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Abstract This study aimed to explore naringin’s potential to promote the osteogenic differentiation of MC3T3-E1 under oxidative stress. It delved into Nar’s connection with the Wnt/β-catenin and PI3K/Akt signaling pathways. Initially, 2911 OP-related genes were analyzed, revealing close ties with the PI3K/Akt and Wnt pathways alongside oxidative stress. Nar’s potential targets—ESR1, HSP90AA1, and ESR2—were identified through various databases and molecular docking studies confirmed Nar’s affinity with ESR1 and HSP90AA1. Experiments established optimal concentrations for Nar and H2O2. H2O2 at 0.3 mmol/L damaged MC3T3-E1 cells, alleviated by 0.1 µmol/L Nar. Successful establishment of oxidative stress models was confirmed by DCFH-DA probe and NO detection. Nar exhibited the ability to enhance osteogenic differentiation, counteracting oxidative damage. It notably increased osteoblast-related protein expression in MC3T3-E1 cells under oxidative stress. The study found Nar’s positive influence on GSK-3β phosphorylation, β-catenin accumulation, and pathway-related protein expression, all critical in promoting osteogenic differentiation. The research concluded that Nar effectively promotes osteogenic differentiation in MC3T3-E1 cells under oxidative stress. It achieved this by activating the Wnt/β-catenin and PI3K/Akt pathways, facilitating GSK-3β phosphorylation, and enhancing β-catenin accumulation, pivotal in osteogenesis.

BackgroundThe aim of the present study was to investigate the intrinsic relationship between cultural values and social network index among college students. In addition, the present study explored the mediating role of self-monitoring in the relationship between horizontal collectivism cultural values and social network index, as well as the moderating role of self-efficacy, to provide a theoretical approach based on the intrinsic mechanism for college students to establish a good social network.MethodsA simple random cluster sampling method was used to investigate 376 college students with cultural values scale, self-monitoring scale, self-efficacy scale, and social network index scale, structural equation model was constructed using M-plus and SPSS.ResultsThe result indicated that individual horizontal collectivist cultural values positively predict social network index (β = 0.477). Self-monitoring plays an intermediary role between cultural values and social network index, and self-efficacy plays a moderating role between self-monitoring and social network index.ConclusionThe level of an individual’s social network activity is affected by the cultural values of horizontal collectivism and self-monitoring. Improving individual self-monitoring ability and self-efficacy can effectively improve the interpersonal relationships of college students.

Fermented meat products is the meat products with special flavor, color, texture and longer shelf life formed by a series of changes under natural or artificially controlled conditions by the action of microorganisms or enzymes. Fermented meat products is popular with consumers, but they are rich in protein and have a great potential for high levels of biogenic amines. Among them, histamine and tyramine are the most toxic. Consumption of tyramine-rich foods might cause headache, hypertension and other adverse reactions. Therefore, it is extremely necessary to control the tyramine content in fermented meat products. In this paper, the formation pathways, control methods and effects of tyramine in fermented meat products are reviewed. Among them, the main formation pathway is the decarboxylation of tyrosine by the action of decarboxylase, in addition to the existence of chemical pathways related to lipid oxidation products, while the more effective control methods are the addition of auxiliaries and the inoculation of fermentation agents. This paper aims to provid a theoretical support for reducing the tyramine content in fermented meat products and improving the safety of fermented meat products.

Sarcopenic obesity (SO) is a metabolic disorder with increasing prevalence. It is characterized by a reduction in skeletal muscle mass and strength. Resveratrol (RSV) is one of the most frequently used herbs in the treatment of skeletal muscle atrophy. However, the precise mechanism of the action of RSV in SO remains unclear. The objective of this study was to examine the pharmacological mechanism of RSV in the context of SO through the lens of network pharmacology, to validate these findings through in vivo experimentation. A list of potential RSV targets was compiled by retrieving the data from multiple databases. This list was then cross-referenced with a list of potential targets related to SO. The intersections of RSV- and SO-related targets were analyzed using Venn diagrams. To identify the core genes, a protein-protein interaction (PPI) network of the intersection targets was constructed and subsequently analyzed. Molecular docking was used to predict RSV binding to its core targets. A high-fat diet was used to induce SO in mice. These findings indicated that RSV may prevent SO by acting on 11 targets. Among these, interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor (TNF) are considered core targets. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment results indicated that the anti-SO effect of RSV was predominantly linked to metabolic disease-related pathways, including those associated with nonalcoholic fatty liver disease. The anti-inflammatory effects of RSV were confirmed in vivo in an SO mouse model. This study contributes to a more comprehensive understanding of the key mechanisms of the action of RSV against SO and provides new possibilities for drug development in the pathological process of SO.

Abstract Cardiac function is under neural regulation; however, brain regions in the cerebral cortex responsible for regulating cardiac function remain elusive. In this study, retrograde trans‐synaptic viral tracing is used from the heart to identify a specific population of the excitatory neurons in the primary motor cortex (M1) that influences cardiac function in mice. Optogenetic activation of M1 glutamatergic neurons increases heart rate, ejection fraction, and blood pressure. By contrast, inhibition of M1 glutamatergic neurons decreased cardiac function and blood pressure as well as tyrosine hydroxylase (TH) expression in the heart. Using viral tracing and optogenetics, the median raphe nucleus (MnR) is identified as one of the key relay brain regions in the circuit from M1 that affect cardiac function. Then, a mouse model of cardiac injury is established caused by myocardial infarction (MI), in which optogenetic activation of M1 glutamatergic neurons impaired cardiac function in MI mice. Moreover, ablation of M1 neurons decreased the levels of norepinephrine and cardiac TH expression, and enhanced cardiac function in MI mice. These findings establish that the M1 neurons involved in the regulation of cardiac function and blood pressure. They also help the understanding of the neural mechanisms underlying cardiovascular regulation.

