The intestinal microbiota and cellular therapy: implications for impact and mechanisms.

ABSTRACT: The microbiota, comprising bacteria, fungi, and viruses residing within our bodies, functions as a key modulator in host health and states, including immune responses. Studies have linked microbiota and microbiota-derived metabolites to immune cell functions. In this review, we probe the complex relationship between the human microbiota and clinical outcomes of cellular therapies that leverage immune cells to fight various cancers. With a particular emphasis on hematopoietic cell transplantation and chimeric antigen receptor T-cell therapy, we explore the potential mechanisms underpinning this interaction. We also highlight the interventional applications of the microbiota in cellular therapy while outlining future research directions in the field.

Self-Oxygenated Hydrogel Enhances Immune Cell Response and Infiltration Via Triggering Dual DNA Damage to Activate cGAS-STING and Inhibiting CAFs.

Immune checkpoint inhibitors (ICIs) offer promise in breaking through the treatment and survival dilemma of triple-negative breast cancer (TNBC), yet only immunomodulatory subtype and ≈5% TNBC patients respond as monotherapy due to lack of effector immune cells (internal problem) and physical barrier (external limitation) formed by cancer-associated fibroblasts (CAFs). A hydrogel drug-delivery platform, ALG@TBP-2/Pt(0)/nintedanib (ALG@TPN), is designed to induce strong immune functions and the dual elimination of the internal and external tumor microenvironment (TME). Activated by white light, through type I and II photodynamic therapy (PDT), TBP-2 generates large amounts of reactive oxygen species (ROS) intracellularly, oxidizing mitochondrial DNA (mtDNA). The unique catalase activity of Pt(0) converts endogenous H2O2 to O2, reducing the anoxia-limiting PDT and enhancing ROS generation efficacy. Abundant ROS can oxidize Pt(0) to cytotoxic Pt(II), damaging the nuclear DNA (nDNA). Dual damage to mtDNA and nDNA might bi-directionally activate the cGAS/STING pathway and enhance the immune cell response. Besides, nintedanib demonstrates a significant inhibitory effect on CAFs, weakening the immune barrier and deepening immune cell infiltration. Overall, the study provides a self-oxygenating hydrogel with the "PDT/chemotherapy/anti-CAFs" effect, triggering the cGAS/STING pathway to reshape the TME. Both internal and external interventions increase anti-TNBC immune responses.

Regulation of endocrine cell alternative splicing revealed by single-cell RNA sequencing in type 2 diabetes pathogenesis.

The prevalent RNA alternative splicing (AS) contributes to molecular diversity, which has been demonstrated in cellular function regulation and disease pathogenesis. However, the contribution of AS in pancreatic islets during diabetes progression remains unclear. Here, we reanalyze the full-length single-cell RNA sequencing data from the deposited database to investigate AS regulation across human pancreatic endocrine cell types in non-diabetic (ND) and type 2 diabetic (T2D) individuals. Our analysis demonstrates the significant association between transcriptomic AS profiles and cell-type-specificity, which could be applied to distinguish the clustering of major endocrine cell types. Moreover, AS profiles are enabled to clearly define the mature subset of ß-cells in healthy controls, which is completely lost in T2D. Further analysis reveals that RNA-binding proteins (RBPs), heterogeneous nuclear ribonucleoproteins (hnRNPs) and FXR1 family proteins are predicted to induce the functional impairment of ß-cells through regulating AS profiles. Finally, trajectory analysis of endocrine cells suggests the ß-cell identity shift through dedifferentiation and transdifferentiation of ß-cells during the progression of T2D. Together, our study provides a mechanism for regulating ß-cell functions and suggests the significant contribution of AS program during diabetes pathogenesis.

CPADS: a web tool for comprehensive pancancer analysis of drug sensitivity.

