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Ting Dai, Qian-Biao Gu, Ying-Jie Peng, Chuan-Lin Yu, Peng Liu, Ya-Qiong He Department of Radiology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People’s Hospital), Changsha, Hunan, People’s Republic of ChinaCorrespondence: Ya-Qiong He, Email yaqionghe2021@163.comPurpose: This study aims to explore the value of radiomics combined with clinical parameters in predicting recurrence-free survival (RFS) after the resection of hepatocellular carcinoma (HCC).Patients and Methods: In this retrospective study, a total of 322 patients with HCC who underwent contrast-enhanced computed tomography (CT) and radical surgical resection were enrolled and randomly divided into a training group (n = 223) and a validation group (n = 97). In the training group, Univariate and multivariate Cox regression analyses were employed to obtain clinical variables related to RFS for constructing the clinical model. The least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses were employed to construct the radiomics model, and the clinical-radiomics model was further constructed. Model prediction performance was subsequently assessed by the area under the time-dependent receiver operating characteristic curve (AUC) and calibration curve. Additionally, Kaplan-Meier analysis was used to evaluate the model’s value in predicting RFS. Correlations between radiomics features and pathological parameters were analyzed.Results: The clinical-radiomics model predicted RFS at 1, 2, and 3 years more accurately than the clinical or radiomics model alone (training group, AUC = 0.834, 0.765 and 0.831, respectively; validation group, AUC = 0.715, 0.710 and 0.793, respectively). The predicted high-risk subgroup based on the clinical-radiomics nomogram had shorter RFS than predicted low-risk subgroup in data sets, enabling risk stratification of various clinical subgroups. Correlation analysis revealed that the rad-score was positively related to microvascular invasion (MVI) and Edmondson-Steiner grade.Conclusion: The clinical-radiomics model effectively predicts RFS in HCC patients and identifies high-risk individuals for recurrence.Keywords: Hepatocellular carcinoma, computed tomography, radiomics, recurrence-free survival

Zi-Jie Tang,1,2 Jing-Run Yang,3 Chong-Li Yu,2 Mei-Han Dong,1,2 Rui Wang,2 Cheng-Xin Li1,2 1Graduate School, Medical School of Chinese People’s Liberation Army (PLA), Beijing, 100853, People’s Republic of China; 2Department of Dermatology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China; 3Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, People’s Republic of ChinaCorrespondence: Cheng-Xin Li; Rui Wang, Department of Dermatology, the First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, People’s Republic of China, Tel +86-18501969456, Email chengxinlidr@yeah.net; wr0699@163.comBackground: Psoriasis is a frequent form of chronic inflammation in dermatology that is unmistakably linked to the metabolic syndrome (MetS) and its elements. This study was to explore the current status and new developments in the global research, and the holistic landscape of this field more intuitively through bibliometric analysis of scientific output and activity.Methods: Publications regarding psoriasis and MetS were searched and chosen from the database of the Web of Science Core Collection. Excel 2019, VOSviewer, and CiteSpace software were utilized to conduct bibliometric analysis.Results: There were 1096 publications included. The scientific outputs in this field had increased from 2004 to 2022, and the expansion could continue in the following years. The United States contributed the most publications (241, 21.99%) and had the most citation frequency (13,489 times). The University of California System was the most productive affiliation. Girolomoni G., Armstrong A.W., Gisondi P. and Gelfand J.M. were key and influential researchers. Journal of the European Academy of Dermatology and Venereology published the greatest number of articles (65 articles). By analyzing keyword frequency and clustering, we have identified the following areas of research interest and frontiers: prevalence, risk, association, gene expression, waist circumference, adipose tissue inflammation, vascular inflammation, cardiovascular disease, psoriatic arthritis, and fibrosis.Conclusion: This bibliometric analysis elucidates research domain of psoriasis and MetS, portraying present hotspots and future emerging trends. This field has generated significant interest and displays potential for further growth. The United States has made distinguished contributions, and currently dominates this field.Keywords: psoriasis, metabolic syndrome, gene expression, vascular, inflammation

Chen-Lin Yu,1,2,* Hsiang-Lin Lee,3,4,* Shun-Fa Yang,2,5 Shih-Wei Wang,1,6 Ching-Pin Lin,4,7 Yi-Hsien Hsieh,2,5 Hui-Ling Chiou8,9 1Institute of Biomedical Science, Mackay Medical College, New Taipei City, Taiwan; 2Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 3Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan; 4School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 5Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan; 6Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 7Division of Hepatology and Gastroenterology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan; 8School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan; 9Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan*These authors contributed equally to this workCorrespondence: Yi-Hsien Hsieh; Hui-Ling Chiou, Tel +886-4-2473-0022, Fax +886-4- 2472-3229, Email hyhsien@csmu.edu.tw; hlchiou@csmu.edu.twObjective: Protodioscin (PD), a steroidal saponin, has a diverse pharmacological activity including neuroprotection, male fertility improvement, and cytotoxicity against various cancers cell lines of different origins. However, the effect of PD on hepatocellular carcinoma (HCC) is still unclear.Methods: Cell viability, colony formation and flow cytometry analysis for apoptosis profile, mitochondrial membrane potential endoplasmic reticulum (ER) expansion were employed to determine the effect of PD against HCC cells. Transient transfection of siRNA, immunofluorescent imaging and immunoprecipitation were used to elucidate the anti-cancer mechanism of PD. The in vivo toxicity and efficacy of PD were assessed by a xenograft mouse model.Results: PD induced apoptosis, loss of mitochondrial membrane potential and ER expansion in HCC cells. Either downregulation of Mfn1 or Bak reversed PD-induced apoptosis and loss of mitochondrial membrane potential. Further analysis revealed that Mfn1 and Bak will form a complex with IP3R to facilitate the transfer of Ca2+ from ER to mitochondria and apoptosis. In addition, our tumour xenograft model further verifies the in vivo anti-tumour effect of PD.Conclusion: Our study sheds light on the understanding of the anti-HCC effects of PD and may open new aspects for the development of novel treatment for human hepatocellular carcinoma.Graphical Abstract: Keywords: hepatocellular carcinoma, protodioscin, mitochondrial, apoptosis, endoplasmic reticulum

Song-Chou Hsieh,1 Chang-Youh Tsai,2 Chia-Li Yu3 1Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, 2Section of Allergy, Immunology & Rheumatology, Taipei Veterans General Hospital, 3Department of Internal Medicine, Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan Abstract: Lupus nephritis (LN) is one of the most frequent and serious complications in the patients with systemic lupus erythematosus. Autoimmune-mediated inflammation in both renal glomerular and tubulointerstitial tissues is the major pathological finding of LN. In clinical practice, the elevated anti-dsDNA antibody titer concomitant with reduced complement C3 and C4 levels has become the predictive and disease-activity surrogate biomarkers in LN. However, more and more evidences suggest that autoantibodies other than anti-dsDNA antibodies, such as anti-nucleosome, anti-C1q, anti-C3b, anti-cardiolipin, anti-endothelial cell, anti-ribonuclear proteins, and anti-glomerular matrix (anti-actinin) antibodies, may also involve in LN. Researchers have demonstrated that the circulating preformed and in situ-formed immune complexes as well as the direct cytotoxic effects by those cross-reactive autoantibodies mediated kidney damage. On the other hand, many efforts had been made to find useful urine biomarkers for LN activity via measurement of immune-related mediators, surface-enhanced laser desorption/ionization time-of-flight mass spectrometry proteomic signature, and assessment of mRNA and exosomal-derived microRNA from urine sediment cell. Our group had also devoted to this field with some novel findings. In this review, we briefly discuss the possible mechanisms of LN and try to figure out the potential serum and urine biomarkers in LN. Finally, some of the unsolved problems in this field are discussed. Keywords: anti-dsDNA antibodies, serum biomarkers, urine biomarkers, THP

OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs), which are the most specific autoantibody marker in patients with rheumatoid arthritis (RA), correlate with disease activity; however, the role of ACPAs in RA pathogenesis has not been elucidated. We hypothesized that ACPAs may directly stimulate mononuclear cells to produce inflammatory cytokines. Thus, we identified cognate antigens of ACPAs on monocyte/macrophages and examined their immunopathologic roles in the pathogenesis of RA. METHODS: ACPAs were purified from pooled ACPA-positive RA sera by cyclic citrullinated peptide-conjugated affinity column. After coculture of U937 cells with ACPAs, the tumor necrosis factor alpha (TNFalpha) production and NF-kappaB DNA binding activity of the cells were measured by enzyme-linked immunosorbent assay. The cognate antigens of ACPAs on the U937 cell surface were probed by ACPAs, and the reactive bands were examined via proteomic analysis. RESULTS: ACPAs specifically enhanced TNFalpha production and increased the DNA-binding activity of NF-kappaB in U937 cells. Proteomic analysis revealed that Grp78 protein (72 kd) was one of the cognate antigens of ACPAs. The truncated form of cell surface-expressed Grp78 (55 kd) on U937 cells contained citrulline capable of binding with ACPAs. After citrullination, glutathione S-transferase-tagged recombinant Grp78 (97.52 kd) became a 72-kd fragment and bound with ACPAs. ACPAs also bound to human monocytes and lymphocytes to promote TNFalpha production. CONCLUSION: We clearly demonstrated that ACPAs enhance NF-kappaB activity and TNFalpha production in monocyte/macrophages via binding to surface-expressed citrullinated Grp78. [ABSTRACT FROM AUTHOR]