Abstract It is significant to predict welding quality during gas metal arc welding process. The welding defect detection algorithm has been developed based on convolutional neural network (CNN). The sensing system and image processing algorithm for molten pools has been developed. It overcomes the interference caused by the arc light to obtain clear images of the molten pool's boundaries. The molten pools images are used to build up training set and test set for training and testing the CNN model. The model is designed to extract the visual features of molten pool images to predict the penetration state, the welding crater, and slags. Through optimizing the network parameters such as kernel-size, batch-size and learning rate, the prediction accuracy is higher than 95%. Moreover, the model enhances additional focus on the welding crater based on the welder experience. The mechanisms between molten pool characteristics and welding defects were analyzed based on the welder experience and the visual features of the model. It is found that the model judges the occurrence of burn-through with the black hole in the middle zone of the molten pool. When the surface pores are generated, the model exhibits a strong response to circular voids in the semi-solid region at the trailing end of the molten pool. The size and shape of fusion holes exhibit a strong correlation with the molten state. When the shape of the crater does not appear concave, it often signifies excessive penetration. It contributes to enhancing the algorithm's robustness during various welding scenarios.

Although physics exercise has been utilized to prevent and treat a variety of metabolic diseases, its role in obesity-related kidney diseases remains poorly understood. In this study, we assessed the protective potential of moderate intensity continuous training (MICT) against high fat diet (HFD)-induced kidney injury and found that MICT could significantly reduce obesity indexes (body weight, serum glucose, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol) and kidney injury indexes (serum creatinine and the expression of Kim-1 mRNA) in HFD-fed mice. PAS staining and Masson staining displayed that MICT maintained the morphological structure of kidney subunits and reduced kidney fibrosis in HFD-fed mice. By kidney RNA-seq, we identified several genes and pathways (Cd9, Foxq1, Mier3, TGF-β signaling pathway etc.) that might underlie HFD-induced kidney injury and MICT-mediated protective effects. In conclusion, this study revealed the protective role of MICT in HFD-induced kidney injury and suggested potential targets for the prevention and treatment of obesity-related kidney diseases.

Introduction. The development of combinatorial adjuvants is a promising strategy to boost vaccination efficiency. Accumulating evidence indicates that manganese exerts strong immunocompetence and will become an enormous potential adjuvant. Here, we described a novel combination of Mn2+ plus aluminum hydroxide (AH) adjuvant that significantly exhibited the synergistic immune effect. Methodology. Initially, IsdB3 proteins as the immune-dominant fragment of IsdB proteins derived from Staphylococcus aureus (S. aureus) were prepared. IsdB3 proteins were identified by western blotting. Furthermore, we immunized C57/B6 mice with IsdB3 proteins plus Mn2+ and AH adjuvant. After the second immunization, the proliferation of lymphocytes was measured by the cell counting kit-8 (CCK-8) and the level of IFN-γ, IL-4, IL-10, and IL-17 cytokine from spleen lymphocytes in mice and generation of the antibodies against IsdB3 in serum was detected with ELISA, and the protective immune response was assessed through S. aureus challenge. Results. IsdB3 proteins plus Mn2+ and AH obviously stimulated the proliferation of spleen lymphocytes and increased the secretion of IFN-γ, IL-4, IL-10, and IL-17 cytokine in mice, markedly enhanced the generation of the antibodies against IsdB3 in serum, observably decreased bacterial load in organs, and greatly improved the survival rate of mice. Conclusion. These data showed that the combination of Mn2+ and AH significantly acted a synergistic effect, reinforced the immunogenicity of IsdB3, and offered a new strategy to increase vaccine efficiency.

Abstract The evolution of excitons from 2D to 3D is of great importance in photo-physics, yet the layer-dependent exciton polarizability hasn’t been investigated in 2D semiconductors. Here, we determine the exciton polarizabilities for 3- to 11-layer black phosphorus—a direct bandgap semiconductor regardless of the thickness—through frequency-resolved photocurrent measurements on dual-gate devices and unveil the carrier screening effect in relatively thicker samples. By taking advantage of the broadband photocurrent spectra, we are also able to reveal the exciton response for higher-index subbands under the gate electrical field. Surprisingly, dark excitons are brightened with intensity even stronger than the allowed transitions above certain electrical field. Our study not only sheds light on the exciton evolution with sample thickness, but also paves a way for optoelectronic applications of few-layer BP in modulators, tunable photodetectors, emitters and lasers.

Preclinical studies rarely test the efficacy of therapies in both sexes. The field of oncology is no exception in this regard. In a model of syngeneic, orthotopic, metastasized pancreatic ductal adenocarcinoma we evaluated the impact of sex on pathological features of this disease as well as on the efficacy and possible adverse side effects of a novel, small molecule-based therapy inhibiting KRAS:SOS1, MEK1/2 and PI3K signaling in male and female C57BL/6J mice. Male mice had less tumor infiltration of CD8-positive cells, developed bigger tumors, had more lung metastasis and a lower probability of survival compared to female mice. These more severe pathological features in male animals were accompanied by higher distress at the end of the experiment. The evaluated inhibitors BI-3406, trametinib and BKM120 showed synergistic effects in vitro. This combinatorial therapy reduced tumor weight more efficiently in male animals, although the drug concentrations were similar in the tumors of both sexes. These results underline the importance of sex-specific preclinical research and at the same time provide a solid basis for future studies with the tested compounds.