Drug therapy is vital in cancer treatment. Accurate analysis of drug sensitivity for specific cancers can guide healthcare professionals in prescribing drugs, leading to improved patient survival and quality of life. However, there is a lack of web-based tools that offer comprehensive visualization and analysis of pancancer drug sensitivity. We gathered cancer drug sensitivity data from publicly available databases (GEO, TCGA and GDSC) and developed a web tool called Comprehensive Pancancer Analysis of Drug Sensitivity (CPADS) using Shiny. CPADS currently includes transcriptomic data from over 29 000 samples, encompassing 44 types of cancer, 288 drugs and more than 9000 gene perturbations. It allows easy execution of various analyses related to cancer drug sensitivity. With its large sample size and diverse drug range, CPADS offers a range of analysis methods, such as differential gene expression, gene correlation, pathway analysis, drug analysis and gene perturbation analysis. Additionally, it provides several visualization approaches. CPADS significantly aids physicians and researchers in exploring primary and secondary drug resistance at both gene and pathway levels. The integration of drug resistance and gene perturbation data also presents novel perspectives for identifying pivotal genes influencing drug resistance. Access CPADS at https://smuonco.shinyapps.io/CPADS/ or https://robinl-lab.com/CPADS.

Remodeling the immune microenvironment for gastric cancer therapy through antagonism of prostaglandin E2 receptor 4.

Gastric cancer is highly prevalent among digestive tract tumors. Due to the intricate nature of the gastric cancer immune microenvironment, there is currently no effective treatment available for advanced gastric cancer. However, there is promising potential for immunotherapy targeting the prostaglandin E2 receptor subtype 4 (EP4) in gastric cancer. In our previous study, we identified a novel small molecule EP4 receptor antagonist called YY001. Treatment with YY001 alone demonstrated a significant reduction in gastric cancer growth and inhibited tumor metastasis to the lungs in a mouse model. Furthermore, administration of YY001 stimulated a robust immune response within the tumor microenvironment, characterized by increased infiltration of antigen-presenting cells, T cells, and M1 macrophages. Additionally, our research revealed that YY001 exhibited remarkable synergistic effects when combined with the PD-1 antibody and the clinically targeted drug apatinib, rather than fluorouracil. These findings suggest that YY001 holds great promise as a potential therapeutic strategy for gastric cancer, whether used as a standalone treatment or in combination with other drugs.

Prognostic Value of a Combined Nomogram Model Integrating 3-Dimensional Deep Learning and Radiomics for Head and Neck Cancer.

OBJECTIVE: The preoperative prediction of the overall survival (OS) status of patients with head and neck cancer (HNC) is significant value for their individualized treatment and prognosis. This study aims to evaluate the impact of adding 3D deep learning features to radiomics models for predicting 5-year OS status. METHODS: Two hundred twenty cases from The Cancer Imaging Archive public dataset were included in this study; 2212 radiomics features and 304 deep features were extracted from each case. The features were selected by univariate analysis and the least absolute shrinkage and selection operator, and then grouped into a radiomics model containing Positron Emission Tomography /Computed Tomography (PET/CT) radiomics features score, a deep model containing deep features score, and a combined model containing PET/CT radiomics features score +3D deep features score. TumorStage model was also constructed using initial patient tumor node metastasis stage to compare the performance of the combined model. A nomogram was constructed to analyze the influence of deep features on the performance of the model. The 10-fold cross-validation of the average area under the receiver operating characteristic curve and calibration curve were used to evaluate performance, and Shapley Additive exPlanations (SHAP) was developed for interpretation. RESULTS: The TumorStage model, radiomics model, deep model, and the combined model achieved areas under the receiver operating characteristic curve of 0.604, 0.851, 0.840, and 0.895 on the train set and 0.571, 0.849, 0.832, and 0.900 on the test set. The combined model showed better performance of predicting the 5-year OS status of HNC patients than the radiomics model and deep model. The combined model was shown to provide a favorable fit in calibration curves and be clinically useful in decision curve analysis. SHAP summary plot and SHAP The SHAP summary plot and SHAP force plot visually interpreted the influence of deep features and radiomics features on the model results. CONCLUSIONS: In predicting 5-year OS status in patients with HNC, 3D deep features could provide richer features for combined model, which showed outperformance compared with the radiomics model and deep model.

