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Abstract Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to meet the high energy and biosynthetic demands required for their proliferation. High mobility group A1 (HMGA1) is a structural transcription factor and frequently overexpressed in human colorectal cancer (CRC). Here, we show that HMGA1 promotes CRC progression by driving lipid synthesis in a AOM/DSS-induced CRC mouse model. Using conditional knockout (Hmga1 △IEC) and knock-in (Hmga1 IEC-OE/+) mouse models, we demonstrate that HMGA1 enhances CRC cell proliferation and accelerates tumor development by upregulating fatty acid synthase (FASN). Mechanistically, HMGA1 increases the transcriptional activity of sterol regulatory element-binding protein 1 (SREBP1) on the FASN promoter, leading to increased lipid accumulation in intestinal epithelial cells. Moreover, a high-fat diet exacerbates CRC progression in Hmga1 △IEC mice, while pharmacological inhibition of FASN by orlistat reduces tumor growth in Hmga1 IEC-OE/+ mice. Our findings suggest that targeting lipid metabolism could offer a promising therapeutic strategy for CRC.

Abstract Although there have been remarkable advances in the treatment of hepatocellular carcinoma (HCC), the prognosis remains poor in those with advanced stage and more effective therapeutic options are urgently needed. Lenvatinib (Len), a multiple receptor tyrosine kinase inhibitor, is an emerging molecular targeted agent for HCC, whose immunomodulatory activities have been investigated. However, Len utilization is limited because of its low metabolic stability, poor bioavailability and dose-dependent toxicity, rendering its direct use insufficient for immune modulation. Stimuli-responsive nanoparticles, which are drug-targeted delivery platforms for on-demand drug release, facilitate deeper and uniform tumour penetration, providing alternative solutions to overcome current limitations. Ultrasound (US) exhibits superior tissue penetration abilities and can produce reactive oxygen species (ROS) at the tumour site to treat deeper tumours. In addition, US serves as an excellent and selective drug delivery mediator for tumour treatment. Herein, we designed US-triggered lenvatinib nanoparticles (Len-RNPs) for selective drug delivery that utilize US-triggered ROS to induce in situ oxidation reactions, resulting in nanoparticle disintegration. Len-RNPs mitigate the toxicity of Len and effectively trigger robust systemic anti-tumour immune responses in a H22 tumour model, resulting in a tumour suppression rate of 95.7%, with 60% of mice being cured. Our study elucidates a novel and precise strategy of combining Len and US therapy for enhanced HCC immunotherapy.

Abstract Background Systemic lupus erythematosus (SLE) is linked to host gut dysbiosis. Here we performed faecal gut microbiome sequencing to investigate SLE-pathogenic gut microbes and their potential mechanisms. Methods There were 134 healthy controls (HCs) and 114 SLE cases for 16 S ribosomal RNA (rRNA) sequencing and 97 HCs and 124 SLE cases for shotgun metagenomics. Faecal microbial changes and associations with clinical phenotypes were evaluated, and SLE-associated microbial genera were identified in amplicon analysis. Next, metagenomic sequencing was applied for accurate identification of microbial species and discovery of their metabolic pathways and immunogenic peptides both relevant to SLE. Finally, contribution of specific taxa to disease development was confirmed by oral gavage into lupus-prone MRL/lpr mice. Results SLE patients had gut microbiota richness reduction and composition alteration, particularly lupus nephritis and active patients. Proteobacteria/Bacteroidetes (P/B) ratio was remarkably up-regulated, and Escherichia was identified as the dominantly expanded genus in SLE, followed by metagenomics accurately located Escherichia coli and Escherichia unclassified species. Significant associations primarily appeared among Escherichia coli, metabolic pathways of purine nucleotide salvage or peptidoglycan maturation and SLE disease activity index (SLEDAI), and between multiple epitopes from Escherichia coli and disease activity or renal involvement phenotype. Finally, gavage with faecal Escherichia revealed that it upregulated lupus-associated serum traits and aggravated glomerular lesions in MRL/lpr mice. Conclusion We characterize a novel SLE exacerbating Escherichia outgrowth and suggest its contribution to SLE procession may be partially associated with metabolite changes and cross-reactivity of gut microbiota-associated epitopes and host autoantigens. The findings could provide a deeper insight into gut Escherichia in the procession of SLE.