Objective: This study was to use adenoviral vector-mediated nuclear factor-kappaBp65 (NF-kappaBp65)-specific siRNA (Ad-siRNA(NF-kappaBp65)) to suppress the progression of early osteoarthritis (OA) in rat model, and therefore to explore a new gene therapy for OA.Methods: Reverse transcription polymerase chain reaction was performed to confirm the silencing effect of Ad-siRNA(NF-kappaBp65) in cultured rat chondrocytes. Transection of the medial collateral ligament plus partial medial meniscectomy was operated in the knee of rats to establish OA model. Histological analysis was made to assess the morphological change of cartilage and synovium, and enzyme-linked immunosorbent assay was made to measure the expression of cytokines, such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), in synovial fluid. The silencing effect of Ad-siRNA(NF-kappaBp65) on NF-kappaBp65 in cartilage and synovium of knee was measured with Western blot and the activation of NF-kappaB was measured with electrophoretic mobility shift assays.Results: Ad-siRNA(NF-kappaBp65) can inhibit the activation of NF-kappaB and the expression of NF-kappaBp65 in cartilage and synovium of the knee, restrain the induction of IL-1beta and TNF-alpha in synovial fluid, alleviate the inflammation of synovium and reduce the degradation of cartilage in early phase of experimental OA.Conclusions: Ad-siRNA(NF-kappaBp65) can suppress the progression of the early experimental OA which suggests that Ad-siRNA(NF-kappaBp65) has potential to be a useful preventive and therapeutic agent for OA. [ABSTRACT FROM AUTHOR]

On 8 April 2024, a rare total solar eclipse (TSE) passed over western New York State (NYS), the first since 1925 and the last one until 2079. The NYS Mesonet (NYSM) consisting of 126 weather stations with 55 on the totality path provides unprecedented surface, profile, and flux data and camera images during the TSE. Here we use NYSM observations to characterize the TSE's impacts at the surface, in the planetary boundary layer (PBL), and on surface fluxes and CO 2 concentrations. The TSE-induced peak surface cooling occurs 17 min after the totality and is 2.8°C on average with a maximum of 6.8°C. It results in night-like surface inversion, calm winds, and reduced vertical motion and mixing, leading to the shallowing of the PBL and its moistening. Surface sensible, latent and ground heat fluxes all decrease whereas near-surface CO 2 concentration rises as photosynthesis slows down., Competing Interests: The authors declare no conflicts of interest relevant to this study., (© 2024. The Author(s).)

Background: Differential counting (DC) of different cell types in bone marrow (BM) aspiration smears is crucial for diagnosing hematological diseases. However, a clinically applicable method for automatic DC has yet to be developed., Objective: This study developed and validated an artificial intelligence (AI)-based algorithm for identifying and classifying nucleated cells in BM smears., Methods: In the development phase, a mask region-based convolutional neural network (Mask R-CNN)-based AI model was trained to detect and classify individual BM cells. We used a large data set of expert-annotated images representing a variety of disease categories. The BM slides were stained with Liu's stain or Wright-Giemsa stain. Consensus meetings were held to ensure experts from different institutes applied consistent criteria in classifying cells. Subsequently, the performance of the AI algorithm in identifying cell images and determining cell ratios was evaluated using a multinational clinical dataset., Results: The AI model was trained on 542 slides (85.1 % stained with Liu's stain and 14.9 % with Wright-Giemsa stain) containing 597,222 annotated cells. It achieved an accuracy of 0.94 for the testing dataset containing 26,170 cells. The performance of the AI model was further validated using another multinational real-world dataset (data obtained from three centers in Taiwan and one in the United States) comprising 200,639 cells. The AI model achieved an accuracy of 0.881 in classifying individual cells and demonstrated high precision in classifying blasts (0.927), bands and polymorphonuclear neutrophils (0.955), plasma cells (0.930), and lymphocytes (0.789). When the differential counting percentage of each cell type was assessed, a strong correlation (ρ > 0.8) between the AI and manual methods was observed for most cell categories., Conclusions: In this study, an AI algorithm was developed and clinically validated using large, multinational datasets. Our algorithm can locate and classify BM cells simultaneously and has potential clinical applicability for automating BM differential counting., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: NTUH and aetherAI Co., Ltd. own the intellectual property and possible commercial profit of the AI-based product derived from this study. Authors who are employees of the manufacturer of the AI-based product (aetherAI Co., Ltd.) contributed to study design, data annotation, software development, and website development for annotation, AI model development, clinical research, manuscript writing, manuscript review, and manuscript editing., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Importance: Viloxazine is a novel nonstimulant medication approved for the treatment of attention-deficit/hyperactivity disorder (ADHD)., Objectives: To investigate the whether viloxazine is associated with effective and acceptable outcomes when treating children and adolescents with ADHD and to evaluate these outcomes' associations with viloxazine doses and duration of treatment., Data Sources: The MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, PsycINFO, and ClinicalTrial.gov databases were searched from database inception to June 23, 2024., Study Selection: Two reviewers independently screened for double-blind, fixed-dose randomized clinical trials (RCTs) that compared viloxazine with placebo for pediatric patients with ADHD., Data Extraction and Synthesis: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. Data extraction was completed independently by 2 authors and cross-checked for errors. Random-effects pairwise and dose-response meta-analyses were conducted., Main Outcomes and Measures: The primary outcome was the improvement of ADHD symptoms (measured by ADHD Rating Scale-5), and the secondary outcomes were all-cause discontinuation, dropout due to adverse effects, and serious adverse effects., Results: A total of 5 dose-response RCTs were included, with 1560 participants (1011 [64.8%] male; mean [SD] age, 10.6 [6.7] years). Viloxazine was associated with better outcomes in ADHD treatment compared with placebo (mean difference, 5.47 points; 95% CI, 4.03-6.91 points). The dose-response curve was bell-shaped, suggesting that doses greater than 400 mg or greater than 7 mg/kg might not be associated with more efficacy. The temporal trends analysis showed ascent curves tapering off at approximately weeks 4 to 6. The curve for 100 mg/d declined more rapidly, while the curves for 200 mg/d and 400 mg/d declined more gradually. The overall discontinuation rate due to adverse effects was 4.15% in the viloxazine group (45 of 1084), while viloxazine compared with placebo was associated with 2.48-fold higher risk of discontinuation due to adverse effects (risk ratio, 2.48; 95% CI, 1.26-4.88)., Conclusions and Relevance: In this meta-analysis, viloxazine was associated with better efficacy in treating children and adolescents with ADHD than placebo. A moderate dose (200-400 mg or 6-8 mg/kg) may provide optimal treatment outcomes. Future studies are warranted to assess the long-term effect of viloxazine. Viloxazine was relatively well tolerated for children and adolescents with ADHD.

Background and Purpose: Scientists have been exploring anti-angiogenic strategies to inhibit angiogenesis and prevent tumor growth. Vasculogenic mimicry (VM) in glioblastoma multiforme (GBM) poses a challenge, complicating anti-angiogenesis therapy. A novel drug, GN25 (3-[{1,4-dihydro-5,8-dimethoxy-1,4-dioxo-2-naphthalenyl}thio]-propanoic acid), can inhibit tumor formation. This study aims to investigate the microenvironmental effects and molecular mechanisms of GN25 in anti-angiogenesis and anti-VM., Experimental Approach: MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) assay was used to evaluate the cell viability of different concentrations of GN25 in human umbilical vein endothelial cells (HUVEC) and Uppsala 87 malignant glioma (U87MG) cells. Functional assays were used to investigate the effects of GN25 on angiogenesis-related processes, whereas gelatin zymography, enzyme-linked immunosorbent assays, and Western blotting were utilized to assess the influence on matrix metalloproteinase (MMP)-2 and vascular endothelial growth factor (VEGF) secretion and related signaling pathways., Key Results: GN25 suppressed migration, wound healing, and tube formation in HUVECs and disrupted angiogenesis in a rat aorta ring and zebrafish embryo model. GN25 dose-dependently reduced phosphatidylinositol 3-kinase/AKT and inhibited MMP-2/VEGF secretion in HUVECs. In U87MG cells, GN25 inhibited migration, wound healing, and VM, accompanied by a decrease in MMP-2 and VEGF secretion. The results indicate that GN25 effectively inhibits angiogenesis and VM formation in HUVECs and U87MG cells without affecting preexisting vascular structures., Conclusion and Implications: This study elaborated GN25's potential as an anti-angiogenic agent by elucidating its inhibitory effects on classical angiogenesis. VM provides valuable insights for developing novel therapeutic strategies against tumor progression and angiogenesis-related diseases. These results indicate the potential of GN25 as a promising candidate for angiogenesis-related diseases., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Serine protease 50 (PRSS50/TSP50) is highly expressed in spermatocytes. Our study investigated its role in testicular development and spermatogenesis. Initially, PRSS50 knockdown was observed to impair DNA synthesis in spermatocytes. To further explore this, we generated PRSS50 knockout ( Prss50 -/- ) mice ( Mus musculus ), which exhibited abnormal spermatid nuclear compression and reduced male fertility. Furthermore, dysplastic seminiferous tubules and decreased sex hormones were observed in 4-week-old Prss50 -/- mice, accompanied by meiotic progression defects and increased apoptosis of spermatogenic cells. Mechanistic analysis indicated that PRSS50 deletion resulted in increased phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and elevated levels of MAP kinase phosphatase 3 (MKP3), a specific ERK antagonist, potentially accounting for testicular dysplasia in adolescent Prss50 -/- mice. Taken together, these findings suggest that PRSS50 plays an important role in testicular development and spermatogenesis, with the MKP3/ERK signaling pathway playing a significant role in this process.