Effects of multiple stressors on freshwater food webs: Evidence from a mesocosm experiment.

Natural and anthropogenic pressures exert influence on ecosystem structure and function by affecting the physiology and behavior of organisms, as well as the trophic interactions within assemblages. Therefore, understanding how multiple stressors affect aquatic ecosystems can improve our ability to manage and protect these ecosystems and contribute to understanding fundamental ecological principles. Here, we conducted a mesocosm experiment to ascertain the individual and combined effects of multiple stressors on trophic interactions within species in freshwater ecosystems. Furthermore, we investigated how species respond to such changes by adapting their food resources. To mimic a realistic food web, we selected fish and shrimp as top predators, gastropods, zooplankton and zoobenthos as intermediate consumers, with producers (macrophytes, periphyton and phytoplankton) and detritus as basal resources. Twelve different treatments included a control, nutrient loading only, herbicide exposure only, and a combination of nutrient loading and herbicide exposure, each replicated under ambient temperature, constant warming and multiple heat waves to simulate environmental stressors. Our results demonstrated that antagonistic interactions between environmental stressors were widespread in trophic interactions, with a more pronounced and less intense impact observed for the high trophic level species. The responses of freshwater communities to environmental stressors are complex, involving direct effects on individual species as well as indirect effects through species interactions. Moreover, our results confirmed that the combinations of stressors, but not individual stressors, led to a shift to herbivory in top predators, indicating that multiple stressors can be more detrimental to organisms than individual stressors alone. These findings elucidate how changes in the resource utilization of species induced by environmental stressors can potentially influence species interactions and the structural dynamics of food webs in freshwater ecosystems.

PNMC: Four-dimensional conebeam CT reconstruction combining prior network and motion compensation.

Four-dimensional conebeam computed tomography (4D CBCT) is an efficient technique to overcome motion artifacts caused by organ motion during breathing. 4D CBCT reconstruction in a single scan usually divides projections into different groups of sparsely sampled data based on the respiratory phases. The reconstructed images within each group present poor image quality due to the limited number of projections. To improve the image quality of 4D CBCT in a single scan, we propose a novel reconstruction scheme that combines prior knowledge with motion compensation. We apply the reconstructed images of the full projections within a single routine as prior knowledge, providing structural information for the network to enhance the restoration structure. The prior network (PN-Net) is proposed to extract features of prior knowledge and fuse them with the sparsely sampled data using an attention mechanism. The prior knowledge guides the reconstruction process to restore the approximate organ structure and alleviates severe streaking artifacts. The deformation vector field (DVF) extracted using deformable image registration among different phases is then applied in the motion-compensated ordered-subset simultaneous algebraic reconstruction algorithm to generate 4D CBCT images. Proposed method has been evaluated using simulated and clinical datasets and has shown promising results by comparative experiment. Compared with previous methods, our approach exhibits significant improvements across various evaluation metrics.

SHP-1 inhibition targets leukaemia stem cells to restore immunosurveillance and enhance chemosensitivity by metabolic reprogramming.

Leukaemia stem cells (LSCs) in acute myeloid leukaemia present a considerable treatment challenge due to their resistance to chemotherapy and immunosurveillance. The connection between these properties in LSCs remains poorly understood. Here we demonstrate that inhibition of tyrosine phosphatase SHP-1 in LSCs increases their glycolysis and oxidative phosphorylation, enhancing their sensitivity to chemotherapy and vulnerability to immunosurveillance. Mechanistically, SHP-1 inhibition leads to the upregulation of phosphofructokinase platelet (PFKP) through the AKT-ß-catenin pathway. The increase in PFKP elevates energy metabolic activities and, as a consequence, enhances the sensitivity of LSCs to chemotherapeutic agents. Moreover, the upregulation of PFKP promotes MYC degradation and, consequently, reduces the immune evasion abilities of LSCs. Overall, our study demonstrates that targeting SHP-1 disrupts the metabolic balance in LSCs, thereby increasing their vulnerability to chemotherapy and immunosurveillance. This approach offers a promising strategy to overcome LSC resistance in acute myeloid leukaemia.

