Search

Many biological problems are understudied due to experimental limitations and human biases. Although deep learning is promising in accelerating scientific discovery, its power compromises when applied to problems with scarcely labeled data and data distribution shifts. We develop a deep learning framework-Meta Model Agnostic Pseudo Label Learning (MMAPLE)-to address these challenges by effectively exploring out-of-distribution (OOD) unlabeled data when conventional transfer learning fails. The uniqueness of MMAPLE is to integrate the concept of meta-learning, transfer learning and semi-supervised learning into a unified framework. The power of MMAPLE is demonstrated in three applications in an OOD setting where chemicals or proteins in unseen data are dramatically different from those in training data: predicting drug-target interactions, hidden human metabolite-enzyme interactions, and understudied interspecies microbiome metabolite-human receptor interactions. MMAPLE achieves 11% to 242% improvement in the prediction-recall on multiple OOD benchmarks over various base models. Using MMAPLE, we reveal novel interspecies metabolite-protein interactions that are validated by activity assays and fill in missing links in microbiome-human interactions. MMAPLE is a general framework to explore previously unrecognized biological domains beyond the reach of present experimental and computational techniques., (© 2024. The Author(s).)

Epigallocatechin gallate (EGCG)-based nanosystems have garnered significant attention for their ability to alleviate inflammation due to their excellent anti-inflammatory properties and enhanced drug delivery capabilities. However, the degradation of EGCG in strongly acidic environments poses a challenge for potential administration, particularly in oral formulations, where gastric resistance is essential. In this study, we develop a "disintegration and reorganization" strategy to create acid-resistant antioxidant nanoparticles (EGA NPs) based on EGCG and 5-aminosalicylic acid (5-ASA) for mitigating inflammation in colitis and acute kidney injury. At acidic pH, the ester bond in EGCG breaks down, producing two building blocks. These, together with 5-ASA and formaldehyde, form oligomers through a combination of phenol-aldehyde condensation and the Mannich reaction. The resulting oligomers self-assemble into EGA NPs, which exhibit significant stability under both acidic and neutral pH conditions. This stability makes them suitable for oral administration, allowing them to withstand harsh gastric conditions, as well as for intravenous injection. Importantly, these oligomers retain the antioxidant and anti-inflammatory properties of EGCG, effectively scavenging reactive oxygen species and reducing intracellular oxidative stress. Additionally, EGA shows potential as a drug carrier, efficiently loading the anti-inflammatory agent curcumin (Cur) to form Cur@EGA NPs. In vivo studies demonstrate the efficacy of Cur@EGA and EGA in alleviating acute colitis and kidney injury following oral and intravenous administration, respectively. These nanoparticulate formulations exhibit superior inflammation reduction compared to free Cur in vivo. Overall, our findings introduce a novel acid-resistant nanoplatform based on EGCG for the treatment of acute inflammation.

Introduction: Hepatocellular carcinoma (HCC) is a global health problem with increasing morbidity and mortality, and exploring the diagnosis and treatment of HCC at the gene level has been a research hotspot in recent years., Methods: In this paper, a series of differentially expressed genes were found from the biochip related to HCC by bioinformatic analysis, then CNDP1 was finally selected for in-depth study according to the function and research progress of each gene. As the rate-limiting enzyme of carnosine hydrolysis, CNDP1 participates in the progress of many diseases, but its function has not been revealed in HCC. In the follow-up study, the low expression of CNDP1 in liver cancer tissues and cells was verified, then the pcDNA3.1-CNDP1 was used to improve the expression level of CNDP1 in HCC cell lines. Furthermore, this paper found that CNDP1 overexpression could significantly suppress cell prolifer-ation, migration, and invasion of HCC cell lines., Results: Mechanismly, the GeneMANIA database predicted that CNDP1 could interact with various proteins that regulate the PI3K-AKT-mTOR signaling pathway, which is overactivated in HCC. And this study showed that CNDP1 overexpression could effectively inhibit the activation of PI3K-AKT-mTOR signaling pathways, more significantly, inhibition of PI3K-AKT-mTOR signaling pathway could disrupt the anti-cancer effect of CNDP1 on HCC., Conclusion: In conclusion, we confirmed that CNDP1 was lowly expressed in HCC tissues and cells, and had potential anti-cancer activity. This discovery will lay a cytological foundation for expanding the biological function of CNDP1 and the diagnosis and treatment of HCC in the future., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Anaerobic digestion (AD) is an environmentally friendly technology that simultaneously stabilizes biowaste and produces biogas. Conventional AD faces challenges such as inadequate substrate degradation and low methane purity. Pressure-centric regulation serves as an AD optimization strategy that can enhance the digestion efficiency and generate higher-energy-value biogas. However, limited reviews have been undertaken to focus on this technology. This review is designed to discuss innovations in ex-situ high-pressure pretreatment and in-situ high-pressure anaerobic digestion (HPAD) processes. Moreover, comprehensive understandings on the intrinsic mechanisms of HPAD are critically examined, including physicochemical reaction principles and microbial responses. The constraints currently curtailing these technologies and potential mitigation strategies are also scrutinized. Additionally, current knowledge gaps and future research directions on mechanisms, model fitting, and engineering practices are presented. Overall, this work highlights the feasibility of pressure-centric regulated AD and provides novel insights to overcome existing technical barriers in its application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Anthocyanins are polyphenolic pigments that have hypoglycemic, antioxidation, anti-aging, and other effects. Research has shown that polyphenols can optimize the processing of dough and improve the texture and nutritional characteristics of dough products. The formation of gluten networks is decisive for the quality of flour products. The effects of purple cabbage anthocyanin (PCA) extract on the structure, microscopic morphology, and network formation of gluten protein were studied, and the types of cross-linking between PCA and gluten protein are discussed., Results: The results show that PCA extract increased the free sulfhydryl (SH) group content and the free amino group of gluten proteins, stimulated an increase in the β-sheet ratio and the decrease of α-helix ratio, and increased the gluten index significantly (P < 0.05). The PCA extract also induced gluten protein aggregation, increased the height of protein molecular chains, and stimulated the formation of gluten networks. When PCA extract concentrations were 4 g kg -1 and 8 g kg -1 , the gluten network was more homogeneous, continuous, and dense., Conclusion: Appropriate anthocyanins have a positive effect on the properties of gluten and promote the formation of gluten networks. Excessive anthocyanins destroy gluten protein interaction and harm gluten cross-linking. This study may provide a useful source of data for the production of functional flour products rich in anthocyanins. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Inspired by the well-known Papez circuit theory and neuroscience knowledge of reinforcement learning, a double dueling deep Q network (DQN) is built incorporating the electroencephalogram (EEG) signals of the frontal lobe as prior information, which is named frontal lobe double dueling DQN (FLD3QN). The framework of FLD3QN is constructed in accord with the brain emotion mechanism which takes the frontal lobe and the thalamus as the core, in which the part of the Papez circuit is simulated by the bifrontal lobe residual convolution neural network (BiFRCNN). Moreover, a step penalty factor is designed to constrain the number of mistakes of the agent. The ablation studies results on the public EEG emotion dataset DEAP verified the important roles of the frontal lobe and the Papez circuit in modeling the procedure of learning rewards during the perception of emotions, with a great increase in the average accuracies by 25.24% and 23.31% in valence and arousal dimensions.

Purpose: Radiation-induced intestinal injury (RIII) commonly occur during abdominal-pelvic cancer radiation therapy; however, no effective prophylactic or therapeutic agents are available to manage RIII currently. This study aimed to clarify the potential of probiotic consortium supplementation in alleviating RIII., Methods and Materials: Male C57BL/6J mice were orally administered a probiotic mixture comprising Bifidobacterium longum BL21, Lactobacillus paracasei LC86, and Lactobacillus plantarum Lp90 for 30 days before exposure to 13 Gy of whole abdominal irradiation. The survival rates, clinical scores, and histologic changes in the intestines of mice were assessed. The impacts of probiotic consortium treatment on intestinal stem cell proliferation, differentiation, and epithelial barrier function; oxidative stress; and inflammatory cytokines were evaluated. A comprehensive examination of the gut microbiota composition was conducted through 16S rRNA sequencing, while changes in metabolites were identified using liquid chromatography-mass spectrometry., Results: The probiotic consortium alleviated RIII, as reflected by increased survival rates, improved clinical scores, and mitigated mucosal injury. The probiotic consortium treatment exhibited enhanced therapeutic effects at the histologic level compared with individual probiotic strains, although there was no corresponding improvement in survival rates and colon length. Moreover, the probiotic consortium stimulated intestinal stem cell proliferation and differentiation, enhanced the integrity of the intestinal epithelial barrier, and regulated redox imbalance and inflammatory responses in irradiated mice. Notably, the treatment induced a restructuring of the gut microbiota composition, particularly enriching short-chain fatty acid-producing bacteria. Metabolomic analysis revealed distinctive metabolic changes associated with the probiotic consortium, including elevated levels of anti-inflammatory and antiradiation metabolites., Conclusions: The probiotic consortium attenuated RIII by modulating the gut microbiota and metabolites, improving inflammatory symptoms, and regulating oxidative stress. These findings provide new insights into the maintenance of intestinal health with probiotic consortium supplementation and will facilitate the development of probiotic-based therapeutic strategies for RIII in clinical practice., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Perfluorooctanoic acid (PFOA), an emerging pollutant, has been frequently detected in organic solid waste. It becomes a major concern for compost application, but studies on its toxic effects during composting are rare. This study evaluated the impact of PFOA presence at the environmentally relevant level on the humification process and microbiology during composting. The results showed that the PFOA presence (15.5 μg/kg dry) caused 45.5 % and 40.5 % decreases in the total organic carbon and humic acid-like substances, respectively. PFOA negatively affected microbial activity during the thermophilic period, as evidenced by the increases in reactive oxygen species and lactate dehydrogenase concentration. It altered the microbial community with an enrichment of Bacteroidota, conducive to resisting press. Unexpectedly, the PFOA presence induced hormesis at the maturity period, consistent with stimulated carbon metabolism (i.e., glycolysis and oxidative phosphorylation). The modulated microbial metabolism stimulated the catabolic metabolism of small-molecule humus precursors and reduced intracellular quinone availability. Furthermore, the secretion of auxiliary activities for crude fiber degradation was suppressed, which decreased the generation of extracellular quinone, and thereby impeded the humification process. These findings deciphered the metabolic response of composting to PFOA presence and highlighted the potential carbon loss of PFOA-containing composting., 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.)

