Fe Crystalline Phases in Fe/C Composites Modulated the Selective Adsorption of Pb(II) from Industrial Wastewater with Cd(II): An Electronic-Scale Perspective.

Fe oxide or Fe0-based materials display weak removal capacity for Pb(II), especially in the presence of Cd(II), and the electronic-scale mechanisms are not reported. In this study, Fe3C(220) modified black carbon (BC) [Fe3C(220)@BC] with high adsorption and selectivity for Pb(II) from industrial wastewater with Cd(II) was developed. The quantitative experiment suggested that Fe species accounted for 80.5-100 and 18.4-33.8% of Pb(II) and Cd(II) removal, respectively. Based on X-ray absorption near-edge structure analysis, 57.3% of adsorbed Pb2+ was reduced to Pb0; however, 61.6% of Cd2+ existed on Fe3C@BC. Density functional theory simulation unraveled that Cd(II) adsorption was attributed to the cation-π interaction with BC, whereas that of Pb(II) was ascribed to the stronger interactions with different Fe phases following the order: Fe3C(220) > Fe0(110) > Fe3O4(311). Crystal orbital bond index and Hamilton population analyses were innovatively applied in the adsorption system and displayed a unique discovery: the stronger Pb(II) adsorption on Fe phases was mediated by a combination of covalent and ionic bonding, whereas ionic bonding was mainly accounted for Cd(II) adsorption. These findings open a new chapter in understanding the functions of different Fe phases in mediating the fate and transport of heavy metals in both natural and engineered systems.

[ZHANG Weihua's experience in treatment of cervical spondylotic radiculopathy with ulna-tibia needling therapy combined with decompression-loosening manual manipulation].

The paper introduces professor ZHANG Weihua's experience in treatment of cervical spondylotic radiculopathy (CSR) with ulna-tibia needling therapy combined with decompression-loosening manual manipulation. Using "palpating, detecting and imaging observing", professor ZHANG Weihua gives the accurate diagnosis for the location, the stage and the severity of the disease. According to the nature of the disease, CSR is treated in three stages. He proposes the academic thought, "taking the tendons as the outline, regarding the meridians as the essential, rooting at qi and blood, co-regulating tendons and bones". The ulna-tibia needling therapy and decompression-loosening manual manipulation are combined in treatment. In the ulna-tibia needling therapy, the acupuncture is delivered at the lower 1/3 of the cutaneous regions of taiyang and shaoyang meridians, on the ulnar region (belt-like distribution). The decompression-loosening manual manipulation is operated in 3 steps, i.e. relaxing the nape region, decompressing and relaxing (includes positioning rotational wrenching, upward and backward elevation) and supination wrenching, and analgesia and regulating tendons; and the manipulation for analgesia and regulating tendons is supplemented to enhance the effect.

Disulfiram downregulates ferredoxin 1 to maintain copper homeostasis and inhibit inflammation in cerebral ischemia/reperfusion injury.

In the current study, we aimed to investigate whether disulfiram (DSF) exerts a neuroprotective role in cerebral ischemiareperfusion (CI-RI) injury by modulating ferredoxin 1 (FDX1) to regulate copper ion (Cu) levels and inhibiting inflammatory responses. To simulate CI-RI, a transient middle cerebral artery occlusion (tMCAO) model in C57/BL6 mice was employed. Mice were administered with or without DSF before and after tMCAO. Changes in infarct volume after tMCAO were observed using TTC staining. Nissl staining and hematoxylin-eosin (he) staining were used to observe the morphological changes of nerve cells at the microscopic level. The inhibitory effect of DSF on initial inflammation was verified by TUNEL assay, apoptosis-related protein detection and iron concentration detection. FDX1 is the main regulatory protein of copper death, and the occurrence of copper death will lead to the increase of HSP70 stress and inflammatory response. Cuproptosis-related proteins and downstream inflammatory factors were detected by western blotting, immunofluorescence staining, and immunohistochemistry. The content of copper ions was detected using a specific kit, while electron microscopy was employed to examine mitochondrial changes. We found that DSF reduced the cerebral infarction volume, regulated the expression of cuproptosis-related proteins, and modulated copper content through down regulation of FDX1 expression. Moreover, DSF inhibited the HSP70/TLR-4/NLRP3 signaling pathway. Collectively, DSF could regulate Cu homeostasis by inhibiting FDX1, acting on the HSP70/TLR4/NLRP3 pathway to alleviate CI/RI. Accordingly, DSF could mitigate inflammatory responses and safeguard mitochondrial integrity, yielding novel therapeutic targets and mechanisms for the clinical management of ischemia-reperfusion injury.