UBES: Unified scatter correction using ultrafast Boltzmann equation solver for conebeam CT.

A semi-analytical solution to the unified Boltzmann equation is constructed to exactly describe the scatter distribution on a flat-panel detector for high-quality conebeam CT (CBCT) imaging. The solver consists of three parts, including the phase space distribution estimator, the effective source constructor and the detector signal extractor. Instead of the tedious Monte Carlo solution, the derived Boltzmann equation solver achieves ultrafast computational capability for scatter signal estimation by combining direct analytical derivation and time-efficient one-dimensional numerical integration over the trajectory along each momentum of the photon phase space distribution. The execution of scatter estimation using the proposed ultrafast Boltzmann equation solver (UBES) for a single projection is finalized in around 0.4 seconds. We compare the performance of the proposed method with the state-of-the-art schemes, including a time-expensive Monte Carlo (MC) method and a conventional kernel-based algorithm using the same dataset, which is acquired from the CBCT scans of a head phantom and an abdominal patient. The evaluation results demonstrate that the proposed UBES method achieves comparable correction accuracy compared with the MC method, while exhibits significant improvements in image quality over learning and kernel-based methods. With the advantages of MC equivalent quality and superfast computational efficiency, the UBES method has the potential to become a standard solution to scatter correction in high-quality CBCT reconstruction.

A bibliometric analysis of international publication trends in brain atrophy research (2008-2023).

Background: Brain atrophy is a type of neurological and psychiatric disorder characterized by a decrease in brain tissue volume and weight for various reasons and can have a serious impact on the quality of life of patients. Although there are many studies on brain atrophy, there is a lack of relevant bibliometric studies. Therefore, this study aims to provide a visual analysis of global trends in brain atrophy research over the past 16 years. Methods: CiteSpace and VOSviewer were used to visually analyze publication output, scientific collaborations, cocitations, publishing journals, and keywords to determine the current status and future trends of brain atrophy research. Materials published from 2008 to 2023 were collected from the Web of Science Core Collection (WoSCC) database. This study placed no restrictions on the types of literature and focused on English language publications. Results: A total of 3,371 publications were included in the analysis. From 2008 to 2023, the number of publications increased annually. In terms of national and academic institutions, universities in the United States and University College London rank first in publication out. Barkhof Frederik and Zivadinov Robert are the most prolific researchers in this field. The publication with the highest cocitation strength is "Deep gray matter volume loss drives disability worsening in multiple sclerosis." Keyword clustering analysis showed that "Alzheimer's disease" and "multiple sclerosis" are current popular topics. The analysis of emergent words indicates that "cerebral small vessel disease," "neurodegeneration," and "cortex/gray matter volume" may become hot research topics in the coming years. Conclusion: This study analyses papers on brain atrophy from the past 16 years, providing a new perspective for research in this field. In the past 16 years, research on brain atrophy has received increasing attention. The quality of articles in this field is generally high. Extensive national cooperation already exists. The statistical results indicate that a stable core author group in the field of brain atrophy has almost formed.

Quantitative analysis of molecular transport in the extracellular space using physics-informed neural network.

The brain extracellular space (ECS), an irregular, extremely tortuous nanoscale space located between cells or between cells and blood vessels, is crucial for nerve cell survival. It plays a pivotal role in high-level brain functions such as memory, emotion, and sensation. However, the specific form of molecular transport within the ECS remain elusive. To address this challenge, this paper proposes a novel approach to quantitatively analyze the molecular transport within the ECS by solving an inverse problem derived from the advection-diffusion equation (ADE) using a physics-informed neural network (PINN). PINN provides a streamlined solution to the ADE without the need for intricate mathematical formulations or grid settings. Additionally, the optimization of PINN facilitates the automatic computation of the diffusion coefficient governing long-term molecule transport and the velocity of molecules driven by advection. Consequently, the proposed method allows for the quantitative analysis and identification of the specific pattern of molecular transport within the ECS through the calculation of the Péclet number. Experimental validation on two datasets of magnetic resonance images (MRIs) captured at different time points showcases the effectiveness of the proposed method. Notably, our simulations reveal identical molecular transport patterns between datasets representing rats with tracer injected into the same brain region. These findings highlight the potential of PINN as a promising tool for comprehensively exploring molecular transport within the ECS.

