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Ischemia-free liver transplantation (IFLT) is developed as a novel clinical approach to avoid ischemia-reperfusion injury (IRI). This study aims to identify the most distinguished programmed cell death pathway in grafts undergoing IFLT versus conventional liver transplantation (CLT) and to explore the underlying mechanism. Ferroptosis is the most distinct programmed cell death form between IFLT and CLT grafts. Among various cell death inhibitors, the ferroptosis inhibitor (Ferrostain-1) is the most effective one to prevent hepatocytes from damage induced by oxygen deprivation/reoxygenation (OGD/R). Hepatocyte ferroptosis is significantly alleviated in IFLT versus CLT grafts in both human beings and pigs. Ubiquitination enzyme screening identifies augmented amounts of ubiquitin-specific protease 19 (USP19) in IFLT versus CLT grafts. The upregulation of USP19 in the grafts is correlated with reduced pathological Suzuki's score, lower post-transplant peak liver enzyme level, and less early allograft dysfunction in liver transplant recipients. USP19 overexpression mitigates post-transplant liver injury in mice. Mechanistically, USP19 inhibits the degradation of solute carrier family 7 member 11 (SLC7A11) by removing its K63-linked ubiquitin chains. Notably, USP19 overexpression reduces ferroptosis and IRI in a SLC7A11-dependent manner in mice. Collectively, USP19-mediated suppression of hepatocyte ferroptosis via deubiquitinating SLC7A11 is a key mechanism by which IFLT abrogates graft IRI., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Immune evasion by tumors is promoted by low T cell infiltration, ineffective T cell activity directed against the tumor, and reduced tumor antigen presentation. The TET2 DNA dioxygenase gene is frequently mutated in hematopoietic malignancies and loss of TET enzymatic activity is found in a variety of solid tumors. We showed previously that vitamin C (VC), a cofactor of TET2, enhances tumor-associated T cell recruitment and checkpoint inhibitor therapy responses in a TET2-dependent manner. Using single-cell RNA sequencing (scRNA-seq) analysis performed on B16-OVA melanoma tumors, we have shown here that an additional function for TET2 in tumors is to promote expression of certain antigen presentation machinery genes, which is potently enhanced by VC. Consistently, VC promoted antigen presentation in cell-based and tumor assays in a TET2-dependent manner. Quantifying intercellular signaling from the scRNA-seq dataset showed that T cell-derived IFN-γ-induced signaling within the tumor and tumor microenvironment requires tumor-associated TET2 expression, which is enhanced by VC treatment. Analysis of patient tumor samples indicated that TET activity directly correlates with antigen presentation gene expression and with patient outcomes. Our results demonstrate the importance of tumor-associated TET2 activity as a critical mediator of tumor immunity, which is augmented by high-dose VC therapy.

Graves' disease (GD) is an autoimmune condition that can progress to Graves' ophthalmopathy (GO), leading to irreversible damage to orbital tissues and potential blindness. The pathogenic mechanism is not fully understood. In this study, we conducted single-cell multi-omics analyses on healthy individuals, patients with GD without GO, newly diagnosed patients with GO, and treated patients with GO. Our findings revealed gradual systemic inflammation during GO progression, marked by overactivation of cytotoxic effector T cell subsets, and expansion of specific T cell receptor clones. Importantly, we observed a decline in the immunosuppressive function of activated Treg (aTreg) accompanied by a cytotoxic phenotypic transition. In vitro experiments revealed that dysfunction and transition of GO-autoreactive Treg were regulated by the yin yang 1 (YY1) upon secondary stimulation of thyroid stimulating hormone receptor (TSHR) under inflammatory conditions. Furthermore, adoptive transfer experiments of the GO mouse model confirmed infiltration of these cytotoxic Treg into the orbital lesion tissues. Notably, these cells were found to upregulate inflammation and promote pathogenic fibrosis of orbital fibroblasts (OFs). Our results reveal the dynamic changes in immune landscape during GO progression and provide direct insights into the instability and phenotypic transition of Treg, offering potential targets for therapeutic intervention and prevention of autoimmune diseases.

Lung adenocarcinoma (LUAD) is one of the leading causes of cancer-related deaths worldwide, with a 5-year survival rate of approximately 19%. With the advent of screening and diagnostic techniques such as low-dose spiral CT and liquid biopsy, the detection rate of early stage LUAD is increasing. Even in stage I LUAD, the cumulative 5-year recurrence rate after radical surgical resection is 17.9%. This may be related to the presence of microscopic residual disease (MRD), a potential source of recurrence and metastasis. Circulating tumour cells (CTCs) are key biomarkers in liquid biopsies, but the ability of dynamic CTC detection to monitor MRD and warn of recurrence in patients with early LUAD has not been validated. Here, we conducted a prospective study using the telomerase reverse transcriptase-based CTC detection method (TBCD) to evaluate perioperative and follow-up CTC levels for dynamic monitoring to evaluate its clinical efficacy in predicting postoperative recurrence in early-stage LUAD. By longitudinal dynamic monitoring of CTC, we accurately predicted recurrence within 2 years after surgery, with an AUC of 0.9786, demonstrating the clinical values of CTC in predicting recurrence. The median lead time from positive detection of CTC to radiological recurrence was 183 days, with the earliest CT recurrence predicted 354 days in advance. Taken together, our study demonstrates that longitudinal monitoring of CTC is effective in early warning of LUAD recurrence and provides valuable information on early detection and intervention strategies for the management of LUAD., Competing Interests: Declarations. Ethics approval and consent to participate: The study complied with all relevant ethical regulations and was approved by the Ethics Committee of the National Cancer Center/Cancer Hospital of Peking Union Medical College, Chinese Academy of Medical Sciences (No. 21/093–2764). All participants provided written informed consent. Consent for publication: Written informed consent was obtained from all patients or their guardians. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The nasal mucosa is composed of multiple layers of barrier structures and is the first line of defense against infection by respiratory pathogenic microorganisms. A large number of commensal microorganisms are present in the nasal mucosa that mediate and regulate nasal mucosal barrier function. The objective of this research was to investigate the effects of commensal microorganisms on the nasal mucosal barrier. The results revealed that the strain of Bacillus velezensis (B. velezensis) NSV2 from the nasal cavity has good probiotic abilities to resist Pasteurella multocida, Staphylococcus aureus, Escherichia coli and Salmonella typhimurium. Lambs were subsequently administered intranasally with B. velezensis NSV2 at 3, 12, 21, and 26 days old, respectively. For the microbial barrier, although B. velezensis NSV2 reduces the diversity of nasal microbiota, it significantly increased the relative abundance of beneficial bacteria in the nasal cavity, and reduced the abundance of potential pathogenic bacteria. For the mucus barrier, the number of goblet cells in the nasal mucosa significantly increased after B. velezensis NSV2 treatment. For the immune barrier, B. velezensis NSV2 also significantly increased the number of IgA + B cells, CD3 + T cells and dendritic cells in the nasal mucosa, as well as the mRNA expression of interleukin (IL) 6, IL11, CCL2, and CCL20 (P < 0.05). The protein level of CCL20 also significantly raised in nasal washings (P < 0.05). Moreover, the heat-inactivated and culture products of B. velezensis NSV2 also drastically induced the expression of CCL20 in nasal mucosa explants (P < 0.05), but lower than that of the live bacteria. This study demonstrated that a symbiotic strain of B. velezensis NSV2 could improve the nasal mucosal barrier, and emphasized the important role of nasal symbiotic microbiota., Competing Interests: Declarations. Ethical approval: All animal procedures and experiments were performed according to protocols approved by the Institutional Animal Care and Use Committee of Nanjing Agricultural University (SYXK-2017-0027) and followed the National Institutes of Health guidelines. Competing interests: There are no conflicts of interest (financial, professional or personal) related to this manuscript., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Polycyclic Aromatic Hydrocarbons (PAHs) exposure has been linked to asthma, but their individual and combined effects in children remain unclear. Using data from the 2003-2012 National Health and Nutrition Examination Survey (NHANES), we investigated the associations between PAHs and asthma through logistic regression, Weighted Quantile Sum (WQS) regression, Quantile g Computation (qg computation), and Bayesian Kernel Machine Regression (BKMR). Subgroup analyses revealed a significant impact of PAHs on asthma, particularly in males. The WQS model showed a marginally significant combined effect of 9 PAHs on asthma (Odds Ratio = 1.37, 95% Confidence Interval: 1.06-1.75). BKMR also indicated a positive association between combined PAH exposure and asthma. 2-Hydroxyfluorene and 1-Hydroxypyrene were identified as the most significant contributors. These findings suggest that mixed PAH exposure is associated with asthma risk in children.