The most frequently used sulfonamide is sulfamethazine (SMZ) because it is often found in foods made from livestock, which is hazardous for individuals. Here, we have developed an easy, quick, selective, and sensitive analytical technique to efficiently detect SMZ. Recently, transition metal oxides have attracted many researchers for their excellent performance as a promising sensor for SMZ analysis because of their superior redox activity, electrocatalytic activity, electroactive sites, and electron transfer properties. Further, Cu-based oxides have a resilient electrical conductivity; however, to boost it to an extreme extent, a composite including two-dimensional (2D) graphitic carbon nitride (g-C 3 N 4 ) nanosheets needs to be constructed and ready as a composite (denoted as g-C 3 N 4 /Cu 2 Y 2 O 5 ). Moreover, several techniques, including X-ray diffraction analysis, scanning electron microscopy analysis, energy-dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, and Raman spectroscopy were employed to analyze the composites. The electrochemical measurements have revealed that the constructed g-C 3 N 4 /Cu 2 Y 2 O 5 composites exhibit great electrochemical activity. Nevertheless, the sensor achieved outstanding repeatability and reproducibility alongside a low limit of detection (LOD) of 0.23 µM, a long linear range of 2 to 276 µM, and an electrode sensitivity of 8.86 µA µM -1 cm -2 . Finally, the proposed GCE/g-C 3 N 4 /Cu 2 Y 2 O 5 electrode proved highly effective for detection of SMZ in food samples, with acceptable recoveries. The GCE/g-C 3 N 4 /Cu 2 Y 2 O 5 electrode has been successfully applied to SMZ detection in food and water samples.

Objective: Psilocybin-assisted therapy has shown promising efficacy on clinical depressive symptoms. However, diverse psychological support or psychotherapy was performed with psilocybin treatment. This study aimed to explore the association of psychological protocols with the efficacy of psilocybin-assisted therapy for depressive symptoms., Method: Five major databases were systemic searched for clinical trials addressing psilocybin-assisted therapy for patients with clinical depressive symptoms. A Bayesian random-effects meta-analysis and meta-regression were performed. The effect size was mean difference (with 95% credible interval) measured by 17-Item Hamilton Depression Rating Scale., Results: There were 10 eligible studies including 515 adult patients with clinically diagnosed depression. The psychological protocols could be categorized into four types: (i) manualized directive psychotherapy(k=1); (ii) manualized nondirective psychological support(k=3), (iii) non-manualized nondirective psychological support(k=5); and (iv) non-manualized supportive psychotherapy(k=1). The pooled standard mean difference of psilocybin-assisted therapy was 10.08 (5.03-14.70)., Conclusion: Compared with manualized nondirective psychological support, the other three psychological approaches did not differ significantly. The improvement of depressive symptoms was not associated with the psychological protocols in adult patients receiving psilocybin-assisted therapy., Systemic Review Registration: Open Science Framework: identifier (osf.io/3YUDV)., 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 Chen, Cheng, Kao, Tseng, Hsu, Yu, Yang, Thompson, Hsu and Liang.)

Increased production of advanced glycation end products (AGEs) among reducing sugars (glucose, fructose, galactose, or ribose) and amino acids/proteins via non-enzymatic Maillard reaction can be found in lifestyle-related disease (LSRD), metabolic syndrome (MetS), and obesity and immune-related diseases. Increased serum levels of AGEs may induce aging, diabetic complications, cardiovascular diseases (CVD), neurodegenerative diseases (NDD), cancer, and inflamm-aging (inflammation with immunosenescence). The Maillard reaction can also occur among reducing sugars and lipoproteins or DNAs to alter their structure and induce immunogenicity/genotoxicity for carcinogenesis. AGEs, as danger-associated molecular pattern molecules (DAMPs), operate via binding to receptor for AGE (RAGE) or other scavenger receptors on cell surface to activate PI3K-Akt-, P38-MAPK-, ERK1/2-JNK-, and MyD88-induced NF-κB signaling pathways to mediate various pathological effects. Recently, the concept of "inflamm-aging" became more defined, and we have unveiled some interesting findings in relation to it. The purpose of the present review is to dissect the potential molecular basis of inflamm-aging in patients with diabetes and immune-mediated diseases caused by different AGEs.

Electroencephalographic Neurofeedback Training (EEG NFT) aims to improve sport performance by teaching athletes to control their mental states, leading to better cognitive, emotional, and physical outcomes. The psychomotor efficiency hypothesis suggests that optimizing brain function could enhance athletic ability, indicating the potential of EEG NFT. However, evidence for EEG-NFT's ability to alter critical brain activity patterns, such as sensorimotor rhythm and frontal midline theta-key for concentration and relaxation-is not fully established. Current research lacks standardized methods and comprehensive studies. This shortfall is due to inconsistent EEG target selection and insufficient focus on coherence in training. This review aims to provide empirical support for EEG target selection, conduct detailed control analyses, and examine the specificity of electrodes and frequencies to relation to the psychomotor efficiency hypothesis. Following the PRISMA method, 2,869 empirical studies were identified from PubMed, Science Direct, Web of Science, Embase, CNKI, and PsycINFO. Thirteen studies met the inclusion criteria: (i) proficient skill levels; (ii) use of EEG; (iii) neurofeedback training (NFT); (iv) motor performance metrics (reaction time, precision, dexterity, balance); (v) control group for NFT comparison; (vi) peer-reviewed English-language publication; and (vii) randomized controlled trial (RCT) design. Studies indicate that NFT can enhance sports performance, including improvements in shooting accuracy, golf putting, and overall motor skills, as supported by the psychomotor efficiency hypothesis. EEG NFT demonstrates potential in enhancing sports performance by optimizing performers' mental states and psychomotor efficiency. However, the current body of research is hampered by inconsistent methodologies and a lack of standardized EEG target selection. To strengthen the empirical evidence supporting EEG NFT, future studies need to focus on standardizing target selection, employing rigorous control analyses, and investigating underexplored EEG markers. These steps are vital to bolster the evidence for EEG NFT and enhance its effectiveness in boosting sport performance., 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. The reviewer ES declared a past co-authorship with the authors M-YC to the handling editor., (Copyright © 2024 Cheng, Yu, An, Wang, Tsai, Qi and Wang.)