The stigma associated with functional neurological disorder (FND) is greater than that associated with other neurological conditions, seriously affecting the quality of life of patients and increasing the burden on caregivers. This article reviews the concept, the current situation and harms, the influence factors and intervention strategies of FND stigma. The aim is to further develop our country as a reference for the study of stigma in FND.

Nuclear energy is used more and more widely as a clean energy source, but nuclear energy facilities are risky, and when a nuclear leak occurs, it is necessary to detect equipment in a nuclear radiation environment. In the nuclear radiation environment, due to the impact of high-energy particles on the camera sensor, the collected image contains a lot of radiation noise, which greatly reduces the visual perception of the image. Aiming at the problem that radiation noise reduces image quality, a radiation image compound filtering algorithm combining median filtering and multi-frame average filtering is proposed based on radiation noise characteristics. Compared with several common filtering algorithms, the radiation noise image is filtered under the same radiation dose and achieve the highest Peak Signal Noise Rate (PSNR) and Structural Similarity (SSIM), and compared with the multi-frame average filtering method, the number of image frames required by the algorithm in this paper is greatly reduced. Experimental results show that the algorithm can effectively eliminate radiation noise and is more suitable for image filtering in radiation environment.

CO2 conversion is gradually seen as a better way for society to effectively use carbon sources and avoid climate crisis associated with fossil CO2 emissions. And the decision to deploy CO2 technology scale should be relied on its environmental impact. In this work, life cycle assessment model evaluates the environmental performance of CO2 conversion by photocatalytic reaction process with two different catalysts (NiAl-LDH and Co-ZIF-9). Six impact categories considered in this analysis, including climate change, acidification potential, depletion of abiotic resources, eutrophication potential, ozone layer depletion potential, and photochemical oxidation potential. Results indicated that CO2 conversion with Co-ZIF-9 photocatalyst has a better environmental impact than the NiAl-LDH photocatalyst route. Moreover, the Co-ZIF-9 catalyst scenario also has a lower total environmental burden than the conventional CO production route. Sensitivity analysis shows that recycle performance of the catalyst is highly sensitive to the production process in two scenarios. This study could provide a framework for robust decisions in CO2 conversion by photocatalytic reaction, which is useful for policymakers to decide the feasibility of industrialization.

Abstract Accurately assigning standardized diagnosis and procedure codes from clinical text is crucial for healthcare applications. However, this remains challenging due to the complexity of medical language. This paper proposes a novel model that incorporates extreme multi-label classification tasks to enhance International Classification of Diseases (ICD) coding. The model utilizes deformable convolutional neural networks to fuse representations from hidden layer outputs of pre-trained language models and external medical knowledge embeddings fused using a multimodal approach to provide rich semantic encodings for each code. A probabilistic label tree is constructed based on the hierarchical structure existing in ICD labels to incorporate ontological relationships between ICD codes and enable structured output prediction. Experiments on medical code prediction on the MIMIC-III database demonstrate competitive performance, highlighting the benefits of this technique for robust clinical code assignment.