Nickel-based hydroxides [Ni(OH) 2 ] have attracted significant attention as effective oxygen evolution reaction (OER) catalysts. In recent years, defect engineering has been extensively utilized in Ni(OH) 2 modification research. Numerous studies have confirmed that the generation of defects can expose more active sites and regulate electronic states, particularly through the introduction of Al cationic vacancies, which enhance conductivity and thereby improve the catalytic performance. The traditional method for producing cationic vacancies is electrochemical etching. However, this method generates a limited number of vacancies in the catalysts and has the complex etching process. Herein, we found that when NiAl layered double hydroxides were treated using a hydrothermal process at 100 °C in a KOH solution, more Al cationic vacancies were generated. Compared to the traditional method with an Al leaching efficiency of 24%, our proposed method achieved an Al leaching efficiency of 44%. Meanwhile, the electrochemical results showed that the overpotential was reduced by 110 mV at 10 A/g. Further experiments showed that the enhanced OER activities resulting from an increased number of cationic defects lead to structural distortions, which broaden the e g * band, significantly affecting the rate of electron transfer between the electrocatalyst and external circuitry, thereby enhancing the OER activity. This work presents a promising approach to creating cationic defects in Ni(OH) 2 for high-performance electrocatalysts.

The efficient, sensitive, and rapid detection of Salmonella typhimurium ( S. typhimurium ) in food and food products is important to ensure food safety and health. This study developed a fluorescence biosensing assay that integrated recombinase-aided amplification (RAA) and CRISPR/Cas12a with a zeolitic imidazolate framework-8@fluorescein sodium (ZIF-8@FLS) nanocomposite for the sensitive detection of S. typhimurium . In this approach, using RAA as a preamplification module, CRISPR/Cas12a-AChE as a target recognition and dual-enzyme cascade amplification module, and the prepared ZIF-8@FLS with high porosity and rapid pH responsiveness as a fluorescence signal explosive amplification module, the RAA-CRISPR/Cas12a-ZIF-8@FLS biosensor was constructed. Under optimal conditions, it exhibited an excellent linear relationship for S. Typhimurium , with a sensitive detection limit as low as 1.3 × 10 2 CFU/mL and could complete sample detection within 2 h relying on the RAA and ZIF-8@FLS explosive fluorescence rapid response, demonstrating its significant advantages in specificity, sensitivity, and reliability in food-borne pathogens detection.

Cyanobacterial blooms pose environmental and health risks due to their production of toxic secondary metabolites. While current methods for assessing these risks have focused primarily on bloom frequency and intensity, the lack of comprehensive and comparable data on cyanotoxins makes it challenging to rigorously evaluate these health risks. In this study, we examined 750 metagenomic data sets collected from 103 lakes worldwide. Our analysis unveiled the diverse distributions of cyanobacterial communities and the genes responsible for cyanotoxin production across the globe. Our approach involved the integration of cyanobacterial biomass, the biosynthetic potential of cyanotoxin, and the potential effects of these toxins to establish potential cyanobacterial health risks. Our findings revealed that nearly half of the lakes assessed posed medium to high health risks associated with cyanobacteria. The regions of greatest concern were East Asia and South Asia, particularly in developing countries experiencing rapid industrialization and urbanization. Using machine learning techniques, we mapped potential cyanobacterial health risks in lakes worldwide. The model results revealed a positive correlation between potential cyanobacterial health risks and factors such as temperature, N 2 O emissions, and the human influence index. These findings underscore the influence of these variables on the proliferation of cyanobacterial blooms and associated risks. By introducing a novel quantitative method for monitoring potential cyanobacterial health risks on a global scale, our study contributes to the assessment and management of one of the most pressing threats to both aquatic ecosystems and human health., Importance: Our research introduces a novel and comprehensive approach to potential cyanobacterial health risk assessment, offering insights into risk from a toxicity perspective. The distinct geographical variations in cyanobacterial communities coupled with the intricate interplay of environmental factors underscore the complexity of managing cyanobacterial blooms at a global scale. Our systematic and targeted cyanobacterial surveillance enables a worldwide assessment of cyanobacteria-based potential health risks, providing an early warning system., Competing Interests: The authors declare no conflict of interest.

Large lakes play an important role in water resource supply, regional climate regulation, and ecosystem support, but they face threats from frequent extreme drought events, necessitating an understanding of the mechanisms behind these events. In this study, we developed an explainable machine learning (ML) model that combines the Bayesian optimized (BO) long short-term memory (LSTM) model and the integrated gradients (IG) interpretation method to simulate and explain lake water level variations. In addition, the hydrological drought trends and extreme drought events in Poyang Lake from 1960 to 2022 were identified using the standardized water level index (SWI) and run theory. The analysis revealed that the frequency of hydrological droughts in Poyang Lake increased from 1960 to 2022, especially in the autumn after 2003. By selecting the flows of the catchment and the Yangtze River as the input features, the BO-LSTM model accurately predicted the water level of Poyang Lake. The IG method was then used to interpret the prediction results from three aspects: the importance ranking of the input features, their roles in the seasonal drought trends, and their roles in extreme drought events. The results indicate that (1) the most influential factor affecting the water level of Poyang Lake was the inflow of the Ganjiang River in the catchment. (2) The increase in the lake outflow caused by the Yangtze River's draining effect was the reason for the intensification of the autumn drought in Poyang Lake. (3) The extreme hydrological drought events were primarily caused by low catchment inflows. Overall, this research provides a new approach that balances prediction accuracy with interpretability for predicting and understanding the hydrological processes in large river-connected lakes. Moreover, this method was also applied to the attribution analysis of hydrological drought in Poyang Lake, providing theoretical support for regional water resource management., 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.)

Interleukin-1 (IL-1) is a pro-inflammatory cytokine that exerts a wide range of neurological and immunological effects throughout the central nervous system (CNS) and is associated with the etiology of affective and cognitive disorders. The cognate receptor for IL-1, Interleukin-1 Receptor Type 1 (IL-1R1), is primarily expressed on non-neuronal cells (e.g., endothelial cells, choroidal cells, ventricular ependymal cells, astrocytes, etc.) throughout the brain. However, the presence and distribution of neuronal IL-1R1 (nIL-1R1) has been controversial. Here, for the first time, a novel genetic mouse line that allows for the visualization of IL-1R1 mRNA and protein expression (Il1r1 GR/GR ) was used to map all brain nuclei and determine the neurotransmitter systems which express nIL-1R1 in adult male mice. The direct responsiveness of nIL-1R1-expressing neurons to both inflammatory and physiological levels of IL-1β in vivo was tested. Neuronal IL-1R1 expression across the brain was found in discrete glutamatergic and serotonergic neuronal populations in the somatosensory cortex, piriform cortex, dentate gyrus, and dorsal raphe nucleus. Glutamatergic nIL-1R1 comprises most of the nIL-1R1 expression and, using Vglut2-Cre-Il1r1 r/r mice, which restrict IL-1R1 expression to only glutamatergic neurons, an atlas of glutamatergic nIL-1R1 expression across the brain was generated. Analysis of functional outputs of these nIL-1R1-expressing nuclei, in both Il1r1 GR/GR and Vglut2-Cre-Il1r1 r/r mice, reveals IL-1R1 + nuclei primarily relate to sensory detection, processing, and relay pathways, mood regulation, and spatial/cognitive processing centers. Intracerebroventricular (i.c.v.) injections of IL-1 (20 ng) induces NFκB signaling in IL-1R1 + non-neuronal cells but not in IL-1R1 + neurons, and in Vglut2-Cre-Il1r1 r/r mice IL-1 did not change gene expression in the dentate gyrus of the hippocampus (DG). GO pathway analysis of spatial RNA sequencing 1mo following restoration of nIL-1R1 in the DG neurons reveals IL-1R1 expression downregulates genes related to both synaptic function and mRNA binding while increasing select complement markers (C1ra, C1qb). Further, DG neurons exclusively express an alternatively spliced IL-1R Accessory protein isoform (IL-1RAcPb), a known synaptic adhesion molecule. Altogether, this study reveals a unique network of neurons that can respond directly to IL-1 via nIL-1R1 through non-autonomous transcriptional pathways; earmarking these circuits as potential neural substrates for immune signaling-triggered sensory, affective, and cognitive disorders., Competing Interests: Declarations Ethical approval All experiments were approved by the Florida Atlantic University Institutional Animal Care and Use Committee under protocol A22-39 and A22-14. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

A fundamental understanding of hot carrier relaxation in metal nanostructures is essential for realizing their application potential in energy conversion and photocatalysis. Despite previous investigations of the relaxation of hot carriers generated by surface plasmon resonance (SPR) excitation and interband transitions (IBTs), the hot carrier relaxation lifetimes and their associated mechanisms remain unclear. Herein, we demonstrate two distinct hot carrier relaxation channels in gold plasmonic nanostructures. The experimental observations reveal that the hot carrier relaxation is faster following SPR excitation than that from IBTs in gold nanoparticles and nanorods. The experimental results and theoretical calculations indicate that the numerous plasmon-induced hot carriers undergo surface-mediated carrier-carrier scattering in large gold nanostructures, whereas almost all IBT-induced hot carriers experience bulk carrier-carrier scattering. These findings advance our understanding of hot carrier relaxation and contribute to a clearer microscopic description of scattering channels in plasmonic nanostructures.

