121 research outputs found
Epigenetic Silencing of the MLH1 Promoter in Relation to the Development of Gastric Cancer and its use as a Biomarker for Patients with Microsatellite Instability: a Systematic Analysis
Knowledge-refined Denoising Network for Robust Recommendation
Knowledge graph (KG), which contains rich side information, becomes an
essential part to boost the recommendation performance and improve its
explainability. However, existing knowledge-aware recommendation methods
directly perform information propagation on KG and user-item bipartite graph,
ignoring the impacts of \textit{task-irrelevant knowledge propagation} and
\textit{vulnerability to interaction noise}, which limits their performance. To
solve these issues, we propose a robust knowledge-aware recommendation
framework, called \textit{Knowledge-refined Denoising Network} (KRDN), to prune
the task-irrelevant knowledge associations and noisy implicit feedback
simultaneously. KRDN consists of an adaptive knowledge refining strategy and a
contrastive denoising mechanism, which are able to automatically distill
high-quality KG triplets for aggregation and prune noisy implicit feedback
respectively. Besides, we also design the self-adapted loss function and the
gradient estimator for model optimization. The experimental results on three
benchmark datasets demonstrate the effectiveness and robustness of KRDN over
the state-of-the-art knowledge-aware methods like KGIN, MCCLK, and KGCL, and
also outperform robust recommendation models like SGL and SimGCL
A106: Aerobic Exercise Modulates GPCR/cAMP/PKA Signaling Pathway and Complement-Microglia Axis to Prevent Synaptic Loss in APP/PS1 Mice
Purpose: Synaptic failure serves as a primary contributor to memory dysfunction in Alzheimer\u27s disease (AD). Physical exercise has demonstrated the potential to thwart and delay degenerative alterations in memory functions linked to AD. Investigating the underlying mechanisms may unveil crucial insights into early pathological changes, offering breakthroughs for both understanding and treating AD. Methods: We utilized 3-month-old APP/PS1 mice and subjected them to a 12-week aerobic exercise intervention. The spatial learning and memory functions of the mice were assessed using the Morris water maze test, while Golgi staining was employed to determine dendritic spine density in each mouse group. To analyze the potential mechanisms mediating the effects of exercise intervention in the AD brain, we conducted RNA sequencing. Subsequently, pathway enrichment analysis, immunofluorescence, real-time quantitative PCR, and western blotting were employed to elucidate the impact of regular aerobic exercise on the GPCR/cAMP/PKA signaling pathway and complement-microglia axis. Results: Our findings reveal that a 12-week aerobic exercise intervention significantly enhanced spatial learning and memory function in APP/PS1 mice. Moreover, it led to a substantial increase in dendritic spine density and elevated expression of postsynaptic density protein 95 (PSD-95) in the cortex and hippocampus. Aerobic exercise demonstrated the ability to improve the expression of certain genes and enhance synaptic pathways in the brains of APP/PS1 mice. This suggests that aerobic exercise facilitates synaptic growth in APP/PS1 mice by modulating G protein-coupled receptors (GPCRs) and activating the cAMP signaling pathway, with significant alterations observed in the expressions of Hcar1 and Vipr2 genes. Furthermore, exercise intervention resulted in the significant down-regulation (P \u3c 0.05 or P \u3c 0.01) of cAMP, p-PKA/PKA, GluA1, and CaMKII protein expressions in the brain tissue of APP/PS1 mice, which were subsequently up-regulated after exercise (P \u3c 0.01). Notably, regular aerobic exercise effectively suppressed the activation of IBA-1+ microglia cells (P \u3c 0.01), reversed changes in M1 phenotype markers (Cd86 and iNOS) and M2 phenotype markers (Arg-1) of microglia cells (P \u3c 0.05), reduced the production of promoters C1q and central factor C3 in the macrosomatic cascade (P \u3c 0.05), and prevented the colocalization of microglia and PSD-95 (P \u3c 0.01). Conclusion: In conclusion, our results indicate that physical exercise plays a pivotal role in fostering early synaptic growth and averting synaptic loss in Alzheimer\u27s disease (AD). This effect may be attributed to the regulation of the G protein-coupled receptors (GPCRs)/cAMP/PKA signaling pathway and the suppression of complement-mediated microglial phagocytosis of synapses. This mechanistic insight underscores the inherent contribution of exercise to health promotion, offering potential avenues for synaptic-focused interventions in the early stages of AD treatment
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Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma.
Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer histotype, characterized by high biological aggressiveness and scarce treatment options. Recently, we have established a clinically relevant murine HCC model by co-expressing activated forms of v-akt murine thymoma viral oncogene homolog (AKT) and oncogene c-mesenchymal-epithelial transition (c-Met) proto-oncogenes in the mouse liver via hydrodynamic tail vein injection (AKT/c-MET mice). Tumor cells from these mice demonstrated high activity of the AKT/ mammalian target of rapamycin (mTOR) and Ras/ Mitogen-activated protein kinase (MAPK) signaling cascades, two pathways frequently co-induced in human HCC. Methods: Here, we investigated the therapeutic efficacy of sorafenib, regorafenib, the MEK inhibitor PD901 as well as the pan-mTOR inhibitor MLN0128 in the AKT/c-Met preclinical HCC model. Results: In these mice, neither sorafenib nor regorafenib demonstrated any efficacy. In contrast, administration of PD901 inhibited cell cycle progression of HCC cells in vitro. Combined PD901 and MLN0128 administration resulted in a pronounced growth constraint of HCC cell lines. In vivo, treatment with PD901 or MLN0128 alone moderately slowed HCC growth in AKT/c-MET mice. Importantly, the simultaneous administration of the two drugs led to a stable disease with limited tumor progression in mice. Mechanistically, combined mitogen-activated extracellular signal-regulated kinase (MEK) and mTOR inhibition resulted in a stronger cell cycle inhibition and growth arrest both in vitro and in vivo. Conclusions: Our study indicates that combination of MEK and mTOR inhibitors might represent an effective therapeutic approach against human HCC
hSef potentiates EGF-mediated MAPK signaling through affecting EGFR trafficking and degradation
Sef (similar expression to fgf genes) was identified as an effective antagonist of fibroblast growth factor (FGF) in vertebrates. Previous reports have demonstrated that Sef interacts with FGF receptors (FGFRs) and inhibits FGF signaling, however, its role in regulating epidermal growth factor receptor (EGFR) signaling remains unclear. In this report, we found that hSef localizes to the plasma membrane (PM) and is subjected to rapid internalization and well localizes in early/recycling endosomes while poorly in late endosomes/lysosomes. We observed that hSef interacts and functionally colocalizes with EGFR in early endosomes in response to EGF stimulation. Importantly, we demonstrated that overexpression of hSef attenuates EGFR degradation and potentiates EGF-mediated mitogen-activated protein kinase (MAPK) signaling by interfering EGFR trafficking. Finally, our data showed that, with overexpression of hSef, elevated levels of Erk phosphorylation and differentiation of rat pheochromocytoma (PC12) cells occur in response to EGF stimulation. Taken together, these data suggest that hSef plays a positive role in the EGFR-mediated MAPK signaling pathway. This report, for the first time, reveals opposite roles for Sef in EGF and FGF signalings
An analysis of microbiota-targeted therapies in patients with avian influenza virus subtype H7N9 infection
BACKGROUND: Selective prophylactic decontamination of the digestive tract is a strategy for the prevention of secondary nosocomial infection in patients with avian influenza virus subtype H7N9 infection. Our aim was to summarize the effectiveness of these therapies in re-establishing a stable and diverse microbial community, and reducing secondary infections. METHODS: Comprehensive therapies were dependent on the individual clinical situation of subjects, and were divided into antiviral treatment, microbiota-targeted therapies, including pro- or pre-biotics and antibiotic usage, and immunotherapy. Quantitative polymerase chain reaction and denaturing gradient gel electrophoresis (DGGE) were used for real-time monitoring of the predominant intestinal microbiome during treatment. Clinical information about secondary infection was confirmed by analyzing pathogens isolated from clinical specimens. RESULTS: Different antibiotics had similar effects on the gut microbiome, with a marked decrease and slow recovery of the Bifidobacterium population. Interestingly, most fecal microbial DGGE profiles showed the relative stability of communities under the continual suppression of the same antibiotics, and significant changes when new antibiotics were introduced. Moreover, we found no marked increase in C-reactive protein, and no cases of bacteremia or pneumonia, caused by probiotic use in the patients, which confirmed that the probiotics used in this study were safe for use in patients with H7N9 infection. Approximately 72% of those who subsequently suffered exogenous respiratory infection by Candida species or multidrug-resistant Acinetobacter baumannii and Klebsiella pneumoniae were older than 60Â years. The combination of probiotics and prebiotics with antibiotics seemed to fail in these patients. CONCLUSIONS: Elderly patients infected with the influenza A (H7N9) virus are considered a high-risk group for developing secondary bacterial infection. Microbiota restoration treatment reduced the incidence of enterogenous secondary infection, but not exogenous respiratory infection. The prophylactic effects of microbiota restoration strategies for secondary infection were unsatisfactory in elderly and critically ill patients