Atovaquone enhances antitumor efficacy of TCR-T therapy by augmentation of ROS-induced ferroptosis in hepatocellular carcinoma.

T-cell receptor (TCR) engineered T-cell therapy has recently emerged as a promising adoptive immunotherapy approach for tumor treatment, yet hindered by tumor immune evasion resulting in poor therapeutic efficacy. The introduction of ferroptosis-targeted inducers offers a potential solution, as they empower T cells to induce ferroptosis and exert influence over the tumor microenvironment. Atovaquone (ATO) stands as a prospective pharmaceutical candidate with the potential to target ferroptosis, effectively provoking an excessive generation and accumulation of reactive oxygen species (ROS). In this study, we evaluated the effectiveness of a combination therapy comprising ATO and TCR-T cells against hepatocellular carcinoma (HCC), both in vitro and in vivo. The results of lactate dehydrogenase and cytokine assays demonstrated that ATO enhanced cytotoxicity mediated by AFP-specific TCR-T cells and promoted the release of IFN-γ in vitro. Additionally, in an established HCC xenograft mouse model, the combined therapy with low-dose ATO and TCR-T cells exhibited heightened efficacy in suppressing tumor growth, with no apparent adverse effects, comparable to the results achieved through monotherapy. The RNA-seq data unveiled a significant activation of the ferroptosis-related pathway in the combination therapy group in comparison to the TCR-T cells group. Mechanistically, the synergy between ATO and TCR-T cells augmented the release of IFN-γ by TCR-T cells, while concurrently elevating the intracellular and mitochondrial levels of ROS, expanding the labile iron pool, and impairing the integrity of the mitochondrial membrane in HepG2 cells. This multifaceted interaction culminated in the potentiation of ferroptosis within the tumor, primarily induced by an excess of ROS. In summary, the co-administration of ATO and TCR-T cells in HCC exhibited heightened vulnerability to ferroptosis. This heightened susceptibility led to the inhibition of tumor growth and the stimulation of an anti-tumor immune response. These findings suggest that repurposing atovaquone for adoptive cell therapy combination therapy holds the potential to enhance treatment outcomes in HCC.

Urantide alleviates atherosclerosis-related liver and kidney injury via the Wnt/ß-catenin signaling pathway in ApoE(-/-) mice.

OBJECTIVE: To investigate the role of urantide in the prevention and treatment of atherosclerosis (AS)-related liver and kidney injury by antagonizing the urotensin II/urotensin receptor (UII/UT) system and regulating the Wnt/ß-catenin signaling pathway. METHODS: Atherosclerotic ApoE-/- mice were treated with 20 mg/kg, 30 mg/kg, and 40 mg/kg urantide for 14 days. RESULTS: When ApoE-/- mice developed AS, significant pathological changes occurred in the liver and kidney, and the UII/UT system in tissue was highly activated; furthermore, the Wnt/ß-catenin signalling pathway was activated, and proteins related to this signalling pathway, such as GSK-3ß, AXIN2, CK­1, and APC, were significantly downregulated. After urantide treatment, the pathological damage to the liver and kidney was effectively improved, the activity of the UII/UT system was effectively inhibited, and the expression of the Wnt/ß-catenin signalling pathway and related proteins was restored. Wnt/ß-catenin signals were mainly localized in the cytoplasm, renal tubules, and interstitium. CONCLUSION: Urantide could improve AS-related liver and kidney injury by antagonizing the UII/UT system, and the improvements in liver and kidney function in atherosclerotic ApoE-/- mice may be related to inhibition of the Wnt/ß-catenin signalling pathway.