A predictive model for therapy failure in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor therapy.

Although tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20-30% of people still experienced therapy failure. Data from 1,955 consecutive subjects with chronic-phase CML diagnosed by the European LeukemiaNet (ELN) recommendations from 1 center receiving initial TKI imatinib or a second-generation (2G-) TKI therapy were interrogated to develop a clinical prediction model for TKI therapy failure. This model was subsequently validated in 3,454 subjects from 76 other centers. Using the predictive clinical co-variates associated with TKI therapy failure, we developed a model that stratified subjects into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (p < 0.001). There was good discrimination and calibration in the external validation dataset, and the performance was consistent with that of the training dataset. Our model had the better prediction discrimination than the Sokal and ELTS scores did, with the greater time-dependent area under the receiver-operator characteristic curve (AUROC) values and a better ability to re-defined the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G-TKI therapy failure in people with chronic-phase CML.

Propofol ameliorates cognitive deficits following splenectomy in aged rats by inhibiting ferroptosis via the SIRT1/Nrf2/GPX4 pathway.

The aim of this study was to investigate the mechanism by which propofol reduces postoperative cognitive dysfunction after splenectomy in aged rats. The rats in the model group and propofol group were subjected to splenectomy, and anesthetized with isoflurane and propofol, respectively. Utilizing the western blotting to assess the expression of sirtuin-1 (SIRT1) in the hippocampus. Molecular docking technology was used to predict the binding ability of propofol and SIRT1. Behavioral tests were performed using the Morris water maze, and the hippocampus was isolated for mechanistic investigations. Molecular docking showed that propofol and SIRT1 had a strong binding affinity. The expression of SIRT1 and its related proteins Nrf2, HO-1, NQO1, and GPX4 in the model rats was decreased compared with the sham group. Moreover, the model group exhibited cognitive decline, such as extended escape latency and decreased number of platform crossings. Pathological analysis showed that the number of apoptotic neurons, the levels of oxidative stress and neuroinflammation, the iron deposition, and the expressions of ACSL4 and TFR1 were increased, while the expressions of SLC7A11 and FTH1 were decreased in the hippocampal CA1 region within the model group. These pathological changes in the propofol group were, however, less than those in the model group. Nevertheless, the SIRT1 inhibitor increased these pathological changes compared with the propofol group. Compared with isoflurane, propofol inhibits ferroptosis in the hippocampus of splenectomized rats by causing less downregulation of the SIRT1/Nrf2/GPX4 pathway, thereby reducing the negative impact on cognitive function.

Assessment of Global Antibiotic Exposure Risk for Crops: Incorporating Soil Adsorption via Machine Learning.

The overuse and misuse of antibiotics could significantly increase their accumulation in soils. Consequently, antibiotics possibly enter food chain through crop uptake, posing a threat to global food security. Assessing the exposure risks of antibiotics for crops is crucial for addressing this global issue. In this study, we assessed global antibiotic exposure risk for crops, incorporating a machine learning adsorption model based on 4893 data sets from nine antibiotics. The optimized machine learning adsorption model, using the eXtreme Gradient Boosting algorithm and the class-specific modeling strategy, demonstrated relatively good performance. Notably, we introduced unsaturated soil conditions and considered spatiotemporal variations in soil moisture and temperature for the first time in such a risk assessment. Global distributions of antibiotic exposure risk for crops were predicted for March, June, September, and December. The results indicate that soil moisture significantly influences the exposure risk assessment. Relatively high exposure risk for crops was observed during months with colder local temperatures: generally June for the Southern Hemisphere and December for the Northern Hemisphere. The resulting map highlights high-risk agricultural regions, including southern Canada, western Russia, and southern Australia.

Discovery of Novel Acethydrazide-Containing Flavonol Derivatives as Potential Antifungal Agents.

