A new framework for assessment of park management in smart cities: a study based on social media data and deep learning.

Urban park management assessment is critical to park operation and service quality. Traditional assessment methods cannot comprehensively assess park use and environmental conditions. Besides, although social media and big data have shown significant advantages in understanding public behavior or preference and park features or values, there has been little relevant research on park management assessment. This study proposes a deep learning-based framework for assessing urban park intelligent management from macro to micro levels with comment data from social media. By taking seven parks in Wuhan City as the objects, this study quantitatively assesses their overall state and performance in facilities, safety, environment, activities, and services, and reveals their main problems in management. The results demonstrate the impacts of various factors, including park type, season, and specific events such as remodeling and refurbishment, on visitor satisfaction and the characteristics of individual parks and their management. Compared with traditional methods, this framework enables real-time intelligent assessment of park management, which can accurately reflect park use and visitor feedback, and improve park service quality and management efficiency. Overall, this study provides important reference for intelligent park management assessment based on big data and artificial intelligence, which can facilitate the future development of smart cities.

Remodeling of intestinal epithelium derived extracellular vesicles by nanoparticles and its bioeffect on tumor cell migration.

Extracellular vesicles (EVs) are an effective tool to elucidate the bioeffect of nanomedicines. To clarify the interaction between oral nanomedicines and intestinal epithelial cells, and their bioeffects on downstream cells, polystyrene nanoparticles (PS-NPs) with different sizes were used as the model nanomedicines for EVs induction. Caco-2 monolayers were selected as the model of the intestinal epithelium and DLD-1 cells as the colorectal cancer model proximal to the gastrointestinal tract. It is found that compared with small-sized (25, 50, 100 nm) PS-NPs, the large-sized (200 and 500 nm) exhibited higher co-localization with multivesicular bodies and lysosomes, and more significant reduction of lysosomal acidification in Caco-2 cells. Proteomic and western-blotting analysis showed that the EVs remodeled by large-sized PS-NPs exhibited a higher extent of protein expression changes. The in vitro and in vivo signaling pathway detection in DLD-1 cells and DLD-1 cell xenograft nude mice showed that the remodeled EVs by large-sized PS-NPs inhibited the activation of multiple signaling pathways including Notch3, EGF/EGFR, and PI3K/Akt pathways, which resulted in the inhibition of tumor cell migration. These results primarily clarify the regulation mechanisms of nanomedicines-EVs-receptor cells chain. It provides a new perspective for the rational design and bioeffect evaluation of oral drug nanomaterials and sets up the fundamental knowledge for novel tumor therapeutics in the future.

CRISPR-Cas-mediated Multianalyte Synthetic Urine Biomarker Test for Portable Diagnostics.

Creating synthetic biomarkers for the development of precision diagnostics has enabled detection of disease through pathways beyond those used for traditional biofluid measurements. Synthetic biomarkers generally make use of reporters that provide readable signals in the biofluid to reflect the biochemical alterations in the local disease microenvironment during disease incidence and progression. The pharmacokinetic concentration of the reporters and biochemical amplification of the disease signal are paramount to achieving high sensitivity and specificity in a diagnostic test. Here, a cancer diagnostic platform is built using one format of synthetic biomarkers: activity-based nanosensors carrying chemically stabilized DNA reporters that can be liberated by aberrant proteolytic signatures in the tumor microenvironment. Synthetic DNA as a disease reporter affords multiplexing capability through its use as a barcode, allowing for the readout of multiple proteolytic signatures at once. DNA reporters released into the urine are detected using CRISPR nucleases via hybridization with CRISPR RNAs, which in turn produce a fluorescent or colorimetric signal upon enzyme activation. In this protocol, DNA-barcoded, activity-based nanosensors are constructed and their application is exemplified in a preclinical mouse model of metastatic colorectal cancer. This system is highly modifiable according to disease biology and generates multiple disease signals simultaneously, affording a comprehensive understanding of the disease characteristics through a minimally invasive process requiring only nanosensor administration, urine collection, and a paper test which enables point-of-care diagnostics.

Effect of modification of polystyrene nanoparticles with different bile acids on their oral transport.

Bile acid-modified nanomedicine is a promising strategy to improve oral bioavailability. However, the efficiencies of different bile acids have not been clarified. To clarify this issue, deoxycholic acid (DCA) and cholic acid (CA) and glycocholic acid (GCA) were conjugated to carboxylated polystyrene nanoparticle (CPN). The endocytosis, intracellular and transcellular transport among the NPs were compared in Caco-2 cells, and their oral pharmacokinetics profiles were studied in C57BL/6 J mice. It was found that DCPN demonstrated higher uptake and transcytosis rate. With modification by different bile acids, the transport pathways of the NPs were altered. In mice, GCPN showed the highest absorption speed and oral bioavailability. It was found that the synergic effect of hydrophobicity and ASBT affinity might lead to the difference between in vitro and in vivo transport. This study will build a basis for the rational design of bile acid-modified nanomedicines.