Application of checklist-based nursing care process in patients undergoing intervention for coronary chronic total occlusions: a quasi-randomized study.

BACKGROUND: Coronary chronic total occlusion (CTO) interventions are more complex than general percutaneous coronary intervention (PCI) procedures. However, only a few nursing methods are specifically applied to patients undergoing CTO interventions. And the conventional nursing effect is not ideal, urgent need to explore more effective nursing methods. The checklist is a simple and effective tool for error management and performance improvement that has been widely used in many fields. But there have been no reports of the checklist being used to improve care for CTO patients. OBJECTIVE: This study aimed to investigate the effectiveness of a checklist-based nursing care process in patients undergoing Coronary chronic total occlusion (CTO) interventions, including duration of care, patient anxiety, improved patient satisfaction, and occurrence of adverse events. METHODS: A total of 120 CTO patients undergoing percutaneous coronary intervention (PCI) were selected at our hospital and divided into an intervention group (n = 60, adopted the checklist-based nursing care process for patient care) and a control group (n = 60, adopted nursing care according to the existing workflow) according to different nursing interventions. After surgery, the nurse in charge of the patient completed the nursing according to the "List of postoperative care for CTO patients" filled in by the patient within 24 h after surgery, conducted a doctor satisfaction survey, recorded adverse events, and completed the postoperative Self-Rating Anxiety Scale (SAS) score and patient satisfaction survey before the patient was discharged. Subsequently, the Qc team checks the completion of the patient's checklist for safety and the completion of the questionnaire. Finally, the differences between the two groups in preoperative nursing time, incidence of adverse events caused by nurses' omission or inadequate guidance, patient anxiety, and doctor and patient satisfaction were compared. RESULTS: The intervention grouphad significantly shorter preoperative nursing care time and significantly lower the total number of adverse events than the control group (P < 0.05).The postoperative Self-Rating Anxiety Scale (SAS) score of the intervention group was significantly lower than that of the control group (P < 0.05).The satisfaction of doctors and patients in the intervention groupwas significantly higher than that in the control group (P < 0.05). CONCLUSION: The application of the checklist-based nursing care process in patients with CTO intervention can significantly reduce the preoperative nursing care time, reduce patient anxiety, improve patients' and doctors' satisfaction with nursing care, and effectively reduce the occurrence of adverse events caused by nurses' omissions or inadequate instructions. TRIAL REGISTRATION: The protocol of the trial was registered retrospectively of Chinese Clinical Trial Registry (registration number ChiCTR2200056804, reg date17/02/2022).

Cooled infrared coaxial four-mirror system design with a low F-number.

A low F-number and 100% cold stop efficiency are beneficial for improving the performance of optical systems and have a wide range of applications in various thermal imaging scenarios. The cooled infrared coaxial four-mirror system can meet these two requirements, improve system integration, and reduce adjustment costs and difficulties. However, the secondary obstruction caused by the central hole of the third mirror will generate potential stray light. A structure model is proposed in which the primary mirror and the quaternary mirror are processed on the same mirror blank. In this model, a method is given to calculate system parameters using the obstruction ratio and magnification of each mirror. To evaluate the performance of the method, two design examples with different F-numbers (1.4, 1.0) were constructed. The influence of initial structural constraints on the exit pupil position and secondary obstruction was analyzed based on the design objectives of the examples. The aberrations were optimized by targeting the spot. In the optimization process, the incident coordinates and directions of the restricted edge field rays in the tertiary mirror and the quaternary mirror were limited to achieve control of the obstruction caused by the holes in the center of the mirrors. In the results, the RMS spot radius of the two design examples is smaller than the Airy disk radius, and the axial beam wavefront deviation RMS values are 0.026λ and 0.024λ, respectively. Moreover, the obstruction caused by the central holes of the mirrors is controlled within the given field of view. The results show that the proposed model and method can be used to design a low F-number cooled infrared coaxial four-mirror system and have good application prospects.

Assessing the role of combination of stem cell and light-based treatments on skin wound repair: A meta-analysis.