In recent years, the Alzheimer’s disease (AD) epidemic has become one of the largest global healthcare crises. Besides, the available systemic therapies for AD are still inadequate. Due to the insufficient therapeutic options, new treatment strategies are urgently needed to achieve a satisfactory therapeutic effect. Marine bio-resources have been accepted as one of the most economically viable and sustainable sources with potential applications for drug discovery and development. In this study, a marine cyanobacteria–Synechococcus sp. XM-24 was selected as the object of research, to systematically investigate its therapeutic potential mechanisms for AD. The major active compounds derived from the Synechococcus sp. biomass were identified via pyrolysis-gas chromatography-mass spectrometry (GC-MS), and 22 compounds were identified in this strain. The most abundant chemical compounds was (E)-octadec-11-enoic acid, with the peak area of 30.6%. Follow by tridecanoic acid, 12-methyl- and hexadecanoic acid, with a peak area of 23.26% and 18.23%, respectively. GC-MS analysis also identified indolizine, isoquinoline, 3,4-dihydro- and Phthalazine, 1-methyl-, as well as alkene and alkane from the strain. After the chemical toxicity test, 10 compounds were finally collected to do the further analysis. Then, network pharmacology and molecular docking were adopted to systematically study the potential anti-AD mechanism of these compounds. Based on the analysis, the 10 Synechococcus-derived active compounds could interact with 128 related anti-AD targets. Among them, epidermal growth factor receptor (EGFR), vascular endothelial growth factor A (VEGFA) and mitogen-activated protein kinase 3 (MAPK3) were the major targets. Furthermore, the compounds N-capric acid isopropyl ester, (E)-octadec-11-enoic acid, and 2H-Pyran-2,4(3H)-dione, dihydro-6-methyl- obtained higher degrees in the compounds-intersection targets network analysis, indicating these compounds may play more important role in the process of anti-AD. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that these active compounds exert the anti-AD effects mainly through PI3K-Akt signaling pathway, neuroactive ligand-receptor interaction and ras signaling pathway. Our study identified Synechococcus-derived bioactive compounds have the potential for application to AD by targeting multiple targets and related pathways, which will provide a foundation for future research on applications of marine cyanobacteria in the functional drug industry.

The engine casing components operate in high-temperature and high-pressure environments. Process holes are drilled when defects occur. Welding is employed in the repair of process holes as a process for permanently joining materials. The traditional welding method relies on padding, which results in poor back formation of process holes. Additionally, the shape of the process holes imposes high requirements on the size of the droplet transition. The conventional approach of adjusting a welding current makes it difficult to achieve stable droplet transition and precise formation of small holes. It poses a challenge for the robotic welding process. To deal with this problem, the influence of the high-frequency vibration GTAW process on the directional transition of molten droplets is studied. The molten droplet directional transition process is developed. The impact of vibration energy on the molten pool is reduced. Welding repair experiments for process holes are successfully conducted. When the frequency is 3 Hz, the transition of droplets changes from a continuous one-droplet transition to a discontinuous liquid bridge transition. The residual height and mechanical properties of the repaired area are tested. The experimental results indicated that the residual height after dual-side repair is ≤0.7 mm. The X-ray and fluorescent penetration tests have a 100% first-pass qualification rate. The repaired area demonstrates a hardness of 480 HV and a room-temperature tensile strength of 1069 MPa. The repair process requirements for the casing are met.

BackgroundAlterations in Mitochondrial DNA methylation (MTDM) exist in many tumors, but their role in breast cancer (BC) development remains unclear.MethodsWe analyzed BC patient data by combining scRNA-seq and bulk sequencing. Weighted co-expression network analysis (WGCNA) of TCGA data identified mitochondrial DNA methylation (MTDM)-associated genes in BC. COX regression and LASSO regression were used to build prognostic models. The biological function of MTDM was assessed using various methods, such as signaling pathway enrichment analysis, copynumber karyotyping analysis, and quantitative analysis of the cell proliferation rate. We also evaluated MTDM-mediated alterations in the immune microenvironment using immune microenvironment, microsatellite instability, mutation, unsupervised clustering, malignant cell subtype differentiation, immune cell subtype differentiation, and cell-communication signature analyses. Finally, we performed cellular experiments to validate the role of the MTDM-associated prognostic gene NCAPD3 in BC.ResultsIn this study, MTDM-associated prognostic models divided BC patients into high/low MTDM groups in TCGA/GEO datasets. The difference in survival time between the two groups was statistically significant (P

BackgroundPANoptosis, a cell death pathway involving pyroptosis, apoptosis, and necroptosis, is pivotal in the development of malignancy. However, in the field of breast cancer, the interaction between PANoptosis and tumor cells has not been thoroughly explored.MethodsWe downloaded breast cancer data and GSE176078 single-cell sequencing dataset from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases to obtain PANoptosis-associated genes. To construct prognostic models, COX and LASSO regression was used to identify PANoptosis-associated genes with prognostic value. Finally, immune infiltration analysis and differential analysis of biological functions were performed.ResultsRisk grouping was performed according to the prognostic model constructed by COX regression and LASSO regression. The low-risk group showed a better prognosis (P < 0.05) and possessed higher levels of immune infiltration and expression of immune checkpoint-related genes. In addition, the lower the risk score, the higher the degree of microsatellite instability (MSI). Meanwhile, radixin (RDX), the gene with the highest hazard ratio (HR) value among PANoptosis prognosis-related genes, was explicitly expressed in artery Iendothelial cells (ECs) and was widely involved in signaling pathways such as immune response and cell proliferation, possessing rich biological functions.ConclusionWe demonstrated the potential of PANoptosis-based molecular clustering and prognostic features in predicting the survival of breast cancer patients. Furthermore, this study has led to a deeper understanding of the role of PANoptosis in breast cancer and has the potential to provide new directions for immunotherapy of breast cancer.