The increasing desire for aesthetically pleasing teeth has resulted in the widespread use of tooth whitening treatments. Clinical tooth whitening products currently rely on hydrogen peroxide formulations to degrade dental pigments through oxidative processes. However, they usually cause side effects such as tooth sensitivity and gingival irritation due to the use of high concentrations of hydrogen peroxide or long-time contact. In recent years, various novel materials and reaction patterns have been developed to tackle the issues related to H 2 O 2 -based tooth whitening. These can be broadly classified as advanced oxidation processes (AOPs). AOPs generate free radicals that have potent oxidizing properties, which can thereby increase the oxidation power and/or reduce the exposure time and can probably minimize the side effects of tooth bleaching. While there have been several reviews on clinical tooth whitening and the application of novel nanomaterials, a review based on the concept of AOPs in tooth bleaching application has not yet been conducted. This review describes the common types and mechanisms of AOPs, summarizes the latest research progress of new tooth bleaching materials based on AOPs, and proposes a model for tooth bleaching and a rate control step at the molecular level. The paper also reviews the shortcomings and suggests future development directions.

Objectives: China has experienced a notable upsurge in pertussis cases post-COVID-19, alongside an age shift to older children, increased vaccine escape, and a notable rise in the prevalence of macrolide-resistant Bordetella pertussis (MRBP). Here, we present a genomic epidemiological investigation of these events., Methods: We performed a retrospective observational study using culture-positive B. pertussis isolated in Shanghai, China between 2016 and 2024. We analysed strain and pertussis epidemiology dynamics by integrating whole-genome sequencing of 723 strains with antimicrobial susceptibility, transcriptomic profile, and clinical data. We compared the genome sequences of Shanghai strains with 6450 Chinese and global strains., Results: From pre-COVID-19 (before December 2019) to post-COVID-19, patients shifted from predominantly infants (90%, 397/442) to a higher proportion of infections in older children (infant: 16%, 132/844), with the share of vaccinated individuals surging from 31% (107/340) to 88% (664/756). The MRBP prevalence increased from 60% (267/447) to 98% (830/845). The emergence and expansion of a ptxP3-lineage macrolide-resistant clone, MR-MT28, which is uniquely capable of causing substantial infections among older children and vaccinated individuals, was temporally strongly associated with the pertussis upsurge and epidemiological transition. While MR-MT28 showed increased expression of genes encoding pertussis toxin, it was associated with significantly milder clinical symtoms and a lower hospitalization rate. MR-MT28 likely originated in China around 2016, after acquiring several key mutations including a novel prn150 allele, and has been detected across multiple regions in China. Additionally, 26% (50/195) of MR-MT28 has evolved into predicted PRN-deficient strains, with an IS481 insertion being the predominant mechanism., Conclusions: We report that the post-COVID-19 upsurge of pertussis in China is associated with ptxP3-MR-MT28, and provide evidence that pathogen evolution is likely the primary factor driving pertussis upsurge, age shift and vaccine escape. MR-MT28 poses a high risk of global spread and warrants global surveillance., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

The potential of circular RNAs (circRNAs) as biomarkers and therapeutic targets is becoming increasingly evident, yet their roles in cardiac regeneration and myocardial renewal remain largely unexplored. Here, we investigated the function of circIGF1R and related mechanisms in cardiac regeneration. Through analysis of circRNA sequencing data from neonatal and adult cardiomyocytes, circRNAs associated with regeneration were identified. Our data showed that circIGF1R expression was high in neonatal hearts, decreased with postnatal maturation, and up-regulated after cardiac injury. The elevation was validated in patients diagnosed with acute myocardial infarction (MI) within 1 week. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and myocardial tissue from mice after apical resection and MI, we observed that circIGF1R overexpression enhanced cardiomyocyte proliferation, reduced apoptosis, and mitigated cardiac dysfunction and fibrosis, while circIGF1R knockdown impeded endogenous cardiac renewal. Mechanistically, we identified circIGF1R binding proteins through circRNA precipitation followed by mass spectrometry. RNA pull-down Western blot and RNA immunoprecipitation demonstrated that circIGF1R directly interacted with DDX5 and augmented its protein level by suppressing ubiquitin-dependent degradation. This subsequently triggered the β-catenin signaling pathway, leading to the transcriptional activation of cyclin D1 and c-Myc. The roles of circIGF1R and DDX5 in cardiac regeneration were further substantiated through site-directed mutagenesis and rescue experiments. In conclusion, our study highlights the pivotal role of circIGF1R in facilitating heart regeneration and repair after ischemic insults. The circIGF1R/DDX5/β-catenin axis emerges as a novel therapeutic target for enhancing myocardial repair after MI, offering promising avenues for the development of regenerative therapies., Competing Interests: Competing interests: The authors declare that they have no competing interests., (Copyright © 2024 Tian-Kai Shan et al.)

Background Context: This study's purpose was to evaluate the biomechanical performance of plate-nail and dual-plate fixation for the treatment of AO/OTA 41-C2 tibial plateau fractures., Methods: Twenty synthetic tibias were selected and randomly divided into a plate-nail group ( n = 10) and a dual-plate group ( n = 10). After the artificial tibias were osteotomized to simulate AO/OTA 41-C2 tibial plateau fractures in both groups, the plate-nail and the dual-plate methods, respectively, were used for fixation, and then axial compression loading, three-point bending, torsion, and axial failure tests were carried out. The data of each group were recorded and statistically analyzed., Results: In the axial compression test, the average stiffness of the plate-nail group was higher than that of the dual-plate group ( p < 0.05). The displacement generated in the plate-nail group was significantly smaller than that in the dual-plate group ( p < 0.05). In the resisting varus test, the stress of the plate-nail group was significantly higher than that of the dual-plate group ( p < 0.05). In the resisting valgus test, the stress of the plate-nail group was slightly higher than that of the dual-plate group, but the difference was not statistically significant ( p > 0.05). In the static torsion test, the load applied to the plate-nail group was smaller than that of the dual-plate group when rotated to 5° ( p < 0.05). In the axial compression failure test, the average ultimate load of the plate-nail group was significantly higher than that of the dual-plate group ( p < 0.05)., Conclusion: The treatment of AO/OTA 41-C2 tibial plateau fractures with plate-nail fixation is superior to that with dual-plate fixation in resisting axial stress and preventing tibial varus deformity, while dual-plate fixation has better resisting torsional ability.

Postoperative rehemorrhage following intracerebral hemorrhage surgery is intricately associated with a high mortality rate, yet there is now no effective clinical treatment. In this study, we developed a hemoglobin (Hb)-responsive in situ implantable DNA hydrogel comprising Hb aptamers cross-linked with two complementary chains and encapsulating deferoxamine mesylate (DFO). Functionally, the hydrogel generates signals upon postoperative rehemorrhage by capturing Hb, demonstrating a distinctive "self-diagnosis" capability. In addition, the ongoing capture of Hb mediates the gradual disintegration of the hydrogel, enabling the on-demand release of DFO without compromising physiological iron-dependent functions. This process achieves self-treatment by inhibiting the ferroptosis of neurocytes. In a collagenase and autologous blood injection model-induced mimic postoperative rehemorrhage model, the hydrogel exhibited a 5.58-fold increase in iron absorption efficiency, reducing hematoma size significantly (from 8.674 to 4.768 cubic millimeters). This innovative Hb-responsive DNA hydrogel not only offers a therapeutic intervention for postoperative rehemorrhage but also provides self-diagnosis feedback, holding notable promise for enhancing clinical outcomes.