Background and objective: The circular RNA hsa_circ_0007755 is markedly upregulated in hypertrophic scars (HS), yet its functional roles in this fibroproliferative disorder remain to be elucidated. This investigation aims to delineate the regulatory mechanisms of hsa_circ_0007755 in HS and to decode its downstream molecular signaling pathways. Methods: We established a murine model of HS. Tissue histopathology was assessed using Hematoxylin and Eosin and Masson's trichrome staining. Peripheral blood from the animals was collected and the ratio of T-helper 1 (Th1) to T-helper 2 (Th2) cells was quantified via flow cytometry. The proliferation and apoptosis rates of human hypertrophic scar fibroblasts (hHSFs) were evaluated using the Cell Counting Kit-8 assay and flow cytometry, respectively. The invasive capacity of hHSFs was assessed via a Transwell assay. Co-culture experiments of hHSFs with T cells were conducted, and alterations in Th1/Th2 ratios were monitored using flow cytometry. Levels of cytokines, fibrosis-associated proteins, nuclear factor-kappaB (NF-κB) pathway-related protein, and C-X-C Motif Chemokine Ligand 2 (CXCL2) were quantified using Enzyme-Linked Immunosorbent Assay or Western blot analysis. The interactions between hsa_circ_0007755, miR-27b-3p, and CXCL2 were investigated using dual-luciferase reporter assays and RNA immunoprecipitation. Results: Both hsa_circ_0007755 and CXCL2 were highly expressed in HS, whereas miR-27b-3p was downregulated. Knockdown of hsa_circ_0007755 inhibited the proliferation and invasion of hHSFs, promoted apoptosis, and reduced the expression of fibrotic proteins α-SMA and Collagen I, as well as the phosphorylation of the inflammatory pathway protein p65. Co-culture experiments confirmed that hHSFs lowly expressing hsa_circ_0007755 showed a decreased Th1 cell proportion and an increased Th2 cell proportion, alongside lower levels of TNF-α and INF-γ and higher levels of IL-4 and IL-10. The effects of either knocking down or overexpressing hsa_circ_0007755 were reversed by knocking down either miR-27b-3p or CXCL2, respectively. hsa_circ_0007755 acted as a ''molecular sponge'' for miR-27b-3p, sequestering and diminishing its availability, thereby alleviating its suppression of the target gene CXCL2. Conclusion: hsa_circ_0007755 plays a pivotal role in modulating the immune response of HS by influencing the miR-27b-3p/CXCL2 axis, regulating the function and proportion of Th1 and Th2 cells, and thereby affecting the inflammatory and fibrotic processes in scar tissue.

This study was aimed to retrospectively analyze the potential of non-invasive serum biomarkers in clinically predicting the detrusor underactivity (DU) in benign prostatic hyperplasia (BPH) patients with lower urinary tract symptoms (LUTS) and low prostate volume (PV). The study enrolled 196 patients with BPH and LUTS at our hospital in the period from January 2018 to October 2023. The patients were divided into two groups based on the projected isovolumetric pressure (PIP): the DU and the control groups. The patients included in the study had PV of less than 50 mL. A total of 93 and 103 cases were placed in the DU and control groups, respectively. Univariate analysis exhibited that the age was associated with DU occurrence (p = 0.004), and the serum prostate specific antigen (PSA) might act as DU protective factor (p = 0.001). However, there was no statistically significant relation between pre-selected serum hematological parameters and the DU diagnosis accuracy. Multivariate analysis suggested that only the age (OR (odds ratio) 1.07, 95% CI (confidence interval) 1.03–1.12, p = 0.001) and PSA (OR 0.79, 95% CI 0.69–0.90, p < 0.001) were the independent predictors of DU. In this study, it was observed that the pre-selected serum hematological parameters had no relevance in diagnosing DU in low PV male patients. Nonetheless, it was found that the age and PSA could be the independent non-invasive predictors of male patients with LUTS and low PV, who were unable to undergo urodynamic examinations.

Abstract Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several targetable domains. EP300/CBP are critical gene-regulatory targets in cancer, with existing high potency inhibitors of either the catalytic HAT domain or protein-binding bromodomain (BRD). A domain-specific inhibitory approach to multidomain-containing proteins may identify exceptional-responding tumor types, thereby expanding a therapeutic index. Here, we discover that targeting EP300/CBP using the domain-specific inhibitors, A485 (HAT) or CCS1477 (BRD) have different effects in select tumor types. Group 3 medulloblastoma (G3MB) cells are especially sensitive to BRD, compared with HAT inhibition. Structurally, these effects are mediated by the difluorophenyl group in the catalytic core of CCS1477. Mechanistically, bromodomain inhibition causes rapid disruption of genetic dependency networks that are required for G3MB growth. These studies provide a domain-specific structural foundation for drug discovery efforts targeting EP300/CBP and identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB.