The meta-analysis aims to evaluate and compare the impact of the combination of stem cells (SCs) and light-based treatments (LBTs) on skin wound (SW) repair. Examinations comparing SCs to LBT with SCs for SW repair was among the meta-analysis from various languages that met the inclusion criteria. Using continuous random-effect models, the results of these investigations were examined, and the mean difference (MD) with 95% confidence intervals was computed (CIs). Seven examinations from 2012 to 2022 were recruited for the current analysis including 106 animals with SWs. Photobiomodulation therapy (PBT) plus SCs had a significantly higher wound closure rate (WCR) (MD, 9.08; 95% CI, 5.55-12.61, p < 0.001) compared to SCs in animals with SWs. However, no significant difference was found between PBT plus SCs and SCs on wound tensile strength (WTS) (MD, 2.01; 95% CI, -0.42 to 4.44, p = 0.10) in animals with SWs. The examined data revealed that PBT plus SCs had a significantly higher WCR, however, no significant difference was found in WTS compared to SCs in animals with SWs. Nevertheless, caution should be exercised while interacting with its values since all the chosen examinations were found with a low sample size and a low number of examinations were found for the comparisons studied for the meta-analysis.

Interactions between climate warming, herbicides, and eutrophication in the aquatic food web.

Understanding the interactive effects of multiple environmental stressors on biological communities is crucial for effective environmental management and biodiversity conservation. Here, we present the results of an outdoor mesocosm experiment examining how an aquatic food web responds to the individual and combined effects of climate warming, heat waves, nutrient enrichment, and herbicide exposure. To assess ecosystem functioning, we examined energy flow, using stable isotope analysis integrated with the bioenergetics food web approach to quantify energy fluxes among trophic levels. Our results revealed that the combined effects of these stressors altered the pattern of energy fluxes within the food web. Under warming conditions, there was an increase in energy flux from producers and primary consumers to secondary consumers. However, we did not observe a significant increase in energy flux in primary consumers, potentially due to enhanced top-down control. Nutrient enrichment increased energy flux from producers to higher trophic levels while simultaneously decreasing detrital energy flux. Herbicide exposure did not significantly affect herbivory energy flux but did reduce detritivory energy flux, particularly from detritus to primary consumers. The interactive effects we observed were primarily antagonistic or additive, although we also detected reversed and synergistic effects. The responses to multiple stressors varied across different energy flow pathways, leading to an asymmetric response. Furthermore, our results also revealed significant differences in the effects of constant warming and heat waves, either alone or in combination with water pollution. The asymmetric response of energy flow pathways and the prevalence of antagonistic effects present significant challenges for ecosystem restoration. Together, our findings provide novel and clear evidence of the complex mechanisms by which the coexistence of stressors can differently affect the pathways of energy flux across trophic levels in aquatic ecosystems. Regulatory strategies for ecosystems should comprehensively consider responses at multi-trophic levels using a network perspective, especially in the face of combinations of global and local stressors.

Design, synthesis, and biological studies of novel sulfonamide derivatives as farnesoid X receptor agonists.

Farnesoid X receptor (FXR) is considered as a promising target for the treatment of NASH. Although many non-steroidal FXR agonists have been reported, the structure types are quite scarce and mainly limited to the isoxazole scaffold derived from GW4064. Therefore, it is crucial to expand the structure types of FXR agonist to explore wider chemical space. In this study, the structure-based scaffold hopping strategy was performed by hybrid FXR agonist 1 and T0901317, which resulted in the discovery of sulfonamide FXR agonist 19. Molecular docking study reasonably explained the SAR in this series, and compound 19 fitted well with the binding pocket in a similar mode to the co-crystal ligand. In addition, compound 19 exhibited considerable selectivity against other nuclear receptors. In NASH model, compound 19 alleviated the typical histological features of fatty liver, including steatosis, lobular inflammation, ballooning, and fibrosis. Moreover, compound 19 exhibited acceptable safety profiles with no acute toxicity to major organ. These results suggested that the novel sulfonamide FXR agonist 19 might be a promising agent for the treatment of NASH.