Background: Tumor-derived exosomal miRNAs play crucial roles in cancer diagnosis. Current studies aim to identify exosomal miRNAs associated with colorectal cancer (CRC) that are noninvasive, sensitive, and specific., Patients and Methods: Exosomes were extracted from CRC patients and healthy donors via ultracentrifugation, followed by verification via transmission electron microscopy (TEM), qNano, and Western blot analysis. The differential expression levels and clinical characteristics of miR-205-5p were analyzed in CRC via data from The Cancer Genome Atlas (TCGA). Real-time quantitative PCR was used to assess the expression levels of exosomal miRNAs in 157 primary CRC patients, 20 patients with benign diseases, and 135 healthy donors. Predictions regarding target genes were made to guide further exploration of the disease's etiopathogenesis through bioinformatics., Results: Compared with that in healthy donors, the expression of miR-205-5p in colorectal cancer (CRC) patients was significantly lower, as determined through analysis of the TCGA database. We conducted a prediction and analysis of the functional enrichment of downstream target genes regulated by miR-205-5p. A lower level of exosomal miR-205-5p in the serum of CRC patients than in that of healthy controls (p < 0.0001) and patients with benign disease (p < 0.0001) was observed. Furthermore, the expression levels of exosomal miR-205-5p were significantly lower in early-stage CRC patients than in the comparison groups (p<0.001 and p < 0.0001). Notably, the expression levels of exosomal miR-205-5p significantly increased postoperatively (p = 0.0053)., Conclusions: The present study demonstrated that serum exosomal miR-205-5p may be a diagnostic biomarker for CRC., (© 2024. The Author(s).)

MicroRNA (miRNA) detection is a critical aspect of disease diagnosis, and recent studies indicate that miRNA-622 could be a potential target for lung cancer. Herein, Cu single atoms were anchored on graphitic carbon nitride (Cu SAs@CN) as a coreaction accelerator applied in luminol-H 2 O 2 system, thereby establishing an efficient and sensitive electrochemiluminescence (ECL) biosensor for miRNA-622 detection. Cu SAs@CN was explored to possess excellent enzyme-like activities that promote the generation of abundant reactive oxygen species, which amplified ECL emission. Meanwhile, in order to improve the accuracy and sensitivity for miRNA-622 detection, the highly specific trans-cleavage ability of CRISPR/Cas12a was combined with a catalytic hairpin assembly strategy. Therefore, an ECL biosensor for miRNA-622 detection was systematically constructed as a proof of concept, achieving an ultralow limit of detection of 1.09 fM, and the feasibility was demonstrated in human serum samples. The findings of this research provide a promising strategy to enhance the ECL response using versatile single-atom catalysts, thus advancing the development of ECL biosensing applications.

Currently, chemicals and waste are recognized as key drivers of habitat degradation and biodiversity loss in aquatic ecosystems. To ensure vibrant habitats for aquatic species and maintain a sustainable aquatic food supply system, Japan promulgated its Environmental Quality Standards for the Conservation of Aquatic Life (EQS-CAL), based on its own aquatic life water quality criteria (ALWQC) derivation method and application mechanism. Here we overview Japan's EQS-CAL framework and highlight their best practices by examining the framework systems and related policies. Key experiences from Japan's EQS-CAL system include: (1) Classifying six types of aquatic organisms according to their adaptability to habitat status; (2) Using a risk-based chemical screening system for three groups of chemical pollutants; (3) Recommending a five-step method for determining ALWQC values based on the most sensitive life stage of the most sensitive species; (4) Applying site-specific implementation mechanisms through a series of Plan-Do-Check-Act loops. This paper offers scientific references for other jurisdictions, aiding in the development of more resilient ALWQC systems that can maintain healthy environments for aquatic life and potentially mitigate ongoing threats to human societies and global aquatic biodiversity., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Currently ischemic stroke poses a serious disease burden globally, and high fasting plasma glucose is one of the important risk factors. The aim of this study was to investigate the disease burden of ischemic stroke due to fasting glucose during 1990-2019 in China, to estimate the effect of age, period, and cohort on the trend of ischemic stroke disease burden, and to predict the disease burden of ischemic stroke in 2020-2030., Methods: Ischemic stroke burden data were obtained by screening from the Global Burden of Disease Study 2019 (GBD 2019) database for high-risk populations in China. Annual average percentage change (AAPC) was calculated using the Joinpoint regression model to assess the trend of ischemic stroke burden between 1990 and 2019. Age-period-cohort models were introduced to estimate the independent effects of age, period, and cohort on ischemic stroke burden, and to predict the ischemic stroke burden in 2020-2030 based on Bayesian age-period-cohort models., Results: From 1990 to 2019, the number of ischemic stroke deaths due to high fasting plasma glucose in China continued to increase with an AAPC of 3.61. Trends in age-standardized incidence rates did not show statistical significance. In the age-period-cohort analysis, the age effect of ischemic stroke burden showed a continuously increasing trend over the study period. The period effect showed an overall favorable trend over the study period. The overall and cohort effects for males showed an overall increasing trend, whereas the cohort effect for females showed a decreasing trend after a decreasing trend for the 1945 birth cohort., Conclusions: This study found that ischemic stroke due to high fasting plasma glucose in China has generally fluctuated between 1990 and 2019, with a decreasing trend in recent years, and projections also suggest that it will continue to show a decreasing trend in the future. Age and period of birth were the main elements influencing the burden of disease, especially among the elderly and men. Policies should be used to promote the prevention of known risk factors and to strengthen health management for key populations., 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 Tang, Xie and Liu.)

Graphene supported electrocatalysts have demonstrated remarkable catalytic performance for oxygen reduction reaction (ORR). However, their durability and cycling performance are greatly limited by Oswald ripening of platinum (Pt) and graphene support corrosion. Moreover, comprehensive studies on the mechanisms of catalysts degradation under 0.6-1.6 V versus RHE (Reversible Hydrogen Electrode) is still lacking. Herein, degradation mechanisms triggered by different defects on graphene supports are investigated by two cycling protocols. In the start-up/shutdown cycling (1.0-1.6 V vs. RHE), carbon oxidation reaction (COR) leads to shedding or swarm-like aggregation of Pt nanoparticles (NPs). Theoretical simulation results show that the expansion of vacancy defects promotes reaction kinetics of the decisive step in COR, reducing its reaction overpotential. While under the load cycling (0.6-1.0 V vs. RHE), oxygen containing defects lead to an elevated content of Pt in its oxidation state which intensifies Oswald ripening of Pt. The presence of vacancy defects can enhance the transfer of electrons from graphene to the Pt surface, reducing the d-band center of Pt and making it more difficult for the oxidation state of platinum to form in the cycling. This work will provide comprehensive understanding on Pt/Graphene catalysts degradation mechanisms., (© 2024 Wiley‐VCH GmbH.)

Background: To investigate whether protein induced by vitamin K antagonist-II (PIVKA-II) combined with alpha-fetoprotein (AFP) can improve the diagnostic and differential diagnostic accuracy of childhood hepatic tumors., Methods: A multi-center prospective observational study was performed at nine regional institutions around China. Children with hepatic mass (Group T) were divided into hepatoblastoma group (Group T HB ) and hemangioendothelioma group (Group T HE ), children with extrahepatic abdominal mass (Group C). Peripheral blood was collected from each patient prior to surgery or chemotherapy. The area under the curve (AUROC) was used to evaluate the diagnostic efficiency of PIVKA-II and the combined tumor markers with AFP., Results: The mean levels of PIVKA-II and AFP were both significantly higher in Group T than Group C (p = 0.001, p < 0.001), in Group T HB than Group T HE (p = 0.018, p = 0.013) and in advanced HB than non-advanced HB (p = 0.001, p = 0.021). For the diagnosis of childhood hepatic tumors, AUROC of PIVKA-II (cut-off value 32.6 mAU/mL) and AFP (cut-off value 120 ng/mL) was 0.867 and 0.857. The differential diagnostic value of PIVKA-II and AFP in hepatoblastoma from hemangioendothelioma was further assessed, AUROC of PIVKA-II (cut-off value 47.1mAU/mL) and AFP (cut-off value 560 ng/mL) was 0.876 and 0.743. The combined markers showed higher AUROC (0.891, 0.895 respectively) than PIVKA-II or AFP alone., Conclusions: The serum level of PIVKA-II was significantly higher in children with hepatic tumors, especially those with malignant tumors. The combination of PIVKA-II with AFP further increased the diagnostic performance., Trial Registration: Clinical Trials, NCT03645655. Registered 20 August 2018, https://www., Clinicaltrials: gov/ct2/show/NCT03645655 ., (© 2024. The Author(s).)