The orbital modulation and surface lattice reconstruction represent an effective strategy to regulate the interaction between catalyst interface sites and intermediates, thereby enhancing catalytic activity and selectivity. In this study, the crystal surface of Au-K/CeO2 catalyst can undergo reversible transformation by tuning the coordination environment of Ce, which enables the activation of the Cβ-H bond and the oxidative cleavage of the Cβ-O and Cα-Cβ bonds, leading to the  cleavage of 2-phenoxy-1-phenylethanol. The t2g orbitals of Au 5d hybridize with the 2p orbitals of lattice oxygen in CeO2 via π-coordination, modulating the coordination environment of Ce 4f and reconstructing the lattice oxygen in the CeO2 framework, as well as increasing the oxygen vacancies. The interface sites formed by the synergy between Au clusters in the reconstructed Ce-OL1-Au structure and doped K play dual roles. On the one hand, it activates the Cβ-H bond, facilitating the enolization of the pre-oxidized 2-phenoxy-1-phenylethanone. On the other hand, through single-electron transfer involving Ce3+ 4f1 and the adsorption by oxygen vacancies, it enhances the oxidative cleavage of the Cβ-O and Cα-Cβ bonds. This study elucidates the complex mechanistic roles of the structure and properties of Au-K/CeO2 catalyst in the selective catalytic oxidation of lignin β-O-4 bond., (© 2024 Wiley‐VCH GmbH.)

High-plex proteomic technologies have made substantial contributions to mechanism studies and biomarker discovery in complex diseases, particularly cancer. Despite technological advancements, inherent limitations in individual proteomic approaches persist, impeding the achievement of comprehensive quantitative insights into the proteome. In this study, we employed two widely used proteomic technologies, mass spectrometry (MS) and reverse phase protein array (RPPA) to analyze identical samples, aiming to systematically assess the outcomes and performance of the different technologies. Additionally, we sought to establish an integrated workflow by combining these two proteomic approaches to augment the coverage of protein targets for discovery purposes. We used 14 fresh frozen tissue samples from triple-negative breast cancer (TNBC: seven tumors versus seven adjacent non-cancerous tissues) and cell line samples to evaluate both technologies and implement this dual-proteomic strategy. Using a single-step protein denaturation and extraction protocol, protein samples were subjected to reverse-phase liquid chromatography (LC) followed by electrospray ionization (ESI)-mediated MS/MS for proteomic profiling. Concurrently, identical sample aliquots were analyzed by RPPA for profiling of over 300 proteins and phosphoproteins that are in key signaling pathways or druggable targets in cancer. Both proteomic methods demonstrated the expected ability to differentiate samples by groups, revealing distinct proteomic patterns under various experimental conditions, albeit with minimal overlap in identified targets. Mechanism-based analysis uncovered divergent biological processes identified with the two proteomic technologies, capitalizing on their complementary exploratory potential., (© 2024 Wiley‐VCH GmbH.)

The metabolic reprogramming of macrophages is a potential therapeutic strategy for sepsis treatment, but the mechanism underlying this reprogramming remains unclear. Since glycolysis can drive macrophage phenotype switching, the rate-limiting enzymes in glycolysis may be key to treating sepsis. Here, we found that, compared with other isoenzymes, the expression of 6-phosphofructokinase, muscle type (PFKM) was the most upregulated in monocytes from septic patients. Recombinant thrombomodulin (rTM) treatment downregulated the protein expression of PFKM in macrophages. Both rTM treatment and Pfkm knockout protected mice from sepsis and reduced the production of the proinflammatory cytokines IL-1β, IL-6, TNF-α, and IL-27, whereas PFKM overexpression increased the production of these cytokines. Mechanistically, rTM treatment inhibited glycolysis in macrophages by decreasing PFKM expression in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. HIF-1α overexpression increased methyltransferase-like 3 (METTL3) expression, elevated the m 6 A level on Pfkm, and upregulated the protein expression of PFKM. METTL3 silence attenuated HIF-1α-mediated PFKM expression. These findings provide insight into the underlying mechanism of macrophage reprogramming for the treatment of sepsis., Competing Interests: Declarations Conflict of interest The authors have no relevant financial or nonfinancial interests to disclose. Ethics approval and consent to participate The study was approved by the Ethics Committee of Xuzhou Medical University (ethical approval number: XYFY2022-KL442-01). All animal studies and all experimental protocols were approved by the Institutional Animal Care and Use Committee of Xuzhou Medical University. Consent for publication All the authors approved the submission of the manuscript to this journal., (© 2024. The Author(s).)

The preservation of the left colic artery (LCA) during rectal cancer resection remains a topic of controversy, and there is a notable absence of robust evidence regarding the outcomes associated with LCA preservation. And the advantages of robotic-assisted laparoscopy (RAL) surgery in rectal resection remain uncertain. The objective of this study was to assess the influence of LCA preservation surgery and RAL surgery on intraoperative and postoperative complications of rectal cancer resection. Patients who underwent laparoscopic (LSC) or RAL with or without LCA preservation resection for rectal cancer between April 2020 and May 2023 were retrospectively assessed. The patients were categorized into two groups: low ligation (LL) which with preservation of LCA and high ligation (HL) which without preservation of LCA. A one-to-one propensity score-matched analysis was performed to decrease confounding. The primary outcome was operative findings, operative morbidity, and postoperative genitourinary function. A total of 612 patients were eligible for this study, and propensity score matching yielded 139 patients in each group. The blood loss of the LL group was significantly less than that of the HL group (54.42 ± 12.99 mL vs. 65.71 ± 7.37 mL, p<0.001). The urinary catheter withdrawal time in the LL group was significantly shorter than that in the HL group (4.87 ± 2.04 d vs. 6.06 ± 2.43d, p<0.001). Anastomotic leakage in the LL group was significantly lower than that in HL group (1.44% vs. 7.91%, p = 0.011). The rate of urinary dysfunction and sexual dysfunction in LL group is both significantly lower than HL group. Blood loss and number of harvested lymph nodes (LNs) of both RAL subgroups in LL and HL groups were significantly more than that in LSC subgroups. The anastomotic leakage in the RAL subgroup of HL group was significantly lower than that in LSC subgroup (0% vs. 14.89%, p = 0.018). LCA preservation surgery for rectal cancer may help reduce the blood loss, urinary catheter withdrawal time, the rate of anastomotic leakage and ileus, and postoperative genitourinary function outcomes. RAL can reduce the probability of blood loss and improve harvest LNs in patients with rectal cancer., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics approval and consent to participate We identified that the Ethics Committee of Northern Jiangsu Province People’s Hospital approved this research (2020KY-137), including any relevant details. Informed consent was obtained from each patient preoperatively. The study was also registered on ClinicalTrials (NCT06376227)., (© 2024. The Author(s).)

Despite death marking the end of life, several gene expression and miRNA-mediated post-transcriptional regulation events may persist or be initiated. The silkworm (Bombyx mori) is a valuable model for exploring life processes, including death. In this study, we combined transcriptomics and miRNAomics analyses of young, old, and postmortem silkworms across the entire process after death to unravel the dynamics of gene expression and miRNA-mediated post-transcriptional regulation. In total, 171 genes exhibited sustained differential expression in postmortem silkworms compared to the pre-death state, which are primarily involved in nerve signaling, transport, and immune response. Postmortem time-specific genes were associated with cell cycle regulation, thermogenesis, immunity, and zinc ion homeostasis. We found that the down-regulated expression of 36 genes related to transcription, epigenetic modification, and homeostasis resulted in a significant shift in global gene expression patterns at 2 h post-death. We also identified five mRNA-miRNA pairs (i.e., bmo-miR-2795-mhca, 2784-achi, 2762-oa1, 277-5p-creb, and 1000-tcb1) associated with stress hormone regulation, transcription activity, and signal transduction. The roles of these pairs were validated through in vivo experiments using miRNA mimics in silkworms. The findings provide valuable insights into the intricate mechanisms underlying the transcriptional and miRNA-mediated post-transcriptional regulation events in animals after death., (© The Author(s) 2024. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.)

