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Abstract Despite the importance of cellular senescence in human health, how damaged cells undergo senescence remains elusive. We have previously shown that promyelocytic leukemia nuclear body (PML-NBs) translocation of the ciliary FBF1 is essential for senescence induction in stressed cells. Here we discover that an early cellular event occurring in stressed cells is the transient assembly of stress-induced nucleus-to-cilium microtubule arrays (sinc-MTs). The sinc-MTs are distinguished by unusual polyglutamylation and unique polarity, with minus-ends nucleating near the nuclear envelope and plus-ends near the ciliary base. KIFC3, a minus-end-directed kinesin, is recruited to plus-ends of sinc-MTs and interacts with the centrosomal protein CENEXIN1. In damaged cells, CENEXIN1 co-translocates with FBF1 to PML-NBs. Deficiency of KIFC3 abolishes PML-NB translocation of FBF1 and CENEXIN1, as well as senescence initiation in damaged cells. Our study reveals that KIFC3-mediated nuclear transport of FBF1 along polyglutamylated sinc-MTs is a prerequisite for senescence induction in mammalian cells.

Abstract Optical coherence tomography (OCT) can be used to image microstructures of human kidneys. However, current OCT probes exhibit inadequate field-of-view, leading to potentially biased kidney assessment. Here we present a robotic OCT system where the probe is integrated to a robot manipulator, enabling wider area (covers an area of 106.39 mm by 37.70 mm) spatially-resolved imaging. Our system comprehensively scans the kidney surface at the optimal altitude with preoperative path planning and OCT image-based feedback control scheme. It further parameterizes and visualizes microstructures of large area. We verified the system positioning accuracy on a phantom as 0.0762 ± 0.0727 mm and showed the clinical feasibility by scanning ex vivo kidneys. The parameterization reveals vasculatures beneath the kidney surface. Quantification on the proximal convoluted tubule of a human kidney yields clinical-relevant information. The system promises to assess kidney viability for transplantation after collecting a vast amount of whole-organ parameterization and patient outcomes data.

Abstract Recent advances in computer vision and deep learning techniques have facilitated significant progress in video scene understanding, thus helping film and television practitioners achieve accurate video editing. However, so far, publicly available semantic segmentation datasets are mostly limited to indoor scenes, city streets, and natural images, often ignoring example objects in action movies, which is a research gap that needs to be urgently filled. In this paper, we introduce a large-scale, high-precision semantic segmentation dataset of props in Chinese martial arts movie clips, named ChineseMPD. Specifically, this dataset first establishes segmentation rules and general review criteria for audiovisual data, and then provides semantic segmentation annotations for six weapon props (Gun, Sword, Stick, Knife, Hook, and Arrow) with a summary of 32,992 objects.To the best of our knowledge, this dataset is the largest semantic segmentation dataset for movie props to date. ChineseMPD dataset not only significantly expands the application of traditional tasks of computer vision such as object detection and scene understanding, but also opens up new avenues for interdisciplinary research.

Abstract Green finance plays a critical role in promoting regional green innovation. However, the precise influence of green finance on diverse facets of green innovation remains underexplored. This study empirically analyses the diverse effects of green finance on heterogeneous green innovation by applying the negative binomial model, the threshold model, andthe spatial error model using China’s regional data from 2010 to 2019. The results indicate that green finance has a positive impact on regional green innovation performance, primarily through significant contributions to fossil energy carbon reduction, energy conservation and recovery, and clean energy technology innovation. The effect of green finance is also influenced by the level of local environmental supervision, exhibiting a significant threshold effect. In addition, the development of green innovation in the region can have a siphoning effect on the resources of surrounding areas, hindering their innovation development. These findings highlight the necessity for strategic government policy-making, which should leverage the diverse impacts of green finance on various forms of green innovation. Customizing green financial instruments to suit regional environmental regulatory conditions and the green innovation levels of neighboring regions could significantly aid in promoting regional green transformation and growth.

The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRASG12C mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells. Collectively, our results suggest a novel therapeutic strategy to treat patients bearing G12Ci resistant cancers with ferroptosis inducers.

Background Fracture healing can be impeded or even compromised by various factors, resulting in a growing number of patients suffering. The lncRNA LINC-PINT has garnered attention for its latent role in enhancing fracture healing, but its specific functions in this process remain unclear.Objectives The primary objective of this study is to investigate the clinical relevance and underlying molecular mechanisms of LINC-PINT in delayed fracture healing (DFH), while also assessing its potential as an early diagnostic biomarker.Materials and methods The expression levels of LINC-PINT were measured in the serum of DFH patients and those with normal fracture healing using RT-qPCR. In MC3T3-E1 cells, the study investigated the influence on the expression of differentiation-related protein, cell viability, and apoptosis through the modulation of LINC-PINT and miR-324-3p. To elucidate the targeting relationship between LINC-PINT, miR-324-3p, and BMP2, a dual-luciferase reporter assay was employed.Results The findings revealed a significant downregulation of LINC-PINT expression in DFH patients. LINC-PINT showed high sensitivity and specificity as a diagnostic marker for DFH. In MC3T3-E1 cells, LINC-PINT overexpression markedly enhanced the expression levels of ALP, OCN, Runx2, and OPN, improved cell viability, and inhibited apoptosis. LINC-PINT negatively regulated miR-324-3p, and the effects of LINC-PINT were counteracted by miR-324-3p. LINC-PINT was found to regulate BMP2 by targeting miR-324-3p.Conclusion LINC-PINT could serve as an early diagnostic biomarker for DFH and slow the progression of DFH by modulating BMP2 through the targeted regulation of miR-324-3p. This research presents new molecular targets for the diagnosis and treatment of DFH.

Graphic design, as a product of the burgeoning new media era, has seen its users’ requirements for images continuously evolve. However, external factors such as light and noise often cause graphic design images to become distorted during acquisition. To enhance the definition of these images, this paper introduces a novel image enhancement model based on visual features. Initially, a histogram equalization (HE) algorithm is applied to enhance the graphic design images. Subsequently, image feature extraction is performed using a dual-flow network comprising convolutional neural network (CNN) and Transformer architectures. The CNN employs a residual dense block (RDB) to embed spatial local structure information with varying receptive fields. An improved attention mechanism module, attention feature fusion (AFF), is then introduced to integrate the image features extracted from the dual-flow network. Finally, through image perception quality guided adversarial learning, the model adjusts the initial enhanced image’s color and recovers more details. Experimental results demonstrate that the proposed algorithm model achieves enhancement effects exceeding 90% on two large image datasets, which represents a 5%–10% improvement over other models. Furthermore, the algorithm exhibits superior performance in terms of peak signal-to-noise ratio (PSNR) and structural similarity index measure (SSIM) image quality evaluation metrics. Our findings indicate that the fusion model significantly enhances image quality, thereby advancing the field of graphic design and showcasing its potential in cultural and creative product design.