Chemoautotrophs, the crucial contributors to biological carbon fixation, derive energy from reducing specific inorganic substances and utilize CO 2 for growth. However, the release of extracellular free organic carbon (EFOC) by chemoautotrophic microorganisms can inhibit their own growth and metabolism. To reduce the feedback inhibition effect, a low-release biochar (BC-LR) was applied to adsorb EFOC. BC-LR not only adsorbed EFOC, but also selectively adsorbed the main inhibitory component, low molecular weight organics, in EFOC. In contrast, ordinary biochar could not effectively adsorb EFOC and its addition inhibited microbial growth and CO 2 fixation. In Transwell culture, BC-LR promoted microbial growth by 190% and CO 2 fixation by 29%, and exhibited better economic advantage, when compared with granular activated carbon. These findings provide a novel insight into the interaction between biochar and autotrophic microbial metabolism, offering an economically feasible approach to mitigate feedback inhibition of metabolites and promoting biological CO 2 fixation., 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.)

This study evaluated the reflection of long-term anaerobic system exposed to sulfate and propionate. Fe@C was found to efficiently mitigate anaerobic sulfate inhibition and enhance propionate degradation. With influent propionate of 12000mgCOD/L and COD/SO 4 2- ratio of 3.0, methane productivity and sulfate removal were only 0.06 ± 0.02L/gCOD and 63 %, respectively. Fe@C helped recover methane productivity to 0.23 ± 0.03L/gCOD, and remove sulfate completely. After alleviating sulfate stress, less organic substrate was utilized to form extracellular polymeric substances for self-protection, which enhanced mass transfer in anaerobic sludge. Microbial community succession, especially for alteration of key sulfate-reducing bacteria and propionate-oxidizing bacteria, was driven by Fe@C, thus enhancing sulfate reduction and propionate degradation. Acetotrophic Methanothrix and hydrogenotrophic unclassified&#95;f&#95;Methanoregulaceae were enriched to promote methanogenesis. Regarding propionate metabolism, inhibited methylmalonyl-CoA degradation was a limiting step under sulfate stress, and was mitigated by Fe@C. Overall, this study provides perspective on Fe@C's future application on sulfate and propionate rich wastewater treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Traumatic brain injury (TBI) among elderly individuals poses a significant global health concern due to the increasing ageing population., Methods: We searched PubMed, Cochrane Library, and Embase from database inception to Feb 1, 2024. Studies performed in inpatient settings reporting in-hospital mortality of elderly people (≥60 years) with TBI and/or identifying risk factors predictive of such outcomes, were included. Data were extracted from published reports, in-hospital mortality as our main outcome was synthesized in the form of rates, and risk factors predicting in-hospital mortality was synthesized in the form of odds ratios. Subgroup analyses, meta-regression and dose-response meta-analysis were used in our analyses., Findings: We included 105 studies covering 2217,964 patients from 30 countries/regions. The overall in-hospital mortality of elderly patients with TBI was 16 % (95 % CI 15 %-17 %) from 70 studies. In-hospital mortality was 5 % (95 % CI, 3 %-7 %), 18 % (95 % CI, 12 %-24 %), 65 % (95 % CI, 59 %-70 %) for mild, moderate and severe subgroups from 10, 7, and 23 studies, respectively. A decrease in in-hospital mortality over years was observed in overall (1981-2022) and in severe (1986-2022) elderly patients with TBI. Older age 1.69 (95 % CI, 1.58-1.82, P < 0.001), male gender 1.34 (95 % CI, 1.25-1.42, P < 0.001), clinical conditions including traffic-related cause of injury 1.22 (95 % CI, 1.02-1.45, P = 0.029), GCS moderate (GCS 9-12 compared to GCS 13-15) 4.33 (95 % CI, 3.13-5.99, P < 0.001), GCS severe (GCS 3-8 compared to GCS 13-15) 23.09 (95 % CI, 13.80-38.63, P < 0.001), abnormal pupillary light reflex 3.22 (95 % CI, 2.09-4.96, P < 0.001), hypotension after injury 2.88 (95 % CI, 1.06-7.81, P = 0.038), polytrauma 2.31 (95 % CI, 2.03-2.62, P < 0.001), surgical intervention 2.21 (95 % CI, 1.22-4.01, P = 0.009), pre-injury health conditions including pre-injury comorbidity 1.52 (95 % CI, 1.24-1.86, P = 0.0020), and pre-injury anti-thrombotic therapy 1.51 (95 % CI, 1.23-1.84, P < 0.001) were related to higher in-hospital mortality in elderly patients with TBI. Subgroup analyses according to multiple types of anti-thrombotic drugs with at least two included studies showed that anticoagulant therapy 1.70 (95 % CI, 1.04-2.76, P = 0.032), Warfarin 2.26 (95 % CI, 2.05-2.51, P < 0.001), DOACs 1.99 (95 % CI, 1.43-2.76, P < 0.001) were related to elevated mortality. Dose-response meta-analysis of age found an odds ratio of 1.029 (95 % CI, 1.024-1.034, P < 0.001) for every 1-year increase in age on in-hospital mortality., Conclusions: In the field of elderly patients with TBI, the overall in-hospital mortality and its temporal-spatial feature, the subgroup in-hospital mortalities according to injury severity, and dose-response meta-analysis of age were firstly comprehensively summarized. Substantial key risk factors, including the ones previously not elucidated, were identified. Our study is thus of help in underlining the importance of treating elderly TBI, providing useful information for healthcare providers, and initiating future management guidelines. This work underscores the necessity of integrating elderly TBI treatment and management into broader health strategies to address the challenges posed by the aging global population., Review Registration: PROSPERO CRD42022323231., 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.)

In this paper, a novel Moth-Flame Optimization (MFO) algorithm, namely MFO algorithm enhanced by Multiple Improvement Strategies (MISMFO) is proposed for solving parameter optimization in Multi-Kernel Support Vector Regressor (MKSVR), and the MISMFO-MKSVR model is further employed to deal with the software effort estimation problems. In MISMFO, the logistic chaotic mapping is applied to increase initial population diversity, while the mutation and flame number phased reduction mechanisms are carried out to improve the search efficiency, as well the adaptive weight adjustment mechanism is used to accelerate convergence and balance exploration and exploitation. The MISMFO model is verified on fifteen benchmark functions and CEC 2020 test set. The results show that the MISMFO has advantages over other meta-heuristic algorithms and MFO variants in terms of convergence speed and accuracy. Additionally, the MISMFO-MKSVR model is tested by simulations on five software effort datasets and the results demonstrate that the proposed model has better performance in software effort estimation problem. The Matlab code of MISMFO can be found at https://github.com/loadstar1997/MISMFO ., (© 2024. The Author(s).)

Biogeochemical processes mediated by plants and soil in coastal marshes are vulnerable to environmental changes and biological invasion. In particular, tidal inundation and salinity stress will intensify under future rising sea level scenarios. In this study, the interactive effects of flooding regimes (non-waterlogging vs. waterlogging) and salinity (0, 5, 15, and 30 parts per thousand (ppt)) on photosynthetic carbon allocation in plant, rhizodeposition, and microbial communities in native (Phragmites australis) and invasive (Spartina alterniflora) marshes were investigated using mesocosm experiments and 13 CO 2 pulse-labeling techniques. The results showed that waterlogging and elevated salinity treatments decreased specific root allocation (SRA) of 13 C, rhizodeposition allocation (RA) 13 C, soil 13 C content, grouped microbial PLFAs, and the fungal 13 C proportion relative to total PLFAs- 13 C. The lowest SRA, RA, and fungal 13 C proportion occurred under the combined waterlogging and high (30 ppt) salinity treatments. Relative to S. alterniflora, P. australis displayed greater sensitivity to hydrological changes, with a greater reduction in rhizodeposition, soil 13 C content, and fungal PLFAs. S. alterniflora showed an earlier peak SRA but a lower root/shoot 13 C ratio than P. australis. This suggests that S. alterniflora may transfer more photosynthetic carbon to the shoot and rhizosphere to facilitate invasion under stress. Waterlogging and high salinity treatments shifted C allocation towards bacteria over fungi for both plant species, with a higher allocation shift in S. alterniflora soil, revealing the species-specific microbial response to hydrological stresses. Potential shifts towards less efficient bacterial pathways might result in accelerated carbon loss. Over the study period, salinity was the primary driver for both species, explaining 33.2-50.8 % of 13 C allocation in the plant-soil-microbe system. We propose that future carbon dynamics in coastal salt marshes under sea-level rise conditions depend on species-specific adaptive strategies and carbon allocation patterns of native and invasive plant-soil systems., 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.)

Although multiple myeloma (MM) responds well to immunotherapeutic treatment, certain portions of MM are still unresponsive or relapse after immunotherapy. Other immune molecules are needed for the immunotherapy of MM. Here, we revealed that leukocyte immunoglobulin-like receptor B4 (LILRB4) was highly expressed in multiple myeloma cell lines and patient samples and that the expression of LILRB4 was adversely correlated with the overall survival of MM patients. Knockdown of LILRB4 efficiently delayed the growth of MM cells both in vitro and in vivo. Mechanistically, IKZF1 transactivated LILRB4 expression to trigger the downstream of STAT3-PFKFB1 pathways to support MM cell proliferation. Blockade of LILRB4 signaling by blocking antibodies can effectively inhibit MM progression. Our data show that targeting LILRB4 is potentially an additional therapeutic strategy for the immunotherapeutic treatment of MM., (© 2024. The Author(s).)