IntroductionFatigue has attracted broad attention in recent years due to its high morbidity rates. The use of functional foods to relieve fatigue-associated symptoms is becoming increasingly popular and has achieved relatively good results. In this study, network pharmacology and molecular docking strategies were used to establish the material basis and mechanisms of Chinese herbal compounds in fatigue treatment. According to traditional medicine theories and relevant guidance documents published by the Chinese Ministry of Health, four herbal medicines, including Eucommia ulmoides Oliver bark, Eucommia ulmoides Oliver male flower, Panax notoginseng, and Syzygium aromaticum (EEPS), were selected to constitute the anti-fatigue herbal compound that may be suitable as functional food ingredients.MethodsThe major active ingredients in EEPS were identified via comprehensive literature search and Traditional Chinese Medicine Systems Pharmacology database search. Corresponding targets for these ingredients were predicted using SwissTargetPrediction. The network was constructed using Cytoscape 3.9.1 to obtain key ingredients. Prediction of absorption, distribution, metabolism, excretion and toxicity properties was performed using the ADMETIab 2.0 database. The anti-fatigue targets were retrieved from GeneCards v5.13, OMIM, TTD and DisGeNET 7.0 databases. Then, the potential targets of EEPS in fatigue treatment were screened through a Venn diagram. A protein–protein interaction (PPI) network of these overlapping targets was constructed, and the hub targets in the network selected through topological screening. Gene Ontology and KEGG pathway enrichment analyses were performed using the DAVID database and the bioinformatics online platform. Finally, AutoDock tools were used to verify the binding capacity between the key active ingredients and the core targets.Results and DiscussionThis study identified the active ingredients and potential molecular mechanisms of EEPS in fatigue treatment, which will provide a foundation for future research on applications of herbal medicines in the functional food industry.

Glycolysis, as a multi-step oxidation process, plays important roles in the energy supply for living cells, including malignant tumor cells. Recent studies have revealed that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (named PFKFB3), a bifunctional enzyme in glycolysis, is upregulated in a variety of malignant solid tumors and has been regarded as a potential biomarker for the diagnosis and treatment of tumor patients. Based on the structure of selective PFKFB3 inhibitors, we designed and synthesized a radio-metal radiolabeled small molecule, 68Ga-5, which also showed potent selectivity in enzymatic and biochemical tests (with an IC50 value of 12.5 nM). According to further in vitro and in vivo evaluations, 68Ga-5 showed promising properties as a PET ligand, and selective accumulation in PFKFB3-positive tumors was observed in PET images (with max SUV values of 0.60). Our results indicated that radio-metal radiolabeled aminoquinoxaline derivative, as represented by 68Ga-5, held the potential to be developed as selective PFKFB3-targeted PET tracers, and further investigation and optimization would also be required for this scaffold.

ObjectiveIschemic heart disease (IHD) has a high prevalence and mortality rate, imposing a heavy burden on patients and society, and there is still a need to optimize treatment options for IHD patients. Cardiac shock wave therapy (CSWT) is gaining popularity as a new treatment for IHD patients. The objective of this meta-analysis is to reassess the effects of CSWT on IHD patients in light of the limited number of clinical studies included in previously published reviews, inconsistent methodological quality, and unclear outcomes.MethodsFrom database creation until September 1, 2022, 4 English databases and 3 Chinese databases were rigorously searched for any current controlled trials of CSWT for IHD. The Cochrane Risk of Bias Assessment Tool was used for methodological quality assessment. Review Manager v.5.4 software was used for meta-analysis.ResultsNineteen published controlled trials totaling 1,254 subjects were included. Results showed that CSWT could enhance left ventricular function and myocardial viability, improve cardiac function and alleviate angina pectoris symptoms. The effects of CSWT and control groups on SAQ scores and exercise time were not statistically significant.ConclusionAccording to this systematic review and meta-analysis, CSWT may be beneficial for a number of IHD clinical indications. To verify these findings, more RCT studies with bigger sample numbers and higher methodological standards are required in the future.

IntroductionHeat-clearing and detoxifying Chinese medicines have been documented to have anti-Alzheimer’s disease (AD) activities according to the accumulated clinical experience and pharmacological research results in recent decades. In this study, Fibraurea recisa Pierre (FRP), the classic type of Heat-clearing and detoxifying Chinese medicine, was selected as the object of research.Methods12 components with anti-AD activities were identified in FRP by a variety of methods, including silica gel column chromatography, multiple databases, and literature searches. Then, network pharmacology and molecular docking were adopted to systematically study the potential anti-AD mechanism of these compounds. Consequently, it was found that these 12 compounds could act on 235 anti-AD targets, of which AKT and other targets were the core targets. Meanwhile, among these 235 targets, 71 targets were identified to be significantly correlated with the pathology of amyloid beta (Aβ) and Tau.Results and discussionIn view of the analysis results of the network of active ingredients and targets, it was observed that palmatine, berberine, and other alkaloids in FRP were the key active ingredients for the treatment of AD. Further, Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis revealed that the neuroactive ligand-receptor interaction pathway and PI3K-Akt signaling pathway were the most significant signaling pathways for FRP to play an anti-AD role. Findings in our study suggest that multiple primary active ingredients in FRP can play a multitarget anti-AD effect by regulating key physiological processes such as neurotransmitter transmission and anti-inflammation. Besides, key ingredients such as palmatine and berberine in FRP are expected to be excellent leading compounds of multitarget anti-AD drugs.

This study aims to investigate the prevalence of locomotive syndrome (LS) and to examine the relationship of LS with musculoskeletal symptoms (pain, generalized joint laxity (GJL)) in young Chinese adults. Our study population (n = 157; mean age of 19.8 ± 1.2 years) comprises college student residents at Tsinghua University in Beijing, China. Three screening methods were used to evaluate LS: 25-question Geriatric Locomotive Function Scale (GLFS-25), a two-step test, and a stand-up test. Musculoskeletal pain was assessed by self-report and visual analog scale (VAS), and joint body laxity was evaluated using the GJL test. The prevalence of LS was 21.7% of all participants. Musculoskeletal pain affected 77.8% of the college students with LS and was strongly associated with LS. A total of 55.0% of college students with LS had four or more site joints that were positive for GJL, and higher scores of GJL were associated with a higher prevalence rate of LS. Young Chinese college students have a relatively high prevalence of LS, and musculoskeletal pain and GJL were significantly related to LS. The present results suggest that we need early screening of musculoskeletal symptoms and LS health education in young adults to prevent the mobility limitations of LS in the future.