Abstract Purpose Currently, postoperative wound infection and poor healing of total knee arthroplasty have been perplexing both doctors and patients. We hereby innovatively invented a new dressing system to reduce the incidence of postoperative wound complications. Methods We enrolled 100 patients who received primary unilateral total knee arthroplasty and then applied the new dressing system. The data collected included the number of dressing changes, postoperative hospital stay, Visual Analogue Scale score (VAS), the Knee Society Score (KSS), the Knee Injury and Osteoarthritis Outcome Score (KOOS), ASEPSIS scores, The Stony Brook Scar Evaluation Scale (SBSES), wound complications, dressing cost, the frequency of shower and satisfaction. Subsequently, a statistical analysis of the data was performed. Results Our findings demonstrated the average number of postoperative dressing changes was 1.09 ± 0.38, and the average postoperative hospital stay was 3.72 ± 0.98 days. The average cost throughout a treatment cycle was 68.97 ± 12.54 US dollars. Collectively, the results of VAS, KSS, and KOOS revealed that the pain and function of patients were continuously improved. The results of the four indexes of the ASEPSIS score were 0, whereas the SBSES score was 3.58 ± 0.52 and 4.69 ± 0.46 at two weeks and one month after the operation, respectively. We observed no wound complications until one month after the operation. Remarkably, the satisfaction rate of the patients was 91.85 ± 4.99% one month after the operation. Conclusion In this study, we invented a new dressing system for surgical wounds after total knee arthroplasty and further confirmed its clinical feasibility and safety. Chinese clinical trial registry ChiCTR2000033814, Registered 13/ June/2020.

Background Due to economic development changes in domestic fertility policy, the incidence of acute pancreatitis in pregnancy (APIP) has been gradually increasing. The clinical characteristics of APIP of different etiologies are different, and there may be significant differences in the prognosis for mothers and infants, but previous studies on this are relatively few. Objective To analyze the clinical characteristics and maternal and neonatal outcomes in pregnancy complicated with acute pancreatitis patients of different etiologies. Methods A total of 48 inpatients with APIP in Beijing Friendship Hospital, Capital Medical University from 2016 to 2022 were collected, which were divided into the biliary group (n=27) and hyperlipidemic group (n=21). The laboratory indicators and maternal and infant outcomes in the two groups were compared. Results The biliary group had a longer time of onset to visit, a smaller gestational week at admission, more previous pregnancies, and lower percentage of diarrhea and cessation of defecation than the hyperlipidemic group (P0.05). The birth weight of the biliary group was smaller than the hyperlipidemia group, while the birth length was shorter than the hyperlipidemia group. The incidence of neonatal jaundice, respiratory distress, and ventilator-assisted breathing was higher than the hyperlipidemia group (P

To evaluate the ovarian reserve (OR) in women with antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE), especially SLE-associated APS, and to determine the association between OR and clinical and laboratory parameters.

Abstract Aberrant stem cell-like activity and impaired differentiation are central to the development of colorectal cancer (CRC). To identify functional mediators of these key cellular programs, we engineer a dual endogenous reporter system by genome-editing the SOX9 and KRT20 loci of human CRC cell lines to express fluorescent reporters, broadcasting aberrant stem cell-like and differentiation activity, respectively. By applying a CRISPR screen targeting 78 epigenetic regulators with 542 sgRNAs to this platform, we identify factors that contribute to stem cell-like activity and differentiation in CRC. Perturbation single cell RNA sequencing (Perturb-seq) of validated hits nominate SMARCB1 of the BAF complex (also known as SWI/SNF) as a negative regulator of differentiation across an array of neoplastic colon models. SMARCB1 is a dependency and required for in vivo growth of human CRC models. These studies highlight the utility of biologically designed endogenous reporter platforms to uncover regulators with therapeutic potential.