Objective: Screening and predicting potential targets for gastrodin antioxidant stress based on network pharmacology methods, and exploring the effect of gastrodin on lead acetate induced oxidative stress in PC12 cells through cell experiments., Methods: Through the Pharmaper database Predict the target of action of gastrodin. Through OMIM and GeneCards to collect oxidative stress targets from database, and intersect with drug targets to obtain drug disease intersection targets; Construct a PPI network diagram using the STRING database. Perform GO enrichment analysis and KEGG pathway enrichment analysis on intersection targets through the DAVID platform. Lead acetate (PbAc) exposure was used to establish a lead poisoning cell model, and intracellular ROS levels, ALB, AKT1, and Caspase-3 levels were measured., Results: A total of 288 targets of gastrodin action, 638 targets related to oxidative stress, and 62 drug disease intersection targets were obtained, among which core targets such as ALB, AKT1, CASP3 may be closely related to oxidative stress. KEGG pathway analysis showed that gastrodin antioxidant stress mainly involved in lipid, cancer pathway and other signaling pathways. The results of the cell experiment showed that 50 μM is the optimal effective concentration for PbAc induced ROS production in PC12 cells. Gastrodin significantly increased the ROS content of PC12 cells treated with PbAc, Upregulation of ALB expression and downregulation of AKT1 and CASP3 expression., Conclusions: Gastrodin may alleviate PbAc-induced ROS in PC12 cells, indicating potential protective effects against oxidative stress. Further studies are needed to confirm these findings and explore the underlying mechanisms., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The aim of this study is to investigate the adverse effects of benzophenones (BPs) on the intestinal tract of mice and the potential mechanism. F1-generation ICR mice were exposed to BPs (benzophenone-1, benzophenone-2, and benzophenone-3) by breastfeeding from birth until weaning, and by drinking water after weaning until maturity. The offspring mice were executed on postnatal day 56, then their distal colons were sampled. AB-PAS staining, HE staining, immunofluorescence, Transmission Electron Microscope, immunohistochemistry, Western Blot and RT-qPCR were used to study the effects of BPs exposure on the colonic tissues of offspring mice. The results showed that colonic microvilli appeared significantly deficient in the high-dose group, and the expression of tight junction markers Zo-1 and Occludin was significantly down-regulated and the number of goblet cells and secretions were reduced in all dose groups, and the expression of secretory cell markers MUC2 and KI67 were decreased, as well as the expression of intestinal stem cell markers Lgr5 and Bmi1, suggesting that BPs exposure caused disruption of intestinal barrier and imbalance in the composition of the intestinal stem cell pool. Besides, the expression of cellular inflammatory factors such as macrophage marker F4/80 and tumor necrosis factor TNF-α was elevated in the colonic tissues of all dose groups, and the inflammatory infiltration was observed, which means the exposure of BPs caused inflammatory effects in the intestinal tract of F1-generation mice. In addition, the contents of Notch/Wnt signaling pathway-related genes, such as Dll-4, Notch1, Hes1, Ctnnb1and Sfrp2 were significantly decreased in each high-dose group (P < 0.05), suggesting that BPs may inhibit the regulation of Notch/Wnt signaling pathway. In conclusion, exposure to BPs was able to imbalance colonic homeostasis, disrupt the intestinal barrier, and trigger inflammation in the offspring mice, which might be realized through interfering with the Notch/Wnt signaling pathway., 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.)

Background: Ferroptosis, a unique type of cell death triggered by iron-dependent lipid peroxidation, plays a critical role in the pathogenesis of Alzheimer's disease (AD), a debilitating condition marked by memory loss and cognitive impairment due to the accumulation of beta-amyloid (Aβ) and hyperphosphorylated Tau protein. Increasing evidence suggests that inhibitors of ferroptosis could be groundbreaking in the treatment of AD., Method: In this study, we established in vitro ferroptosis using erastin-, RSL-3-, hemin-, and iFSP1-induced PC-12 cells. Using MTT along with Hoechst/PI staining, we assessed cell viability and death. To determine various aspects of ferroptosis, we employed fluorescence probes, including DCFDA, JC-1, C11 BODIPY, Mito-Tracker, and PGSK, to measure ROS production, mitochondrial membrane potential, lipid peroxidation, mitochondrial morphology, and intracellular iron levels. Additionally, Western blotting, biolayer interferometry technology, and shRNA were utilized to investigate the underlying molecular mechanisms. Furthermore, p-CAX APP Swe/Ind- and pRK5-EGFP-Tau P301L overexpressing PC-12 cells, along with Caenorhabditis elegans (C. elegans) strains CL4176, CL2331, and BR5270, were employed to examine ferroptosis in AD models., Results: Here, we conducted a screening of our natural medicine libraries and identified the ethanol extract of Penthorum chinense Pursh (PEE), particularly its ethyl acetate fraction (PEF), displayed inhibitory effects on ferroptosis in cells. Specifically, PEF inhibited the generation of ROS, lipid peroxidation, and intracellular iron levels. Furthermore, PEF demonstrated protective effects against H 2 O 2 -induced cell death, ROS production, and mitochondrial damage. Mechanistic investigations unveiled PEF's modulation of intracellular iron accumulation, GPX4 expression and activity, and FSP1 expression. In p-CAX APP Swe/Ind and pRK5-EGFP-Tau P301L overexpressing PC-12 cells, PEF significantly reduced cell death, as well as ROS and lipid peroxidase production. Moreover, PEF ameliorated paralysis and slowing rate in Aβ and Tau transgenic C. elegans models, while inhibiting ferroptosis, as evidenced by decreased DHE intensity, lipid peroxidation levels, iron accumulation, and expression of SOD-3 and gst-4., Conclusion: Our findings highlight the suppressive effects of PEF on ferroptosis in AD cellular and C. elegans models. This study helps us better understand how ferroptosis affects AD and emphasizes the potential of PCP as a candidate for AD intervention., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Introduction: Self-efficacy (SE), defined as an individual's belief in their ability to complete a task, is linked to top-down attentional control, influencing motor performance in sports. Although the behavioral effects of SE are well-documented, there is a lack of research on the mechanisms through which SE affects sports performance. Our research aims to elucidate the neurophysiological mechanisms that underlie the impact of self-efficacy on sports performance. Specifically, we intend to explore the effects of low and high SE on frontal midline theta (Fmθ) activity, associated with sustained top-down attention, and on motor performance., Methods: We recruited thirty-four professional golfers to perform 60 putts, during which their electroencephalographic activity was monitored. SE levels were assessed using a visual analog scale from 0 to 10 before each putt, with scores categorized into higher or lower SE based on each golfer's individual average score., Results: Paired t -tests indicated that trials with higher SE scores had a higher putting success rate than those with lower SE scores (53.3% vs. 46.7%). Furthermore, trials associated with higher SE scores exhibited lower Fmθ activity compared to those with lower SE scores (4.49 vs. 5.18)., Discussion: Our results suggest that higher SE is associated with reduced top-down attentional control, leading to improved putting performance. These findings support Bandura's theory of SE, which suggests that the effects of efficacy beliefs are mediated by cognitive, motivational, emotional, and decision-making processes. This study sheds light on the intermediate processes of SE by examining its impact on the anticipation of outcomes, sports performance, and attentional control prior to putting., 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 Yu, Kao, Wu, Hung, Chang, Yang, Wang and Hung.)