In this study, a series of novel hydrazide-containing flavonol derivatives was designed, synthesized, and evaluated for antifungal activity. In the in vitro antifungal assay, most of the target compounds exhibited potent antifungal activity against seven tested phytopathogenic fungi. In particular, compound C32 showed the best antifungal activity against Rhizoctonia solani (EC50 = 0.170 µg/mL), outperforming carbendazim (EC50 = 0.360 µg/mL) and boscalid (EC50 = 1.36 µg/mL). Compound C24 exhibited excellent antifungal activity against Valsa mali, Botrytis cinerea, and Alternaria alternata with EC50 values of 0.590, 0.870, and 1.71 µg/mL, respectively. The in vivo experiments revealed that compounds C32 and C24 were potential novel agricultural antifungals. 3D quantitative structure-activity relationship (3D-QSAR) models were used to analyze the structure-activity relationships of these compounds. The analysis results indicated that introducing appropriate electronegative groups at position 4 of a benzene ring could effectively improve the anti-R. solani activity. In the antifungal mechanism study, scanning electron microscopy and transmission electron microscopy analyses revealed that C32 disrupted the normal growth of hyphae by affecting the structural integrity of the cell membrane and cellular respiration. Furthermore, compound C32 exhibited potent succinate dehydrogenase (SDH) inhibitory activity (IC50 = 8.42 µM), surpassing that of the SDH fungicide boscalid (IC50 = 15.6 µM). The molecular dynamics simulations and docking experiments suggested that compound C32 can occupy the active site and form strong interactions with the key residues of SDH. Our findings have great potential for aiding future research on plant disease control in agriculture.

The effect of thermal treatment on the transformation and transportation of arsenic and cadmium in soil.

Thermal treatment can effectively decontaminate soils but alter their properties. Previous research mainly focused on volatile organic compounds and metals, i.e. Hg, neglecting non-volatile metal(loid)s. This study aimed to investigate Cd and As transformation during aerobic and anaerobic calcination. The results showed that both aerobic and anaerobic calcination increased soil pH by reducing soil organic matter (SOM) content, which also influenced the cation exchange capacity (CEC) and the leaching behavior of Cd and As in the soil. The total concentrations of Cd and As in the calcined soils varied depending on the calcination temperature and atmosphere. When the aerobic calcination temperature exceeded 700 °C, Cd volatilized as CdCl2, while anaerobic calcination at relatively low temperatures (600 °C) involved reductive reactions, resulting in the formation of metallic Cd with a lower boiling point. Similarly, As volatilized at 800 °C aerobically and 600 °C anaerobically. The formation of As-based minerals, particularly Ca3(AsO4)2, hindered its gasification, whereas anaerobic calcination promoted volatilization efficiency through the generation of C-As(III) based gaseous components with lower boiling points. Contrasting trends were observed in the TCLP-extractable Cd and As contents of the calcined soils. Over 70% of TCLP-extractable Cd contents were suppressed after thermal treatment, attributed to the elevated pH and reduced CEC of the soil, as well as volatilization. However, TCLP-extractable As contents increased with elevated temperatures, likely due to the desorption of AsO43- and re-adsorption of gaseous As2O3 during cooling. These findings have implications for assessing the environmental impact of thermal treatment and provide insights for remediation strategies concerning Cd and As-contaminated soils.

Active Assembly of CsPbBr3 Nanorods into Microcolumns by Electric Field in Nonpolar Solvent.

High-precision, controllable, mass-producible assembly of nanoparticles into complex structures or devices holds immense importance in the application across various fields but it remains challenging. Here a highly controllable and reversible active assembly of colloidal CsPbBr3 nanorods, driven by an external electric field is achieved. This approach enables the nanorods dynamically orient themselves, assemble into chains, aggregate into columns, and eventually form an ordered column array, with the electric field intensity varying from 0 to 50 V µm-1 at 100 kHz. The nanorods inside the columns align parallel to the electric field, leading to a well-ordered structure. With the analysis of the interactions among the nanorods, a quantitative interpretation of the assembly is proposed. Monte Carlo calculation is also introduced to simulate the assembly process and the results prove to be in great agreement with the experimental observations. This electric field-driven assembly presents an exciting opportunity to pave the way for next-generation sensors and photonic devices based on well-developed colloidal nanoparticles.

Design, Synthesis, Antifungal Activity, and 3D-QSAR Study of Novel Quinoxaline-2-Oxyacetate Hydrazide.