Objective: Baicalin has antioxidative, antiviral, and anti-inflammatory properties. However, its ability to alleviate oxidative stress (OS) and DNA damage in liver cells exposed to aflatoxin B1 (AFB1), a highly hepatotoxic compound, remains uncertain. In this study, the protective effects of baicalin on AFB1-induced hepatocyte injury and the mechanisms underlying those effects were investigated. Methods: Stable cell lines expressing CYP3A4 were established using lentiviral vectors to assess oxidative stress levels by conducting assays to determine the content of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Additionally, DNA damage was evaluated by 8-hydroxy-2-deoxyguanosine (8-OHdG) and comet assays. Transcriptome sequencing, molecular docking, and in vitro experiments were conducted to determine the mechanisms underlying the effects of baicalin on AFB1-induced hepatocyte injury. In vivo, a rat model of hepatocyte injury induced by AFB1 was used to evaluate the effects of baicalin. Results: In vitro, baicalin significantly attenuated AFB1-induced injury caused due to OS, as determined by a decrease in ROS, MDA, and SOD levels. Baicalin also considerably decreased AFB1-induced DNA damage in hepatocytes. This protective effect of baicalin was found to be closely associated with the TP53-mediated ferroptosis pathway. To elaborate, baicalin physically interacts with P53, leading to the suppression of the expression of GPX4 and SLC7A11, which in turn inhibits ferroptosis. In vivo findings showed that baicalin decreased DNA damage and ferroptosis in AFB1-treated rat liver tissues, as determined by a decrease in the expression of γ-H2AX and an increase in GPX4 and SLC7A11 levels. Overexpression of TP53 weakened the protective effects of baicalin. Conclusions: Baicalin can alleviate AFB1-induced OS and DNA damage in liver cells via the TP53-mediated ferroptosis pathway. In this study, a theoretical foundation was established for the use of baicalin in protecting the liver from the toxic effects of AFB1.

Summary: The resected pⅢA-N2 non-small-cell lung cancer (NSCLC) patients who could benefit from postoperative radiotherapy (PORT) are not well-defined. The study explored the role of PORT on EGFR mutant and wild-type NSCLC patients. We retrospectively searched for resected pIIIA-N2 lung adenocarcinoma patients who underwent EGFR mutation testing. 80 patients with EGFR wild-type and 85 patients with EGFR mutation were included. 62 patients received PORT. In overall population, the median disease-free survival (DFS) was improved in PORT arm compared to non-PORT arm (22.9 vs. 16.1 months; p = 0.036), along with higher 2-year locoregional recurrence-free survival (LRFS) rate (88.3% vs. 69.3%; p = 0.004). In EGFR wild-type patients, PORT was associated with a longer median DFS (23.3 vs. 17.2 months; p = 0.044), and a higher 2-year LRFS rate (86.8% vs. 61.9%; p = 0.012). In EGFR mutant patients, PORT was not significantly correlated with improved survival outcomes. EGFR wild-type may a biomarker to identify the cohort that benefits from PORT.

Abstract Chemotherapy is a primary treatment for esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapeutic drugs is an important hurdle to effective treatment. Understanding the mechanisms underlying chemotherapy resistance in ESCC is an unmet medical need to improve the survival of ESCC. Herein, we demonstrate that ferroptosis triggered by inhibiting high mobility group AT-hook 1 (HMGA1) may provide a novel opportunity to gain an effective therapeutic strategy against chemoresistance in ESCC. HMGA1 is upregulated in ESCC and works as a key driver for cisplatin (DDP) resistance in ESCC by repressing ferroptosis. Inhibition of HMGA1 enhances the sensitivity of ESCC to ferroptosis. With a transcriptome analysis and following-up assays, we demonstrated that HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a key transporter maintaining intracellular glutathione homeostasis and inhibiting the accumulation of malondialdehyde (MDA), thereby suppressing cell ferroptosis. HMGA1 acts as a chromatin remodeling factor promoting the binding of activating transcription factor 4 (ATF4) to the promoter of SLC7A11, and hence enhancing the transcription of SLC7A11 and maintaining the redox balance. We characterized that the enhanced chemosensitivity of ESCC is primarily attributed to the increased susceptibility of ferroptosis resulting from the depletion of HMGA1. Moreover, we utilized syngeneic allograft tumor models and genetically engineered mice of HMGA1 to induce ESCC and validated that depletion of HMGA1 promotes ferroptosis and restores the sensitivity of ESCC to DDP, and hence enhances the therapeutic efficacy. Our finding uncovers a critical role of HMGA1 in the repression of ferroptosis and thus in the establishment of DDP resistance in ESCC, highlighting HMGA1-based rewiring strategies as potential approaches to overcome ESCC chemotherapy resistance. Schematic depicting that HMGA1 maintains intracellular redox homeostasis against ferroptosis by assisting ATF4 to activate SLC7A11 transcription, resulting in ESCC resistance to chemotherapy.