Bladder cancer (BC) is a serious and common malignant tumor of the urinary system. Accurate and convenient diagnosis and treatment of BC is a major challenge for the medical community. Due to the limited medical resources, the existing diagnosis and treatment protocols for BC without the assistance of artificial intelligence (AI) still have certain shortcomings. In recent years, with the development of AI technologies such as deep learning and machine learning, the maturity of AI has made it more and more applied to the medical field, including improving the speed and accuracy of BC diagnosis and providing more powerful treatment options and recommendations related to prognosis. Advances in medical imaging technology and molecular-level research have also contributed to the further development of such AI applications. However, due to differences in the sources of training information and algorithm design issues, there is still room for improvement in terms of accuracy and transparency for the broader use of AI in clinical practice. With the popularization of digitization of clinical information and the proposal of new algorithms, artificial intelligence is expected to learn more effectively and analyze similar cases more accurately and reliably, promoting the development of precision medicine, reducing resource consumption, and speeding up diagnosis and treatment. This review focuses on the application of artificial intelligence in the diagnosis and treatment of BC, points out some of the challenges it faces, and looks forward to its future development.

2319 aluminum alloy parts was prepared by wire arc additive manufacturing technology. The corrosion properties of additively manufactured 2319 aluminum alloy and 2219 aluminum alloy sheets were systematically investigated by electrochemical tests and localized corrosion tests. The results of electrochemical tests showed that the 2219 aluminum alloy sheet has a lower corrosion current density than the additively manufactured 2319 aluminum alloy. Localized corrosion test results indicated that the additively manufactured 2319 aluminum alloy exhibited a higher intergranular corrosion depth and more severe corrosion morphology than the 2219 aluminum alloy sheet. This suggests that the 2219 aluminum alloy sheet has higher corrosion resistance than the additively manufactured 2319 aluminum alloy. The poor corrosion resistance of additively manufactured 2319 aluminum alloy could be attributed to the formation of a coarse continuous Al2Cu phase along the grain boundary. Based on this, heat treatment was used to dissolve the Al2Cu, which can effectively improve the corrosion resistance of additively manufactured 2319 aluminum alloy to the same level as that of the 2219 aluminum alloy sheet.

Abstract Background Photodynamic therapy (PDT) is a promising interventional treatment approach that contributes to antitumor immunity. It has been reported that PDT can enhance the effectiveness of immune checkpoint inhibitors (ICIs), but its mechanism is yet unclear. Herein, we implemented bioinformatics analysis to detect common pathways and potential biomarkers in non-small cell lung cancer (NSCLC), PDT, and NSCLC immunotherapy to investigate potential links between PDT, immunotherapy and NSCLC, and their clinical impact. Methods Differentially expressed genes in NSCLC- and NSCLC immunotherapy-related data in the GEO database were intersected with PDT-related genes in the GeneCards database to obtain candidate genes and shared pathways. Enrichment analysis and protein–protein interaction were established to identify key genes in functionally enriched pathways. The expression profiles and the prognostic significance of key genes were depicted. Results Bioinformatics analysis showed that HIF-1α was screened as a prognostic gene in hypoxia, HIF-1, and PD-L1-related signaling pathways, which was associated with clinical response in NSCLC patients after PDT and immunotherapy. In vivo experiments showed that PDT could inhibit tumor growth and upregulate HIF-1α and PD-L1 expressions in NSCLC tissues with a positive correlation, which might influence the blocking activity of ICIs on the HIF-1, and PD-L1-related signaling pathways. Conclusions PDT might improve the clinical response of ICIs by upregulating tumor HIF-1α and PD-L1 expressions in NSCLC.

Summary: Ferroptosis is a form of nonapoptotic cell death characterized by iron-dependent peroxidation of polyunsaturated phospholipids. However, much remains unknown about the regulators of ferroptosis. Here, using CRISPR-Cas9-mediated genetic screening, we identify protein arginine methyltransferase 1 (PRMT1) as a crucial promoter of ferroptosis. We find that PRMT1 decreases the expression of solute carrier family 7 member 11 (SLC7A11) to limit the abundance of intracellular glutathione (GSH). Moreover, we show that PRMT1 interacts with ferroptosis suppressor protein 1 (FSP1), a GSH-independent ferroptosis suppressor, to inhibit the membrane localization and enzymatic activity of FSP1 through arginine dimethylation at R316, thus reducing CoQ10H2 content and inducing ferroptosis sensitivity. Importantly, genetic depletion or pharmacological inhibition of PRMT1 in mice prevents ferroptotic events in the liver and improves the overall survival under concanavalin A (ConA) exposure. Hence, our findings suggest that PRMT1 is a key regulator of ferroptosis and a potential target for antiferroptosis therapeutics.

Cardiovascular diseases (CVDs) are a major challenge in global health. Despite significant advances in treatment and management, the incidence and mortality rates of CVDs have been rising in recent years, particularly in the United States. With continuous advancements in medical technology, perioperative transesophageal echocardiography (TEE) has become a key technology in cardiac surgery, enhancing surgical success rates and patient safety. The application of TEE spans preoperative planning, intraoperative monitoring, and postoperative evaluation, especially in complex procedures such as mitral valve repair and aortic valve replacement, where it plays an indispensable role. Simultaneously, the introduction of artificial intelligence (AI) brings new prospects for TEE image analysis and diagnostic support, significantly improving diagnostic accuracy and real-time decision-making capabilities. However, the application of TEE technology faces challenges such as high costs, uneven technological diffusion, and the high skill requirements for medical personnel. Therefore, establishing standardized training protocols and strengthening multidisciplinary collaboration are crucial. This paper reviews the application of TEE in cardiac surgery and its path toward educational and practical standardization from a global perspective, emphasizing its importance in improving the postoperative quality of life for patients and exploring future directions in technological innovation and educational optimization.