Myocardial infarction (MI) causes peripheral organ injury, in addition to cardiac dysfunction, including in the liver, which is known as cardiac hepatopathy. Aerobic exercise (AE) can effectively improve liver injury, although the mechanism and targets are currently not well established. Irisin, mainly produced by cleavage of the fibronectin type III domain-containing protein 5 (FNDC5), is a responsible for the beneficial effects of exercise training. In this study, we detected the effect of AE on MI-induced liver injury and explored the role of irisin alongside the benefits of AE. Wildtype and Fndc5 knockout mice were used to establish an MI model and subjected to AE intervention. Primary mouse hepatocytes were treated with lipopolysaccharide (LPS), rhirisin, and a phosphoinositide 3-kinase (PI3K) inhibitor. The results showed that AE significantly promoted M2 polarization of macrophages and improved MI-induced inflammation, upregulated endogenous irisin protein expression and activated the PI3K/ protein kinase B (Akt) signaling pathway in the liver of MI mice, while knockout of Fndc5 attenuated the beneficial effects of AE. Exogenous rhirisin significantly inhibited the LPS-induced inflammatory response, which was attenuated by the PI3K inhibitor. These results suggest that AE could effectively activate the FNDC5/irisin-PI3K/Akt signaling pathway, promote the polarization of M2 macrophages, and inhibit the inflammatory response of the liver after MI.

The prediction of travel mode preference, like many other choice prediction problems, may depend on categorical features of the choice options or the choice makers. Such categorical features need to be meaningfully encoded for better modeling and understanding. Problem-invariant encoding representations of the categorical features, such as one-hot encoding or label encoding, can severely limit the power of prediction models. We propose deep neural networks with entity embeddings for travel mode choice prediction. We adopt the entity embedding technique to jointly learn meaningful representation of categorical variables and accurate travel mode predictions. Experiments using the London travel dataset show that deep neural networks with entity embedding technique outperform neural networks with other encoding techniques, as well as tree-based models. Besides, we found that the learned embeddings can boost the performances of tree-based models by substituting categorical features with the neural network learned features. Finally, we verify that entity embedding can learn meaningful representations of the categorical features using feature visualization at low dimensional space.

Short-term traffic prediction consists a crucial component in intelligent transportation systems. With the explosion of automated traffic monitoring sensors and the flourishing of deep learning techniques, a growing body of deep neural network models have been employed to tackle this problem. In particular, convolutional neural networks (CNN) and long short-term memory (LSTM) recurrent networks have demonstrated their advantages in modeling and predicting the spatiotemporal evolution of traffic flows. In this paper, we propose a novel Convolutional LSTM neural network architecture for multi-lane short-term traffic prediction. Compared to existing methods, we highlight the importance of (1) applying multiple features to characterize traffic conditions; (2) explicitly considering the routing between neighbouring lanes and downstream/upstream traffics; and (3) predicting multiple time-step traffic in a rolling-prediction manner. Experiments on 10 months 5-minute interval observations of the US I-101 Northern freeway at California Bay Area verify the proposed model. The results show that our model has considerable advantages in predicting multi-lane short-term traffic flow.

The intestine barrier, the front line of normal body defense, relies on its structural integrity, microbial composition and barrier immunity. The intestinal mucosal surface is continuously exposed to a complex and dynamic community of microorganisms. Although it occupies a relatively small proportion of the intestinal microbiota, Lactobacilli has been discovered to have a significant impact on the intestine tract in previous studies. It is undeniable that some Lactobacillus strains present probiotic properties through maintaining the micro-ecological balance via different mechanisms, such as mucosal barrier function and barrier immunity, to prevent infection and even to solve some neurology issues by microbiota–gut–brain/liver/lung axis communication. Notably, not only living cells but also Lactobacillus derivatives (postbiotics: soluble secreted products and para-probiotics: cell structural components) may exert antipathogenic effects and beneficial functions for the gut mucosal barrier. However, substantial research on specific effects, safety and action mechanisms in vivo should be done. In clinical application of humans and animals, there are still doubts about the precise evaluation of Lactobacilli’s safety, therapeutic effect, dosage and other aspects. Therefore, we provide an overview of central issues on the impacts of Lactobacillus casei (L. casei) and their products on the intestinal mucosal barrier and some diseases and highlight the urgent need for further studies.

Kirsten rat sarcoma virus (KRAS) mutations are widespread in pancreatic ductal adenocarcinoma (PDAC) and contribute significantly to tumor initiation, progression, tumor relapse/resistance, and prognosis of patients. Although inhibitors against KRAS mutations have been developed, this therapeutic approach is not routinely used in PDAC patients. We investigated the anti-tumor efficacy of two KRAS inhibitors BI-3406 (KRAS::SOS1 inhibitor) and sotorasib (KRAS G12C inhibitor) alone or in combination with MEK1/2 inhibitor trametinib and/or PI3K inhibitor buparlisib in seven PDAC cell lines. Whole transcriptomic analysis of combined inhibition and control groups were comparatively analyzed to explore the corresponding mechanisms of inhibitor combination. Both KRAS inhibitors and corresponding combinations exhibited cytotoxicity against specific PDAC cell lines. BI-3406 enhance the efficacy of trametinib and buparlisib in BXPC-3, ASPC-1 and MIA PACA-2, but not in CAPAN-1, while sotorasib enhances the efficacy of trametinib and buparlisib only in MIA PACA-2. The whole transcriptomic analysis demonstrates that the two triple-inhibitor combinations exert antitumor effects by affecting related cell functions, such as affecting the immune system, cell adhesion, cell migration, and cytokine binding. As well as directly involved in RAF/MEK/ERK pathway and PI3K/AKT pathway affect cell survival. Our current study confirmed inhibition of KRAS and its downstream pathways as a potential novel therapy for PDAC and provides fundamental data for in vivo evaluations.