Bile Acid Conjugation on Solid Nanoparticles Enhances ASBT-Mediated Endocytosis and Chylomicron Pathway but Weakens the Transcytosis by Inducing Transport Flow in a Cellular Negative Feedback Loop.

Bile acid-modified nanoparticles provide a convenient strategy to improve oral bioavailability of poorly permeable drugs by exploiting specific interactions with bile acid transporters. However, the underlying mechanisms are unknown, especially considering the different absorption sites of free bile acids (ileum) and digested fat molecules from bile acid-emulsified fat droplets (duodenum). Here, glycocholic acid (GCA)-conjugated polystyrene nanoparticles (GCPNs) are synthesized and their transport in Caco-2 cell models is studied. GCA conjugation enhances the uptake by interactions with apical sodium-dependent bile acid transporter (ASBT). A new pathway correlated with both ASBT and chylomicron pathways is identified. Meanwhile, the higher uptake of GCPNs does not lead to higher transcytosis to the same degree compared with unmodified nanoparticles (CPNs). The pharmacological and genomics study confirm that GCA conjugation changes the endocytosis mechanisms and downregulates the cellular response to the transport at gene levels, which works as a negative feedback loop and explains the higher cellular retention of GCPNs. These findings offer a solid foundation in the bile acid-based nanomedicine design, with utilizing advantages of the ASBT-mediated uptake, as well as inspiration to take comprehensive consideration of the cellular response with more developed technologies.

Lipid raft-mediated and upregulated coordination pathways assist transport of glycocholic acid-modified nanoparticle in a human breast cancer cell line of SK-BR-3.

Bile acid transporter-targeting has been proven to be an effective strategy to improve drug delivery to hepatocytes and enterocytes. With increasing discoveries of bile acid transporter expression on tumor cells, bile acid-modified anticancer drugs are gradually attaining interests. In our previous study, we confirmed the efficacy of glycocholic acid-conjugated polystyrene nanoparticles (GCPN) on apical sodium bile acid transporter (ASBT)-expressed SK-BR-3 cells. However, the transport mechanisms remain unknown, due to the nanosized carriers are unlikely to be pumped through the narrow cavities of ASBT. To clarify their transport pathways, in this article, pharmacological inhibition and gene knocking-down studies were performed, which revealed that GCPN were primarily internalized via non-caveolar lipid raft-mediated endocytosis. Proteomics was analyzed to explore the in-depth mechanisms. In total 561 proteins were identified and statistical overrepresentation test was used to analyze the gene ontology (GO) upregulated pathways based on the highly expressed proteins. It was found that multiple pathways were upregulated and might coordinate to assist the location of the GCPN-ASBT complex and the recycling of ASBT. Among the highly expressed proteins, myelin and lymphocyte protein 2 (MAL2) was selected and confirmed to colocalize with GCPN, which further supported the lipid raft-mediated process. These findings will help set up a platform for designing the bile acid-modified nanomedicines and regulating their transport to improve their anticancer efficacy.

Phenotype stability, expansion potential, and senescence of embryonic tendon cells in vitro.

Embryonic tendon cells have been studied in vitro to better understand mechanisms of tendon development. Outcomes of in vitro cell culture studies are easily affected by phenotype instability of embryonic tendon cells during expansion in vitro to achieve desired cell numbers, yet this has not been characterized. In the present study, we characterized phenotype stability, expansion potential, and onset of senescence in chick embryo tendon cells from low to high cell doublings. We focused on cells of Hamburger-Hamilton stages (HH) 40 and HH42, where HH40 is the earliest stage associated with substantial increases in extracellular matrix and mechanical properties during embryonic tendon development. HH40 and HH42 cells both downregulated expression levels of tendon phenotype markers, scleraxis and tenomodulin, and exhibited onset of senescence, based on p16 and p21 expression levels, cell surface area, and percentage of ß-galactosidase positive cells, before significant decreases in proliferation rates were detected. These findings showed that embryonic tendon cells destabilize phenotype and become senescent earlier than they begin to decline in proliferation rates in vitro. Additionally, embryonic stage of isolation appears to have no effect on proliferation rates, whereas later stage HH42 cells downregulate phenotype and become susceptible to senescence sooner than earlier stage HH40 cells. Based on our data, we recommend chick embryo tendon cells be used before a maximum cumulative doubling level of 12 (passage 4 in this study) to avoid phenotype destabilization and onset of senescence.