Background: Intensive care unit (ICU) mortality prediction helps to guide therapeutic decision making for critically ill patients. Several scoring systems based on statistical techniques have been developed for this purpose. In this study, we developed a machine-learning model to predict patient mortality in the very early stage of ICU admission., Methods: This study was performed with data from all patients admitted to the intensive care units of a tertiary medical center in Taiwan from 2009 to 2018. The patients' comorbidities, co-medications, vital signs, and laboratory data on the day of ICU admission were obtained from electronic medical records. We constructed random forest and extreme gradient boosting (XGBoost) models to predict ICU mortality, and compared their performance with that of traditional scoring systems., Results: Data from 12,377 patients was allocated to training (n = 9901) and testing (n = 2476) datasets. The median patient age was 70.0 years; 9210 (74.41%) patients were under mechanical ventilation in the ICU. The areas under receiver operating characteristic curves for the random forest and XGBoost models (0.876 and 0.880, respectively) were larger than those for the Acute Physiology and Chronic Health Evaluation II score (0.738), Sequential Organ Failure Assessment score (0.747), and Simplified Acute Physiology Score II (0.743). The fraction of inspired oxygen on ICU admission was the most important predictive feature across all models., Conclusion: The XGBoost model most accurately predicted ICU mortality and was superior to traditional scoring systems. Our results highlight the utility of machine learning for ICU mortality prediction in the Asian population., Competing Interests: Conflicts of interest: Dr. Po-Hsun Huang and Dr. Der-Cherng Tarng, editorial board members at Journal of the Chinese Medical Association , have no roles in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Objective: Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Despite extensive research, no definitive cure or effective disease-modifying treatment for PD exists to date. Therefore, the identification of novel therapeutic agents with neuroprotective properties is of utmost importance. Here, we aimed to investigate the potential neuroprotective effects of Carpesii fructus extract (CFE) in both cellular and Caenorhabditis elegans (C. elegans) models of PD., Methods: The neuroprotective effect of CFE in H 2 O 2 - or 6-OHDA-induced PC-12 cells and α-synuclein-overexpressing PC-12 cells were investigated by determining the cell viability, mitochondrial damage, reactive oxygen species (ROS) production, apoptosis, and α-synuclein expression. In NL5901, BZ555, and N2 worms, the expression of α-synuclein, motive ability, the viability of dopaminergic neurons, lifespan, and aging-related phenotypes were investigated. The signaling pathway was detected by Western blotting and validated by employing small inhibitors and RNAi bacteria., Results: In cellular models of PD, CFE significantly attenuated H 2 O 2 - or 6-OHDA-induced toxicity, as evidenced by increased cell viability and reduced apoptosis rate. In addition, CFE treatment suppressed ROS generation and restored mitochondrial membrane potential, highlighting its potential as a mitochondrial protective agent. Furthermore, CFE reduced the expression of α-synuclein in wide type (WT)-, A53T-, A30P-, or E46K-α-synuclein-overexpressing PC-12 cells. Our further findings reveal that CFE administration reduced α-synuclein expression and improved its induced locomotor deficits in NL5901 worms, protected dopaminergic neurons against 6-OHDA-induced degeneration in BZ555 worms, extended lifespan, delayed aging-related phenotypes, and enhanced the ability of stress resistance in N2 worms. Mechanistic studies suggest that the neuroprotective effects of CFE may involve the modulation of the MAPK signaling pathway, including ERK, JNK, and p38, whereas the interference of these pathways attenuated the neuroprotective effect of CFE in vitro and in vivo., Conclusion: Overall, our study highlights the potential therapeutic value of CFE as a neuroprotective agent in the context of PD. Furthermore, elucidation of the active compounds of CFE will provide valuable insights for the development of novel therapeutic strategies for PD., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Long-term environmental monitoring surveys are designed to achieve a desired precision (measured by variance) of resource conditions based on natural variability information. Over time, increases in resource variability and in data use to address issues focused on small areas with limited sample sizes require bolstering of attainable precision. It is often prohibitive to do this by increasing sampling effort. In cases with spatially overlapping monitoring surveys, composite estimation offers a statistical way to obtain a precision-weighted combination of survey estimates to provide improved population estimates (more accurate) with improved precisions (lower variances). We present a composite estimator for overlapping surveys, a summary of compositing procedures, and a case study to illustrate the procedures and benefits of composite estimation. The study uses the two terrestrial monitoring surveys administered by the Bureau of Land Management (BLM) that entirely overlap. Using 2015-18 data and 13 land-health indicators, we obtained and compared survey and composite indicator estimates of percent area meeting land-health standards for sagebrush communities in Wyoming's Greater Sage-Grouse (Centrocercus urophasianus) Core and NonCore conservation areas on BLM-managed lands. We statistically assessed differences in indicator estimates between the conservation areas using composite estimates and estimates of the two surveys individually. We found composite variance to be about six to 24 units lower than 37% of the survey variances and composite estimates to differ by about six to 10 percentage points from six survey estimates. The composite improvements resulted in finding 11 indicators to statistically differ (p <0.05) between the conservation areas compared to only six and seven indicators for the individual surveys. Overall, we found composite estimation to be an efficient and useful option for improving environmental monitoring information where two surveys entirely overlap and suggest how this estimation method could be beneficial where environmental surveys partially overlap and in small area applications., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: The research landscape examining social cognition (SC) impairment in patients with major depressive disorders (MDD) and bipolar disorders (BD) is notably scarce. Presently, assessments predominantly rely on static stimuli and self-reported measures, which may not capture the dynamic dimensions of social cognition., Objectives: This study aimed to validate the Chinese version of Movie Assessment of Social Cognition (MASC-CH) and to investigate whether MDD and BD exhibit distinct patterns of SC impairments, shedding light on potential differences between these two mood disorders., Methods: The study encompassed 197 participants, aged 18-65, distributed as follows: 21 BD, 20 MDD, and 156 healthy controls (HC). We focused on examining "cognitive" and "emotional" SC scores and "undermentalizing" and "overmentalizing" error patterns, with nonsocial inference as a control. Additional assessments included the Reading Mind in the Eyes Test (RMET) and the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). We also explored the association between depression severity (measured by the Hamilton Depressive Rating Scale, HDRS) and distinct SC dimensions between MDD and BD., Results: The MASC-CH exhibited strong validity and reliability for SC assessment. In group comparisons, BD participants scored significantly lower on MASC-CH, while the MDD group scores were not significantly different from HC. Specifically, BD individuals had notably lower cognitive SC scores and made more undermentalizing and absence of mentalizing errors than MDD and HC. Additionally, a negative correlation between HDRS score and overmentalizing was observed in BD, not in the MDD., Conclusions: The findings indicate that depression severity scores in BD were inversely related to MASC-CH scores. In contrast, this relationship was not observed in the MDD group. These results underscore the importance of SC impairments as distinguishing characteristics of both BD and MDD. It provides valuable insights into the distinct social-cognitive profiles of both mood disorders., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, with the second highest mortality rate in all cancer. Energy reprogramming is one of the hallmarks of cancer, and emerging evidence showed that targeting glycolysis is a promising strategy for HCC treatment. Cryptocaryone has been shown to display promising anti-cancer activity against numerous types of cancer. Previous study also indicated that cryptocaryone induces cytotoxicity by inhibiting glucose transport in cancer cells, but the detailed mechanism still needs to be elucidated. Therefore, this study aimed to investigate the relationship between the anti-cancer effect and glycolytic metabolism of cryptocaryone in human HCC cells. In this study, we found that cryptocaryone potently induced growth inhibition by apoptotic cell death in HCC cells. Cryptocaryone also suppressed the ATP synthesis, lactate production and glycolytic capacity of HCC cells. Mechanistic investigations showed that phosphorylation of Akt and c-Src, as well as the expression of HK1 were impeded by cryptocaryone. Moreover, cryptocaryone markedly increased the expression level of transcription factor FoxO1. Importantly, clinical database analysis confirmed the negative correlation between HK1 and FoxO1. High expression levels of HK-1 were positively correlated with poorer survival in patients with HCCs. These results suggest that cryptocaryone may promote cell apoptosis by inhibiting FoxO1-mediated aerobic glycolysis through Akt and c-Src signaling cascades in human HCC cells. This is the first study to indicate that cryptocaryone exerts anti-cancer property against human HCC cells. Cryptocaryone is a potential natural product worthy of further development into a promising candidate for HCC treatment.

One of the hallmarks of intractable psoriasis is neutrophil infiltration in skin lesions. However, detailed molecular mechanisms of neutrophil chemotaxis and activation remain unclear. Here, we demonstrate a significant upregulation of epidermal fatty acid binding protein (E-FABP, FABP5) in the skin of human psoriasis and psoriatic mouse models. Genetic deletion of FABP5 in mice by global knockout and keratinocyte conditional (Krt6a-Cre) knockout, but not myeloid cell conditional (LysM-Cre) knockout, attenuates psoriatic symptoms. Immunophenotypic analysis shows that FABP5 deficiency specifically reduces skin recruitment of Ly6G + neutrophils. Mechanistically, activated keratinocytes produce chemokines and cytokines that trigger neutrophil chemotaxis and activation in an FABP5-dependent manner. Proteomic analysis further identifies that FABP5 interacts with valosin-containing protein (VCP), a key player in NF-κB signaling activation. Silencing of FABP5, VCP, or both inhibits NF-κB/neutrophil chemotaxis signaling. Collectively, these data demonstrate dysregulated FABP5 as a molecular mechanism promoting NF-κB signaling and neutrophil infiltration in psoriasis pathogenesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) presents a significant challenge to global healthcare systems, with current treatments offering only modest relief and often bringing unwanted side effects, necessitating the exploration of more effective and safer drugs. In this study, we employed the Caenorhabditis elegans ( C. elegans ) model, specifically the AD-like CL4176 strain expressing the human Aβ (1-42) protein, to investigate the potential of Reineckia carnea extract and its fractions. Our results showed that the Reineckia carnea ether fraction (REF) notably diminished the paralysis rates of CL4176 worms. Additionally, REF also attenuated the neurotoxicity effects prompted by Tau proteins in the BR5270 worms. Moreover, REF was observed to counteract the accumulation of Aβ and pTau proteins and their induced oxidative stress in C. elegan s AD-like models. Mechanistic studies revealed that REF's benefits were associated with the induction of autophagy in worms; however, these protective effects were nullified when autophagy-related genes were suppressed using RNAi bacteria. Together, these findings highlight Reineckia carnea ether fraction as a promising candidate for AD treatment, warranting further investigation into its autophagy-inducing components and their molecular mechanisms.