Background: Reduced muscle strength, as measured by handgrip strength (HS), has been associated with an increased risk of cardiovascular disease (CVD). The aim of this study was to examine the association between different HS indexes and CVD risk factors in elderly Chinese individuals. We also determine optimal cutoffs of HS indexes for predicting CVD risk factors. Methods: Data were obtained from 603 men and 789 women aged ≥60 years (average age 66.8 ± 6.4 y). These study participants were recruited in the suburb area of Tianjin, China. An individual was considered a patient when they exhibited any one of three CVD risk factors: diabetes mellitus, hypertension and dyslipidemia. All participants were interviewed face-to-face. In addition, serum samples were collected from all participants, and all participants underwent measures of anthropometry and HS. Results: The optimal cutoffs were 0.376 of HS/weight in men and 0.726 of HS/body fat mass in women for predicting diabetes mellitus. The adjusted odds ratios (ORs) of at least one CVD risk factor for those with low muscle strength identified by HS/body fat mass were 2.14 (95% confidence interval [CI]: 1.53, 3.44; p

The aberrant activation of the phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) pathway is common in pancreatic ductal adenocarcinomas (PDAC). The application of inhibitors against PI3K and AKT has been considered as a therapeutic option. We investigated PDAC cell lines exposed to increasing concentrations of MK-2206 (an AKT1/2/3 inhibitor) and Buparlisib (a pan-PI3K inhibitor). Cell proliferation, metabolic activity, biomass, and apoptosis/necrosis were evaluated. Further, whole-exome sequencing (WES) and RNA sequencing (RNA-seq) were performed to analyze the recurrent aberrations and expression profiles of the inhibitor target genes and the genes frequently mutated in PDAC (Kirsten rat sarcoma virus (KRAS), Tumor protein p53 (TP53)). MK-2206 and Buparlisib demonstrated pronounced cytotoxic effects and limited cell-line-specific effects in cell death induction. WES revealed two sequence variants within the direct target genes (PIK3CA c.1143C > G in Colo357 and PIK3CD c.2480C > G in Capan-1), but a direct link to the Buparlisib response was not observed. RNA-seq demonstrated that the expression level of the inhibitor target genes did not affect the efficacy of the corresponding inhibitors. Moreover, increased resistance to MK-2206 was observed in the analyzed cell lines carrying a KRAS variant. Further, increased resistance to both inhibitors was observed in SU.86.86 carrying two TP53 missense variants. Additionally, the presence of the PIK3CA c.1143C > G in KRAS-variant-carrying cell lines was observed to correlate with increased sensitivity to Buparlisib. In conclusion, the present study reveals the distinct antitumor effects of PI3K/AKT pathway inhibitors against PDAC cell lines. Aberrations in specific target genes, as well as KRAS and TP53, individually or together, affect the efficacy of the two PI3K/AKT pathway inhibitors.

Casein kinase II (CK2) and cyclin-dependent kinases (CDKs) frequently interact within multiple pathways in pancreatic ductal adenocarcinoma (PDAC). Application of CK2- and CDK-inhibitors have been considered as a therapeutic option, but are currently not part of routine chemotherapy regimens. We investigated ten PDAC cell lines exposed to increasing concentrations of silmitasertib and dinaciclib. Cell proliferation, metabolic activity, biomass, and apoptosis/necrosis were evaluated, and bioinformatic clustering was used to classify cell lines into sensitive groups based on their response to inhibitors. Furthermore, whole exome sequencing (WES) and RNA sequencing (RNA-Seq) was conducted to assess recurrent mutations and the expression profile of inhibitor targets and genes frequently mutated in PDAC, respectively. Dinaciclib and silmitasertib demonstrated pronounced and limited cell line specific effects in cell death induction, respectively. WES revealed no genomic variants causing changes in the primary structure of the corresponding inhibitor target proteins. RNA-Seq demonstrated that the expression of all inhibitor target genes was higher in the PDAC cell lines compared to non-neoplastic pancreatic tissue. The observed differences in PDAC cell line sensitivity to silmitasertib or dinaciclib did not depend on target gene expression or the identified gene variants. For the PDAC hotspot genes kirsten rat sarcoma virus (KRAS) and tumor protein p53 (TP53), three and eight variants were identified, respectively. In conclusion, both inhibitors demonstrated in vitro efficacy on the PDAC cell lines. However, aberrations and expression of inhibitor target genes did not appear to affect the efficacy of the corresponding inhibitors. In addition, specific aberrations in TP53 and KRAS affected the efficacy of both inhibitors.

