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Alveolar bone defect reconstruction is a common challenge in stomatology. To address this, a thermosensitive/photosensitive gelatin methacrylate (GelMA) gel was developed based on various air solubilities and light-curing technologies. The gel was synthesized by using a freeze-ultraviolet (FUV) method to form a porous and quickly (within 15 min) solidifying modified network structure. Unlike other gel scaffolds limited by complex preparation procedures and residual products, this FUV-GelMA gel shows favorable manufacturing ability, promising biocompatibility, and adjustable macroporous structures. The results from a rat model suggested that this gel scaffold creates a conducive microenvironment for mandible reconstruction and vascularization. In vitro experiments further confirmed that the FUV-GelMA gel promotes osteogenic differentiation of human bone marrow mesenchymal stem cells and angiogenesis of human umbilical vein endothelial cells. Investigation of the underlying mechanism focused on the p38 mitogen-activated protein kinase (MAPK) pathway. We found that SB203580, a specific inhibitor of p38 MAPK, abolished the therapeutic effects of the FUV-GelMA gel on osteogenesis and angiogenesis, both in vitro and in vivo. These findings introduced a novel approach for scaffold-based tissue regeneration in future clinical applications.

Cobalt-catalyzed borylative reduction of azobenzenes using pinacolborane is developed. The simple cobalt chloride catalyst and reaction conditions make this protocol attractive for hydrazobenzene synthesis. This borylative reduction shows good functional group compatibility and can be readily scaled up to the gram scale. Preliminary mechanistic studies clarified the proton source of the hydrazine products. This cobalt-catalyzed azobenzene borylative reaction provides a practical protocol to prepare synthetically useful diborylated hydrazines.

The excess production of reactive oxygen species (ROS) will delay tooth extraction socket (TES) healing. In this study, we developed an injectable thermosensitive hydrogel (NBP@BP@CS) used to treat TES healing. The hydrogel formulation incorporated black phosphorus (BP) nanoflakes, recognized for their accelerated alveolar bone regeneration and ROS-scavenging properties, and dl-3-n-butylphthalide (NBP), a vasodilator aimed at enhancing angiogenesis. In vivoinvestigations strongly demonstrated that NBP@BP@CS improved TES healing due to antioxidation and promotion of alveolar bone regeneration by BP nanoflakes. The sustained release of NBP from the hydrogel promoted neovascularization and vascular remodeling. Our results demonstrated that the designed thermosensitive hydrogel provided great opportunity not only for ROS elimination but also for the promotion of osteogenesis and angiogenesis, reflecting the “three birds with one stone” concept, and has tremendous potential for rapid TES healing.

Androgen deprivation therapy (ADT) is the first line of treatment for metastatic prostate cancer (PCa) that effectively delays the tumor progression. However, it also increases the risk of venous thrombosis event (VTE) in patients, a leading cause of mortality. How a pro-thrombotic cascade is induced by ADT remains poorly understood. Here, we report that protein disulfide isomerase A2 (PDIA2) is upregulated in PCa cells to promote VTE formation and enhance PCa cells resistant to ADT. Using various in vitro and in vivo models, we demonstrated a dual function of PDIA2 that enhances tumor-mediated pro-coagulation activity via tumor-derived extracellular vehicles (EVs). It also stimulates PCa cell proliferation, colony formation, and xenograft growth androgen-independently. Mechanistically, PDIA2 activates the tissue factor (TF) on EVs through its isomerase activity, which subsequently triggers a pro-thrombotic cascade in the blood. Additionally, TF-containing EVs can activate the Src kinase inside PCa cells to enhance the AR signaling ligand independently. Androgen deprivation does not alter PDIA2 expression in PCa cells but enhances PDIA2 translocation to the cell membrane and EVs via suppressing the clathrin-dependent endocytic process. Co-recruitment of AR and FOXA1 to the PDIA2 promoter is required for PDIA2 transcription under androgen-deprived conditions. Importantly, blocking PDIA2 isomerase activity suppresses the pro-coagulation activity of patient plasma, PCa cell, and xenograft samples as well as castrate-resistant PCa xenograft growth. These results demonstrate that PDIA2 promotes VTE and tumor progression via activating TF from tumor-derived EVs. They rationalize pharmacological inhibition of PDIA2 to suppress ADT-induced VTE and castrate-resistant tumor progression.