Blood retinal barrier (BRB) damage is an important pathogenesis of diabetic retinopathy, and alleviating BRB damage has become a key target for DR treatment. We previously found that Lycopene seed polyphenols (LSP) maintained BRB integrity by inhibiting NLRP3 inflammasome-mediated inflammation. However, it is still unknown whether LSP inhibits retinal neovascularization with abnormal capillaries and its mechanism of action. Here, we employed db/db mice and hRECs to find that LSP increases the level of glycolipid metabolism, maintains the morphology of retinal endothelial cells and inhibits acellular capillary neogenesis. Mechanistic studies revealed that LSP inhibits the NLRP3 inflammasome, reduces cell apoptosis in retinal tissue, increases tight junction protein (TJ) expression, and reduces vascular endothelial growth factor (VEGF) and Ve-Cadherin in vivo and in vitro. Collectively, this study finds that LSP inhibits inflammation and angiogenesis to improve BRB function to ameliorate 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 © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Due to the high heterogeneity among hepatocellular carcinoma (HCC) patients receiving transarterial chemoembolization (TACE), the prognosis of patients varies significantly. The decision-making on the initiation and/or repetition of TACE under different liver functions is a matter of concern in clinical practice. Thus, we aimed to develop a prediction model for TACE candidates using risk stratification based on varied liver function., Methods: A total of 222 unresectable HCC patients who underwent TACE as their only treatment were included in this study. Cox proportional hazards regression was performed to select the independent risk factors and establish a predictive model for the overall survival (OS). The model was validated in patients with different Child-Pugh class and compared to previous TACE scoring systems., Results: The five independent risk factors, including alpha-fetoprotein (AFP) level, maximal tumor size, the increase of albumin-bilirubin (ALBI) grade score, tumor response, and the increase of aspartate aminotransferase (AST), were used to build a prognostic model (ASARA). In the training and validation cohorts, the OS of patients with ASARA score ≤ 2 was significantly higher than that of patients with ASARA score > 2 (P < 0.001, P = 0.006, respectively). The ASARA model and its modified version "AS(ARA)" can effectively distinguish the OS (P < 0.001, P = 0.004) between patients with Child-Pugh class A and B, and the C-index was 0.687 and 0.706, respectively. For repeated TACE, the ASARA model was superior to Assessment for Retreatment with TACE (ART) and ALBI grade, maximal tumor size, AFP, and tumor response (ASAR) among Child-Pugh class A patients. For the first TACE, the performance of AS(ARA) was better than that of modified hepatoma arterial-embolization prognostic (mHAP), mHAP3, and ASA(R) models among Child-Pugh class B patients., Conclusions: The ASARA scoring system is valuable in the decision-making of TACE repetition for HCC patients, especially Child-Pugh class A patients. The modified AS(ARA) can be used to screen the ideal candidate for TACE initiation in Child-Pugh class B patients with poor liver function., (Copyright © 2022 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Enhancing the clearance of proteins associated with Alzheimer's disease (AD) emerges as a promising approach for AD therapeutics. This study explores the potential of Radix Stellariae, a traditional Chinese medicine, in treating AD. Utilizing transgenic C. elegans models of AD, we demonstrated that a 75% ethanol extract of Radix Stellariae (RSE) (at 50 µg/mL) effectively diminishes Aβ and Tau protein expression, and alleviates their induced impairments including paralysis, behavioral dysfunction, neurotoxicity, and ROS accumulation. Additionally, RSE enhances the stress resistance of C. elegans. Further investigations revealed that RSE promotes autophagy, a critical cellular process for protein degradation, in these models. We found that inhibiting autophagy-related genes negated the neuroprotective effects of RSE, suggesting a central role for autophagy in the actions of RSE. In PC-12 cells, we observed that RSE not only inhibited Aβ fibril formation but also promoted the degradation of AD-related proteins and reduced their cytotoxicity. Mechanistically, RSE was found to induce autophagy via modulating PI3K/AKT/mTOR and AMPK/mTOR signaling pathways. Importantly, inhibiting autophagy counteracted the beneficial effects of RSE on the clearance of AD-associated proteins. Moreover, we identified Dichotomine B, a β-carboline alkaloid, as a key active constituent of RSE in mitigating AD pathology in C. elegans at concentrations ranging from 50 to 1000 µM. Collectively, our study presents novel discoveries that RSE alleviates AD pathology and toxicity primarily by inducing autophagy, both in vivo and in vitro. These findings open up new avenues for exploring the therapeutic potential of RSE and its active component, Dichotomine B, in treating neurodegenerative diseases like AD., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Over the course of literacy development, children learn to recognize word sounds and meanings in print. Yet, they do so differently across alphabetic and character-based orthographies such as English and Chinese. To uncover cross-linguistic influences on children's literacy, we asked young Chinese-English simultaneous bilinguals and English monolinguals (N = 119, ages 5-10) to complete phonological and morphological awareness (MA) literacy tasks. Children completed the tasks in the auditory modality in each of their languages during functional near-infrared spectroscopy neuroimaging. Cross-linguistically, comparisons between bilinguals' two languages revealed that the task that was more central to reading in a given orthography, such as phonological awareness (PA) in English and MA in Chinese, elicited less activation in the left inferior frontal and parietal regions. Group comparisons between bilinguals and monolinguals in English, their shared language of academic instruction, revealed that the left inferior frontal was less active during phonology but more active during morphology in bilinguals relative to monolinguals. MA skills are generally considered to have greater language specificity than PA skills. Bilingual literacy training in a skill that is maximally similar across languages, such as PA, may therefore yield greater automaticity for this skill, as reflected in the lower activation in bilinguals relative to monolinguals. This interpretation is supported by negative correlations between proficiency and brain activation. Together, these findings suggest that both the structural characteristics and literacy experiences with a given language can exert specific influences on bilingual and monolingual children's emerging brain networks for learning to read., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

This study examined autophagy-lysosome pathway (ALP) perturbations in synovial monocytes/macrophages from patients with gouty arthritis (GA) and the associations of ALP perturbations with cell death. Synovial fluid mononuclear cells (SFMCs) and synovial tissues (STs) from patients with GA, as well as monosodium urate (MSU) crystal-exposed macrophages, underwent immunoblotting, quantitative polymerase chain reaction, and immunofluorescence analyses of markers linked to the ALP (microtubule-associated protein 1 light chain 3B [LC3B], p62, cathepsin D [CTSD], and lysosome-associated membrane protein 2 [LAMP2]) and cell death (caspase-3). GA STs underwent immunohistochemistry and immunofluorescence analyses to determine the distributions of LC3B-positive autophagosomes and macrophages. GA SFMCs and STs exhibited impaired autophagic degradation, indicated by elevated levels of LC3B and p62, along with CTSD upregulation and caspase-3 activation. Macrophages from GA STs exhibited significant accumulation of LC3B-positive autophagosomes. The temporal effects of MSU crystals on the ALP and the associations of these effects with cell death were investigated using a macrophage model of GA. MSU crystal-exposed macrophages exhibited early (2 h) autophagosome formation but later (6-24 h) autophagic flux impairment, demonstrated by p62 accumulation, lysosomal inhibitor failure to increase LC3B accumulation, and LC3B colocalization with p62. These macrophages exhibited autophagic flux impairment because of CTSD inactivation-mediated lysosomal dysfunction, which caused immature CTSD to accumulate within damaged LAMP2-positive lysosomes. This accumulation coincided with caspase-3-dependent cell death (24 h) that was unaffected by CTSD inhibition. These findings indicate that GA involves MSU crystal-induced impairment of autophagic degradation via CTSD inactivation-mediated lysosomal dysfunction, which promotes apoptosis in macrophages., Competing Interests: Declaration of competing interest The authors have no potential conflicts of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Neuronal CX3CL1 suppressed microglial inflammation by binding to its receptor CX3CR1 expressed on microglia. Neuronal autophagy was prominently activated by cerebral ischemia, whereas CX3CL1 expression in autophagic neurons was conversely down-regulated to exacerbate microglial inflammation. Accordingly, this study was meant to investigate whether ischemia-activated microglial inflammation could be repressed by promoting CX3CL1 expression via the attenuation of neuronal autophagy. Immunofluorescence showed that autophagy predominantly occurred in neurons but barely in microglia. Western blot and immunofluorescence demonstrated that attenuating HT22 autophagy significantly increased its CX3CL1 expression and subsequently mitigated the BV2-mediated inflammatory responses, as indicated by decreased inflammatory factors of NF-κB-p65, IL-6, IL-1β, TNF-α, and PGE2. Meanwhile, CCK-8, Nissl staining, and FJC staining showed that an OGD (Oxygen-glycogen deprivation)-created neuronal injury was greatly alleviated by CX3CL1-suppressed microglial inflammation. Contrarily, elevating HT22 autophagy markedly decreased its CX3CL1 expression, which consequently worsened microglial inflammation and the neuronal injury. Our data suggests that attenuating neuronal autophagy may be an effective method to alleviate a microglial inflammatory injury after an ischemic stroke., (Copyright ® 2023 National Research University Higher School of Economics.)