BackgroundThe assessment of image quality (IQA) plays a pivotal role in the realm of image-based computer-aided diagnosis techniques, with fundus imaging standing as the primary method for the screening and diagnosis of ophthalmic diseases. Conventional studies on fundus IQA tend to rely on simplistic datasets for evaluation, predominantly focusing on either local or global information, rather than a synthesis of both. Moreover, the interpretability of these studies often lacks compelling evidence. In order to address these issues, this study introduces the Local and Global Attention Aggregated Deep Neural Network (LGAANet), an innovative approach that integrates both local and global information for enhanced analysis.MethodsThe LGAANet was developed and validated using a Multi-Source Heterogeneous Fundus (MSHF) database, encompassing a diverse collection of images. This dataset includes 802 color fundus photography (CFP) images (302 from portable cameras), and 500 ultrawide-field (UWF) images from 904 patients with diabetic retinopathy (DR) and glaucoma, as well as healthy individuals. The assessment of image quality was meticulously carried out by a trio of ophthalmologists, leveraging the human visual system as a benchmark. Furthermore, the model employs attention mechanisms and saliency maps to bolster its interpretability.ResultsIn testing with the CFP dataset, LGAANet demonstrated remarkable accuracy in three critical dimensions of image quality (illumination, clarity and contrast based on the characteristics of human visual system, and indicates the potential aspects to improve the image quality), recording scores of 0.947, 0.924, and 0.947, respectively. Similarly, when applied to the UWF dataset, the model achieved accuracies of 0.889, 0.913, and 0.923, respectively. These results underscore the efficacy of LGAANet in distinguishing between varying degrees of image quality with high precision.ConclusionTo our knowledge, LGAANet represents the inaugural algorithm trained on an MSHF dataset specifically for fundus IQA, marking a significant milestone in the advancement of computer-aided diagnosis in ophthalmology. This research significantly contributes to the field, offering a novel methodology for the assessment and interpretation of fundus images in the detection and diagnosis of ocular diseases.

Background Physician transfer is an alternate option to patient transfer for expedient performance of mechanical thrombectomy in patients with acute ischemic stroke. Methods and Results We conducted a systematic review to identify studies that evaluate the effect of physician transfer in patients with acute ischemic stroke who undergo mechanical thrombectomy. A search of PubMed, Scopus, and Web of Science was undertaken, and data were extracted. A statistical pooling with random‐effects meta‐analysis was performed to examine the odds of reduced time interval between stroke onset and recanalization, functional independence, death, and angiographic recanalization. A total of 12 studies (11 nonrandomized observational studies and 1 nonrandomized controlled trial) were included, with a total of 1894 patients. Physician transfer was associated with a significantly shorter time interval between stroke onset and recanalization with a pooled mean difference estimate of −62.08 (95% CI, −112.56 to −11.61]; P=0.016; 8 studies involving 1419 patients) with high between‐study heterogeneity in the estimates (I2=90.6%). The odds for functional independence at 90 days were significantly higher (odds ratio, 1.29 [95% CI, 1.00–1.66]; P=0.046; 7 studies with 1222 patients) with physician transfer with low between‐study heterogeneity (I2=0%). Physician transfer was not associated with higher odds of near‐complete or complete angiographic recanalization (odds ratio, 1.18 [95% CI, 0.89–1.57; P=0.25; I2=2.8%; 11 studies with 1856 subjects). Conclusions Physician transfer was associated with a significant reduction in the mean of time interval between symptom onset and recanalization and increased odds for functional independence at 90 days with physician transfer compared with patient transfer among patients who undergo mechanical thrombectomy.

Background No studies have investigated whether high-sensitivity C reactive protein (hsCRP) can be used to predict the forced expiratory volume in 1 s (FEV1)/estimated value of FEV1 (FEV1%pred). This study aimed to assess the association between hsCRP and FEV1%pred in middle-aged and elderly individuals without underlying lung disease.Methods The data for this study were obtained from a prospective cohort study that included 1047 middle-aged and elderly citizens from Beijing aged 40–75 years without any evidence of underlying lung diseases with FEV1 >70% after receiving inhalational bronchodilators. The baseline analysis of the participants was performed from 30 May 2018 to 31 October 2018. Restricted cubic spline regression and multivariate linear regression models were used to assess the non-linear association and linear association between hsCRP and FEV1/FEV in 6 s (FEV6) and FEV1%pred, respectively.Results The hsCRP values of 851 participants were recorded; the values were normal in 713 (83.8%) participants. The remaining 196 participants (18.7%) had missing data. A non-linear association was observed between normal hsCRP values and FEV1/FEV6. hsCRP was linearly and negatively correlated with FEV1%pred, and each 1 SD increase in hsCRP was significantly associated with a 2.4% lower in FEV1%pred. Significantly higher FEV1/FEV6 differences were observed in the female subgroup than those in the male subgroup (p=0.011 for interaction).Conclusions hsCRP had a non-linear association with FEV1/FEV6 and a linear negative association with FEV1%pred in individuals with normal hsCRP values. hsCRP can be used to predict FEV1%pred, which can be used to predict the development of chronic obstructive pulmonary disease. hsCRP has a stronger association with lung function in women than that in men.Trial registration number NCT03532893.

A closed-form, analytical, and unified model for the surface potential from source to drain in nanowire (NW) gate-all-around (GAA) tunneling field effect transistors (TFETs) is proposed and validated. Foremost, the correctness of the dual modulation effect in GAA-TFETs is demonstrated. Building on that, the model comprehensively considers the effects of the channel depletion region, drain depletion region, and channel inversion charges. Furthermore, a compact current model for GAA-TFETs, based on the derived surface potential expression, is presented, with a discussion on ambipolar conduction—an essential factor for device model integrity. The model’s accuracy and flexibility are validated through TCAD simulations and measurement data from NW-GAA-TFETs, yielding promising results.

With the development of the brain-computer interface, it is possible to assess the image quality based on an electroencephalogram (EEG) signal, which is essential to construct a quality assessment system that accords with the characteristics of the human visual system. However, as the complexity of image degradation levels rises, the analysis of brain features becomes progressively more challenging, leading the neural mechanisms still unclear. In this paper, an image quality assessment experiment with three levels of degradation to explore the neural mechanisms of subjects when confronted with images degraded at multiple levels. Subsequently, we proposed a dynamic model combined with Topological Data Analysis (TDA) and Grey Theory to extract the feature of brain response to different distortion-level images, which is called grey-topological data analysis (Grey-TDA) in this paper. The results indicate that the proposed method is effective in identifying brain responses under stimuli of varying image qualities, which contributes to the research of image quality assessment from the perspective of brain cognition.

Background: Irritability, defined as proneness to anger, can reach a pathological extent. It is a defining symptom of disruptive mood dysregulation disorder and one of the most common reasons youths present for psychiatric evaluation and care. Aberrant responses to frustrative nonreward (FNR), the response to omission of expected reward, are central to the pathophysiology of irritability. FNR is a translational construct to study irritability across species. The development of preclinical FNR models would advance mechanistic studies of the important and relatively understudied clinical phenomenon of irritability. Methods: We used FNR as a conceptual framework to develop a novel mouse behavioral paradigm named alternate poking reward omission. Juvenile mice were exposed to alternate poking reward omission and then examined with a battery of behavioral tests to determine the behavioral effect of FNR. Results: FNR increased locomotion and aggression regardless of sex. These behavioral changes elicited by FNR resemble the symptoms observed in youth with severe irritability. FNR had no effect on anxiety-like, depression-like, or nonaggressive social behaviors. Conclusions: Our alternate poking reward omission paradigm effectively elevated aggression and locomotion in juvenile mice. These frustration effects are directly related to behavioral symptoms of youth with severe irritability. Our novel behavioral paradigm lays the groundwork for further mechanistic studies of frustration and irritability in rodents.