Background: In the context of modern agriculture, the proliferation of chemical use calls for enhanced pesticide detection to safeguard food quality and public health. The development of accurate testing methodologies is imperative to mitigate the environmental impact of pesticides and ensure the integrity of ecosystems, thereby reflecting the pressing need for advancements in agricultural safety protocols. Therefore, the development of highly sensitive monitoring technology for detecting pesticide residues in agricultural products is necessary for safeguarding human health, ensuring food safety, and maintaining environmental sustainability., Results: Herein, a controllable surface charge on single tungsten atom-modified gold nanoparticles was used to create an electrostatic force with positively charged pesticide residues. Moreover, hydrogen bonds formed by single-atom sites can induce analyte-adsorbed nanoparticle aggregation, and the sizes of single-tungsten-atom-decorated AuNPs can maintain a gap between each other, resulting in improved SERS detection sensitivity through analyte enrichment at gold nanoparticle hotspots. In terms of the detection limits for pesticide residue analysis, we can effectively achieve an ultrahigh sensitivity of 0.1 ppb for acetamiprid, paraquat and carbendazim, which is among the best SERS sensitivities at the state of the art. For apple sample analysis, our work demonstrated good reproductivity (RSD<6 %) and a strong linear relationship (R 2  ≥ 0.97) for 4 pesticide residues after optimizing the pretreatment process, which proves the enormous potential in quantitative analysis., Significance: Single-atom sites hotspot are firstly successfully achieved and uniformly dispersed between Au nanoparticle, which can effectively increase the sensitivity, keep stability of the Raman scattering signals and possess a significant improvement beyond that of undecorated hotspots when applied in pesticide residue detection. This method can be employed as a universal strategy to capture pesticide residues at hotspots for SERS detection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Ethnopharmacological Relevance: Gynostemma pentaphyllum (Thunb.) Makino (G. pentaphyllum) is an oriental herb documented to treat many diseases, including obesity, hyperlipidemia, metabolic syndromes and aging. However, the anti-obesity mechanism of G. pentaphyllum remains poorly understood., Aim of the Study: To reveal the anti-obesity mechanism of G. pentaphyllum Extract (GPE) in High-Fat Diet (HFD)-induced obese mice through untargeted metabolomics, Real-Time Quantitative PCR (RT-qPCR), and immunohistochemical experiments. Additionally, to tentatively identify the active constituents through LC-MS/MS and molecular docking approaches., Materials and Methods: GPE was prepared using ethanol reflux and purified by HP-20 macroporous resins. The components of GPE were identified by Liquid Chromatography- Mass Spectrometry (LC-MS) system. Forty-two C57BL/6 J mice were randomly and evenly divided into six groups, with seven mice in each group: the control group, obese model group, Beinaglutide group (positive control), and GPE low, medium, and high-dose groups (50 mg/kg, 100 mg/kg, and 200 mg/kg of 80% ethanol extract). Body weight, liver weight, blood glucose, blood lipids, and liver histopathological changes were assessed. Untargeted metabolomics was employed to characterize metabolic changes in obese mice after GPE treatment. The expression of genes related to differential metabolites was verified using Real-Time Quantitative PCR (RT-qPCR) and immunohistochemical experiments. The constituents with anti-obesity effects from GPE were tentatively identified through molecular docking approaches., Results: A total of 17 compounds were identified in GPE. GPE significantly lowered body weight, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in obese mice and reduced liver weight and hepatic steatosis. Serum metabolomics identified 20 potential biomarkers associated with GPE treatment in obese mice, primarily related to tryptophan metabolism. GPE treatment downregulated the expression of Slc6a19 and Tph1 and upregulated Ucp1 expression. Molecular docking illustrated that compounds such as 20(R)-ginsenoside Rg3, Araliasaponin I, Damulin B, Gypenoside L, Oleifolioside B, and Tricin7-neohesperidoside identified in GPE exhibited favorable interaction with Tph1., Conclusion: The extract of G. pentaphyllum can inhibit the absorption of tryptophan and its conversion to 5-HT through the Slc6a19/Tph1 pathway, upregulating the expression of Ucp1, thereby promoting thermogenesis in brown adipose tissue, facilitating weight loss, and mitigating symptoms of fatty liver. Triterpenoids such as Araliasaponin I, identified in GPE, could be the potential inhibitor of Tph1 and responsible for the anti-obesity activities., 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.)

Ethnopharmacological Relevance: Radiation-induced heart disease (RIHD) is one of the most serious complications in patients receiving chest radiotherapy, partially offsetting its benefits. At present, there is a lack of effective treatments for RIHD. Ferroptosis is a newly discovered type of cell death that results from iron-dependent lipid peroxide accumulation. It was recently shown that irradiation generates severe ferroptosis, providing new insights for the treatment of RIHD. Abelmoschus manihot (L.) possesses excellent pharmacological properties and is widely used in treating various ischemic heart and brain diseases; however, its efficacy and mechanism in treating RIHD are unknown., Aim: This study aimed to investigate the efficacy and mechanism of total extracts from A. manihot (L.) (TEA) in treating RIHD., Materials and Methods: C57BL/6 mice and H9C2 cells were exposed to irradiation to induce RIHD in vivo and in vitro, respectively. In vivo, we evaluated the protective effects of TEA (150 and 300 mg/kg) on RIHD. Body and heart weight changes of mice were calculated in each group, and malondialdehyde (MDA) level, glutathione/oxidized glutathione (GSH/GSSH) and nicotinamide adenine dinucleotide phosphate (NADPH/NADP + ) ratios, western blot, heart histology, and immunohistochemistry were used to evaluate TEA effectiveness. We identified the potential mechanism of radiation-induced cardiomyocyte injury in H9C2 cells treated with small interfering RNA. We determined the effective dose of TEA (0.6 mg/mL) using a Cell Counting Kit-8 assay. Intracellular Fe 2+ and lipid peroxidation levels were detected by Phen Green™ SK diacetate probe, BODIPY 581/591 C11 staining, and MDA, GSH, and NADPH kits, and the level of target protein was evaluated by immunofluorescence and western blot., Results: Radiation inhibited system Xc-cystine (xCT)/glutathione peroxidase 4 (GPX4) expression and activity in cardiomyocytes in a time and dose-dependent manner. After silencing xCT/GPX4, MDA significantly increased and GSH/GSSH and NADPH/NADP +  ratios were reduced. xCT/GPX4 inhibition drove ferroptosis in radiation-induced H9C2 injury. Oxidative stress in H9C2 was significantly enhanced by irradiation, which also significantly increased NADPH oxidase 4 (NOX4) expression and inhibited nuclear factor E2-related factor 2 (Nrf2) expression in vivo and in vitro. Inhibition of xCT/GPX4 drove ferroptosis in radiation-induced H9C2 injury, which was aggravated by inactivation of Nrf2 and alleviated by inhibition of NOX4. Compared with the ionizing radiation-only group, TEA improved body weight loss, MDA levels, and histological changes induced by irradiation in mice hearts, and increased the ratio of GSH/GSSH and NADPH/NADP + in vivo; it also reduced lipid peroxidation and intracellular Fe 2+ accumulation, restored MDA levels, and elevated the ratios of GSH/GSSH and NADPH/NADP + in irradiation-injured H9C2 cells. TEA up-regulated Nrf2, xCT, and GPX4 expression and inhibited NOX4 expression in vivo and in vitro., Conclusions: Ferroptosis induced by redox imbalance mediated through the NOX4/xCT/GPX4 axis is a potential mechanism behind radiation-induced cardiomyocyte injury, and can be prevented by TEA., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Piezo-photocatalysis combines photocatalysis and piezoelectric effects to enhance catalytic efficiency by creating an internal electric field in the photocatalyst, improving carrier separation and overall performance. This study presents a high-performance piezo-photocatalyst for efficient dye degradation using a synergistic barium titanate (BTO)-MXene composite. The composite was synthesized via a facile method, combining the unique properties of BTO nanoparticles with the high conductivity of MXene. The structural and morphological analysis confirmed the successful formation of the composite, with well-dispersed BTO nanoparticles on the MXene surface. The piezo-photocatalytic activity of the composite was evaluated using a typical dye solution (Rhodamine B: RhB) under ultraviolet irradiation and mechanical agitation. The results revealed a remarkable enhancement in dye degradation (90 % in 15 min for piezo-photocatalysis) compared to individual stimuli (58.2 % for photocatalysis and 95.8 % in 90 min for piezocatalysis), highlighting the synergistic effects between BTO and MXene. The enhanced catalytic performance was attributed to the efficient charge separation and transfer facilitated by the composite's structure, leading to increased reactive species generation and dye molecule degradation. Furthermore, the composite exhibited excellent stability and reusability, showcasing its potential for practical applications in wastewater treatment. Overall, this work represents a promising strategy for designing high-performance synergistic catalysts, addressing the pressing need for sustainable solutions in environmental remediation., 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 The Author(s). Published by Elsevier Inc. All rights reserved.)