Bile acid transporter-mediated oral drug delivery.

Bile acids are synthesized in the liver, stored in the gallbladder, and secreted into the duodenum at meals. Apical sodium-dependent bile acid transporter (ASBT), an ileal Na+-dependent transporter, plays the leading role of bile acid absorption into enterocytes, where bile acids are delivered to basolateral side by ileal bile acid binding protein (IBABP) and then released by organic solute transporter OSTα/ß. The absorbed bile acids are delivered to the liver via portal vein. In this process called "enterohepatic recycling", only 5% of the bile acid pool (~3 g in human) is excreted in feces, indicating the large recycling capacity and high transport efficacy of ASBT-mediated absorption. Therefore, bile acid transporter-mediated oral drug delivery has been regarded as a feasible and potential strategy to improve the oral bioavailability. This review introduces the key factors in enterohepatic recycling, especially the mechanism of bile acid uptake by ASBT, and the development of bile acid-based oral drug delivery for ASBT-targeting, including bile acid-based prodrugs, bile acid/drug electrostatic complexation and bile acid-containing nanocarriers. Furthermore, the specific transport pathways of bile acid in enterocytes are described and the recent finding of lymphatic delivery of bile acid-containing nanocarriers is discussed.

Anisotropic active ligandations in siRNA-Loaded hybrid nanodiscs lead to distinct carcinostatic outcomes by regulating nano-bio interactions.

Active targeting modification is one of the foremost nanomedicine strategies for the efficacy improvement. Compared to the homogeneous ligandation on spherical nanocarriers, non-spherical nanomedicines usually make the ligand modification more complicated. The modified ligands always exhibit anisotropy and heterogeneity. However, there is very little systematic study on these diversified anisotropic modifications. The efficacy difference and underlying mechanism were still unclear. Here, we separately fabricated hybrid nanodiscs (NDs) conjugated with cRGD on the edge and plane surfaces to engineer two anisotropic targeting nanocarriers (E-cRGD-NDs and P-cRGD-NDs, respectively) for gene delivery. The ligand anisotropy endowed NDs with diversified cellular interactions, and caused different efficacies between E-cRGD-NDs and P-cRGD-NDs. Of note, E-cRGD-NDs showed significant superiority in siRNA loading, cellular uptake, silence efficiency, protein expression and even in vivo efficacy. The mechanism investigation revealed the functional anisotropy specifically for E-cRGD-NDs. The edge modification of cRGD efficiently separated the targeting and siRNA loading domains, maximizing their respective functions. These findings reflected the unique effect of ligand anisotropy, also provided a new strategy for the targeting screening of extensive nanomedicines.

The appliances and prospects of aurum nanomaterials in biodiagnostics, imaging, drug delivery and combination therapy.

Aurum nanomaterials (ANM), combining the features of nanotechnology and metal elements, have demonstrated enormous potential and aroused great attention on biomedical applications over the past few decades. Particularly, their advantages, such as controllable particle size, flexible surface modification, higher drug loading, good stability and biocompatibility, especially unique optical properties, promote the development of ANM in biomedical field. In this review, we will discuss the advanced preparation process of ANM and summarize their recent applications as well as their prospects in diagnosis and therapy. Besides, multi-functional ANM-based theranostic nanosystems will be introduced in details, including radiotherapy (RT), photothermal therapy (PTT), photodynamic therapy (PDT), immunotherapy (IT), and so on.

The function and mechanism of preactivated thiomers in triggering epithelial tight junctions opening.

As a unique macromolecular permeation enhancer, thiolated polymers (thiomers), especially the preactivated thiomers, have demonstrated great merits in oral delivery of protein/peptide drugs by triggering epithelial tight junctions (TJs) opening. However, the underlying molecular mechanism remains unclear. To clarify this issue, preactivated thiomers were synthesized and their TJs opening function as well as signaling pathways on MDCK and Caco-2 cell monolayers was investigated. The results showed that preactivated thiomers could reduce TEER and increase the permeation of Na-Flu and FITC-Insulin over 2-fold and 4-fold on MDCK monolayers, respectively, indicating their huge potential as macromolecular permeation enhancers. The signaling pathway study showed that intracellular PTK Src but not FAK, involved in the TJs opening by claudin-4 disruption. Src activation was based on interaction between thiol group of thiomers and cysteine-riched Src upstream membrane receptors, EGFR and IGFR. The deep comprehension of the thiomers-mediated TJs opening mechanisms provides goodness in application of protein/peptide drugs for the oral delivery.