Brucellosis is a zoonotic disease caused by a Gram-negative coccus a facultative intracellular pathogen. Neurobrucellosis has an incidence rate of 3-7% among all patients with brucellosis, while spinal cord involvement is rare and carries a significant mortality risk. This report describes a case of brucellosis myelitis in a 55-year-old male patient who presented with recurrent paralysis, incontinence, and damage to the visual and auditory nerves. The diagnosis of neurobrucellosis involves a serum tube agglutination test, cerebrospinal fluid analysis, a physical examination of the nervous system, and a comprehensive review of the patient’s medical history. The presence of brucellosis was confirmed in cerebrospinal fluid using MetaCAP™ sequencing. Treatment with a combination of rifampicin, doxycycline, ceftriaxone sodium, amikacin, compound brain peptide ganglioside, and dexamethasone resulted in significant improvement of the patient’s clinical symptoms and a decrease in the brucellosis sequence count in cerebrospinal fluid. For the first time, MetaCAP™ sequencing has been used to treat pathogenic microbial nucleic acids, which could be a valuable tool for early diagnosis and treatment of neurobrucellosis.

Background Consumer wearable devices such as wristbands and smartwatches have potential application value in communicable disease surveillance. Objective We investigated the ability of wearable devices to monitor COVID-19 patients of varying severity. Methods COVID-19 patients with mobile phones supporting wearable device applications were selected from Dalian Sixth People Hospital. Physiological parameters from the wearable devices and electronic questionnaires were collected from the device wearing until 14 days post-discharge. Clinical information during hospitalization was also recorded. Based on imaging data, the patients were categorized into the milder group without pneumonia and the more severe group with pneumonia. We plotted the curves of the physiological parameters of the two groups to compare the differences and changes. Results Ninety-eight patients were included in the analysis. The mean age was 39.6 ± 10.5 years, including 45 males (45.9%). There were 24 asymptomatic patients, 10 mild patients, 60 moderate patients, and 4 severe patients. Compared with the milder group, the more severe group had higher heart rate-related parameters, while the heart rate variability (HRV) was the opposite. In the more severe group, the heart rate-related parameters showed a downward trend from 0 to 7 days after the fever resolution. Among them, the resting heart rate and sleep heart rate decreased on the 25th day after the onset and were close to the milder group 1 week after discharge. Conclusions Consumer wearable devices have the potential to monitor respiratory infections. Heart rate-related parameters obtained from these devices can be sensitive indicators of COVID-19 severity and correlate with disease evolution. Trial registration ClinicalTrials.gov NCT04459637.

Summary: The major histocompatibility complex class I (MHC class I)-mediated tumor antigen processing and presentation (APP) pathway is essential for the recruitment and activation of cytotoxic CD8+ T lymphocytes (CD8+ CTLs). However, this pathway is frequently dysregulated in many cancers, thus leading to a failure of immunotherapy. Here, we report that activation of the tumor-intrinsic Hippo pathway positively correlates with the expression of MHC class I APP genes and the abundance of CD8+ CTLs in mouse tumors and patients. Blocking the Hippo pathway effector Yes-associated protein/transcriptional enhanced associate domain (YAP/TEAD) potently improves antitumor immunity. Mechanistically, the YAP/TEAD complex cooperates with the nucleosome remodeling and deacetylase complex to repress NLRC5 transcription. The upregulation of NLRC5 by YAP/TEAD depletion or pharmacological inhibition increases the expression of MHC class I APP genes and enhances CD8+ CTL-mediated killing of cancer cells. Collectively, our results suggest a crucial tumor-promoting function of YAP depending on NLRC5 to impair the MHC class I APP pathway and provide a rationale for inhibiting YAP activity in immunotherapy for cancer.

Abstract Background The European LeukemiaNet (ELN) risk classification system for acute myeloid leukemia (AML) patients has been used worldwide. In 2022, the ELN risk classification system modified risk genes including CEBPA mutation status, myelodysplasia‐related (MR) gene mutations and internal tandem duplications of FLT3 (FLT3‐ITD). Methods We include newly diagnosed de novo AML patients at our center from January 2017 to December 2021, regardless of the further treatment received. Clinical data and date of survival were included. Survival analysis were performed using the Kaplan–Meier method, and the log‐rank test was used to compare survival between different risk groups. Results We include 363 newly diagnosed de novo AML patients from 2017 to 2021 to assess the accuracy of the ELN risk classification system. Their survival results show that the ELN‐2022 risk classification system is not superior to the ELN‐2017 version; for patients with FLT3‐ITD mutations but without FLT3 inhibitor treatment, their survival is similar to the ELN‐2022 adverse risk group. The ELN‐2022 risk classification system cannot accurately clarify ECOG performance status (PS) 2–4 patients, especially in the ELN‐2022 favorable risk group. Conclusion The ELN‐2022 risk stratification system may not be appropriate for patients unable to receive intensive therapy or FLT3 inhibitor; more real‐world data is needed to straify patients with worse ECOG PS and inferior intensive therapy.

Abstract Background Neuromyelitis optica spectrum disorder (NMOSD) is a recurring inflammatory demyelinating disease that is commonly observed in Asian countries like China. Prior investigations have shown that mycophenolate mofetil (MMF) with better biocompatibility compared to azathioprine (AZA), and can prevent relapses of NMOSD, but the efficacy was controversially reported in different NMOSD cases. We aimed to explore the factors that weaken efficacy of MMF in NMOSD. Methods A total of 34 NMOSD patients treated with MMF were prospectively enrolled and grouped according to the therapeutic efficacy as effective group (EG, n = 23) versus less-effective group (LEG, n = 11). The purine metabolites were profiled in serum samples and gut microbiota was analyzed using 16S rRNA sequencing with stool samples from the same patients. Results Purine salvage pathway (PSP) metabolites (inosine, hypoxanthine, xanthine, guanine and uric acid) in the serum of NMOSD patients were elevated in the LEG compared to EG (p

Abstract Astronauts will encounter extended exposure to galactic cosmic radiation (GCR) during deep space exploration, which could impair brain function. Here, we report that in male mice, acute or chronic GCR exposure did not modify reward sensitivity but did adversely affect attentional processes and increased reaction times. Potassium (K+)-stimulation in the prefrontal cortex (PFC) elevated dopamine (DA) but abolished temporal DA responsiveness after acute and chronic GCR exposure. Unlike acute GCR, chronic GCR increased levels of all other neurotransmitters, with differences evident between groups after higher K+-stimulation. Correlational and machine learning analysis showed that acute and chronic GCR exposure differentially reorganized the connection strength and causation of DA and other PFC neurotransmitter networks compared to controls which may explain space radiation-induced neurocognitive deficits.