SenseCare: A Research Platform for Medical Image Informatics and Interactive 3D Visualization
Clinical research on smart healthcare has an increasing demand for
intelligent and clinic-oriented medical image computing algorithms and
platforms that support various applications. To this end, we have developed
SenseCare research platform for smart healthcare, which is designed to boost
translational research on intelligent diagnosis and treatment planning in
various clinical scenarios. To facilitate clinical research with Artificial
Intelligence (AI), SenseCare provides a range of AI toolkits for different
tasks, including image segmentation, registration, lesion and landmark
detection from various image modalities ranging from radiology to pathology. In
addition, SenseCare is clinic-oriented and supports a wide range of clinical
applications such as diagnosis and surgical planning for lung cancer, pelvic
tumor, coronary artery disease, etc. SenseCare provides several appealing
functions and features such as advanced 3D visualization, concurrent and
efficient web-based access, fast data synchronization and high data security,
multi-center deployment, support for collaborative research, etc. In this
paper, we will present an overview of SenseCare as an efficient platform
providing comprehensive toolkits and high extensibility for intelligent image
analysis and clinical research in different application scenarios.Comment: 11 pages, 10 figure
The relationship between sleep quality and daytime dysfunction among college students in China during COVID-19: a cross-sectional study
ObjectiveCollege Students’ sleep quality and daytime dysfunction have become worse since the COVID-19 outbreak, the purpose of this study was to explore the relationship between sleep quality and daytime dysfunction among college students during the COVID-19 (Corona Virus Disease 2019) period.MethodsThis research adopts the form of cluster random sampling of online questionnaires. From April 5 to 16 in 2022, questionnaires are distributed to college students in various universities in Fujian Province, China and the general information questionnaire and PSQI scale are used for investigation. SPSS26.0 was used to conduct an independent sample t-test and variance analysis on the data, multi-factorial analysis was performed using logistic regression analysis. The main outcome variables are the score of subjective sleep quality and daytime dysfunction.ResultsDuring the COVID-19 period, the average PSQI score of the tested college students was 6.17 ± 3.263, and the sleep disorder rate was 29.6%, the daytime dysfunction rate was 85%. Being female, study liberal art/science/ engineering, irritable (due to limited outdoor), prolong electronic entertainment time were associated with low sleep quality (p < 0.001), and the occurrence of daytime dysfunction was higher than other groups (p < 0.001). Logistics regression analysis showed that sleep quality and daytime dysfunction were associated with gender, profession, irritable (due to limited outdoor), and prolonged electronic entertainment time (p < 0.001).ConclusionDuring the COVID-19 epidemic, the sleep quality of college students was affected, and different degrees of daytime dysfunction have appeared, both are in worse condition than before the COVID-19 outbreak. Sleep quality may was inversely associated with daytime dysfunction
Genetic characterization and virulence determinants of multidrug-resistant NDM-1-producing Aeromonas caviae
The emergence of carbapenemase significantly threatens public health. It is prevalent worldwide but rare in Aeromonas caviae. Unlike most bacterial species, A. caviae has two distinct flagella systems, which are closely related to biofilm formation. The ability to form biofilms on host tissues or inert surfaces constitutes an important cause of many persistent infections, which causes difficulties in clinical treatment. Here, we report on a multidrug-resistant (MDR) A. caviae carrying blaNDM–1 with a novel sequence type 1,416. The strong ability of biofilm formation of FAHZZU2447 was verified by a crystal violet assay. The resistome profile and location of the blaNDM–1 gene were determined by antimicrobial susceptibility testing, S1 nuclease pulsed-field gel electrophoresis (S1-PFGE), and Southern blot analysis. Moreover, the strain underwent whole-genome sequencing to identify its genomic characteristics. In addition, the blaNDM–1 gene was located on a ∼243 kb plasmid with genetic context IS1R-blaNDM–1-ble-trpF-dsbD-hp-sul1-qacE. Phylogenetic analysis indicated the transmission of A. caviae in China, Japan, and Thailand. Our study aimed to elucidate the genomic features of blaNDM–1-producing A. caviae, thereby clarifying the distribution of A. caviae worldwide and emphasizing the harmfulness of biofilm formation to the clinic. Further comprehensive surveillance of this species is needed to control further dissemination
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