Acute myeloid leukemia (AML) is one of the most common types of blood cancer in adults and is associated with a poor survival rate. NK cells play a crucial role in combating AML, and alterations in immune checkpoint expression can impair NK cell function against AML. Targeting certain checkpoints may restore this function. CD96, an inhibitory immune checkpoint, has unclear expression and roles on NK cells in AML patients. In this study, we initially evaluated CD96 expression and compared CD96 + NK with the inhibitory receptor and stimulatory receptors on NK cells from AML patients at initial diagnosis. We observed increased CD96 expression on NK cells with dysfunctional phenotype. Further analysis revealed that CD96 + NK cells had lower IFN-γ production than CD96 - NK cells. Blocking CD96 enhanced the cytotoxicity of primary NK and cord blood-derived NK (CB-NK) cells against leukemia cells. Notably, patients with a high frequency of CD96 + NK cells at initial diagnosis exhibited poorer clinical outcomes. Additionally, TGF-β1 was found to enhance CD96 expression on NK cells via SMAD3 signaling. These findings suggest that CD96 is invovled in NK dysfunction against AML blast, and might be a potential target for restoring NK cell function in the fight against AML., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Enzyme-inhibited electrochemical sensor is a promising strategy for detecting organophosphorus pesticides (OPs). However, the poor stability of enzymes and the high oxidation potential of thiocholine signal probe limit their potential applications. To address this issue, an indirect strategy was proposed for highly sensitive and reliable detection of chlorpyrifos by integrating homogeneous reaction and heterogeneous catalysis. In the homogeneous reaction, Hg 2+ with low oxidation potential was employed as signal probe for chlorpyrifos detection since its electroactivity can be inhibited by thiocholine, which was the hydrolysate of acetylthiocholine catalyzed by acetylcholinesterase. Additionally, Co,N-doped hollow porous carbon nanocage@carbon nanotubes (Co,N-HPNC@CNT) derived from ZIF-8@ZIF-67 was utilized as high-performance electrode material to amplify the stripping voltammetry signal of Hg 2+ . Thanks to their synergistic effect, the sensor exhibited outstanding sensing performance, excellent stability and good anti-interference ability. This strategy paves the way for the development of high-performance OP sensors and their application in food safety., 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. Published by Elsevier Ltd.)

Colorectal adenomas (CRAs) represent precancerous lesions that precede the development of colorectal cancer (CRC). Regular monitoring of CRAs can hinder the progression into carcinoma. To explore the utility of tissue DNA and circulating cell-free DNA (cfDNA) in early diagnosis of CRC, we retrospectively sequenced paired tissue and plasma samples from 85 patients with conventional CRAs. The genetic alterations identified were compared with those from 78 stage-I CRC patients (CRC-I) in the ChangKang project. Within the CRA cohort, we pinpointed 12 genes, notably APC , KRAS , and SOX9 , that exhibited significant mutated rates in tissue. Patients harboring KMT2C and KMT2D mutations displayed persistent polyps. By comparing with the mutational profiles of metastatic CRC plasma samples, we found that ZNF717 was exclusively mutated in CRAs, while KMT2C and KMT2D mutations were detected in both CRA and CRC. The presence of cfDNA mutations in plasma was validated through polymerase chain reaction, enhancing the feasibility of using cfDNA mutations for early CRC screening. Compared with CRC-I, CRAs exhibited a reduced frequency of TP53 and PIK3CA somatic mutations and underwent non-neutral evolution more often. We established a random forest model based on 15 characteristic genes to distinguish CRA and CRC, achieving an area under the curve of 0.89. Through this endeavor, we identified two novel genes, CNTNAP5 and GATA6 , implicated in CRC carcinogenesis. Overall, our findings reveal convincing biomarkers markers for detecting CRAs with a propensity for CRC development, highlighting the importance of early genetic screening in CRC prevention., Competing Interests: Authors Yang Pan, Xiaoni Zhang and Jing Zhang are employees in HaploX Biotechnology but have no potential relevant financial or nonfinancial interests to disclose. The other authors have no conflicts of interest to declare., (© 2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

Aristolochic acid I (AAI) is strongly nephrotoxic and can cause "Aristolochic acid nephropathy (AAN)". Aristolochic acid nephropathy is characterized by extensive renal interstitial fibrosis. However, the exact mechanism by which it occurs has not been fully elucidated. lt has been reported that indoleamine 2,3-dioxygenase-1 (IDO1) promotes renal fibrosis in renal disorders, but it is unclear how IDO1 functions in AAI-induced kidney fibrosis. In this work, we systematically examined the role of IDO1 in AAI-induced renal tubulointerstitial fibrosis. The results showed that AAI induced upregulation of IDO1 expression in renal tubular epithelial cells and mouse kidney. Inhibition of IDO1 expression reduced the levels of fibrosis-associated markers α-SMA, COL-I and FN and ameliorated renal tubular epithelial cell fibrosis. It also improved renal function, reduced collagen deposition, and ameliorated interstitial fibrosis in mice. Moreover, we discovered that inhibition of IDO1 decreased the expression of the apoptotic protein BAX, raised the expression of BCL-2 protein, and reduced apoptosis. The above studies suggest that IDO1 is a target of action in renal tubulointerstitial fibrosis caused by AAI, and inhibition of IDO1 may be a viable approach for the therapy of AAI-induced renal tubulointerstitial fibrosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Clinical studies involving observation have uncovered a mutual relationship between allergic disorders and diabetes, yet the precise causal link remains undetermined., Methods: We conducted two-sample bidirectional Mendelian randomization analyses using single nucleotide polymorphisms (SNPs) associated with allergic conditions (asthma, allergic rhinitis, atopic dermatitis) from genome-wide studies and SNPs related to type 2 diabetes from FinnGen. Initially, we evaluated the causal link between allergic disorders and type 2 diabetes through a univariate Mendelian randomization study, incorporating inverse variance weighting, MR-Egger, and the weighted median estimator. To address potential confounding, we employed multivariate Mendelian randomization. Finally, we validated mediators influencing the correlation between asthma and type 2 diabetes., Results: The Inverse variance weighte method showed that asthma genetically increased the risk of type 2 diabetes (Asthma- type 2 diabetes: β(95%CI)＝0.892(0.152～1.632), P  = 0.018). Allergic rhinitis and type 2 diabetes exhibit a mutual protective effect: β(95% CI)＝-1.333(-2.617 to -0.049), P  = 0.042；type 2 diabetes - Allergic rhinitis: β(95%CI)＝-0.002(-0.004 to -0.000), P  = 0.018). The Multivariable Mendelian randomization study results showed that after after excluding confounding factors, asthma still demonstrates statistical significance in relation to type 2 diabetes. Through mediation analysis, it was discovered that lung function and the percentage of monocytes in leukocytes exert an inhibitory effect on the mediation between asthma and type 2 diabetes., Conclusion: The Multivariable Mendelian randomization study indicates asthma as a risk factor for type 2 diabetes.Lung function, and the percentage of monocytes in leukocytes, play an inhibitory role in asthma and type 2 diabetes mediating effects.

Contemporary societies exhibit delayed reproductive age and increased life expectancy. While the male reproductive system demonstrates relatively delayed aging compared to that of females, increasing age substantially impacts its function. A characteristic manifestation is age-induced testosterone decline. Testosterone, a crucial male sex hormone, plays pivotal roles in spermatogenesis and sexual function, and contributes significantly to metabolism, psychology, and cardiovascular health. Aging exerts profound effects on the hypothalamic-pituitary-gonadal axis and Leydig cells, precipitating testosterone reduction, which adversely affects male health. Exogenous testosterone supplementation can partially ameliorate age-related testosterone deficiency; however, its long-term safety remains contentious. Preserving endogenous testosterone production capacity during the aging process warrants further investigation as a potential intervention strategy., Competing Interests: Declarations Ethics approval and consent to participate Not Applicable. Consent for publication Not Applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: The role of admission blood indicators in patients with acute compartment syndrome (ACS) remains debated. Our primary purpose was to observe variations of admission blood indicators in patients with ACS, while our secondary goal was to explore potential biomarkers related to ACS., Methods: We collected information on patients with tibial fracture between January 2013 and July 2023, and divided them into ACS and non-ACS groups. Propensity score matching (PSM) analysis was performed to lower the impact of potential confounding variables such as demographics and comorbidities. Admission blood indicators were analyzed using univariate, logistic regression, and receiver operating characteristic (ROC) curve analyses. Then, we established a nomogram prediction model by using R language software., Results: After propensity PSM analysis, 127 patients were included in each group. Although numerous blood indicators were found to be relevant to ACS on univariate analysis, logistic regression analysis showed that monocytes (MON, p = 0.015), systemic immune-inflammation index (SII, p = 0.011), and creatine kinase myocardial band (CKMB, p < 0.0001) were risk factors for ACS. Furthermore, ROC curve analysis identified 0.79 × 10 9 /L, 1082.55, and 20.99 U/L as the cut-off values to differentiate ACS patients from patients with tibial fracture. We also found that this combination had the highest diagnostic accuracy. Then, we constructed a nomogram prediction model with AUC of 0.869 for the prediction model, with good consistency in the correction curve and good clinical practicality by decision curve analysis., Conclusions: We found that the levels of MON, SII, and CKMB were related to ACS and may be potential biomarkers. We also identified their cut-off values to separate patients with ACS from those with tibial fracture, helping orthopedists promptly evaluate and take early measures. We established a nomogram prediction model that can efficiently predict ACS in patients with tibial fracture., Competing Interests: Declarations Ethics approval and consent to participate Before data collection, this study was approved by the institutional review boards of our hospital (S2020-024-1) in compliance with the Declaration of Helsinki, and an exemption from informed consent was obtained. All data were anonymized before analysis to safeguard patient privacy. Consent for publication Not applicable. Competing interests There are no competing interests., (© 2024. The Author(s).)