As one of the most representative natural products among flavonoids, quercetin (QUE) has been reported to exhibit beneficial effects on gut health in recent years. In this study, we utilized a dextran sulfate sodium (DSS)-induced colitis mice model to explore the protective effects and underlying mechanisms of QUE on colitis. Our data demonstrated that QUE oral gavage administration significantly ameliorates the symptoms and histopathological changes associated with colitis. Additionally, the concentration of mucin-2, the number of goblet cells, and the expression of tight junction proteins (such as ZO-1, Occludin, and Claudin-1) were all found to be increased. Furthermore, QUE treatment regulated the levels of inflammatory cytokines and macrophage polarization, as well as the oxidative stress-related pathway (Nrf2/HO-1) and associated enzymes. Additionally, 16S rDNA sequencing revealed that QUE treatment rebalances the alterations in colon microbiota composition (inlcuding Bacteroidaceae, Bacteroides, and Odoribacter) in DSS-induced colitis mice. The analysis of network dynamics reveals a significant correlation between gut microbial communities and microenvironmental factors associated with inflammation and oxidative stress, in conjunction with the previously mentioned findings. Collectively, our results suggest that QUE has the potential to treat colitis by maintaining the mucosal barrier, modulating inflammation, and reducing oxidation stress, which may depend on the reversal of gut microbiota dysbiosis.

Reanalysis and satellite retrieval are two primary approaches for obtaining large-scale and long-term Aerosol Optical Depth (AOD) datasets. This study evaluates and compares the accuracy, long-term stability, and error characteristics of the MERRA-2, MODIS combined Dark Target and Deep Blue (DT&DB), and VIIRS DB AOD products globally and regionally. The results indicate that the MERRA-2 AOD exhibits the highest accuracy with an expected error (EE, ±0.05 ± 20%) of 83.24% and mean absolute error (MAE) of 0.056, maintaining a stability of 0.010 per decade. However, since the MERRA-2 AOD ceased assimilating observations other than the MODIS AOD in 2014, its accuracy decreased by approximately 5.6% in the EE metric after 2014. The VIIRS Deep Blue (DB) AOD product, with an EE of 79.43% and stability of 0.016 per decade, is slightly less accurate and stable compared to the MERRA-2 AOD. The MODIS DT&DB AOD demonstrates an EE of 76.75% and stability of 0.011 per decade. Regionally, the MERRA-2 AOD performs acceptably in most areas, especially in low-aerosol-loading regions, with an EE > 86% and stability ~0.02 per decade. The VIIRS DB AOD excels in high-aerosol-loading regions, such as the Indian subcontinent, with an EE of 69.14% and a stability of 0.049 per decade. The performance of the MODIS DT&DB AOD falls between that of VIIRS DB and MERRA-2 across most regions. Overall, each product meets the accuracy and stability metrics globally, but users need to select the appropriate product for analysis based on the validation results of the accuracy and stability in different regions.

An optimal spatio-temporal hybrid model (STHM) based on wavelet transform (WT) is proposed to improve the sensitivity and accuracy of detecting slowly evolving faults that occur in the early stage and easily submerge with noise in complex industrial production systems. Specifically, a WT is performed to denoise the original data, thus reducing the influence of background noise. Then, a principal component analysis (PCA) and the sliding window algorithm are used to acquire the nearest neighbors in both spatial and time dimensions. Subsequently, the cumulative sum (CUSUM) and the mahalanobis distance (MD) are used to reconstruct the hybrid statistic with spatial and temporal sequences. It helps to enhance the correlation between high-frequency temporal dynamics and space and improves fault detection precision. Moreover, the kernel density estimation (KDE) method is used to estimate the upper threshold of the hybrid statistic so as to optimize the fault detection process. Finally, simulations are conducted by applying the WT-based optimal STHM in the early fault detection of the Tennessee Eastman (TE) process, with the aim of proving that the fault detection method proposed has a high fault detection rate (FDR) and a low false alarm rate (FAR), and it can improve both production safety and product quality.

2319 aluminum alloy was prepared using wire arc additive manufacturing (WAAM) technique. The solid solution time of achieving improving corrosion resistance in WAAM 2319 aluminum alloy was investigated. The results indicated that the as deposited 2319 aluminum alloy was composed of dendritic grains. Numerous inter-granular intermetallic were continuously distributed along the grain boundary. As the solid solution time increased, the inter-granular intermetallic gradually dissolved into α-Al matrix resulting in discontinuously distribution and more homogeneous element distribution. Electrochemical experiment results indicated that the corrosion potential of WAAM 2319 aluminum alloy gradually increased with the increase of solid solution time. This indicated that increasing solid solution time could effectively increased the corrosion resistance of WAAM 2319 aluminum alloy. Improved corrosion resistance can be attributed to refined and discontinuous inter-granular intermetallic.

Abstract Glioblastoma (GBM) is a lethal cancer characterized by hypervascularity and necrosis associated with hypoxia. Here, it is found that hypoxia preferentially induces the actin‐binding protein, Transgelin (TAGLN), in GBM stem cells (GSCs). Mechanistically, TAGLN regulates HIF1α transcription and stabilizes HDAC2 to deacetylate p53 and maintain GSC self‐renewal. To translate these findings into preclinical therapeutic paradigm, it is found that sodium valproate (VPA) is a specific inhibitor of TAGLN/HDAC2 function, with augmented efficacy when combined with natural borneol (NB) in vivo. Thus, TAGLN promotes cancer stem cell survival in hypoxia and informs a novel therapeutic paradigm.

Abstract Background Mesenchymal stem cells (MSCs) therapies are emerging as a promising approach to therapeutic regeneration. Therapeutic persistence and reduced functional stem cells following cell delivery remain critical hurdles for clinical investigation due to the senescence of freshly isolated cells and extensive in-vitro passage. Methods Cultured adipose-derived stem cells (ASCs) were derived from subcutaneous white adipose tissue isolated from mice fed a normal diet. We performed senescence-associated-β-galactosidase (SA-β-gal) staining, real-time PCR, and Westernblot to evaluate the levels related to cellular senescence markers. Results The mRNA expression levels of senescence markers were significantly increased in the later passage of ASCs. We show that light activation reduced the expression of senescent genes, and SA-β-Gal in all cells at passages. Moreover, the light-activated ASCs-derived exosomes decrease the expression of senescence, and SA-β-Gal in the later passage cells. We further investigated the photoreceptive effect of Opsin3 (Opn3) in light-activated ASCs. Deletion of Opn3 abolished the differences of light activation in reduced expression of senescent genes, increased Ca 2+ influx, and cAMP levels. Conclusions ASCs can undergo cellular senescence in-vitro passage. Photomodulation might be better preserved over senescence and Opn3-dependent activation in aged ASCs. Light-activated ASCs-derived exosomes could be served as e a new protective paradigm for cellular senescence in-vitro passage. Video Abstract