Abstract Background The specific interactions of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), and the lung microbiota in infection are entirely unexplored. Studies in cancer and other infectious diseases suggest that there are important exchanges occurring between host and microbiota that influence the immunological landscape. This can result in alterations in immune regulation and inflammation both locally and systemically. To assess whether Mtb infection modifies the lung microbiome, and identify changes in microbial abundance and diversity as a function of pulmonary inflammation, we compared infected and uninfected lung lobe washes collected serially from 26 macaques by bronchoalveolar lavage over the course of infection. Results We found that Mtb induced an initial increase in lung microbial diversity at 1 month post infection that normalized by 5 months of infection across all macaques. Several core genera showed global shifts from baseline and throughout infection. Moreover, we identified several specific taxa normally associated with the oral microbiome that increased in relative abundance in the lung following Mtb infection, including SR1, Aggregatibacter, Leptotrichia, Prevotella, and Campylobacter. On an individual macaque level, we found significant heterogeneity in both the magnitude and duration of change within the lung microbial community that was unrelated to lung inflammation and lobe involvement as seen by positron emission tomography/computed tomography (PET/CT) imaging. By comparing microbial interaction networks pre- and post-infection using the predictive algorithm SPIEC-EASI, we observe that extra connections are gained by Actinomycetales, the order containing Mtb, in spite of an overall reduction in the number of interactions of the whole community post-infection, implicating Mtb-driven ecological reorganization within the lung. Conclusions This study is the first to probe the dynamic interplay between Mtb and host microbiota longitudinally and in the macaque lung. Our findings suggest that Mtb can alter the microbial landscape of infected lung lobes and that these interactions induce dysbiosis that can disrupt oral-airway boundaries, shift overall lung diversity, and modulate specific microbial relationships. We also provide evidence that this effect is heterogeneous across different macaques. Overall, however, the changes to the airway microbiota after Mtb infection were surprisingly modest, despite a range of Mtb-induced pulmonary inflammation in this cohort of macaques.

Sodium ferric gluconate complex (SFGC) is the third generation of iron supplement of polysaccharide iron (III) complex (PIC). For evaluation of technological level and application value of the prepared SFGC, it would be of great significance to determine the iron content in SFGC in a simple but effective way. This paper introduces the cyclic voltammetry (CV) method for determination of iron content in SFGC. Under established optimal experimental conditions, the content of free iron ions can be directly scanned and calculated, while the total iron content can also be determined by completely acidifying SFGC into Fe3+ ions. After optimizing and screening, the optimal scanning conditions are determined as pH 3 and 0.05 V/s of the scanning rate. Prior CV measurements, 0.4 V of the enrichment potential, and 3 min of the enrichment time are found optimal. It has also been verified that CO32- ions present in the solution show little interference in the system within the experimental range of investigation. The contents of free Fe3+, Fe2+ ions and the total iron determined after acid-hydrolysis of SFGC can be accurately calculated according to the corresponding linear relationships between peak currents and iron concentrations. In this paper, the repeatability and accuracy of the method are verified, and its feasibility as a convenient and effective method to determine the iron supplements is confirmed.

Assessment of the association of muscle strength and muscle mass with osteoporosis (OP) is of special interest as muscles are a potential target for interventions (i.e., strength training). Methods: A cross-sectional descriptive study encompassing people aged ≥ 60 years (average age: 66.9 ± 6.2 years; men, n = 516; women, n = 652) in the Hangu area of Tianjin, China. The study populations were invited to participate in a comprehensive geriatric assessment. OS was identified by measuring the calcaneal using a quantitative ultrasound and a T score of less than –2.5. Muscle characteristics included grip strength and appendicular skeletal muscle mass (ASM). Results: The prevalence of OS in this study was 61.6% (male 52.1%, female 69.1%). Grip strength was negatively related to OS and after adjusting for all other variables, higher grip strength was found to be associated with a lower OS risk (p = 0.023). ASM/height2 was not associated with OS (p = 0.205). Conclusion: Based on our study, muscle strength rather than muscle mass is negatively associated with OS in older people; thus, we should pay more attention to muscle strength training in the early stage of the OS.

Exercise training has been reported to alleviate cardiac fibrosis and ameliorate heart dysfunction after myocardial infarction (MI), but the molecular mechanism is still not fully clarified. Fibroblast growth factor 21 (FGF21) exerts a protective effect on the infarcted heart. This study investigates whether exercise training could increase FGF21 protein expression and regulate the transforming growth factor-β1 (TGF-β1)-Smad2/3-MMP2/9 signaling pathway to alleviate cardiac fibrosis following MI. Male wild type (WT) C57BL/6J mice and Fgf21 knockout (Fgf21 KO) mice were used to establish the MI model and subjected to five weeks of different types of exercise training. Both aerobic exercise training (AET) and resistance exercise training (RET) significantly alleviated cardiac dysfunction and fibrosis, up-regulated FGF21 protein expression, inhibited the activation of TGF-β1-Smad2/3-MMP2/9 signaling pathway and collagen production, and meanwhile, enhanced antioxidant capacity and reduced cell apoptosis in the infarcted heart. In contrast, knockout of Fgf21 weakened the cardioprotective effects of AET after MI. In vitro, cardiac fibroblasts (CFs) were isolated from neonatal mice hearts and treated with H2O2 (100 μM, 6 h). Recombinant human FGF21 (rhFGF21, 100 ng/mL, 15 h) and/or 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR, 1 mM, 15 h) inhibited H2O2-induced activation of the TGF-β1-Smad2/3-MMP2/9 signaling pathway, promoted CFs apoptosis and reduced collagen production. In conclusion, exercise training increases FGF21 protein expression, inactivates the TGF-β1-Smad2/3-MMP2/9 signaling pathway, alleviates cardiac fibrosis, oxidative stress, and cell apoptosis, and finally improves cardiac function in mice with MI. FGF21 plays an important role in the anti-fibrosis effect of exercise training.

Bruton’s tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) in the B-cell receptor (BCR) signaling pathway are considered potential therapeutic targets for the treatment of B-cell lymphomas, among which, diffuse large B-cell lymphoma (DLBCL) is the most common type. Herein, we comparatively evaluated the single and combined application of the BTK inhibitor ibrutinib and the selective PI3Kγ inhibitor AS-605240 in the canine DLBCL cell line CLBL-1. For further comparison, key findings were additionally analyzed in canine B-cell leukemia GL-1 and human DLBCL cell line SU-DHL-4. While ibrutinib alone induced significant anti-proliferative effects on all cell lines in a dose-dependent manner, AS-605240 only induced anti-proliferative effects at high concentrations. Interestingly, ibrutinib and AS-605240 acted synergistically, reducing cell proliferation and increasing apoptosis/necrosis in all cell lines and inducing morphological changes in CLBL-1. Moreover, the combined application of ibrutinib and AS-605240 reduced relative phosphorylation and, in some instances, the levels of the BTK, AKT, GSK3β, and ERK proteins. Comparative variant analysis of RNA-seq data among canine B- and T-lymphoid cell lines and primary B-cell lymphoma samples revealed potentially high-impact somatic variants in the genes that encode PI3K, which may explain why AS-605240 does not singly inhibit the proliferation of cell lines. The combination of ibrutinib and AS-605240 represents a promising approach that warrants further in vivo evaluation in dogs, potentially bearing significant value for the treatment of human DLBCL.

