metabolism, glycerophospholipid metabolism, and sphingolipid metabolism pathways in PSK, while glycerolipid and glycerophospholipid metabolism were still dominant. It revealed that refrigeration was more effective than vacuum in inhibiting the oxidation of PSK. These findings could offer valuable references for the storage, transportation, preservation, and the development and utilization of PSK., Competing Interests: Declaration of competing interest These 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 © 2023. Published by Elsevier Ltd.)

Objective: To summarize application effect and clinical experience of multimodal intraoperative neurophysiological monitoring (IONM) technology in the surgery of neurofibromatosis type 1 (NF1) related peripheral nerve tumors., Methods: A retrospective study was conducted on NF1 patients, who admitted between January 2019 and December 2023 and treated with peripheral nerve tumor resection surgery assisted by multimodal IONM technology. There were 49 males and 45 females. The age ranged from 5 to 78 years, with an average of 33.7 years. Tumor morphological classification included 71 cases of nodular type, 13 cases of diffuse type, and 10 cases of mixed type. Target tumors were distributed in craniofacial region (47 cases), neck (11 cases), trunk (12 cases), and limbs (24 cases). Preoperatively, 44 cases had no obvious neurological symptoms, while the remaining patients had neurological symptoms, including 15 cases of visual impairment, 5 cases of hearing impairment, 16 cases of somatic movement disorders, and 31 cases of somatic sensory disorders, of which 7 cases had more than one symptom. IONM plans were selected based on the relevant nerves and adjacent important structures of the target tumor, including visual evoked potential (17 cases), somatosensory evoked potential (44 cases), motor evoked potential (88 cases), and electromyogram (94 cases)., Results: All surgeries were successfully completed. Ninety-three patients underwent total/near total resection and 1 patient underwent palliative resection. Pathological examination showed 80 cases of neurofibroma and 14 cases of malignant peripheral nerve sheath tumors. Complications included 2 cases of hematoma and 3 cases of incision infection. All patients were followed up 3-61 months (median, 15 months). During follow-up, no significant changes in neurological symptoms or tumor recurrence were found. Among the patients with preoperative visual impairment, there were 14 cases with no improvement in symptoms and 1 with improvement after surgery. Among the patients with somatic movement disorders, there were 11 cases with no improvement in symptoms, 3 cases with improvement, 2 cases with aggravation, 4 newly onset cases, and 1 case with significant impact on daily life after surgery. Among the patients with somatic sensory disorders, there were 17 cases with no improvement in symptoms, 14 cases with improvement, and 13 newly onset cases. The patients with hearing impairment showed improvement after surgery., Conclusion: The clinical manifestations of NF1 related peripheral nerve tumors are complex. Multimodal IONM technology can provide real-time detection of nerve provocation and damage. Surgical treatment with multimodal IONM technology is safe and can reduce complications.