Plant pathogenic fungi pose a major threat to global food security, ecosystem services, and human livelihoods. Effective and broad-spectrum fungicides are needed to combat these pathogens. In this study, a novel antifungal 2-oxyacetate hydrazide quinoxaline scaffold as a simple analogue was designed and synthesized. Their antifungal activities were evaluated against Botrytis cinerea (B. cinerea), Altemaria solani (A. solani), Gibberella zeae (G. zeae), Rhizoctonia solani (R. solani), Colletotrichum orbiculare (C. orbiculare), and Alternaria alternata (A. alternata). These results demonstrated that most compounds exhibited remarkable inhibitory activities and possessed better efficacy than ridylbacterin, such as compound 15 (EC50 = 0.87 µg/mL against G. zeae, EC50 = 1.01 µg/mL against C. orbiculare) and compound 1 (EC50 = 1.54 µg/mL against A. alternata, EC50 = 0.20 µg/mL against R. solani). The 3D-QSAR analysis of quinoxaline-2-oxyacetate hydrazide derivatives has provided new insights into the design and optimization of novel antifungal drug molecules based on quinoxaline.

Outdoor Radon Dose Rate in Canada's Arctic amid Climate Change.

Decades of radiation monitoring data were analyzed to estimate outdoor Radon Dose Rates (RnDRs) and evaluate climate change impacts in Canada's Arctic Regions (Resolute and Yellowknife). This study shows that the RnDR involves dynamic sources and complex environmental factors and processes. Its seasonality and long-term trends are significantly impacted by temperatures and soil-and-above water contents. From 2005 to 2022, Yellowknife's RnDR increased by +0.35 ± 0.06 nGy/h per decade, with the fastest increases occurring in cold months (October to March). The rise is largely attributable to water condition changes over time in these months, which also caused enhanced soil gas emissions and likely higher indoor radon concentrations. In Resolute, the RnDR increased between 2013 and 2022 at +0.62 ± 0.19 nGy/h (or 16% relatively) per decade in summer months, with a positive temperature relationship of +0.12 nGy/h per °C. This work also demonstrates the relevance of local climate and terrain features (e.g., typical active layer depth, precipitation amount/pattern, and ground vegetation cover) in researching climate change implications. Such research can also benefit from using supporting monitoring data, which prove effective and scientifically significant. From the perspective of external exposure to outdoor radon, the observed climate change effects pose a low health risk.

Liensinine sensitizes colorectal cancer cells to oxaliplatin by targeting HIF-1α to inhibit autophagy.

BACKGROUND: Oxaliplatin is the most common chemotherapeutic agent for patients with colorectal cancer. However, its anti-cancer efficacy is restricted by drug resistance occurring through several mechanisms, including autophagy. Liensinine exerts a considerable anti-tumor effect and can regulate autophagy. Inhibition of autophagy is a strategy to reverse resistance to oxaliplatin. The aim of this study was to check if liensinine can enhance the therapeutic efficacy of oxaliplatin in colorectal cancer and if so, elucidate its mechanism. METHODS: Two colorectal cancer cell lines, HCT116 and LoVo, and one normal intestinal epithelial cell, NCM-460 were used for in vitro experiments. Cell Counting Kit-8 (CCK-8), colony formation, and flow cytometry assays were used to evaluate the cytotoxicity of liensinine and oxaliplatin. Network pharmacology analysis and Human XL Oncology Array were used to screen targets of liensinine. Transfections and autophagy regulators were used to confirm these targets. The relationship between the target and clinical effect of oxaliplatin was analyzed. Patient-derived xenograft (PDX) models were used to validate the effects of liensinine and oxaliplatin. RESULTS: CCK-8 and colony formation assays both showed that the combination treatment of liensinine and oxaliplatin exerted synergistic effects. Results of the network pharmacology analysis and Human XL Oncology Array suggested that liensinine can inhibit autophagy by targeting HIF-1α/eNOS. HIF-1α was identified as the key factor modulated by liensinine in autophagy and induces resistance to oxaliplatin. HIF-1α levels in tumor cells and prognosis for FOLFOX were negatively correlated in clinical data. The results from three PDX models with different HIF-1α levels showed their association with intrinsic and acquired resistance to oxaliplatin in these models, which could be reversed by liensinine. CONCLUSIONS: Research on the relationship between HIF-1α levels and the clinical effect of oxaliplatin is lacking, and whether liensinine regulates HIF-1α is unknown. Our findings suggest that liensinine overcomes the resistance of colorectal cancer cells to oxaliplatin by suppressing HIF-1α levels to inhibit autophagy. Our findings can contribute to improving prognosis following colorectal cancer therapy.