Neurodegenerative diseases (NDDs) represent a class of neurological disorders characterized by the progressive degeneration or loss of neurons, impacting millions of individuals globally. In addition to the typical manifestations, pain is a prevalent symptom associated with NDDs, seriously impacting the quality of life for patients. The pathogenesis of pain associated with NDDs is intricate and multifaceted. Currently, the clinical management of NDDs-related pain symptoms predominantly relies on conventional pharmacological agents or physical therapy. However, these approaches often fail to produce satisfactory outcomes. This article summarizes the underlying mechanisms of major NDDs-associated pain: Neuroinflammation, Brain and spinal cord dysfunctions, Mitochondrial dysfunction, Risk gene and pathological protein, as well as Receptor, channel, and neurotransmitter. While numerous studies have investigated the downstream pathological processes associated with these mechanisms, there remains a significant gap in identifying the key initiating factors. Specifically, there is insufficient evidence for the upstream elements that activate microglia and astrocytes in neuroinflammation leading to pain in NDDs. Likewise, there is an absence of upstream factors elucidating how dysfunctions in the brain and spinal cord, as well as mitochondrial impairments, contribute to the development of pain. Furthermore, the specific mechanisms through which hallmark pathological proteins related to NDDs contribute to these pathological processes remain inadequately understood. The objective of this article is to synthesize the existing mechanisms underlying pain associated with NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, Schizophrenia, Amyotrophic lateral sclerosis, and Multiple sclerosis, while also identifying gaps and deficiencies in these mechanisms. This paper offers insights for future research trajectories. Given the intricate pathogenesis of NDDs-related pain, it emphasizes that a promising short-term strategy is combination therapy-intervening concurrently in multiple pathological processes-akin to the cocktail approach utilized in treating acquired immunodeficiency syndrome (AIDS). For long-term advancements, achieving breakthroughs in the treatment of the NDDs themselves will remain essential for alleviating accompanying pain symptoms., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

The endoplasmic reticulum (ER) is an important organelle in eukaryotic cells, responsible for a range of biological functions such as the secretion, modification and folding of proteins, maintaining Ca 2+ homeostasis and the synthesis of steroids/lipids, secreted proteins and membrane proteins. When cells are affected by internal or external factors, including abnormal energy metabolism, disrupted Ca 2+ balance, altered glycosylation, drug toxicity, and so on, the unfolded or misfolded proteins accumulate in the ER, leading to the unfolded protein response (UPR) and ER stress. The abnormal ER stress has been reported to be involved in various pathological processes. MicroRNAs (miRNAs) are non-coding RNAs with the length of approximately 19-25 nucleotides. They control the expression of multiple genes through posttranscriptional gene silencing in eukaryotes or some viruses. Increasing evidence indicates that miRNAs are involved in various cellular functions and biological processes, such as cell proliferation and differentiation, growth and development, and metabolic homeostasis. Hence, miRNAs participate in multiple pathological processes. Recently, many studies have shown that miRNAs play an important role by regulating ER stress in ischemia-reperfusion (I/R) injury, but the relevant mechanisms are not fully understood. In this review, we reviewed the current understanding of ER stress, as well as the biogenesis and function of miRNAs, and focused on the role of miRNAs regulation of ER stress in I/R injury, with the aim of providing new targets for the treatment of I/R injury., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

It remains a mystery why nature evolved the unique structural characteristics of GPI-anchored proteins (GPI-APs) and continues to sustain the complex, energy-intensive process of synthesizing these proteins. GPI-APs, despite their small size, rely on the coordinated activity of nearly 30 genes for their synthesis and remodeling, raising important evolutionary questions. The biological advantages of GPI-APs lie in their ability to rapidly redistribute across the cell membrane, localize within lipid rafts, utilize unique intracellular trafficking pathways, and function as both membrane-bound and soluble proteins. These properties allow GPI-APs to participate in diverse cellular processes such as synaptic plasticity, immune regulation, and signal transduction, highlighting their indispensable roles. Additionally, the shedding capability of GPI-APs extends their functional reach, adding further versatility to their biological roles. This review not only summarizes these key insights but also explores the broader implications of GPI-APs in cell signaling and disease. By understanding the evolutionary necessity of GPI-APs, we can better appreciate their complexity and potential as therapeutic targets., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Copper oxide nanoparticles (CuONPs) have been widely applied, posing potential risks to human health. Although the toxicity of CuONPs on the liver and spleen has been reported, their effects on reproductive health remain unexplored. In this study, we investigate the effects of CuONPs on embryonic development and their potential mechanisms. Our results demonstrate that CuONPs exposure impairs mouse preimplantation embryonic development, particularly affecting the morula-to-blastocyst transition. Additionally, CuONPs were found to reduce the pluripotency of the inner cell mass (ICM) and mouse embryonic stem cells (mESCs). Mechanistically, CuONPs block autophagic flux and impair mitophagy, leading to the accumulation of damaged mitochondria. This mitochondrial dysfunction leads to reduced tricarboxylic acid (TCA) cycle activity and decreased α-ketoglutarate (α-KG) production. Insufficient α-KG induces the failure of DNA demethylation, reducing corresponding chromatin accessibility and consequently inhibiting ICM-specific genes expressions. Similar reduced development and inhibitions of pluripotency gene expression were observed in CuONPs-treated human blastocysts. Moreover, in women undergoing assisted reproductive technology (ART), a negative correlation was found between urinary Cu ion concentrations and clinical outcomes. Collectively, our study elucidates the mitophagy-mediated metabolic mechanisms of CuONPs embryotoxicity, improving our understanding of the potential reproductive toxicity associated with it.

Background: The genetic variant of tumor necrosis factor superfamily member 15 ( TNFSF15 ) is associated with Crohn's disease (CD) and the development of intestinal fibrosis and stricturing. We aimed to investigate its predictive role in disease progression and the impact of ileal fibrosis-associated protein expression in Chinese patients with CD., Methods: We genotyped the single nucleotide polymorphism rs6478109 within the TNFSF15 gene in 428 CD patients and 450 health controls to assess its association with CD. Genotype-phenotype correlation analyses were performed. Mucosal samples from non-diseased terminal ileum were analyzed for TL1A and fibrosis-associated protein expression using western blot and immunohistochemistry., Results: The G allele frequency of rs6478109 was significantly higher among CD patients compared with health controls (63.3% vs. 46.7%, P  <   0.001). Patients with GG genotype were more predisposed to develop the stricturing phenotype, compared with those with AA + AG genotypes with a hazard ratio of 1.426 (95% confidence interval: 1.029-1.977, P  =   0.033). This trend was similarly observed in patients utilizing biological agents, with a hazard ratio of 4.396 (95% confidence interval: 1.780-10.854, P  =   0.001). Furthermore, increased TL1A, pro-fibrotic proteins, and TGFβ1/Smad3 pathway activation were observed in non-diseased ileal mucosa of patients with GG genotype compared with those with AA genotype., Conclusions: The TNFSF15 risk genotype GG could promote the expression of pro-fibrotic proteins and may serve as a predictor for stricturing CD., Competing Interests: The authors declare that there are no conflicts of interest in this study., (© The Author(s) 2024. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University.)

SARS-CoV-2 Omicron and its sub-lineages have become the predominant variants globally since early 2022. As of January 2023, over 664 million confirmed cases and over 6.7 million deaths had been reported globally. Current infection models are limited by the need for large datasets or calibration to specific contexts, making them difficult to apply to different settings. This study aims to develop a generalized multinomial probabilistic model of airborne infection to assist public health decision-makers in evaluating the effectiveness of public health interventions (PHIs) across a broad spectrum of scenarios. The proposed model systematically incorporates group characteristics, epidemiology, viral loads, social activities, environmental conditions, and PHIs. Assumptions about social distance and contact duration that estimate infectivity during short-term group gatherings have been made. The study is differentiated from earlier works on probabilistic infection modeling in the following ways: (1) predicting new cases arising from more than one infectious person in a gathering, (2) incorporating additional key infection factors, and (3) evaluating the effectiveness of multiple PHIs on SARS-CoV-2 infection simultaneously. Although the results show that limiting group size has an impact on infection, improving ventilation has a much greater positive health impact. The proposed model is versatile and can flexibly accommodate other scenarios or airborne diseases by modifying the parameters allowing new factors to be added., (© 2024 Society for Risk Analysis.)