Successful dental pulp regeneration is closely associated with rapid revascularization and angiogenesis, processes driven by the Jagged1(JAG1)/Notch signaling pathway. However, soluble Notch ligands have proven ineffective in activating this pathway. To overcome this limitation, a Notch signaling hydrogel is developed by indirectly immobilizing JAG1, aimed at precisely directing the regeneration of vascularized pulp tissue. This hydrogel displays favorable mechanical properties and biocompatibility. Cultivating dental pulp stem cells (DPSCs) and endothelial cells (ECs) on this hydrogel significantly upregulate Notch target genes and key proangiogenic markers expression. Three-dimensional (3D) culture assays demonstrate Notch signaling hydrogels improve effectiveness by facilitating encapsulated cell differentiation, enhancing their paracrine functions, and promoting capillary lumen formation. Furthermore, it effectively communicates with the Wnt signaling pathway, creating an odontoinductive microenvironment for pulp-dentin complex formation. In vivo studies show that short-term transplantation of the Notch signaling hydrogel accelerates angiogenesis, stabilizes capillary-like structures, and improves cell survival. Long-term transplantation further confirms its capability to promote the formation of pulp-like tissues rich in blood vessels and peripheral nerve-like structures. In conclusion, this study introduces a feasible and effective hydrogel tailored to specifically regulate the JAG1/Notch signaling pathway, showing potential in advancing regenerative strategies for dental pulp tissue., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Pertussis is a highly contagious respiratory illness mainly caused by Bordetella pertussis (BP). Bordetella parapertussis (BPP) can induce symptoms compatible with pertussis, but has been underdiagnosed and underreported. The current pertussis vaccines offer low protection against BPP. Herein, we aim to reveal the epidemiology and genomic evolution of BPP in Shanghai, China., Methods: Children diagnosed with BPP infection from January 2017 to December 2022 in Shanghai, China were enrolled. We performed antimicrobial susceptibility testing (AST), multiple locus variable-number tandem repeat analysis (MLVA), and whole genome sequencing (WGS) analysis. A total of 260 international BPP genomes were chosen for comparison to investigate the genomic diversity and phylogenetic characteristics of Chinese strains within a global context., Results: Sixty patients were diagnosed with BPP infection by culture, with the positive ratio of 3.5‰ (60/17337) for BPP in nasopharyngeal swap samples. The average age of patients was 4.5 ± 0.3 years. BPPs contained four MLVA types including MT6 (65.0%), MT4 (26.7%), untype-1 (6.7%) and MT5 (1.7%), and none of strains showed resistance to macrolides. All strains carried virulence genotype of ptxP37/ptxA13/ptxB3/ptxC3/ptxD3/ptxE3/fim2-2/fim3-10 . MT4 and MT5 strains carried prn54 , whereas MT6 and untype-1 BPPs expressed prn101 . We identified two outbreaks after 2020 caused by MT4 and MT6 strains, each corresponding to distinct WGS-based phylogenetic lineages. The MT4-lineage is estimated to have originated around 1991 and has since spread globally, being introduced to China between 2005 and 2010. In contrast, the MT6-lineage was exclusively identified in China and is inferred to have originated around 2002., Conclusion: We revealed the genomic diversity of BPPs circulating in Shanghai, China, and reported the outbreaks of MT6 and MT4 BPPs after 2020. This is the first report on the emergence and regional outbreak of MT6 BPPs in the world, indicating that continuous surveillance on BPPs are thus required., 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 Fu, Li, Qin, Xie, Yang and Wang.)

Aim: To evaluate the efficacy and safety of triptorelin after radical prostatectomy (RP) in patients with negative lymph nodes., Methods: PRIORITI (NCT01753297) was a prospective, open-label, randomized, controlled, phase 4 study conducted in China and Russia. Patients with high-risk (Gleason score ≥ 8 and/or pre-RP prostate-specific antigen [PSA] ≥ 20 ng/mL and/or primary tumor stage 3a) prostate adenocarcinoma without evidence of lymph node or distant metastases were randomized to receive triptorelin 11.25 mg at baseline (≤ 8 weeks after RP) and at 3 and 6 months, or active surveillance. The primary endpoint was biochemical relapse-free survival (BRFS), defined as the time from randomization to biochemical relapse (BR; increased PSA > 0.2 ng/mL). Patients were monitored every 3 months for at least 36 months; the study ended when 61 BRs were observed., Results: The intention-to-treat population comprised 226 patients (mean [standard deviation] age, 65.3 [6.4] years), of whom 109 and 117 were randomized to triptorelin or surveillance, respectively. The median BRFS was not reached. The 25th percentile time to BRFS (95% confidence interval) was 39.1 (29.9-not estimated) months with triptorelin and 30.0 (18.6-42.1) months with surveillance (p = 0.16). There was evidence of a lower risk of BR with triptorelin versus surveillance but this was not statistically significant at the 5% level (p = 0.10). Chemical castration was maintained at month 9 in 93.9% of patients who had received triptorelin. Overall, triptorelin was well tolerated and had an acceptable safety profile., Conclusion: BRFS was observed to be longer with triptorelin than surveillance, but the difference was not statistically significant., (© 2024 The Author(s). Asia‐Pacific Journal of Clinical Oncology published by John Wiley & Sons Australia, Ltd.)

Background: The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell-cycle withdrawal. This translational study evaluated the effects and underlying mechanism of rhCHK1 (recombinant human checkpoint kinase 1) on the survival and proliferation of cardiomyocyte and myocardial repair after ischemia/reperfusion injury in swine., Methods and Results: Intramyocardial injection of rhCHK1 protein (1 mg/kg) encapsulated in hydrogel stimulated cardiomyocyte proliferation and reduced cardiac inflammation response at 3 days after ischemia/reperfusion injury, improved cardiac function and attenuated ventricular remodeling, and reduced the infarct area at 28 days after ischemia/reperfusion injury. Mechanistically, multiomics sequencing analysis demonstrated enrichment of glycolysis and mTOR (mammalian target of rapamycin) pathways after rhCHK1 treatment. Co-Immunoprecipitation (Co-IP) experiments and protein docking prediction showed that CHK1 (checkpoint kinase 1) directly bound to and activated the Serine 37 (S37) and Tyrosine 105 (Y105) sites of PKM2 (pyruvate kinase isoform M2) to promote metabolic reprogramming. We further constructed plasmids that knocked out different CHK1 and PKM2 amino acid domains and transfected them into Human Embryonic Kidney 293T (HEK293T) cells for CO-IP experiments. Results showed that the 1-265 domain of CHK1 directly binds to the 157-400 amino acids of PKM2. Furthermore, hiPSC-CM (human iPS cell-derived cardiomyocyte) in vitro and in vivo experiments both demonstrated that CHK1 stimulated cardiomyocytes renewal and cardiac repair by activating PKM2 C-domain-mediated cardiac metabolic reprogramming., Conclusions: This study demonstrates that the 1-265 amino acid domain of CHK1 binds to the 157-400 domain of PKM2 and activates PKM2-mediated metabolic reprogramming to promote cardiomyocyte proliferation and myocardial repair after ischemia/reperfusion injury in adult pigs.

Ubiquitination plays a pivotal regulatory role in tumor progression. Among the components of the ubiquitin-proteasome system (UPS), ubiquitin-protein ligase E3 has emerged as a key molecule. Nevertheless, the biological functions of E3 ubiquitin ligases and their potential mechanisms orchestrating glycolysis in gastric cancer (GC) remain to be elucidated. In this study, we conducted a comprehensive transcriptomic analysis to identify the core E3 ubiquitin ligases in GC, followed by extensive validation of the expression patterns and clinical significance of Tripartite motif-containing 50 (TRIM50) both in vitro and in vivo . Remarkably, we found that TRIM50 was downregulated in GC tissues, associated with malignant progression and poor patient survival. Functionally, overexpression of TRIM50 suppressed GC cell proliferation and indirectly mitigated the invasion and migration of GC cells by inhibiting the M2 polarization of tumor-associated macrophages (TAMs). Mechanistically, TRIM50 inhibited the glycolytic pathway by ubiquitinating Phosphoglycerate Kinase 1 (PGK1), thereby directly suppressing GC cell proliferation. Simultaneously, the reduction in lactate led to diminished M2 polarization of TAMs, indirectly inhibiting the invasion and migration of GC cells. Notably, the downregulation of TRIM50 in GC was mediated by the METTL3/YTHDF2 axis in an m6A-dependent manner. In our study, we definitively identified TRIM50 as a tumor suppressor gene (TSG) that effectively inhibits glycolysis and the malignant progression of GC by ubiquitinating PGK1, thus offering novel insights and promising targets for the diagnosis and treatment of GC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Mesenchymal stem cell (MSC)-based therapy is an effective strategy for regenerative therapy. However, safety and ease of use are still issues to be overcome in clinical applications. Exosomes are naturally derived nanoparticles containing bioactive molecules, which serve as ideal cell-free therapeutic modalities. However, issues such as delivery, long-term preservation and activity maintenance of exosomes are other problems that limit their application. In this study, we proposed the use of rapid freeze-dry-thaw macroporous hydrogels for the encapsulation of HucMSC-derived exosomes (HucMSC-Exos) combined with an antimicrobial peptide coating. This exosome-encapsulated hyaluronic acid macroporous hydrogel HD-DP7/Exo can achieve long-term storage and transport by lyophilization and can be rapidly redissolved for treatment. After comprehensively comparing the therapeutic effects of HucMSC-Exos and HucMSC-loaded hydrogels, we found that HucMSC-Exos could also effectively regulate fibroblasts, vascular endothelial cells, and macrophages and inhibit myofibroblast-mediated fibrosis, thus promoting tissue regeneration and inhibiting scar formation in a mouse model of deep second-degree burn infection healing. These properties of lyophilized storage and whole-process-repair make HD-DP7/Exo have potential application value and application prospects., Competing Interests: Declaration of competing interest The authors declare that they have no competition of interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