Abstract Image quality assessment (IQA) is significant for current techniques of image-based computer-aided diagnosis, and fundus imaging is the chief modality for screening and diagnosing ophthalmic diseases. However, most of the existing IQA datasets are single-center datasets, disregarding the type of imaging device, eye condition, and imaging environment. In this paper, we collected a multi-source heterogeneous fundus (MSHF) database. The MSHF dataset consisted of 1302 high-resolution normal and pathologic images from color fundus photography (CFP), images of healthy volunteers taken with a portable camera, and ultrawide-field (UWF) images of diabetic retinopathy patients. Dataset diversity was visualized with a spatial scatter plot. Image quality was determined by three ophthalmologists according to its illumination, clarity, contrast and overall quality. To the best of our knowledge, this is one of the largest fundus IQA datasets and we believe this work will be beneficial to the construction of a standardized medical image database.

Exposure to irreparable stresses induces transient ciliogenesis, enabling communication with PML-NBs via a FBF1 pathway to trigger senescence in mammalian cells. Fbf1 ablation reduces senescence and associated health decline in mice, highlighting cilia as a promising senotherapy target.

This study introduces a novel trifluoromethylating reagent, [(bpy)Cu(O2CCF2SO2F)2], notable for not only its practical synthesis from cost-effective starting materials and scalability but also its nonhygroscopic nature. The reagent demonstrates high efficiency in facilitating trifluoromethylation reactions with various halogenated hydrocarbons, yielding products in good yields and exhibiting broad functional group compatibility. The development of [(bpy)Cu(O2CCF2SO2F)2] represents an advancement in the field of organic synthesis, potentially serving as a valuable addition to the arsenal of existing trifluoromethylating agents.

Abstract Ongoing runoff declines in the Colorado River Basin have been shown to be predominately driven by decreasing albedo from warming‐driven snow‐cover loss, especially in late‐spring (hereafter snowmelt‐radiation feedback). Here, we explore the feedback's impact on annual runoff sensitivity to warming across the western U.S. (WUS) using hydrologic model simulations. For 1°C uniform warming, we show that runoff is most sensitive to warming in modestly snow‐covered, interior mountain headwaters, especially the Rocky Mountains. Runoff sensitivities are most associated with the snowmelt‐radiation feedback in basins with runoff coefficients between 0.2 and 0.6, where runoff sensitivity increases with more snow and lower winter temperature. In aggregate, ∼48% of WUS runoff sensitivity is attributable to the snowmelt‐radiation feedback and is especially pronounced in the warming‐sensitive river basins (annual runoff decreases >5%/°C). We also show that the feedback's impact decreases with increasing temperature, which has unresolved implications for streamflow declines in a less‐snow future.

Background: Sepsis-induced cardiomyopathy (SIC) is a severe myocardial dysfunction secondary to septicemia. It is a major concern owing to the high mortality and morbidity, which are greatly influenced by ferroptosis. Resveratrol (RSV) is a naturally existing agonist of the silent information regulator 1 (Sirt1). It has cardioprotective effects against sepsis-induced myocardial injury, However, the detailed mechanism is unknown. Methods: In this study, cecal ligation and puncture (CLP)-induced septic rats were employed to assess the changes in ferroptosis with RSV administration. According to the different treatments the rats were divided into the following groups: (1) the Sham, (2) CLP, (3) CLP + RSV at various doses (10, 30, and 50 mg/kg), and (4) CLP + Fer-1(a ferroptotic inhibitor) groups. After 24 h, the structure and function of the cardiac system in rats were evaluated, and mitochondrial morphology, ferroptosis-related biomarkers, and the levels of Sirt1/Nrf2 were assessed. Results: The rats that underwent CLP had suffered cardiac dysfunction, accompanied with myocardial damage, impaired mitochondria, elevated lipid peroxidation, and reduced Sirt1/Nrf2 expression in the myocardium. High-dose RSV successfully improved heart function, reversing the abnormalities in a dose-dependent manner. We then used EX527, a selective Sirt1 inhibitor, to further identify the intermediate signaling targets of RSV that regulate ferroptosis. EX527 diminished the curative effects of high-doses RSV. Conclusions: Summarily, our findings suggest a novel mechanism of RSV in reducing SIC: ferroptosis inhibition via upregulation of Sirt1/Nrf2 signaling pathways. This may be an effective therapeutic approach against organ failure in sepsis, particularly SIC.

The predictive business process monitoring mainly focuses on the performance prediction of business process execution, i.e., predicting the next activity, the execution time of the next activity, and the remaining time, respectively, for an ongoing process instance based on the knowledge gained from historical event logs. Although there is a specific relationship between these three tasks, recent research has focused on training separate prediction models for each task, resulting in high costs and time complexity. Additionally, existing technologies are limited in their ability to capture long-distance dependent features in process instances, further impeding prediction performance. To address these issues, this paper proposes the MTLFormer approach, which leverages the self-attention mechanism of the Transformer network and conducts multi-task parallel training through shared feature representation obtained from different tasks. Our approach reduces the time complexity of model training while simultaneously improving prediction performance. We extensively evaluate our approach on four real-life event logs, demonstrating its capability to achieve multi-task online real-time prediction and effectively improve prediction performance.

Highlights Female RAGE−/− mice showed significantly improved glucose and insulin tolerance compared to male RAGE−/− mice. Female RAGE deficiency promotes M2 macrophage polarization in adipose tissues. Female RAGE deficiency prevents oxidative stress in adipose tissues. Female RAGE deficiency protects insulin-AKT signaling in adipose tissues.

Gliomas account for the majority of brain malignant tumors. As the most malignant subtype of glioma, glioblastoma (GBM) is barely effectively treated by traditional therapies (surgery combined with radiochemotherapy), resulting in poor prognosis. Meanwhile, due to its “cold tumor” phenotype, GBM fails to respond to multiple immunotherapies. As its capacity to prime T cell response, dendritic cells (DCs) are essential to anti-tumor immunity. In recent years, as a therapeutic method, dendritic cell vaccine (DCV) has been immensely developed. However, there have long been obstacles that limit the use of DCV yet to be tackled. As is shown in the following review, the role of DCs in anti-tumor immunity and the inhibitory effects of tumor microenvironment (TME) on DCs are described, the previous clinical trials of DCV in the treatment of GBM are summarized, and the challenges and possible development directions of DCV are analyzed.