The multifunctional RNA recognition motif-containing protein Y14/RBM8A participates in mRNA metabolism and is essential for the efficient repair of DNA double-strand breaks (DSBs). Y14 contains highly charged, low-complexity sequences in both the amino- and carboxy-terminal domains. The feature of charge segregation suggests that Y14 may undergo liquid-liquid phase separation (LLPS). Recombinant Y14 formed phase-separated droplets, which were sensitive to pH and salt concentration. Domain mapping suggested that LLPS of Y14 involves multivalent electrostatic interactions and is partly determined by the net charge of its low-complexity regions. Phospho-mimicry of the carboxy-terminal arginine-serine dipeptides of Y14 suppressed phase separation. Moreover, RNA could phase separate into Y14 droplets and modulate Y14 LLPS in a concentration-dependent manner. Finally, the capacity of Y14 in LLPS and coacervation with RNA in vitro correlated with its activity in DSB repair. These results reveal a molecular rule for LLPS of Y14 in vitro and an implication for its co-condensation with RNA in genome stability., (© 2023 Yu et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

Mesenchymal stem cells (MSCs) can differentiate into various tissue cell types including bone, adipose, cartilage, and muscle. Among those, osteogenic differentiation of MSCs has been widely explored in many bone tissue engineering studies. Moreover, the conditions and methods of inducing osteogenic differentiation of MSCs are continuously advancing. Recently, with the gradual recognition of adipokines, the research on their involvement in different pathophysiological processes of the body is also deepening including lipid metabolism, inflammation, immune regulation, energy disorders, and bone homeostasis. At the same time, the role of adipokines in the osteogenic differentiation of MSCs has been gradually described more completely. Therefore, this paper reviewed the evidence of the role of adipokines in the osteogenic differentiation of MSCs, emphasizing bone formation and bone regeneration., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Lupus nephritis (LN) is one of the most severe complications in patients with systemic lupus erythematosus (SLE). Traditionally, LN is regarded as an immune complex (IC) deposition disease led by dsDNA-anti-dsDNA-complement interactions in the subendothelial and/or subepithelial basement membrane of glomeruli to cause inflammation. The activated complements in the IC act as chemoattractants to chemically attract both innate and adaptive immune cells to the kidney tissues, causing inflammatory reactions. However, recent investigations have unveiled that not only the infiltrating immune-related cells, but resident kidney cells, including glomerular mesangial cells, podocytes, macrophage-like cells, tubular epithelial cells and endothelial cells, may also actively participate in the inflammatory and immunological reactions in the kidney. Furthermore, the adaptive immune cells that are infiltrated are genetically restricted to autoimmune predilection. The autoantibodies commonly found in SLE, including anti-dsDNA, are cross-reacting with not only a broad spectrum of chromatin substances, but also extracellular matrix components, including α-actinin, annexin II, laminin, collagen III and IV, and heparan sulfate proteoglycan. Besides, the glycosylation on the Fab portion of IgG anti-dsDNA antibodies can also affect the pathogenic properties of the autoantibodies in that α-2,6-sialylation alleviates, whereas fucosylation aggravates their nephritogenic activity. Some of the coexisting autoantibodies, including anti-cardiolipin, anti-C1q, anti-ribosomal P autoantibodies, may also enhance the pathogenic role of anti-dsDNA antibodies. In clinical practice, the identification of useful biomarkers for diagnosing, monitoring, and following up on LN is quite important for its treatments. The development of a more specific therapeutic strategy to target the pathogenic factors of LN is also critical. We will discuss these issues in detail in the present article.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is currently an effective treatment for malignant hematologic disease, but the immune deficiency and severe infection triggered by slow immune reconstitution are the main causes of high mortality and transplant failure. One of these outstanding problems is thymus damage, which is associated with graft-versus-host disease (GVHD), and preconditioning including irradiation and chemotherapy. Therefore, rapid repair of damaged thymus and rapid proliferation of thymus-derived donor T cells post-transplantation are key to solving the problem. This study was designed to accelerate the recovery of thymus-derived T cells post-transplantation. Wild-type mice with normal immunity were used as recipients in a haplo-HSCT mouse model to mimic clinical haplo-HSCT. A modified cell culture system using Notch ligand Delta4 and IL-7 was established that is capable of inducing and amplifying the differentiation and proliferation of hematopoietic stem cells into precursor T (preT) cells in vitro. The haplo-HSCT protocol included preT and G-CSF-mobilized donor splenic mononuclear cell (MNC) coinfusion in one group and MNC infusion alone in a second group. Thymic GVHD, thymic repair, and thymus-derived T cell development were compared in the 2 groups by polychromatic immunofluorescence tracking, flow cytometry, and detection of T cell receptor Vβ. The thymus homing and T cell regeneration of allogenic preT cells were observed. The functions of preT cells in accelerating immune reconstitution, restoring thymic architecture, weakening graft-versus-host (GVH) effects, and enhancing immunotolerance post-transplantation were demonstrated. Further studies revealed that allogeneic preT cells induced by a culture system containing IL-7 and Delta4 highly express ccr9 and RANKL. Interestingly, RANK expression was promoted after preT cell thymus homing. These results suggest that the RANK/RANKL pathway may play an important role in thymus homing. Our results provide a potential therapeutic option to optimize haplo-HSCT, and also open up a new field of T cell therapy for artificial induction of allogeneic preT cells in vitro to repair the damaged thymus from irradiation and chemotherapy and to compensate for the recovery of immune function in patients with immune deficiency of various etiologies., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: The aim of our study was to provide real-world data on outcomes for elderly Taiwanese patients who underwent transcatheter aortic valve replacement or surgical aortic valve replacement in different risk groups., Methods: From March 2011 through December 2021, 177 patients with severe aortic stenosis who were ≥70 years old and had undergone TAVI (transcatheter aortic valve implantation) or SAVR (surgical aortic valve replacement) in a single center were divided by STS score (<4%, 4-8% and >8%) into three different groups. Then, we compared their clinical characteristics, operative complications, and all-cause mortality., Results: In all risk groups, there were no significant differences in in-hospital mortality, or 1-year and 5-year mortality between patients in the TAVI and SAVR groups. In all risk groups, patients in the TAVI group had shorter hospital stay and higher rate of paravalvular leakage than the SAVR group. After univariate analysis, BMI (body mass index) < 20 was a risk factor for higher 1-year and 5-year mortality. In the multivariate analysis, acute kidney injury was an independent factor for predicting worse outcomes in terms of 1-year and 5-year mortality., Conclusions: Taiwan elderly patients in all risk groups did not have significant differences in mortality rates between the TAVI and the SAVR group. However, the TAVI group had shorter hospital stay and higher rate of paravalvular leakage in all risk groups.

In the era of molecular targeted drugs, elderly patients with acute myeloid leukemia (AML) are still very difficult to treat, especially those older than 70 years. The decline in immune function leads to serious infection and disease recurrence. The microtransplant treatment regimen (MST) chemotherapy combined with allogeneic hematopoietic stem cell infusion is a new cell therapy regimen. The aim of this MST study was to improve the survival of elderly patients by graft versus leukemia action and improving T-cell immune function. From May 2012 to July 2020, one hundred and eleven patients aged 70 to 88 years with de novo AML were analyzed retrospectively. After induction chemotherapy, patients whom complete remission (CR) was achieved were given another 2 cycles of postremission therapy. The MST groups were given allogeneic stem cell infusion after each chemotherapy cycle. CR, leukemia-free survival, and overall survival (OS) were compared between groups. Additionally, the immune function and the T cell receptor (TCR) library of T cells were detected and analyzed. The MST group exhibited an encouragingly high CR rate (63.8%), even in high-risk patients (54%), and this rate was significantly higher than that in the chemotherapy alone group. The 1-year OS of MST patients was 57.7%, and it was 55.9% in the high-risk group. It was only 37.3% in the chemotherapy alone group. Higher numbers of naive T cells were found in the MST population than in the chemotherapy alone group. More updated T-cell clones were observed in MST patients by T-cell receptor repertoire analysis with a next-generation sequencing methodology. These results suggest that MST is a safe and practical regimen conducive to longer-term survival in patients of a highly advanced age with AML. Furthermore, it has broad clinical value in the recovery of immune function in elderly patients., Competing Interests: None., (AJCR Copyright © 2023.)

Diversity and variation in language experiences, such as bilingualism, contribute to heterogeneity in children's neural organization for language and brain development. To uncover sources of such heterogeneity in children's neural language networks, the present study examined the effects of bilingual proficiency on children's neural organization for language function. To do so, we took an innovative person-specific analytical approach to investigate young Chinese-English and Spanish-English bilingual learners of structurally distinct languages. Bilingual and English monolingual children ( N = 152, M ( SD ) age = 7.71(1.32)) completed an English word recognition task during functional near-infrared spectroscopy neuroimaging, along with language and literacy tasks in each of their languages. Two key findings emerged. First, bilinguals' heritage language proficiency (Chinese or Spanish) made a unique contribution to children's language network density. Second, the findings reveal common and unique patterns in children's patterns of task-related functional connectivity. Common across all participants were short-distance neural connections within left hemisphere regions associated with semantic processes (within middle temporal and frontal regions). Unique to more proficient language users were additional long-distance connections between frontal, temporal, and bilateral regions within the broader language network. The study informs neurodevelopmental theories of language by revealing the effects of heterogeneity in language proficiency and experiences on the structure and quality of emerging language neural networks in linguistically diverse learners., Competing Interests: Competing Interests: The authors have declared that no competing interests exist., (© 2023 Massachusetts Institute of Technology.)