G protein-coupled receptors (GPCRs) are expressed in a variety of cell types and tissues, and activation of GPCRs is involved in enormous metabolic pathways, including nutrient synthesis, transportation, storage or insulin sensitivity, etc. This review intends to summarize the regulation of metabolic homeostasis and mechanisms by a series of GPCRs, such as GPR91, GPR55, GPR119, GPR109a, GPR142, GPR40, GPR41, GPR43 and GPR120. With deep understanding of GPCR's structure and signaling pathways, it is attempting to uncover the role of GPCRs in major metabolic diseases, including metabolic syndrome, diabetes, dyslipidemia and nonalcoholic steatohepatitis, for which the global prevalence has risen during last two decades. An extensive list of agonists and antagonists with their chemical structures in a nature of small molecular compounds for above-mentioned GPCRs is provided as pharmacologic candidates, and their preliminary data of preclinical studies are discussed. Moreover, their beneficial effects in correcting abnormalities of metabolic syndrome, diabetes and dyslipidemia are summarized when clinical trials have been undertaken. Thus, accumulating data suggest that these agonists or antagonists might become as new pharmacotherapeutic candidates for the treatment of metabolic diseases., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

The peroxisome is a versatile organelle that performs diverse metabolic functions. PEX3, a critical regulator of the peroxisome, participates in various biological processes associated with the peroxisome. Whether PEX3 is involved in peroxisome-related redox homeostasis and myocardial regenerative repair remains elusive. We investigate that cardiomyocyte-specific PEX3 knockout (Pex3-KO) results in an imbalance of redox homeostasis and disrupts the endogenous proliferation/development at different times and spatial locations. Using Pex3-KO mice and myocardium-targeted intervention approaches, the effects of PEX3 on myocardial regenerative repair during both physiological and pathological stages are explored. Mechanistically, lipid metabolomics reveals that PEX3 promotes myocardial regenerative repair by affecting plasmalogen metabolism. Further, we find that PEX3-regulated plasmalogen activates the AKT/GSK3β signaling pathway via the plasma membrane localization of ITGB3. Our study indicates that PEX3 may represent a novel therapeutic target for myocardial regenerative repair following injury., (© 2024. The Author(s).)

Objective: To construct and internally validate a nomogram that predicts the likelihood of postoperative delirium in a cohort of elderly individuals undergoing hip arthroplasty., Methods: Data for a total of 681 elderly patients underwent hip arthroplasty were retrospectively collected and divided into a model ( n  = 477) and a validation cohort ( n  = 204) according to the principle of 7:3 distribution temporally. The assessment of postoperative cognitive function was conducted through the utilization of The Confusion Assessment Method (CAM). The nomogram model for postoperative cognitive impairments was established by a combination of Lasso regression and logistic regression. The receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis (DCA) were used to evaluate the performance., Results: The nomogram utilized various predictors, including age, body mass index (BMI), education, preoperative Barthel Index, preoperative hemoglobin level, history of diabetes, and history of cerebrovascular disease, to forecast the likelihood of postoperative delirium in patients. The area under the ROC curves (AUC) for the nomogram, incorporating the aforementioned predictors, was 0.836 (95% CI: 0.797-0.875) for the training set and 0.817 (95% CI: 0.755-0.880) for the validation set. The calibration curves for both sets indicated a good agreement between the nomogram's predictions and the actual probabilities., Conclusion: The use of this novel nomogram can help clinicians predict the likelihood of delirium after hip arthroplasty in elderly patients and help prevent and manage it in advance.

Recently, the utilization of hydrogen-bonded organic frameworks (HOFs) with high crystallinity and inherent well-defined H-bonding networks in the field of proton conduction has received increasing attention, but obtaining HOFs with excellent water stability and prominent proton conductivity (σ) remains challenging. Herein, by employing functionalized terephthalic acids, 2,5-dihydroxyterephthalic acid, 2-hydroxyterephthalic acid, 2-nitro terephthalic acid, and terephthalic acid, respectively, four highly water-stable ionic HOFs (iHOFs), [(C 8 H 5 O 6 )(Me 2 NH 2 )]∙2H 2 O (iHOF 1), [(C 8 H 5 O 5 )(Me 2 NH 2 )] (iHOF 2), [(C 8 H 4 NO 6 )(Me 2 NH 2 )] (iHOF 3) and [(C 8 H 5 O 4 )(Me 2 NH 2 )] (iHOF 4) were efficiently prepared by a straightforward synthesis approach in DMF and H 2 O solutions. The alternating-current (AC) impedance testing in humid conditions revealed that all four iHOFs were temperature- and humidity-dependent σ, with the greatest value reaching 10 -2 S·cm -1 . As expected, the high density of free carboxylic acid groups, crystallization water, and protonated [Me 2 NH 2 ] + units offer adequate protons and hydrophilic environments for effective proton transport. Furthermore, the σ values of these iHOFs with different functional groups were compared. It was discovered that it dropped in the following order under 100 °C and 98 % relative humidity (RH): σ iHOF 1 (1.72 × 10 -2 S·cm -1 ) > σ iHOF 2 (4.03 × 10 -3 S·cm -1 ) > σ iHOF 3 (1.46 × 10 -3 S·cm -1 ) > σ iHOF 4 (4.86 × 10 -4 S·cm -1 ). Finally, we investigated the causes of the above differences and the proton transport mechanism inside the framework using crystal structure data, water contact angle tests, and activation energy values. This study provides new motivation to develop highly proton-conductive materials., 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.)

Objective: Postoperative cognitive dysfunction (POCD) is a serious surgical complication. We assessed the different POCD incidences between anesthesia using sevoflurane and sevoflurane combined with dexmedetomidine, with propofol-based sedation in elderly patients who underwent a thoracic surgical procedure., Methods: A total of 90 patients aged 65 to 80 years old who underwent a thoracic surgical procedure at our hospital and 15 nonsurgical participants as controls, were enrolled in this study. Patients were divided in a randomized 1:1:1 ratio into 3 groups. All participants were randomized into a trial with three anesthesia groups (P, PS, PSD) or a control group (C) of healthy matches. All trial groups received distinct anesthetic combinations during surgery, while controls mirrored patient criteria.Group P (propofol and remifentanil were maintained during the surgery), Group PS (propofol, remifentanil, and sevoflurane were maintained during the surgery), and Group PSD (propofol, remifentanil, sevoflurane, and dexmedetomidine were maintained during the surgery).All participants were rated using a series of cognitive assessment scales before and three days after surgery. All participants were interviewed over the telephone, 7 days, 30 days, and 90 days postoperatively., Results: POCD incidences in the PSD (combined anesthetization with propofol, sevoflurane, and dexmedetomidine) group was significantly lower than that in the PS (combined anesthetization with propofol and sevoflurane) group, 1 day post-surgery (10.0% vs. 40.0%, P = 0.008), and the results were consistent at 3 days post-surgery. When the patients were assessed 7 days, 30 days, and 90 days postoperatively, there was no significant difference in POCD incidence among the three groups. Multivariate logistic regression analysis of POCD one day after surgery showed that education level was negatively correlated with incidence of POCD (P = 0.018) and single lung ventilation time was positively correlated with incidence of POCD (P = 0.001)., Conclusion: For elderly patients who underwent a thoracic surgical procedure, dexmedetomidine sedation shows an obvious advantage on improving short-term POCD incidence, which is caused by sevoflurane., (© 2024. The Author(s).)