IntroductionPollution reduction, carbon reduction, green expansion and economic growth—the synergistic effects of the four—have become essential in maintaining urban ecological security and promoting a green and low-carbon transition. And it is inherently consistent with the globally accepted concept of sustainable development. MethodsBased on the evaluation index system and the coupling mechanism of the four, we adopt the entropy method and the coupling coordination model to measure the synergistic level of “pollution reduction, carbon reduction, green expansion and economic growth” in 243 cities above prefecture level in China from 2005 to 2020. Furthermore, the study examined the temporal and spatial evolution and regional differences by utilizing the center of gravity-standard deviation ellipse, Dagum Gini coefficient method, Kernel density estimation, and Markov chain. In addition, the spatial econometric model was used to analyze the driving factors affecting the synergistic development.ResultsThe results show that the overall synergistic level is rising, the spatial distribution characteristics of “high in the east and low in the west.” The standard deviation ellipse shows a “northeast–southwest” pattern, and the center of gravity moves in a “southeast–northwest–southwest” migration trend. Regional differences are mainly rooted in inter-regional differences. The intra-regional differences are East > West > Central, with the most prominent East–West inter-regional differences. Without considering the spatial factor, the synergistic level shows a steady increase and has continuity. Under the spatial condition, the synergistic level has a positive spatial correlation. However, the positive spatial correlation decreases significantly as the years go by. Also, the probability of “rank locking” of synergistic development has been reduced, and there is a leapfrog shift. In terms of driving factors, the innovation level, level of external openness, population size, and industrial structure positively drive synergistic development. While government intervention negatively affects synergistic development. DiscussionsBased on the above findings,policy recommendations are proposed to strengthen the top-level design and build a policy system, play the radiation linkage, apply precise policies according to local conditions, and optimize the industrial structure fully. Which is of great significance for improving the urban ecological resilience and helping to achieve the “double carbon” target.

KIC 6362386 is an eclipsing binary system that exhibits both γ Doradus ( γ Dor)–type pulsations and starspots. In this study, we investigated this binary system using the Kepler photometry and the spectroscopic data from the Large Sky Area Multi-Object Fiber Spectroscopic Telescope. After employing the PHOEBE program for light-curve and radial-velocity-curve synthesis, analyses reveal that the binary is a circle ( e ∼ 0.0006), has a small mass ratio ( q ∼ 0.311), and is a detached system consisting of an F-type primary star and an M-type secondary star with masses and radii of M _1 = 1.43 ± 0.13 M _⊙ , R _1 = 1.68 ± 0.08 R _⊙ and M _2 = 0.44 ± 0.18 M _⊙ , R _2 = 0.46 ± 0.06 R _⊙ , respectively. Utilizing the Padova isochrone, we estimate the age of the binary system to be ${1.58}_{-0.13}^{+0.15}$ Gyr. By analyzing the out-of-eclipse residuals, we identify variations in the residuals attributed to both starspots and stellar pulsations. The autocorrelation function analysis indicates the decay time of starspots is approximately 37 days with the rotation period aligning with the orbital period. Considering the masses, radii, and positions of the two components on the Hertzsprung–Russell diagram, we deduce that the γ Dor–type g-mode pulsations came from the primary star where the main frequency is 0.1642c/d. Consequently, KIC 6362386 becomes a valuable target for the investigation of γ Dor–type pulsations and asteroseismology in a binary system.

We present a comprehensive analysis of oscillations of the helium-rich white dwarf DBV star EPIC 248705247 (SDSS J102106.69+082724.8). We extract the light curves from 79.7 days of K2 Campaign 14 data and identify 21 independent frequencies, including three complete and three incomplete dipole modes, with an average frequency splitting of 20.37 ± 0.40 μ Hz. Our analyses reveal a rotation period of EPIC 248705247 of approximately 6.82 ± 0.07 hr, making it one of the most rapidly rotating DBV stars currently known. We utilize the White Dwarf Evolution Code ( WDEC ) to compute models to look for the seismic best-fitted model, yielding the following stellar parameters: M / M _⊙ = 0.650 ± 0.003, T _eff = 23,660 ± 68 K, $\mathrm{log}({M}_{\mathrm{env}}/{M}_{* })=-2.01\pm 0.01$ and $\mathrm{log}({M}_{\mathrm{He}}/{M}_{* })\,=-4.90\pm 0.05$ . We also explore the phenomenon of mode trapping, as well as the potential influence of a weak magnetic field. We find that this star is located near the red edge of the theoretical instability strip of DBVs. Hence, our asteroseismological analysis of EPIC 248705247 provides the properties and behaviors of a rapidly rotating DBV.

BackgroundThe involvement of retina and its vasculature has been recently described in Alzheimer’s disease (AD). Optical coherence tomography angiography (OCTA) is noninvasively used to assess the retinal blood flow.ObjectiveThis study was to compare vessel density (VD) and blood perfusion density (PD) of the macular in AD patients, mild cognitive impairment (MCI) patients and healthy controls by OCTA, which may provide new ideas for diagnosis of AD or MCI.MethodsAD patients, MCI patients and healthy controls underwent a comprehensive ophthalmic and neurological evaluations, including cognitive function assessments as well as visual acuity, intraocular pressure (IOP), slit lamp examinations, and OCTA. General demographic data, cognitive function, retinal VD and PD were compared among three groups. The correlations among retinal VD, PD and cognitive function, amyloid-beta (Aβ) protein and phosphorylated Tau (p-Tau) protein were further evaluated. The correlations between retinal superficial capillary plexus and cognitive function, Aβ protein and p-Tau protein were also explored.ResultsA total of 139 participants were recruited into this study, including 43 AD patients, 62 MCI patients, and 34 healthy controls. After adjusting for sex, age, history of smoking, history of alcohol intake, hypertension, hyperlipidemia, best corrected visual acuity, and IOP, VD and PD in the nasal and inferior regions of the inner ring, superior and inferior regions of outer ring in the AD group were significantly lower than in the control group (p

Objective: Glucokinase-maturity-onset diabetes of the young (GCK-MODY; MODY2) is a rare genetic disorder caused by mutations in the glucokinase (GCK) gene. It is often under- or misdiagnosed in clinical practice, but correct diagnosis can be facilitated by genetic testing. In this study, we examined the genes of three patients diagnosed with GCK-MODY and tested their biochemical properties, such as protein stability and half-life, to explore the function of the mutant proteins and identify the pathogenic mechanism of GCK-MODY.Methods: Three patients with increased blood glucose levels were diagnosed with MODY2 according to the diagnostic guidelines of GCK-MODY proposed by the International Society for Pediatric and Adolescent Diabetes (ISPAD) in 2018. Next-generation sequencing (whole exome detection) was performed to detect gene mutations. The GCK gene and its mutations were introduced into the pCDNA3.0 and pGEX-4T-1 vectors. Following protein purification, enzyme activity assay, and protein immunoblotting, the enzyme activity of GCK was determined, along with the ubiquitination level of the mutant GCK protein.Results: Genetic testing revealed three mutations in the GCK gene of the three patients, including c.574C>T (p.R192W), c.758G>A (p.C253Y), and c.794G>A (p.G265D). The biochemical characteristics of the protein encoded by wild-type GCK and mutant GCK were different, compared to wild-type GCK, the enzyme activity encoded by the mutant GCK was reduced, suggesting thermal instability of the mutant GST-GCK. The protein stability and expression levels of the mutant GCK were reduced, and the enzyme activity of GCK was negatively correlated with the levels of fasting blood glucose and HbA1c. In addition, ubiquitination of the mutant GCK protein was higher than that of the wild-type, suggesting a higher degradation rate of mutant GCK than WT-GCK.Conclusion:GCK mutations lead to changes in the biochemical characteristics of its encoded proteins. The enzyme activities, protein expression, and protein stability of GCK may be reduced in patients with GCK gene mutations, which further causes glucose metabolism disorders and induces MODY2.