OPN5 is one of the main deep brain photoreceptors (DBPs), converting photoperiodic information into neuroendocrine signals to regulate reproduction in birds. This study investigated the mechanism of OPN5-mediated photoperiodic regulation of reproduction by active immunization against OPN5. 96 female quail were divided into OPN5-immunized and control group under the same photoperiod: 16 L:8 D (d 1 to d 35), 8 L:16 D (d 36 to d 70) and 12 L:12 D (d 71 to d 126). OPN5-immunized group was conducted with OPN5 protein vaccination and control group was given a blank vaccine. Samples were collected on d 1, d 30, d 60, and d 126. Results showed switching photoperiod to 8 L:16 D decreased the laying rate, GSI%, numbers of YFs and WFs, serum levels of PRL, P4 and E2, and pituitary PRL and TSHβ protein expressions in both groups (P < 0.05). Whereas the OPN5-immunized group exhibited higher laying rates than the control group (P < 0.05). The control group showed reduced GnRHR and TSHβ gene expressions in the pituitary and increased GnIH and DIO3 transcript and/or protein abundance in the hypothalamus. (P < 0.05). The OPN5-immunized group had lower DIO3 expression at both mRNA and protein levels. (P < 0.05). Switching photoperiod from 8 L:16 D to 12 L:12 D increased the laying rates, GSI%, numbers of YFs and WFs, serum levels of PRL, and PRL protein expression in both groups (P < 0.05), and the responses were more pronounced in OPN5-immunized group (P < 0.05). In contrast to the control group, quail with OPN5-immunization had higher OPN5 and DIO2 transcript and/or protein levels but lower DIO3 expressions in the hypothalamus along the transition photoperiods (P < 0.05). The results revealed that OPN5 responds to photoperiod transition, and its activation mediates related signaling to up-regulate TSH-DIO2/DIO3 pathway and VIP-PRL secretion to prime quail reproductive functions., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Costly third-party punishment (TPP) is an effective way to enforce fairness norms and promote cooperation. Recent studies have shown that the third party considers not only the proposer's suggested allocation but also the receiver's response to the allocation, which was typically ignored in traditional TPP studies when making punishment decisions. However, it remains unclear whether and how the varying unfair allocations and receivers' responses are integrated into third-party punishment. The current study addressed these issues at behavioral and electrophysiological levels by employing a modified third-party punishment task involving proposers' highly or moderately unfair allocations and the receivers' acceptance or rejection responses. At the behavioral level, participants punished proposers more often when receivers rejected relative to accepted unfair allocations. This effect was further modulated by the unfairness degree of allocations, indicated by a more pronounced rejection-sensitive effect when participants observed the moderately unfair offers. Electrophysiologically, when the receiver rejected the moderately unfair allocations, a stronger late-stage component P300/LPP, which was considered to be involved in allocations of attention resources, was found. Meanwhile, separated from the P300/LPP, the P200 associated with early attention capture demonstrated a rejection-sensitive effect. Together, in the costly TPP studies, the receiver is typically designated as passive and silent, and her/his responses to unfairness are conventionally ignored. However, our results indicate that except for the proposer's distribution behavior, the receiver's response does have an impact on third-party punishment in a way that interacts with the unfairness of allocations., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cytidine base editors (CBEs) hold significant potential in genetic disease treatment and in breeding superior traits into animals. However, their large protein sizes limit their delivery by adeno-associated virus (AAV), given its packing capacity of <4.7 kb. To overcome this, we employed a web-based fast generic discovery (WFG) strategy, identifying several small ssDNA deaminases (Sdds) and constructing multiple Sdd-CBE 1.0 versions. SflSdd-CBE 1.0 demonstrated high C-to-T editing efficiency, comparable to AncBE4max, while SviSdd-CBE 1.0 exhibited moderate C-to-T editing efficiency with a narrow editing window (C3 to C5). Utilizing AlphaFold2, we devised a one-step miniaturization strategy, reducing the size of Sdds while preserving their efficiency. Notably, we administered AAV8 expressing PCSK9 targeted sgRNA and SflSdd-CBEs (nSaCas9) 2.0 into mice, leading to gene-editing events (with editing efficiency up to 15%) and reduced serum cholesterol levels, underscoring the potential of Sdds in gene therapy. These findings offer new single-stranded editing tools for the treatment of rare genetic diseases., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Introduction: PRV infection in swine can cause devastating disease and pose a potential threat to humans. Advancing the interplay between PRV and host is essential to elucidate the pathogenic mechanism of PRV and identify novel anti-PRV targets., Methods: PARP11-KO PK-15 cells were firstly constructed by CRISPR/Cas9 technology. Next, the effect of PARP11-KO on PRV infection was determined by RT-qPCR, TCID50 assay, RNA-seq, and western blot., Results and Discussion: In this study, we identified PARP11 as a host factor that can significantly affect PRV infection. Inhibition of PARP11 and knockout of PARP11 can significantly promoted PRV infection. Subsequently, we further found that PARP11 knockout upregulated the transcription of NXF1 and CRM1, resulting in enhanced transcription of viral genes. Furthermore, we also found that PARP11 knockout could activate the autophagy pathway and suppress the mTOR pathway during PRV infection. These findings could provide insight into the mechanism in which PARP11 participated during PRV infection and offer a potential target to develop anti-PRV therapies., Competing Interests: Authors HY, DL, HO, DP, ZX were employed by Chongqing Jitang Biotechnology Research Institute Co., Ltd. Author HO was employed by Shenzhen Kingsino Technology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Qi, Zhao, Wang, Hu, Wang, Wu, Li, Zhou, Zhang, Qi, Huo, Tu, Zhong, Yuan, Lv, Yan, Ouyang, Pang and Xie.)