Optically Readable, Physically Unclonable Subwavelength Pixel via Multicolor Quantum Dot Printing for Anticounterfeiting.

We present a secure and user-friendly ultraminiaturized anticounterfeiting labeling technique─the color-encoded physical unclonable nanotag. These nanotags consist of subwavelength spots formed by random combinations of multicolor quantum dots, which are fabricated using a cost-efficient printing method developed in this study. The nanotags support over 170,000 different colors and are inherently resistant to cloning. Moreover, their high brightness and color purity, owing to the quantum dots, ensure an ease of readability. Additionally, these nanotags can function as color-encrypted pixels, enabling the incorporation of labels (such as QR codes) into ultrasmall physically unclonable hidden tags with a resolution exceeding 100,000 DPI. The unique blend of compactness, flexibility, and security positions the color-encoded nanotag as a potent and versatile solution for next-generation anticounterfeiting applications.

Interactions of oleanane pentacyclic triterpenoids with human organic anion transporting polypeptide 1B1 and 1B3.

Oleanane pentacyclic triterpenoids have been widely used in clinical practice. However, studies on their interactions with hepatic transporters remain limited. In this study, we systematically investigated the inhibitory effects of 14 oleanane pentacyclic triterpenoids on organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3), two liver-specific uptake transporters. Through fluorescence-based cellular uptake assays, we identified three potent OATP1B1 inhibitors (saikosaponin B1, saikosaponin A and 18ß-glycyrrhetinic acid) and five potent OATP1B3 inhibitors (echinocystic acid, 3-oxo-16α-hydroxy-olean-12-en-28ß-oic acid, chikusetsu saponin IVa, saikosaponin B1 and 18ß-glycyrrhetinic acid). Structural analysis revealed that free oleanane triterpenoids inhibited OATP1B1/1B3 more potently than triterpene glycosides. Despite their similar structures, 18ß-glycyrrhetinic acid exhibited much stronger inhibition on OATP1B1/1B3 than 18α-glycyrrhetinic acid, while both were substrates of OATP1B3. Interestingly, OATP1B3 overexpression significantly increased reactive oxygen species (ROS) levels in HepG2 cells after treatment with 18ß-glycyrrhetinic acid. To conclude, this study highlights the potential interactions of oleanane pentacyclic triterpenoids with OATP1B1/1B3, and provides novel insights into the anti-cancer activity of 18ß-glycyrrhetinic acid.

3D-QSAR-Directed Synthesis of Halogenated Coumarin-3-Hydrazide Derivatives: Unveiling Their Potential as SDHI Antifungal Agents.

The pursuit of new succinate dehydrogenase (SDH) inhibitors is a leading edge in fungicide research and development. The use of 3D quantitative structure-activity relationship (3D-QSAR) models significantly enhances the development of compounds with potent antifungal properties. In this study, we leveraged the natural product coumarin as a molecular scaffold to synthesize 74 novel 3-coumarin hydrazide derivatives. Notably, compounds 4ap (0.28 µg/mL), 6ae (0.32 µg/mL), and 6ah (0.48 µg/mL) exhibited exceptional in vitro effectiveness against Rhizoctonia solani, outperforming the commonly used fungicide boscalid (0.52 µg/mL). Furthermore, compounds 4ak (0.88 µg/mL), 6ae (0.61 µg/mL), 6ah (0.65 µg/mL), and 6ak (1.11 µg/mL) showed significant activity against Colletotrichum orbiculare, surpassing both the SDHI fungicide boscalid (43.45 µg/mL) and the broad-spectrum fungicide carbendazim (2.15 µg/mL). Molecular docking studies and SDH enzyme assays indicate that compound 4ah may serve as a promising SDHI fungicide. Our ongoing research aims to refine this 3D-QSAR model further, enhance molecular design, and conduct additional bioactivity assays.

Developing preclinical dog models for reconstructive severed spinal cord continuity via spinal cord fusion technique.