Magnetron sputtering systems are widely used for depositing industrially important coatings. Research has been conducted to optimize and improve these structures to increase coating effectiveness and target utilization. The paper investigates the engineering problem of uneven target etching caused by an uneven magnetic field in magnetron sputtering equipment. The characteristics of the desired magnetic field distribution required by magnetron sputtering equipment are analyzed, and a corresponding excitation structure and analytical model for cylindrical magnetron sputtering equipment are proposed and calculated. The uniform magnetic field design is realized by analytical modeling of the excitation structure. The axial magnetic field distributions produced by an axisymmetric solenoid system and several similar excitation structures are analyzed and compared. The analytical results were verified through finite element simulations and experiments, demonstrating the accuracy and effectiveness of the method. The excitation structure, which is designed with a uniform magnetic field, can produce an axial component of magnetic flux density with a uniformity deviation of less than 4.3% across 73% of the target surface. The analytical model describes the distribution of the axial component of the magnetic flux density and optimizes the magnetic field. The model enables the simulation of plasma distribution and film growth, aiming to enhance the target utilization rate and substrate deposition rate. The conclusions serve as a reference for designing high-performance magnetron sputtering equipment.

Abstract Background The alpine meadow is one of the most important ecosystems in the Qinghai-Tibet Plateau (QTP), and critically sensitive to climate change and human activities. Thus, it is crucial to precisely reveal the current state and predict future trends in the carbon budget of the alpine meadow ecosystem. The objective of this study was to explore the applicability of the Biome-BGC model (BBGC) in the Qinghai Lake Basin (QLB), identify the key parameters affecting the variation of net ecosystem exchange (NEE), and further predict the future trends in carbon budget in the QLB. Results The alpine meadow mainly acted as carbon sink during the growing season. For the eco-physiological factors, the YEL (Yearday to end litterfall), YSNG (Yearday to start new growth), CLEC (Canopy light extinction coefficient), FRC:LC (New fine root C: new leaf C), SLA (Canopy average specific leaf area), C:Nleaf (C:N of leaves), and FLNR (Fraction of leaf N in Rubisco) were confirmed to be the top seven parameters affecting carbon budget of the alpine meadow. For the meteorological factors, the sensitivity of NEE to precipitation was greater than that to vapor pressure deficit (VPD), and it was greater to radiation than to air temperature. Moreover, the combined effect of two different meteorological factors on NEE was higher than the individual effect of each one. In the future, warming and wetting would enhance the carbon sink capacity of the alpine meadow during the growing season, but extreme warming (over 3.84 ℃) would reduce NEE (about 2.9%) in the SSP5-8.5 scenario. Conclusion Overall, the alpine meadow ecosystem in the QLB generally performs as a carbon sink at present and in the future. It is of great significance for the achievement of the goal of carbon neutrality and the management of alpine ecosystems.

Striking a trade-off between migration and reproduction becomes imperative during long-range migration to ensure proper energy allocation. However, the mechanisms involved in this trade-off remain poorly understood. Here, we used a takeoff assay to distinguish migratory from non-migratory individuals in the fall armyworm, which is a major migratory insect worldwide. Migratory females displayed delayed ovarian development and flew further and faster than non-migratory females during tethered flight. Transcriptome analyses demonstrated an enrichment of fatty acid genes across successive levels of ovarian development and different migratory behaviors. Additionally, genes with roles in phototransduction and carbohydrate digestion along with absorption function were enriched in migratory females. Consistent with this, we identified increased abdominal lipids in migratory females that were mobilized to supply energy to the flight muscles in the thorax. Our study reveals that the fall armyworm faces a trade-off in allocating abdominal triglycerides between migration and reproduction during flight. The findings provide valuable insights for future research on this trade-off and highlight the key energy components involved in this strategic balance.