Pathological ocular angiogenesis is a significant cause of irreversible vision loss and blindness worldwide. Currently, most studies have focused on the angiogenesis factors in ocular vascular diseases, and very few endogenous anti-angiogenic compounds have been found. Moreover, although inflammation is closely related to the predominant processes involved in angiogenesis, the mechanisms by which inflammation regulates pathological ocular angiogenesis remain obscure. In this study, a vascular endothelial cells (VECs)-specific anti-angiogenic factor is identified, apoptosis signal-regulating kinase 1(ASK1)-interacting protein-1 (AIP1) as a key pathogenic regulator in a typical ocular angiogenesis model, oxygen-induced retinopathy (OIR), using single-cell RNA sequencing. It is demonstrated that AIP1 inhibited pathological angiogenesis by preventing a particular inflammatory death pathway, namely pyroptosis, in retinal VECs. The assembly of a noncanonical inflammasome is further uncovered, the NLRP12-ASC-caspase-8 inflammasome, which is promoted by decreased AIP1 in OIR. This inflammasome elicited gasdermin D (GSDMD)-dependent endothelial pyroptosis, which in turn promoted the release of vascular endothelial growth factor (VEGF) and interleukin (IL)-1β. Suppression of NLRP12-CASP8-GSDMD axis and AIP1 upregulation reduced VEGF signaling, limiting new vessel formation. These findings reveal a previously uncharacterized inflammatory angiogenic process involving VECs pyroptosis-inducing retinal neovascularization, paving the way for promising therapeutic avenues targeting angiogenesis via AIP1 or pyroptosis., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

High-performance, versatile epoxy resins (EPs) are used in a variety of fields, but the manufacture of transparent, fireproof, and strong EPs remains a major challenge. The hyperbranched, multifunctional flame retardant (DSi) is prepared by using diethanolamine, polyformaldehyde, diphenylphosphine oxide, and phenyltrimethoxysilane as raw materials in this work. When the additional amount of DSi is only 2 wt.%, the EP-DSi 2 sample reaches a vertical burning (UL-94) V-0, and its limiting oxygen index (LOI) is 32.8%. When the content of DSi is 3 wt.%, the peak heat release rate (PHRR) and total smoke production (TSP) of EP-DSi samples are 43.8% and 21.4% lower than those of EP. The good compatibility of DSi and EP endows EP-DSi with high transparency, and the hyperbranched structure of DSi makes EP-DSi have obviously enhanced mechanical strength and toughness. The enhanced fire safety of EP-DSi is mainly due to the promoting carbonization and radical quenching effects of DSi. This paper offers a comprehensive design concept aimed at creating high-performance epoxy resins with good optical, mechanical, and flame-retardant properties, which have broad application prospects., (© 2024 Wiley‐VCH GmbH.)

The ongoing evolution and immune escape of SARS-CoV-2, alongside the potential threat of SARS-CoV-1 and other sarbecoviruses, underscore the urgent need for effective strategies against their infection and transmission. This study highlights the discovery of nanobodies from immunized alpacas, which demonstrate exceptionally broad and potent neutralizing capabilities against the recently emerged and more divergent SARS-CoV-2 Omicron subvariants including JD.1.1, JN.1, KP.3, KP.3.1.1, as well as SARS-CoV-1 and coronaviruses from bats and pangolins utilizing receptor ACE2. Among these, Tnb04-1 emerges as the most broad and potent, binding to a conserved hydrophobic pocket in the spike's receptor-binding domain, distinct from the ACE2 binding site. This interaction disrupts the formation of a proteinase K-resistant core, crucial for viral-cell fusion. Notably, intranasal administration of Tnb04-1 in Syrian hamsters effectively prevented respiratory infection and transmission of the authentic Omicron XBB.1.5 subvariant. Thus, Thb04-1 holds promise in combating respiratory acquisition and transmission of diverse sarbecoviruses., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Dong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Genomics studies have detected numerous genetic alterations in esophageal squamous cell carcinoma (ESCC). However, the functions of these mutations largely remain elusive, partially due to a lack of feasible animal models. Here, we report a convenient platform with CRISPR-Cas9-mediated introduction of genetic alterations and orthotopic transplantation to generate a series of primary ESCC models in mice. With this platform, we validate multiple frequently mutated genes, including EP300, FAT1/2/4, KMT2D, NOTCH2, and TGFBR2, as tumor-suppressor genes in ESCC. Among them, TGFBR2 loss dramatically promotes tumorigenesis and multi-organ metastasis. Paradoxically, TGFBR2 deficiency leads to Smad3 activation, and disruption of Smad3 partially restrains the progression of Tgfbr2-mutated tumors. Drug screening with tumor organoids identifies that pinaverium bromide represses Smad3 activity and restrains Tgfbr2-deficient ESCC. Our studies provide a highly efficient platform to investigate the in vivo functions of ESCC-associated mutations and develop potential treatments for this miserable malignancy., Competing Interests: Declaration of interests A patent (no. 202010684524.2) for the primary in situ mouse model of esophagus based on organoids has been applied for by West China Hospital, Sichuan University., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ki-67 index (Ki-67i) is integral to the grading of many tumours. There remains considerable variability across pathologists in methods used to determine Ki-67i and in their results. Manual counting (or "eyeballing") is widely used, but digital pathology tools such as web-based image analysis and artificial intelligence-assisted cell detection software have become available in daily pathology practice. This study aims to compare the accuracy and efficiency of manual and two digital methods of Ki-67i determination. H&E and Ki-67 immunohistochemical (IHC) slides/images of 12 gastrointestinal neuroendocrine tumours (GI-NETs) were provided to 8 pathologists to evaluate Ki-67i via manual estimation (ME; the "past"), web-based image analysis using cellular segmentation (AI4Path.ca; the "present"), and software-based image analysis with built-in AI algorithms (QuPath; the "future"). Data collected include Ki67i, time expended, total cells counted, and pathologists' confidence level in the reported result. Deviation of Ki-67i from a gold standard result (GS) was analyzed using multiple linear regression, and results were compared via paired t test. Our results found no statistically significant differences in Ki-67i deviation from GS when comparing ME and AI4P methods for all 12 cases. The QP Ki-67i detection accuracy varied significantly. ME was the method with the least time expenditure. Junior pathologists are less confident in ME. Grading consensus was comparable among all three methods. These findings suggest that while digital pathology can confer increased Ki-67i accuracy in some cases of GI-NETs, higher time expenditure and proper hotspot selection may represent barriers to the adoption of digital pathology methods in the future., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The plasmid encoded mobile colistin resistance (MCRs) enzyme poses a significant challenge to the clinical efficacy of colistin, which is frequently employed as a last resort antibiotic for treating infections caused by multidrug resistant bacteria. This transferase catalyzes the addition of positively charged phosphoethanolamine to lipid A of the outer membrane of gram-negative bacteria, thereby facilitating the acquired colistin resistance. This review aims to summarize and critically discuss recent advancements in the distribution and pathogenesis of mcr-positive bacteria, as well as the various control measures available for treating these infections. In addition, the ecology of mcr genes, colistin-resistance mechanism, co-existence with other antibiotic resistant genes, and their impact on clinical treatment are also analyzed to address the colistin resistance crisis. These insights provide a comprehensive perspective on MCRs and serve as a valuable reference for future therapeutic approaches to effectively combat mcr-positive bacterial infections., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The abnormal expression of N-acetylneuraminic acid (SA) and sialylated glycoproteins in biological fluids are closely associated with various diseases including cancer. However, the low content of SA and the strong interference of complex matrix greatly influence the effective capture of SA in biosamples prior to analysis. Herein, a dual-capture-system strategy based on molecular imprinting and post-imprinting modification (PIM) was proposed to precisely capture SA with improved binding affinity and specificity. After imprinting with SA as template, dynamic imine bonds are introduced by post-imprinting modification, enabling sufficiently high specificity to capture SA through imprinting cavities and the dynamic imine bonds hydrolysis reaction simultaneously. The prepared magnetic PIM polymers (Mag-MIPs-PIM) exhibited significantly high specificity both for SA (IF = 4.24) and sialylated glycoprotein (IF TRF  = 3.50). In addition, the feasibility of Mag-MIPs-PIM for practical application was demonstrated by association with HPLC for the determination of SA in human serum, and an LOD of 0.01 × 10 -2  g L -1 was obtained. The proposed strategy based on molecular imprinting and PIM provides a new inspiration for the improvement of selectivity of the molecularly imprinted polymers., 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.)

Influenza virus is a kind of respiratory pathogen with high morbidity and mortality, which still threatens human health. Existing anti-influenza drugs have various limitations, such as the inability to alleviate body injury and side effects. There remains an urgent need to develop a novel antiviral drug to efficiently inhibit viral infection while avoiding body injury. A series of 2-aminoindole derivatives were synthesized via the TMSOTf-catalyzed reactions of N-arylynamides with sulfilimines and evaluated for their anti-influenza virus activity. The experimental results showed that 2-aminoindole 3h had significant antiviral activity (EC 50  = 8.37 ± 0.65 μM) and the lowest cytotoxicity (CC 50  = 669.26 ± 11.42 μM) in vitro. 2-Aminoindole 3h could inhibit viral replication by effectively binding to RNA-dependent RNA polymerase (RdRp), and could also directly target host cells to inhibit cytokine storms and apoptosis induced by viral infection, thereby improving host cell survival rate. In addition, viral load and organ injury in the lung tissue of infected mice were effectively reduced by 2-aminoindole 3h with satisfactory biosafety. These findings highlight the potential of a valuable therapeutic option against influenza infection while also laying the foundation for further research and development in this area., 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 Masson SAS. All rights reserved.)