The effect of linkers on the self-assembling and anti-tumor efficacy of disulfide-linked doxorubicin drug-drug conjugate nanoparticles.

Drug-drug conjugate nanoparticles (DDC NPs) is a potential method for overcoming poor solubility and nonspecific action in cancer therapy, which is based on its high drug loading efficiency and passive tumor-target properties. Our laboratory has prepared DOX-SS-DOX NPs based on disulfide-linked doxorubicin (DOX) drug-drug conjugate, which showed well physical stability and similar anti-tumor efficacy as liposomes. However, how structures of DDCs influence the self-assembling and anti-tumor efficacy is still seldom clarified and needs further investigation. Here, we discussed the role of linker types, length and linkage site in the NPs self-assembling and anti-tumor efficacy. A series of DOX prodrugs were prepared and all the prodrugs could self-assemble into NPs except DOX-SS-DOX (2), indicating the linker length played an important role during self-assembling process. The linkage sites and types of linker exhibited great influence on in vitro cytotoxicity and in vivo anti-tumor efficacy, particularly, modification on C-14 hydroxyl was more efficient for DOX release than on amino group. Besides, disulfide-bond was not cleaved and DOX-SH release did not occur in the metabolism process. The function of disulfide-bond was to enhance the release of DOX in the hydrolysis process. These findings is meaningful for effective prodrug NPs design for therapeutics.

Transmembrane Pathways and Mechanisms of Rod-like Paclitaxel Nanocrystals through MDCK Polarized Monolayer.

Drug nanocrystals (NCs) appear to be favorable to improving oral bioavailability of poorly water-soluble drugs as evidenced by the great success they have had in the market. However, the pathway and mechanism of drug NCs through epithelial membrane are still unclear. In an attempt to clarify their transport features, paclitaxel nanocrystals (PTX-NCs), and paclitaxel hybrid NCs with lipophilic carbocyanine dyes, were prepared and characterized as the models. The endocytosis, intracellular trafficking, paracellular transport, and transcytosis of PTX-NCs were carefully investigated with Förster resonance energy transfer (FRET) analysis, as well as a colocalization assay, flow cytometry, gene silencing, Western-blot, transepithelial electrical resistance (TEER) study and other approaches on MDCK cells. It was found that rod-like PTX-NCs could transport through the monolayer intact, and the process of endocytosis proved to be time and energy dependent. Endoplasmic reticulum (ER) and Golgi complexes were colocalized with PTX-NCs in cells, so the ER-Golgi complexes/Golgi complexes-basolateral membrane pathway may be involved in the intracellular trafficking and transcytosis of PTX-NCs. It was demonstrated here that cav-1, dynamin, and actin filament modulated the endocytosis process, and Cdc 42 regulated the transcytosis process. In addition, no paracellular transport of PTX-NCs was observed. These findings demonstrated that the rod-like nanocrystals not only enhanced the transcytosis of PTX compared with microparticles of raw drug materials but also changed the pathways of drug delivery. This study certainly provides insight for the oral absorption mechanism of nanocrystals of poorly soluble drugs.

The Effect of Hydrophilic and Hydrophobic Structure of Amphiphilic Polymeric Micelles on Their Transportation in Rats.

In the previous study, we have clarified how the hydrophilic and hydrophobic structures of amphiphilic polymers impact the transport of their micelles (PEEP-PCL, PEG-PCL and PEG-DSPE micelles) in epithelial MDCK cells (Biomaterials 2013, 34: 6284-6298). In this study, we attempt to clarify the behavior of the three micelles in rats. Coumarin-6 loaded micelles were injected into different sections of intestine of rats and observed by confocal laser scanning microscope (CLSM) or orally administrated and conducted pharmacokinetic study. All of the three kinds of micelles were able to cross the intestinal epithelial cells and enter blood circulation. The PEEP-PCL micelles demonstrated the fastest distribution mainly in duodenum, while the PEGDSPE micelles showed the longest distribution with the highest proportion in ileum of the three. No significant difference was observed among the pharmacokinetic parameters of the three micelles. The results were consistent in the two analysis methods mentioned above, yet there were some differences between in vivo and in vitro results reported previously. It might be the distinction between the environments in MDCK model and intestine that led to the discrepancy. The hydrophobicity of nanoparticles could both enhance uptake and hinder the transport across the mucus. However, there was no intact mucus in MDCK model, which preferred hydrophobic nanoparticles. PEEP was the most hydrophilic material constructing the micelles in the study and its uptake would be increased in rats compared to that in MDCK model, while DSPE was more hydrophobic than the others and MDCK model would be more ideal for its uptake. Considering the inconsistency of the results in the two models, whether the methods researchers were generally using at present were reasonable needs further investigation.