Glucose and amino acids are important sources of nutrients in the synthetic milk of dairy cows, and understanding the fate of amino acids is essential to optimize the utilization of amino acids in milk protein synthesis, thereby reducing nutrient inefficiencies during lactation. The purpose of this study was to investigate the effects of LPS and different concentrations of glucose on (1) the expression of inflammatory factors and genes, (2) the glucose metabolism, and (3) amino acid utilization in BMECs. The results showed that there was an interaction (LPS × glucose, p < 0.05) between LPS and glucose content in the inflammatory cytokine genes (IL-6 and TNF-α) and the inflammatory regulatory genes (CXCL2, CXCL8, and CCL5). With the addition of LPS, the HG + LPS group caused downregulated (p < 0.05) expression of IL-6 and TNF-α, compared with the LG + LPS group. Interestingly, compared with the LG + LPS group, the HG + LPS group upregulated (p < 0.05) the expression of CXCL2, CXCL8, and CCL5. LPS supplementation increased (p = 0.056) the consumption of glucose and GLUT1 gene expression (p < 0.05) and tended to increase (p = 0.084) the LDHA gene expression of BMECs under conditions of different concentrations of glucose culture. High glucose content increased (p < 0.001) the consumption of glucose and enhanced (p < 0.05) the GLUT1, HK1, HK2, and LDHA gene expression of BMECs with or without LPS incubation, and there was an interaction (LPS × glucose, p < 0.05) between LPS and glucose concentrations in GLUT1 gene expression. In this study, LPS enhanced (p < 0.05) the consumption of amino acids such as tryptophan, leucine, isoleucine, methionine, valine, histidine, and glutamate, while high levels of glucose decreased (p < 0.01) consumption, except in the case of tyrosine. For histidine, leucine, isoleucine, and valine consumption, there was an interaction (LPS × glucose, p < 0.05) between LPS and glucose levels. Overall, these findings suggest that relatively high glucose concentrations may lessen the LPS-induced BMEC inflammatory response and reduce amino acid consumption, while low glucose concentrations may increase the demand for most amino acids through proinflammatory responses.

Abstract Since its first identification in prostate cancers and prostate tissues, transient receptor potential melastatin-subfamily member 8 (TRPM8) is subsequently found to be overexpressed in a wide range of cancers and is shown to be implicated in tumorigenesis and tumor progression. Here, we used N-(3-aminopropyl)-2-[(3-methylphenyl) methoxy] -N-(2-thienylmethyl) benzamide hydrochloride (AMTB), a specific TRPM8 antagonist, to explore its antitumoral effect on osteosarcoma. We find that AMTB suppresses osteosarcoma cell proliferation, metastasis and induces cellular apoptosis. Xenograft model in nude mice experiments also define that AMTB can increase the sensitivity of tumor cells to cisplatin, the cytotoxic chemotherapeutic regimens in treating osteosarcoma. Molecularly, AMTB specifically antagonizes TRPM8 which is upregulated in osteosarcoma and its expression level in osteosarcoma tissues is negatively related to patients’ prognosis. Finally, RNA sequencing analysis was performed to explore the mechanism underlying the antitumoral effect of AMTB on osteosarcoma cells and the results prove that AMTB suppresses the Transforming Growth Factor β (TGFβ) signaling pathway. Our study provides evidence that TRPM8 could be a potential therapeutic target and AMTB can suppress growth and metastasis of osteosarcoma cells through repressing the TGFβ signaling pathway and increase the sensitivity of tumor cells to cisplatin.

Spaceflight and microgravity has a significant impact on the immune, central nervous, bone, and muscle support and cardiovascular systems. However, limited studies are available on the adverse effects of long-term microgravity on the intestinal microbiota, metabolism, and its relationships. In this study, a ground-based simulated microgravity (SMG) mouse model was established to evaluate the impact of long-term microgravity on gut microbiota and metabolome. After 8 weeks of SMG, alterations of the intestinal microbiota and metabolites were detected using 16S rRNA sequencing and untargeted metabolomics. Compared to the control, no significant differences in α-diversity were observed at weeks 2, 4 and 8. Nevertheless, there were clear differences in community structures at different time points. The phylum Verrucomicrobia significantly declined from 2 to 8 weeks of SMG, yet the relative abundance of Actinobacteria and Deferribacteres expanded remarkably at weeks 8. SMG decreased the genus of Allobaculum and increased Bacteroides significantly throughout the period of 8 weeks. Besides, Genus Akkermansia, Gracilibacter, Prevotella, Odoribacter, Rothia, Sporosarcina, Gracilibacter, Clostridium, and Mucispirillum were identified as biomarkers for SMG group. Desulfovibrio_c21_c20, Akkermansia_muciniphila, and Ruminococcus_gnavus dropped at week 2, which tend to recover at week 4, except for Akkermansia_muciniphila. Bacteroides_uniformis and Faecalibacterium_prausnitzii declined significantly, while Ruminococcus_flavefaciens and Mucispirillum_schaedleri elevated at week 8. Furthermore, intestinal metabolome analysis showed that 129 were upregulated and 146 metabolites were downregulated in SMG. Long-term SMG most affected steroid hormone biosynthesis, tryptophan, cysteine, methionine, arginine, proline metabolism, and histidine metabolism. Correlated analysis suggested that the potential beneficial taxa Allobaculum, Akkermansia, and Faecalibacterium were negatively associated with tryptophan, histidine, arginine, and proline metabolism, but positively with steroid hormone biosynthesis. Yet Bacteroides, Lachnospiraceae_Clostridium, Rothia, Bilophila, and Coprococcus were positively correlated with arginine, proline, tryptophan, and histidine metabolism, while negatively associated with steroid hormone biosynthesis. These results suggest that Long-term SMG altered the community of intestinal microbiota, and then further disturbed intestinal metabolites and metabolic pathways, which have great potential to help understand and provide clues for revealing the mechanisms of long-term SMG involved diseases.