Study Objectives: Perimenopausal insomnia (PMI) is associated with observable performance impairments in visual search tasks. This study examines how various cognitive processing stages contribute to search performance delays in PMI compared to healthy controls (HCs)., Methods: We recruited 76 participants diagnosed with PMI and 63 HCs. Event-related potentials (ERPs) were recorded as participants engaged in a visual search task, reporting the orientation of a color popout target within an array of ellipses. We analyzed group differences in behavioral performance and ERP components across cognitive processing stages., Results: Compared to HCs, PMI patients exhibited behavioral response delays, although accuracy was not different between groups. Electrophysiological analyses revealed group differences across several ERP components. Firstly, the N1 component's amplitude increased bilaterally, suggesting enhanced visual sensory processing. Secondly, a slower and smaller N2pc indicated reduced attentional orienting. Thirdly, a decreased sustained posterior-contralateral negativity amplitude pointed to deficits in target discrimination. Fourthly, an increased amplitude of the stimulus-locked lateralized readiness potential (LRP), with unchanged latency, suggested heightened neural inputs for maintaining motor initiation speed. Fifthly, prolonged response-locked LRP latency indicated slower motor execution. Finally, these changes in ERP components, along with significant correlations between LRP components and insomnia symptoms, suggest potential neural biomarkers for PMI., Conclusions: Our findings provide high-temporal-resolution insights into the neurocognitive disruptions associated with PMI, highlighting how sleep disturbances affect cognitive processing in visual tasks. These insights enhance our understanding of PMI and contribute to discussions on neural mechanisms driving behavioral performance in various conditions., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The regulation of the structure and properties of new starch varieties has been a necessary step in the development of promising products. This study investigated the effects of 1 % xanthan gum (XG) and hydroxypropyl methylcellulose (HPMC) on the physicochemical properties and structure of triticale starch during fermentation. Frequency scanning and rapid viscosity analyzer results showed that the addition of XG or HPMC during fermentation resulted in the reduced loss factor (tanθ) and the increased peak viscosity, indicating that the network gel strength is enhanced. X-ray diffraction and attenuated total reflectance Fourier transform infrared spectroscopy experimental results revealed that adding XG or HPMC in the triticale starch during fermentation increased relative crystallinity (2.7 % and 5.27 %, respectively) and short-range order. Combined with microstructure and thermal analysis, the encapsulation effect of XG or HPMC on triticale starch increased the thermal stability of triticale starch during fermentation, which was specifically reflected by higher residue content (26.69 % and 19.13 %, respectively). This study can provide a theoretical basis for the effect of hydrocolloids on the texture and digestibility of triticale starch fermented products., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The conventional behavior recognition strategy for wearable sensors used in high-temperature environments typically requires an external power supply, and the manufacturing process is cumbersome. Herein, we present a rational design strategy based on fully flexible printable materials and a customized device-manufacturing process for skin-conformable triboelectric nanogenerator sensors. In detail, using high temperature-resistant ink and 3D printing technology to manufacture a coaxial triboelectric nanogenerator (C-TENG) sensor, the C-TENG exhibits high stretchability (>400%), a wide working range (>250 °C), and high output voltage (>100 V). The C-TENG can be worn on various parts of the human body, providing a robust skin-device interface that recognizes diverse human behaviors. Using machine learning algorithms, behaviors such as walking, running, sitting, squatting, climbing stairs, and falling can be identified, achieving 100% behavior recognition accuracy through the selective input and optimization of an appropriate dataset. This paper provides a research perspective for the customization, extension, and rapid fabrication of heat-resistant, fully flexible TENGs.

Aflatoxin B 1 (AFB 1 ) can induce serious liver toxicity in human. While completely avoiding AFB 1 exposure is difficult, dietary intake of natural products may be leveraged to mitigate its adverse health effects. The roots of Lepidium meyenii (Maca) is rich in beneficial polysaccharides. Here we first evaluated dietary safety of MPs and then investigated MPs mitigating effects on the liver toxicity of AFB 1 . A 28-day sub-acute administration of Maca polysaccharides (MPs) demonstrated to be safe in mice at dose 0.2-1.2 g/kg.bw/day that significantly elevated mice stamina. Also, no toxicity was observed in human PC12 cells treated with MPs 25-100 μg/mL which successfully alleviated cobalt-caused cell apoptosis by ∼20%. In terms of anti-AFB 1 hepatoxicity function, MPs 0.4-1.6 g/kg.bw/day significantly alleviated liver tissue damage, lipid accumulation, ROS damage, NF-κB p65, secretion of cytokines such as IL-6 and TNF-α in AFB 1 -treated mice. Flow cytometry found that MPs treatment recovered the elevation of F4/80 in the primary macrophages of AFB 1 -treated mice. At molecular level, MPs treatment activated liver NRF-2/GPX/SOD anti-oxidant system. In human macrophage model, MPs restored the inflammatory AhR/STAT3 pathway and mRNA expressions of Tnf-a, Inos, Arg-1 disrupted by AFB 1 . Our findings not only add to the current understanding on the toxicity mechanism of AFB 1 , but also provide references to the development of dietary intervention strategy using MPs., 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.)

The health risks of particulate matters (PMs) associated with their chemical components and sizes have attracted increasing attention. However, the toxic effect of critical toxic components in size-segregated PMs from specific emission source remains unclear. We present the toxicity of size-segregated elements in PMs via integrating toxic analysis and online single-particle measurements of real-world industrial plants, vehicles, and road dust. The number fractions of elemental carbon (EC)- and Fe-containing particles were 5-11 and 3-12 folds greater than those of other metal-containing particles, respectively. A unimodal distribution with the peak at 0.4 µm was observed for the toxic metals emitted from industrial plants and road dust, while the distribution was relatively flat for vehicles. When integrating the abundance with toxicity of metals, especially Mn, Cu, V, and Fe, the peak for PM toxicity occurred at 0.4 µm for road dust, 0.4-0.7 µm for industrial plants, and 0.8 µm for vehicle-emitted PM. The inhalation risk in the alveolar region increased for these source-emitted PMs due to the efficient deposition of toxic PMs within 0.4-0.8 µm. These results reveal the complex coupling of health risks and size distributions of PMs, and further highlight that the health-oriented control of air pollution should consider PM 1 ., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with a low 5-year survival rate. Treatment options for PDAC patients are limited. Recent studies have shown promising results with MRTX1133, a KRAS G12D inhibitor that demonstrated potent antitumor activity in various types of tumors with KRAS G12D mutation. Resistance to KRAS inhibitors is frequently occurred and one of the main reasons for treatment failure. Understanding resistance mechanisms to novel KRAS inhibitors is crucial to ensure sustained and durable remissions., Methods: Two KRAS G12D inhibitor MRTX1133-resistant PDAC cell lines were established in vitro. The resistance mechanisms to KRAS G12D inhibitor MRTX1133 against PDAC in vitro and in vivo were characterized by RNA sequencing, reverse transcript polymerase chain reaction, cytotoxicity test, plasmid transfection, lentivirus transfection, lipid peroxidation detection, malondialdehyde levels detection, glutathione levels detection, western blot, immunofluorescence, nude mice tumorigenesis experiment and immunohistochemistry., Results: The bioinformatics analysis and transcriptome sequencing showed that ferroptosis was involved in the resistant effect of the KRAS G12D inhibitor treatment, and MGST1 was the key molecule against MRTX1133-induced ferroptosis. Increased expression of MGST1 weakened the cytotoxicity of MRTX1133 by inhibiting lipid peroxidation-induced ferroptosis in KRAS G12D inhibitor-resistant PDAC cells. Knockdown or overexpression of MGST1 conferred sensitivity or resistance to KRAS G12D inhibitor MRTX1133, respectively. Mechanismly, increased nuclear localization and higher levels of active β-catenin were observed in MRTX1133-resistant PDAC cells, which contributed to higher MGST1 expression. Knockdown of CTNNB1 or TCF4 can decreased MGST1 expression. Additionally, we found that PKF-118-310, an antagonist of β-catenin/Tcf4 complex, repressed MGST1 expression. In both in vitro and in vivo models, a synergistic effect was observed when combining MRTX1133 and PKF-118-310 in KRAS G12D inhibitor MRTX1133-resistant PDAC cells and tumors., Conclusion: Our data showed that KRAS G12D inhibitor MRTX1133 combined with PKF-118-310 could enhance the effectiveness of MRTX1133 treatment response through induction of ferroptosis via inhibiting MGST1 expression in MRTX1133-resistant PDAC cells and tumors. This evidence may provide a promising strategy to overcome KRAS G12D inhibitor MRTX1133 resistance in PDAC patients with KRAS G12D mutations., (© 2024. The Author(s).)