Background: Spinal cord injury (SCI) is a severe impairment of the central nervous system, leading to motor, sensory, and autonomic dysfunction. The present study investigates the efficacy of the polyethylene glycol (PEG)-mediated spinal cord fusion (SCF) techniques, demonstrating efficacious in various animal models with complete spinal cord transection at the T10 level. This research focuses on a comparative analysis of three SCF treatment models in beagles: spinal cord transection (SCT), vascular pedicle hemisected spinal cord transplantation (vSCT), and vascularized allograft spinal cord transplantation (vASCT) surgical model. Methods: Seven female beagles were included in the SCT surgical model, while four female dogs were enrolled in the vSCT surgical model. Additionally, twelve female dogs underwent vASCT in a paired donor-recipient setup. Three surgical model were evaluated and compared through electrophysiology, imaging and behavioral recovery. Results: The results showed a progressive recovery in the SCT, vSCT and vASCT surgical models, with no statistically significant differences observed in cBBB scores at both 2-month and 6-month post-operation (both P>0.05). Neuroimaging analysis across the SCT, vSCT and vASCT surgical models revealed spinal cord graft survival and fiber regrowth across transection sites at 6 months postoperatively. Also, positive MEP waveforms were recorded in all three surgical models at 6-month post-surgery. Conclusion: The study underscores the clinical relevance of PEG-mediated SCF techniques in promoting nerve fusion, repair, and motor functional recovery in SCI. SCT, vSCT, and vASCT, tailored to specific clinical characteristics, demonstrated similar effective therapeutic outcomes.

Study on the mechanism of Huangqi Guizhi Wuwu Decoction in treating diabetes peripheral neuropathy based on network pharmacology and molecular docking.

This study aimed to explore the effective substances and mechanism network of Huangqi Guizhi Wuwu Decoction in treating diabetes peripheral neuropathy. Based on the TCM systemic pharmacological analysis platform (TCMP) and UniProt database, the database of active Huqarqu Decoction was constructed, and the related targets of diabetic peripheral neuropathy were collected through the OMIM, CTD, DisGeNET, TTD and GeneCards databases. The intersection targets were obtained to construct the network diagram of Huangqi dis Guizhi Wuwu Decoction-Active Through the String database, the interaction between target proteins was analyzed, and molecular docking between active components and potential targets was carried out. Combined with the DAVID v6.8 database, GO function analysis and KEGG pathway analysis were performed on the targets. Guizhi Wuwu Decoction mainly acts on core targets such as IL6, MAPK3, VE GFA, JUN and ESR1 through quercetin, kaempferol and naringin and regulates the TNF signaling pathway, estrogen signaling pathway and MAPK signaling pathway, thus achieving the effect of treating diabetes peripheral neuropathy. Huangqi Guizhi Wu has multiple targets and regulates multiple signaling pathways in neuropathy, which lays a foundation for future pharmacological research.

Ibuprofen induces hepatic Cyp7a1 expression in mice via the intestinal FXR-FGF15 signaling.

Non-steroidal anti-inflammatory drugs (NSAIDs) may cause drug-induced liver injury (DILI). However, the molecular mechanisms underlying NSAIDs hepatotoxicity remain elusive. Dysregulations of bile acids (BAs) have been implicated in various DILI. In this study, we systematically investigated the effects of ibuprofen, the most commonly used NSAID, on BA metabolism and signaling in adult male C57/BL6 mice after oral administration of ibuprofen (IBU) at clinically relevant doses (30, 100, and 200 mg/kg) for one week. Notably, IBU significantly decreased BA concentrations in the liver in a dose-dependent manner, with a concomitant increase in both mRNA and protein expression of cholesterol 7alpha-hydoxylase (CYP7A1), the rate-limiting enzyme for BA synthesis. Mechanically, IBU altered the composition of gut microbiota and increased cecal BAs, leading to reduced intestinal absorption of BAs and thus deactivated ileal farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) signaling. Additionally, diclofenac and indomethacin also induced hepatic Cyp7a1 expression in mice via their effects on gut microbiota and intestinal BA signaling. To conclude, the current findings suggest that NSAIDs-induced liver injury could be at least partially attributable to the dysregulation of BA metabolism and signaling.

SF3B3-regulated mTOR alternative splicing promotes colorectal cancer progression and metastasis.