Walnut ( Juglans regia L.) is a widely grown nut plant worldwide, including in Guizhou Province, located in southwest China. The high quality and special taste make Guizhou walnuts, particularly those produced in Hezhang County, a "Chinese National Geographical Indication Product" that substantially contributes to the local economy and grower's income. In July 2022, a serious occurrence of leaf spot disease was observed in a walnut plantation area, Shuitang Town, Hezhang County, Guizhou Province, China (27°07'67″N, 104°64'61″E). The causal agent was identified as Didymella segeticola through morphological characterization and amplification and sequencing of the internal transcribed spacer (ITS) region, beta-tubulin ( TUB ) gene, and glyceraldehyde-3-phosphate dehydrogenase ( G3PD ) gene. Koch's postulates, including re-isolation and identification, were performed to confirm its pathogenicity on healthy leaves. To our knowledge, this is the first report of D. segeticola causing leaf spot on walnuts worldwide. Further, to determine its biological characteristics, which could be utilized for future disease management, the effects of temperature, light, and carbon and nitrogen resources on mycelial growth, conidia production, and conidia germination and the effects of humidity on conidia germination were studied. The optimum temperature for mycelial growth of representative strain D. segeticola C27 was 20°C. Increasing the light period significantly decreased conidia production and conidia germination. Maltose and beef extract were the best carbon and nitrogen sources, respectively, for the pathogen. Conidia germination was enhanced at 90% humidity. In vitro screening of effective fungicides was conducted. Among the 20 screened fungicides, difenoconazole showed the best inhibition rate, with an EC 50 (concentration for 50% of the maximal effect) of 0.0007 μg/mL. Tetramycin also showed sufficient inhibitory effects against D. segeticola , with an EC 50 value of 0.0009 μg/mL. Our study provides new insights into the causal agent of walnut leaf spot in Guizhou, China, as well as the first pathogen characteristics and promising candidate fungicides for its management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ao, Shi, Yang, Ouyang, Fan, Siddiqui, Wu, Lv, Deng and Chen.)

Soybean, a crucial global leguminous crop, confronts persistent threats from diverse pathogens, exerting a profound impact on global yields. While genetic dimensions of soybean-pathogen interactions have garnered attention, the intricate biochemical responses remain poorly elucidated. In this study, we applied targeted and untargeted liquid chromatography coupled to mass spectrometry (LC-MS) metabolite profiling to dissect the complex interplay between soybeans and five distinct pathogens. Our analysis uncovered 627 idMS/MS spectra, leading to the identification of four main modules, encompassing flavonoids, isoflavonoids, triterpenoids, and amino acids and peptides, alongside other compounds such as phenolics. Profound shifts were observed in both primary and secondary metabolism in response to pathogenic infections. Particularly notable were the bidirectional changes in total flavonoids across diverse pathogenic inoculations, while triterpenoids exhibited a general declining trend. Noteworthy among the highly inducible total flavonoids were known representative anti-pathogen compounds (glyceollin I), backbone forms of isoflavonoids (daidzein, genistein, glycitein, formononetin), and newly purified compounds in this study (prunin). Subsequently, we delved into the biological roles of these five compounds, validating their diverse functions against pathogens: prunin significantly inhibited the vegetative growth and virulence of Phytophthora sojae; genistein exhibited a pronounced inhibitory effect on the vegetative growth and virulence of Phomopsis longicolla; daidzein and formononetin displayed significant repressive effects on the virulence of P. longicolla. This study underscores the potent utility of metabolomic tools, providing in-depth insights into plant-pathogen interactions from a biochemical perspective. The findings not only contribute to plant pathology but also offer strategic pathways for bolstering plant resistance against diseases on a broader scale., (© 2024. Science China Press.)

Benthic eukaryotic microalgae were analyzed by metabarcoding the partial 18S rRNA gene in Daya Bay bi-monthly in 2021. Altogether 941 eukaryotic microalgal OTUs were detected, belonging to 27 classes of 8 phyla. Dinophyta and Chlorophyta were the dominant phyla. Microalgal community in the mariculture zone differed significantly from those in non-mariculture zone, reflected by low alpha diversity indexes and increasing abundance and richness of chlorophytes and correspondingly decreasing of dinoflagellates. The abundant occurrences of the pico- and nano-sized taxa such as the chlorophyte Picochlorum in the mariculture zone suggested that nutrient enrichment might result in the miniaturization of the benthic eukaryotic microalgae. The co-occurrence network suggested more negative interactions between taxa in the mariculture zone. A total of 41 algal bloom and/or harmful algal bloom (HAB) species were detected in this study, suggesting a high potential risk of HABs in Daya Bay, especially for the recurrent bloom species Scrippsiella acuminata., 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.)