Interactions between alien plants and local enemies in introduced ranges may determine plant invasion success. However, little is known about whether herbivory-induced responses are transmitted across vegetative generations of plants and whether epigenetic changes are involved during this process. In a greenhouse experiment, we examined the effects of herbivory by the generalist herbivore Spodoptera litura on the growth, physiology, biomass allocation and DNA methylation level of the invasive plant Alternanthera philoxeroides in the first- (G1), second- (G2) and third-generation (G3). We also tested the effects of root fragments with different branching orders (i.e., the primary- or secondary-root fragments of taproots) of G1 on offspring performance. Our results showed that G1 herbivory promoted the growth of the plants in G2 that sprouted from the secondary-root fragments of G1 but had a neutral or negative effect on the growth of the plants in G2 from the primary-root fragments. The growth of plants in G3 was significantly reduced by G3 herbivory but not affected by G1 herbivory. Plants in G1 exhibited a higher level of DNA methylation when they were damaged by herbivores than when they were not, while neither plants in G2 nor G3 showed herbivory-induced changes in DNA methylation. Overall, the herbivory-induced growth response within one vegetative generation may represent the rapid acclimatization of A. philoxeroides to the unpredictable generalist herbivores in the introduced ranges. Herbivory-induced trans-generational effects may be transient for clonal offspring of A. philoxeroides , which can be influenced by the branching order of taproots, but be less characterized by DNA methylation.

Preliminary meta-analyses suggested that fluvoxamine was effective in treating COVID-19 infection. However, the reliability of this evidence has not yet been examined. MEDLINE, CENTRAL, EMBASE, PsycINFO, and ClinicalTrials.gov were searched to identify any randomized controlled trials (RCTs) from the inception of the databases to 5 February 2023. We used trial sequential analysis (TSA) to examine the reliability of the current existing evidence on the benefits of fluvoxamine on COVID-19 infection. The primary outcome was clinical deterioration, as defined in the original study (reported as odds ratio (OR), with 95% confidence intervals), and the secondary outcome was hospitalization. In the TSA, we used the relative risk reduction thresholds of 10, 20, and 30%. The updated meta-analysis of the five RCTs showed that fluvoxamine was not associated with lower odds of clinical deterioration when compared with a placebo (OR: 0.81; 0.59-1.11). The effect of fluvoxamine lay within the futility boundary (i.e., lack of effect) when using a 30% relative risk reduction threshold. The effect estimates lay between the superiority and futility boundary using the 10% and 20% threshold, and the required size of information was not reached for these two thresholds. The effect of fluvoxamine on the odds of hospitalization was not statistically significant (0.76; 0.56-1.03). In conclusion, there is no reliable evidence that fluvoxamine, when compared to a placebo, reduces the relative risk of clinical deterioration among adult patients with COVID-19 infection by 30%, and a relative risk reduction of 20% or 10% is still uncertain. The role of fluvoxamine as a COVID-19 treatment cannot be justified.

While genetic analyses have revealed ~100 risk loci associated with osteoarthritis (OA), only eight have been linked to hand OA. Besides, these studies were performed in predominantly European and Caucasian ancestries. Here, we conducted a genome-wide association study in the Han Chinese population to identify genetic variations associated with the disease. We recruited a total of 1136 individuals (n = 420 hand OA-affected; n = 716 unaffected control subjects) of Han Chinese ancestry. We carried out genotyping using Axiom Asia Precisi on Medicine Research Array, and we employed the RegulomeDB database and RoadMap DNase I Hypersensitivity Sites annotations to further narrow down our potential candidate variants. Genetic variants identified were tested in the Geisinger's hand OA cohort selected from the Geisinger MyCode community health initiative (MyCode ® ). We also performed a luciferase reporter assay to confirm the potential impact of top candidate single-nucleotide polymorphisms (SNPs) on hand OA. We identified six associated SNPs ( p -value = 6.76 × 10 -7 -7.31 × 10 -6 ) clustered at 2p13.2 downstream of the CYP26B1 gene. The strongest association signal identified was rs883313 ( p -value = 6.76 × 10 -7 , odds ratio (OR) = 1.76), followed by rs12713768 ( p -value = 1.36 × 10 -6 , OR = 1.74), near or within the enhancer region closest to the CYP26B1 gene. Our findings showed that the major risk-conferring CC haplotype of SNPs rs12713768 and rs10208040 [strong linkage disequilibrium (LD); D' = 1, r 2 = 0.651] drives 18.9% of enhancer expression activity. Our findings highlight that the SNP rs12713768 is associated with susceptibility to and severity of hand OA in the Han Chinese population and that the suggested retinoic acid signaling pathway may play an important role in its pathogenesis.

Question: Are antipsychotic dose equivalents between acute mania and schizophrenia the same?, Study Selection and Analysis: Six databases were systematically searched (from inception to 17 September 2022) to identify blinded randomised controlled trials (RCTs) that used a flexible-dose oral antipsychotic drug for patients with acute mania. The mean and SD of the effective dose and the pre-post changes in manic symptoms were extracted. A network meta-analysis (NMA) under a frequentist framework was performed to examine the comparative efficacy between the antipsychotics. A classic mean dose method (sample size weighted) was used to calculate each antipsychotic dose equivalent to 1 mg/day olanzapine for acute mania. The antipsychotic dose equivalents of acute mania were compared with published data for schizophrenia., Findings: We included 42 RCTs which enrolled 11 396 participants with acute mania. The NMA showed that risperidone was superior to olanzapine (reported standardised mean difference: -022, 95% CI -0.41 to -0.02), while brexpiprazole was inferior to olanzapine (standardised mean difference: 0.36, 95% CI 0.08 to 0.64). The dose equivalents to olanzapine (with SD) were 0.68 (0.23) for haloperidol, 0.32 (0.07) for risperidone, 0.60 (0.11) for paliperidone, 8.00 (1.41) for ziprasidone, 41.46 (5.98) for quetiapine, 1.65 (0.32) for aripiprazole, 1.23 (0.20) for asenapine, 0.53 (0.14) for cariprazine and 0.22 (0.03) for brexpiprazole. Compared with the olanzapine dose equivalents for schizophrenia, those of acute mania were higher for quetiapine (p<0.001, 28.5%) and aripiprazole (p<0.001, 17.0%), but lower for haloperidol (p<0.001, -8.1%) and risperidone (p<0.001, -15.8%)., Conclusions: Antipsychotic drugs have been considered first-line treatment for acute mania, warranting specific dose equivalence for scientific and clinical purposes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. Published by BMJ.)

Background: Protein aggregates are considered key pathological features in neurodegenerative diseases (NDs). The induction of autophagy can effectively promote the clearance of ND-related misfolded proteins., Objective: In this study, we aimed to screen natural autophagy enhancers from traditional Chinese medicines (TCMs) presenting potent neuroprotective potential in multiple ND models., Methods: The autophagy enhancers were broadly screened in our established herbal extract library using the transgenic Caenorhabditis elegans (C. elegans) DA2123 strain. The neuroprotective effects of the identified autophagy enhancers were evaluated in multiple C. elegans ND models by measuring Aβ-, Tau-, α-synuclein-, and polyQ40-induced pathologies. In addition, PC-12 cells and 3 × Tg-AD mice were employed to further validate the neuroprotective ability of the identified autophagy enhancers, both in vitro and in vivo. Furthermore, RNAi bacteria and autophagy inhibitors were used to evaluate whether the observed effects of the identified autophagy enhancers were mediated by the autophagy-activated pathway., Results: The ethanol extract of Folium Hibisci Mutabilis (FHME) was found to significantly increase GFP::LGG-1-positive puncta in the DA2123 worms. FHME treatment markedly inhibited Aβ, α-synuclein, and polyQ40, as well as prolonging the lifespan and improving the behaviors of C. elegans, while siRNA targeting four key autophagy genes partly abrogated the protective roles of FHME in C. elegans. Additionally, FHME decreased the expression of AD-related proteins and restored cell viability in PC-12 cells, which were canceled by cotreatment with 3-methyladenine (3-MA) or bafilomycin A1 (Baf). Moreover, FHME ameliorated AD-like cognitive impairment and pathology, as well as activating autophagy in 3 × Tg-AD mice., Conclusion: FHME was successfully screened from our natural product library as a potent autophagy enhancer that exhibits a neuroprotective effect in multiple ND models across species through the induction of autophagy. These findings offer a new and reliable strategy for screening autophagy inducers, as well as providing evidence that FHME may serve as a possible therapeutic agent for NDs., 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 there are no competing interests associated with the manuscript., (Copyright © 2022 Elsevier GmbH. All rights reserved.)