The arrest of neural crest-derived sympathoadrenal neuroblast differentiation contributes to neuroblastoma formation, and overriding this blocked differentiation is a clear strategy for treating high-risk neuroblastoma. A better understanding of neuroblast or neuroblastoma differentiation is essential for developing new therapeutic approaches. It has been proposed that Krueppel-like factor 7 (KLF7) is a neuroblastoma super-enhancer-associated transcription factor gene. Moreover, KLF7 was found to be intensely active in postmitotic neuroblasts of the developing nervous system during embryogenesis. However, the role of KLF7 in the differentiation of neuroblast or neuroblastoma is unknown. Here, we find a strong association between high KLF7 expression and favorable clinical outcomes in neuroblastoma. KLF7 induces differentiation of neuroblastoma cells independently of the retinoic acid (RA) pathway and acts cooperatively with RA to induce neuroblastoma differentiation. KLF7 alters the GTPase activity and multiple differentiation-related genes by binding directly to the promoters of neuroblast differentiation-associated protein (AHNAK and AHNAK2) and glycerophosphodiester phosphodiesterase domain-containing protein 5 (GDPD5) and regulating their expression. Furthermore, we also observe that silencing KLF7 in neuroblastoma cells promotes the adrenergic-to-mesenchymal transition accompanied by changes in enhancer-mediated gene expression. Our results reveal that KLF7 is an inducer of neuroblast or neuroblastoma differentiation with prognostic significance and potential therapeutic value., (© 2024 Federation of European Biochemical Societies.)

Purpose: As one of the most important breakthroughs in cancer therapy, immune checkpoint inhibitors have greatly prolonged survival of patients with breast cancer. However, their application and efficacy are limited, especially for advanced HER2-negative breast cancer. It has been reported that epigenetic modulation of the histone deacetylase (HDAC) inhibitor chidamide, as well as immune microenvironment modulation of radiotherapy are potentially synergistic with immunotherapy. Thus, the combination of chidamide, radiotherapy and immunotherapy is expected to improve prognosis of patients with advanced HER2-negative breast cancer., Patients and Methods: This is a single-arm, open, prospective clinical trial investigating the efficacy and safety of the combination of HDAC inhibitor chidamide, anti-PD-1 antibody sintilimab, and the novel immuno-radiotherapy, which aims to enhance efficacy of immunotherapy, in subsequent lines of therapy of HER2-negative breast cancer. Our study will include 35 patients with advanced breast cancer that has failed endocrine therapy and first-line chemotherapy. Participants will receive 30 mg of chidamide twice a week, 200 mg of sintilimab once every 3 weeks, combined with immuno-radiotherapy. Radiotherapy will be centrally 8 Gy for at least one lesion, and at least 1 Gy for the other lesions. We will complete three fractions of radiotherapy in one cycle. The primary endpoint is progression-free survival, and secondary endpoints are objective response rate, disease control rate and safety. Moreover, biomarkers including cytokines and lymphocyte subgroups will be explored., Conclusion: As a single-arm clinical trial, the analysis of the influence of each single treatment is limited. Besides, our study is an open study, which involves neither randomization nor blinding. In spite of the abovementioned limitations, this prospective clinical trial will give an insight into subsequent lines of therapy of HER2-negative advanced breast cancer, prolong the survival or achieve long remission for these participants, and identify potential responders., Competing Interests: The authors declare no conflict of interests., (© 2024 Zhang et al.)

We conducted a bi-directional two-sample Mendelian randomization (MR) analysis to investigate the causal associations between immune cell traits and hepatocellular carcinoma (HCC) and identified the mediating factor of metabolites. The exposure factors were immune cell traits, the mediators were metabolites, and the outcome variable was HCC. Inverse-variance weighted method (IVW) was the main method. Weighted median, MR-Egger regression, weighted mode, simple mode, and MR pleiotropy residual sum and outlier (MRPRESSO) methods were used as complementary methods. The results were tested by using the Bayesian weighted Mendelian randomization (BWMR) approach in our MR study. Subsequently, the potential mediating effect was investigated by conducting a two-step mediation analysis. We identified 26 traits with suggestive correlations between immune cell traits and HCC, with 4 immune cell traits among them having causal correlations with HCC. There were no causal correlations between HCC and immune cell traits in the reverse MR analysis. In the mediation analysis, we found a positive causal association between B cell-activating factor receptors (BAFF-R) on IgD+ CD24- B cell and HCC [IVW: odd ratio (OR), 0.845; 95% CI, 0.759-0.942; p = 0.002]. Phenylacetylglutamate (PAG) levels mediated 7.353% of the causal pathway from BAFF-R on IgD+ CD24- B cell and HCC. In conclusion, BAFF-R on IgD+ CD24- B cell lowers risk of HCC, with PAG levels playing a mediating role., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Treatment of advanced triple-negative breast cancer (TNBC) is a great challenge in clinical practice. The immune checkpoints are a category of immunosuppressive molecules that cancer could hijack and impede anti-tumor immunity. Targeting immune checkpoints, such as anti-programmed cell death 1 (PD-1) therapy, is a promising therapeutic strategy in TNBC. The efficacy and safety of PD-1 monoclonal antibody (mAb) with chemotherapy have been validated in TNBC patients. However, the precise mechanisms underlying the synergistic effect of chemotherapy and anti-PD-1 therapy have not been elucidated, causing the TNBC patients that might benefit from this combination regimen not to be well selected. In the present work, we found that IL-23, an immunological cytokine, is significantly upregulated after chemotherapy in TNBC cells and plays a vital role in enhancing the anti-tumor immune response of cytotoxic T cells (CTLs), especially in combination with PD-1 mAb. In addition, the combination of IL-23 and PD-1 mAb could synergistically inhibit the expression of Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), which is a regulatory subunit of PI3K and inhibit p110 activity, and promote phosphorylation of AKT in TNBC-specific CTLs. Our findings might provide a molecular marker that could be used to predict the effects of combination chemotherapy therapy and PD-1 mAb in TNBC., (© 2024. The Author(s).)

Background: Angiogenesis plays a pivotal role in colorectal cancer (CRC), yet its underlying mechanisms demand further exploration. This study aimed to elucidate the significance of angiogenesis-related genes (ARGs) in CRC through comprehensive multi-omics analysis., Methods: CRC patients were categorized according to ARGs expression to form angiogenesis-related clusters (ARCs). We investigated the correlation between ARCs and patient survival, clinical features, consensus molecular subtypes (CMS), cancer stem cell (CSC) index, tumor microenvironment (TME), gene mutations, and response to immunotherapy. Utilizing three machine learning algorithms (LASSO, Xgboost, and Decision Tree), we screen key ARGs associated with ARCs, further validated in independent cohorts. A prognostic signature based on key ARGs was developed and analyzed at the scRNA-seq level. Validation of gene expression in external cohorts, clinical tissues, and blood samples was conducted via RT-PCR assay., Results: Two distinct ARC subtypes were identified and were significantly associated with patient survival, clinical features, CMS, CSC index, and TME, but not with gene mutations. Four genes (S100A4, COL3A1, TIMP1, and APP) were identified as key ARCs, capable of distinguishing ARC subtypes. The prognostic signature based on these genes effectively stratified patients into high- or low-risk categories. scRNA-seq analysis showed that these genes were predominantly expressed in immune cells rather than in cancer cells. Validation in two external cohorts and through clinical samples confirmed significant expression differences between CRC and controls., Conclusion: This study identified two ARG subtypes in CRC and highlighted four key genes associated with these subtypes, offering new insights into personalized CRC treatment strategies., 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 Wei, Xie, Liu, Deng, Chen, Lv, Tang and Hu.)

Oral squamous cell carcinoma (OSCC) is an aggressive cancer that poses a substantial threat to human life and quality of life globally. Lipid metabolism reprogramming significantly influences tumor development, affecting not only tumor cells but also tumor-associated macrophages (TAMs) infiltration. SOAT1 , a critical enzyme in lipid metabolism, holds high prognostic value in various cancers. This study revealed that SOAT1 is highly expressed in OSCC tissues and positively correlated with M2 TAMs infiltration. Increased SOAT1 expression enhanced the capabilities of cell proliferation, tumor sphere formation, migration, and invasion in OSCC cells, upregulated the SREBP1-regulated adipogenic pathway, activated the PI3K/AKT/mTOR pathway and promoted M2-like polarization of TAMs, thereby contributing to OSCC growth both in vitro and in vivo . Additionally, we explored the upstream transcription factors that regulate SOAT1 and discovered that ETS1 positively regulates SOAT1 expression levels. Knockdown of ETS1 effectively inhibited the malignant phenotype of OSCC cells, whereas restoring SOAT1 expression significantly mitigated this suppression. Based on these findings, we suggest that SOAT1 is regulated by ETS1 and plays a pivotal role in the development of OSCC by facilitating lipid metabolism and M2-like polarization of TAMs. We propose that SOAT1 is a promising target for OSCC therapy with tremendous potential., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Microcystins (MCs) have a significant influence on aquatic ecosystems, but little is known about their terrestrial fate and impact. Here, we investigated the fate of two MCs (MC-LR and MC-RR) in the soil-earthworm system, with consideration of their congener-specific impact on earthworm health, soil bacteria, and soil metabolome. Although MCs had little acute lethal effect on earthworms, they caused obvious growth inhibition and setae rupture. Relative to MC-RR, MC-LR exhibited higher bioaccumulation and the resulting dermal lesions and deformation of longitudinal muscles. While the incorporation of both MCs into soils stimulated pathogenic bacteria and depressed oxidative stress tolerant bacteria, the response among soil nitrification and glutathione metabolism differed between the two congeners. The dissipation kinetics of MCs obeyed the first-order model. Earthworms stimulated soil N-cycling enzyme activities, increased the abundance of MC-degrading bacteria, and promoted bacterial metabolic functions related to glutathione metabolism, xenobiotics biodegradation, and metabolism of amino acids that comprise MCs, which accelerated the dissipation of MC-LR and MC-RR by 227% and 82%, respectively. These results provide evidence of significant congener differences in the terrestrial fate and impact of MCs, which will enable a better understanding of their role in mediating soil functions and ecosystem services., 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.)