BACKGROUND: Aberrant alternative splicing (AS) is a pervasive event during colorectal cancer (CRC) development. SF3B3 is a splicing factor component of U2 small nuclear ribonucleoproteins which are crucial for early stages of spliceosome assembly. The role of SF3B3 in CRC remains unknown. METHODS: SF3B3 expression in human CRCs was analyzed using publicly available CRC datasets, immunohistochemistry, qRT-PCR, and western blot. RNA-seq, RNA immunoprecipitation, and lipidomics were performed in SF3B3 knockdown or overexpressing CRC cell lines. CRC cell xenografts, patient-derived xenografts, patient-derived organoids, and orthotopic metastasis mouse models were utilized to determine the in vivo role of SF3B3 in CRC progression and metastasis. RESULTS: SF3B3 was upregulated in CRC samples and associated with poor survival. Inhibition of SF3B3 by RNA silencing suppressed the proliferation and metastasis of CRC cells in vitro and in vivo, characterized by mitochondria injury, increased reactive oxygen species (ROS), and apoptosis. Mechanistically, silencing of SF3B3 increased mTOR exon-skipped splicing, leading to the suppression of lipogenesis via mTOR-SREBF1-FASN signaling. The combination of SF3B3 shRNAs and mTOR inhibitors showed synergistic antitumor activity in patient-derived CRC organoids and xenografts. Importantly, we identified SF3B3 as a critical regulator of mTOR splicing and autophagy in multiple cancers. CONCLUSIONS: Our findings revealed that SF3B3 promoted CRC progression and metastasis by regulating mTOR alternative splicing and SREBF1-FASN-mediated lipogenesis, providing strong evidence to support SF3B3 as a druggable target for CRC therapy.

Clinical Presentation, Management, and Diagnostic Performance of 2021 Criteria for Paraneoplastic Neurologic Syndromes in Childhood.

BACKGROUND AND OBJECTIVES: Paraneoplastic neurologic syndromes (PNSs) are remote neurologic immune-related effects of tumors. The clinical characteristics of pediatric PNSs remain unclear. We retrospectively examined the clinical characteristics of cases of pediatric PNSs and assessed the performance of the 2021 diagnostic criteria in children. METHODS: Patients hospitalized in the Beijing Children's Hospital between June 2015 and June 2023 and fulfilling the description of definite by 2004 diagnostic criteria of PNSs were included. A retrospective analysis of clinical characteristics was conducted, and the 2021 diagnostic criteria were applied to rediagnostic stratification. RESULTS: Among the 42 patients included, the most common neurologic syndrome was opsoclonus-myoclonus syndrome (OMS) (62%), followed by rapidly progressive cerebellar syndrome (26%). Most tumors were neuroblastomas (88%), with few being ovarian teratomas (10%). Approximately 71% (30/42) of patients were classified as definite and 24% (10/42) as probable according to the 2021 criteria. All cases judged as probable exhibited rapidly progressive cerebellar ataxia with neuroblastoma. For OMS, chemotherapy was administered based on the tumor's risk stage, accompanied by regular infusion of IV gamma globulin and oral steroids following tumor diagnosis. Twenty-one patients underwent regular follow-ups over 4.92 (0.58-7.58) years. The initial hospitalization recorded a median score of 12 (7-14) on the Mitchell and Pike OMS rating scale, decreasing to 0 (0-5) at the final follow-up. In cases of rapidly progressive cerebellar syndrome, a similar therapeutic regimen was used. Nine patients underwent regular follow-ups over 4.42 (1.17-7.50) years. The mean modified Rankin scale score at first hospitalization was 4 (3-4), reducing to 1 (0-4) at the final follow-up. Only 17% (5/30) of patients across both groups exhibited poor response to this regimen. Among these 5 patients, 4 belonged to the low-risk group (without chemotherapy). DISCUSSION: OMS followed by rapidly progressive cerebellar ataxia are the most common forms of PNSs in children and are associated with neuroblastoma. An aggressive approach with multiple immunotherapies may improve the prognosis of neuroblastoma-associated PNSs. The 2021 criteria perform well in pediatric PNSs. However, we propose upgrading the classification of antibody-negative rapidly progressive cerebellar ataxia with neuroblastoma to definite diagnosis. This adjustment aims to further improve the diagnostic efficacy of this diagnostic criterion in childhood.