Prehypertension is a public health epidemic associated with various adverse outcomes, but can be reversed by timely intervention. However, little attention has been paid to prehypertension. Complement C3 is a central hub of complement-related immune system. We examined the association between C3 and prehypertension in an adult population for the first time, aiming to investigate whether pro-inflammatory immune response is involved in the prehypertensive state. About 7820 Tianjin residents without hypertension were categorized into sex-specific quintiles based on their serum concentration of complement C3. Adjusted logistic regression models were used separately by gender to assess the association between C3 quintiles and the prevalence of prehypertension. After multiple adjustment, the odds ratios (95% confidence interval) for prehypertension across increasing quintiles of C3 were 1.00 (reference), 1.02 (0.84, 1.25), 1.15 (0.94, 1.42), 1.25 (1.01, 1.54), and 1.71 (1.35, 2.17) (p for trend < 0.0001) among men and were 1.00 (reference), 1.17 (0.92, 1.49), 1.13 (0.88, 1.44), 1.15 (0.89, 1.48), and 1.40 (1.07, 1.84) (p for trend = 0.03) among women. The findings suggested that elevated serum C3 levels are associated with prehypertension. Reducing inflammation may be a potential therapeutic strategy for prehypertension and hypertension that is worthy of further studies and discussion.

ABSTRACT Factors that contribute to enhanced susceptibility to severe bacterial disease after influenza virus infection are not well defined but likely include the microbiome of the respiratory tract. Vaccination against influenza, while having variable effectiveness, could also play a role in microbial community stability. We collected nasopharyngeal samples from 215 individuals infected with influenza A/H3N2 or influenza B virus and profiled the microbiota by target sequencing of the 16S rRNA gene. We identified signature taxonomic groups by performing linear discriminant analysis and effective size comparisons (LEfSe) and defined bacterial community types using Dirichlet multinomial mixture (DMM) models. Influenza infection was shown to be significantly associated with microbial composition of the nasopharynx according to the virus type and the vaccination status of the patient. We identified four microbial community types across the combined cohort of influenza patients and healthy individuals with one community type most representative of the influenza virus-infected group. We also identified microbial taxa for which relative abundance was significantly higher in the unvaccinated elderly group; these taxa include species known to be associated with pneumonia. IMPORTANCE Our results suggest that there is a significant association between the composition of the microbiota in the nasopharynx and the influenza virus type causing the infection. We observe that vaccination status, especially in more senior individuals, also has an association with the microbial community profile. This indicates that vaccination against influenza, even when ineffective to prevent disease, could play a role in controlling secondary bacterial complications.

Abstract Dynamical tuning of the nonlinear optical wavefront allows for a specific spectral response of predefined profiles, enabling various applications of nonlinear nanophotonics. This study experimentally demonstrates the dynamical switching of images generated by an ultrathin silicon nonlinear metasurface supporting a high‐quality leaky mode, which is formed by partially breaking a bound‐state‐in‐the‐continuum (BIC) generated by the collective magnetic dipole (MD) resonance excited in the subdiffractive periodic systems. Such a quasi‐BIC MD state can be excited directly under normal plane wave incidence and leads to a strong near‐field enhancement to further boost the nonlinear process, resulting in a 500‐fold enhancement of the third‐harmonic emission experimentally. Due to sharp spectral features and asymmetry of the unit cell, it allows for effective tailoring of the nonlinear emissions over spectral or polarization responses. Dynamical nonlinear image tuning is experimentally demonstarted via polarization and wavelength control. The results pave the way for nanophotonics applications such as tunable displays, nonlinear holograms, tunable nanolaser, and ultrathin nonlinear nanodevices with various functionalities.

BACKGROUND:Physical performance is an important healthy factor in elder people. Good living habits, which include sleep, can maintain physical strength and physical performance. The aim of the present study was to conduct a cross-sectional study to determine the association between total sleep duration and physical performance. METHODS:Our study population comprised residents of the township central hospital in the suburban of Tianjin, China. We measured muscle strength, walk speed and balance function by grip, 4-m walk test and timed up and go test (TUGT). We divided sleep duration into four groups 8-9h, >9h. RESULTS:A total 898 participants had completed data (392 men and 506 women, mean age 67.71 years). In man, adjusted sleep duration was associated with lower grip in > 9 h group, the mean value (95% CI) was 0.429 (0.409, 0.448), and longer TUGT time was also associated with long sleep duration, 10.46s (9.97 s, 10.95 s). In women, adjusted slower 4-m walk speed present an inverse U-shaped relation with sleep duration, by 0.93 m/s (0.86 m/s, 0.98 m/s), 0.97 m/s (0.96 m/s, 1.00 m/s), 0.97 m/s (0.95 m/s, 0.99 m/s) and 0.92 m/s (0.89 m/s, 0.96 m/s); longer TUGT time were associated with long sleep duration (> 9 h), by 11.23 s (10.70 s, 11.77 s). CONCLUSION:In Chinese community-dwelling elderly, lower muscle strength and lower balance function were associated with long sleep duration in men. Slower walk speed and lower balance function were associated with long sleep duration in women.