Objectives: The aim of this study was to investigate the ameliorative effect of platycodin D (PD) on cognitive dysfunction in type 2 diabetes mellitus (T2DM) and its potential molecular mechanisms of action in vivo and in vitro. Materials and methods: An animal model of cognitive impairment in T2DM was established using a single intraperitoneal injection of streptozotocin (100 mg/kg) after 8 weeks of feeding a high-fat diet to C57BL/6 mice. In vitro, immunofluorescence staining and Western blot were employed to analyze the effects of PD on glucose-induced neurotoxicity in mouse hippocampal neuronal cells (HT22). Results: PD (2.5 mg/kg) treatment for 4 weeks significantly suppressed the rise in fasting blood glucose in T2DM mice, improved insulin secretion deficiency, and reversed abnormalities in serum triglyceride, cholesterol, low-density lipoprotein, and high-density lipoprotein levels. Meanwhile, PD ameliorated choline dysfunction in T2DM mice and inhibited the production of oxidative stress and apoptosis-related proteins of the caspase family. Notably, PD dose-dependently prevents the loss of mitochondrial membrane potential, promotes phosphorylation of phosphatidylinositol 3 kinase and protein kinase B (Akt) in vitro, activates glycogen synthase kinase 3β (GSK3β) expression at the Ser9 site, and inhibits Tau protein hyperphosphorylation. Conclusions: These findings clearly indicated that PD could alleviate the neurological damage caused by T2DM, and the phosphorylation of Akt at Ser473 may be the key to its effect.

Orofacial muscle defect due to congenital anomalies, tumour ablation or traumatic accident that exceeds endogenous regeneration capacity may lead to sustained deficits in masticatory function and nutrition intake. Functional recovery has always been the goal of muscle tissue repair, but currently, there is no suitable model for quantitative analyses of either functional consequences or treatment efficacy of orofacial muscle defect. This study proposed a critical size volumetric muscle loss (VML) model in mouse masseter with impaired mastication on nutrition. Full-thickness VML defects in diameter of 1.0, 1.5, 2.0 and 3.0 mm were generated in the centre of the mouse masseter using a biopsy punch to determine the critical size for functional impairment. In the VML region, myogenesis was dampened but fibrogenesis was activated, as long with a reduction in the density of the neuromuscular junction and an increase in vascular density. Accordingly, persistent fibrosis was observed in the centre region of VML in all diameters. The 2.0 mm diameter was the critical threshold to masticatory function impairment after VML in the masseter. VML of 3.0 mm diameter led to a significant impact on nutrition intake and body weight gain. Autologous muscle graft effectively relieved the fibrosis and functional deficit after VML injury in the masseter. This model serves as a reliable tool in studying functional recovery strategies for orofacial muscle defects., (© 2024 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Prostate cancer causes numerous male deaths annually. Although great progress has been made in the diagnosis and treatment of prostate cancer during the past several decades, much about this disease remains unknown, especially its pathobiology. The kinesin superfamily is a pivotal group of motor proteins, that contains a microtubule-based motor domain and features an adenosine triphosphatase activity and motility characteristics. Large-scale sequencing analyses based on clinical samples and animal models have shown that several members of the kinesin family are dysregulated in prostate cancer. Abnormal expression of kinesins could be linked to uncontrolled cell growth, inhibited apoptosis and increased metastasis ability. Additionally, kinesins may be implicated in chemotherapy resistance and escape immunologic cytotoxicity, which creates a barrier to cancer treatment. Here we cover the recent advances in understanding how kinesins may drive prostate cancer progression and how targeting their function may be a therapeutic strategy. A better understanding of kinesins in prostate cancer tumorigenesis may be pivotal for improving disease outcomes in prostate cancer patients., 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.)

Dual-source drinking water distribution systems (DWDS) over single-source water supply systems are becoming more practical in providing water for megacities. However, the more complex water supply problems are also generated, especially at the hydraulic junction. Herein, we have sampled for a one-year and analyzed the water quality at the hydraulic junction of a dual-source DWDS. The results show that visible changes in drinking water quality, including turbidity, pH, UV 254 , DOC, residual chlorine, and trihalomethanes (TMHs), are observed at the sample point between 10 and 12 km to one drinking water plant. The average concentration of residual chlorine decreases from 0.74 ± 0.05 mg/L to 0.31 ± 0.11 mg/L during the water supplied from 0 to 10 km and then increases to 0.75 ± 0.05 mg/L at the end of 22 km. Whereas the THMs shows an opposite trend, the concentration reaches to a peak level at hydraulic junction area (10-12 km). According to parallel factor (PARAFAC) and high-performance size-exclusion chromatography (HPSEC) analysis, organic matters vary significantly during water distribution, and tryptophan-like substances and amino acids are closely related to the level of THMs. The hydraulic junction area is confirmed to be located at 10-12 km based on the water quality variation. Furthermore, data-driven models are established by machine learning (ML) with test R 2 higher than 0.8 for THMs prediction. And the SHAP analysis explains the model results and identifies the positive (water temperature and water supply distance) and negative (residual chlorine and pH) key factors influencing the THMs formation. This study conducts a deep understanding of water quality at the hydraulic junction areas and establishes predictive models for THMs formation in dual-sources DWDS., 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.)

Neutrophil extracellular traps (NETs) and pyroptosis are critical events in lung injury. This study investigated whether ficolin-A influenced NET formation through pyroptosis to exacerbate lipopolysaccharide (LPS)-induced lung injury. The expression of ficolin-A/2, NETs, and pyroptosis-related molecules was investigated in animal and cell models. Knockout and knockdown (recombinant protein) methods were used to elucidate regulatory mechanisms. The Pearson correlation coefficient was used to analyze the correlation between ficolins and pyroptosis- and NET-related markers in clinical samples. In this study, ficolin-2 (similar to ficolin-A) showed significant overexpression in patients with acute respiratory distress syndrome. In vivo, knockout of Fcna, but not Fcnb, attenuated lung inflammation and inhibited NET formation in the LPS-induced mouse model. DNase I further alleviated lung inflammation and NET formation in Fcna knockout mice. In vitro, neutrophils derived from Fcna -/-  mice showed less pyroptosis and necroptosis than those from the control group after LPS stimulation. Additionally, GSDMD knockdown or Nod-like receptor protein 3 inhibitor reduced NET formation. Addition of recombinant ficolin-2 protein to human peripheral blood neutrophils promoted NET formation and pyroptosis after LPS stimulation, whereas Fcn2 knockdown had the opposite effect. Acute respiratory distress syndrome patients showed increased levels of pyroptosis- and NET-related markers, which were correlated positively with ficolin-2 levels. In conclusion, these results suggested that ficolin-A/2 exacerbated NET formation and LPS-induced lung injury via gasdermin D-mediated pyroptosis., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Oxaliplatin resistance poses a significant challenge in colorectal cancer (CRC) therapy, necessitating further investigation into the underlying molecular mechanisms. This study aimed to elucidate the regulatory role of SNHG4 in oxaliplatin resistance and ferroptosis in CRC. Our findings revealed that treatment with oxaliplatin led to downregulation of SNHG4 expression in CRC cells, while resistant CRC cells exhibited higher levels of SNHG4 compared to parental cells. Silencing SNHG4 attenuated oxaliplatin resistance and reduced the expression of resistance-related proteins MRD1 and MPR1. Furthermore, induction of ferroptosis effectively diminished oxaliplatin resistance in both parental and resistant CRC cells. Notably, ferroptosis induction resulted in decreased SNHG4 expression, whereas SNHG4 overexpression suppressed ferroptosis. Through FISH, RIP, and RNA pull-down assays, we identified the cytoplasmic localization of both SNHG4 and PTEN, establishing that SNHG4 directly targets PTEN, thereby reducing mRNA stability in CRC cells. Silencing PTEN abrogated the impact of SNHG4 on oxaliplatin resistance and ferroptosis in CRC cells. In vivo experiments further validated the influence of SNHG4 on oxaliplatin resistance and ferroptosis in CRC cells through PTEN regulation. In conclusion, SNHG4 promotes resistance to oxaliplatin in CRC cells by suppressing ferroptosis through instability of PTEN, thus serves as a target for patients with oxaliplatin-base chemoresistance., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)