Alveolar bone regeneration has been strongly linked to macrophage polarization. M1 macrophages aggravate alveolar bone loss, whereas M2 macrophages reverse this process. Berberine (BBR), a natural alkaloid isolated and refined from Chinese medicinal plants, has shown therapeutic effects in treating metabolic disorders. In this study, we first discovered that culture supernatant (CS) collected from BBR-treated human bone marrow mesenchymal stem cells (HBMSCs) ameliorated periodontal alveolar bone loss. CS from the BBR-treated HBMSCs contained bioactive materials that suppressed the M1 polarization and induced the M2 polarization of macrophages in vivoand in vitro. To clarify the underlying mechanism, the bioactive materials were applied to different animal models. We discovered macrophage colony-stimulating factor (M-CSF), which regulates macrophage polarization and promotes bone formation, a key macromolecule in the CS. Injection of pure M-CSF attenuated experimental periodontal alveolar bone loss in rats. Colony-stimulating factor 1 receptor (CSF1R) inhibitor or anti-human M-CSF (M-CSF neutralizing antibody, Nab) abolished the therapeutic effects of the CS of BBR-treated HBMSCs. Moreover, AKT phosphorylation in macrophages was activated by the CS, and the AKT activator reversed the negative effect of the CSF1R inhibitor or Nab. These results suggest that the CS of BBR-treated HBMSCs modulates macrophage polarization via the M-CSF/AKT axis. Further studies also showed that CS of BBR-treated HBMSCs accelerated bone formation and M2 polarization in rat teeth extraction sockets. Overall, our findings established an essential role of BBR-treated HBMSCs CS and this might be the first report to show that the products of BBR-treated HBMSCs have active effects on alveolar bone regeneration.

Plant viral diseases can seriously affect the yield and quality of crops. In this work, a convenient and highly sensitive biosensor for the visual detection of plant viral disease is proposed by the PCR-induced generation of DNAzyme. In the absence of nucleic acid for a target plant virus, the primers prohibited the production of G-quadruplex by forming a hairpin structure. However, PCR amplification occurred and generated a number of specific PCR products with free G-quadruplex sequences at both ends in the presence of the target cDNA. A catalytically active G-quadruplex DNAzyme was formed with the help of K+and hemin, resulting in the formation of colored products visible to the naked eye and a strong absorbance by the addition of ABTS2−and H2O2. The absorbance and the logarithm of target cDNA concentrations showed a good linear relationship in the range of 10 fM–1.0 nM, with a linear regression equation of A= 0.1402 lg c+ 0.3761 (c: fM) and a detection limit of 0.19 fM. This method was successfully applied to the analysis of emerging tobacco mosaic virus (TMV) infections in tobacco leaf samples collected in the field due to its flexibility and convenience, indicating a potential application for the early detection of plant viral disease.

ABSTRACT The production of ordinary Portland cement (OPC) is responsible for a significant part of global C[O.sub.2] emission. For decades, the raw material and high burn temperature (up to 1500[degrees]C) [...]

ABSTRACT This study reports on the effect of dry ice on the hydration and hardening behavior of Portland cement. Dry ice was directly added to fresh Portland cement paste, with [...]

ABSTRACT There are some drawbacks, such as bleeding, poor cohesiveness, etc, because the water to cement (W/C) ratio of dry-mixed masonry mortar is greater. Therefore, the influences of the slaked [...]

ABSTRACT Sulphoaluminate cement-based dual liquid high water material has some defects, such as longer setting time, higher bleeding capacity and lower strength and so on. In order to improve its [...]

Pancreatic cancer (PC) is the most hypoxic cancer type among solid tumors. The dynamic changes of RNA N6-methyl-adenosine (m6A) contribute to tumor cells adaption to hypoxic microenvironmental. However, the regulatory mechanisms of hypoxia response in PC remains elusive. Here, we reported that the m6A demethylase ALKBH5 mediated a decrease of total mRNA m6A modification during hypoxia. Subsequently, methylated RNA immunoprecipitation sequencing (MeRIP-seq) combined with RNA sequencing (RNA-seq) revealed transcriptome-wide gene expression alteration and identified histone deacetylase type 4 (HDAC4) as a key target gene of m6A modification under hypoxic conditionds. Mechanistically, m6A methylation recognized by m6A reader-YTHDF2 enhanced the stability of HDAC4, and then promoted glycolytic metabolism and migration of PC cells. Our assays also demonstrated that hypoxia-induced HDAC4 enhanced HIF1a protein stability, and overexpressed HIF1a promoted transcription of ALKBH5 in hypoxic pancreatic cancer cells. Together, these results found a ALKBH5/HDAC4/HIF1α positive feedback loop for cellular response to hypoxia in pancreatic cancer. Our studies uncover the crosstalk between histone acetylation and RNA methylation modification on layer of epigenetic regulation.

The development of environmentally friendly, green, and nontoxic adhesives with excellent dry and wet adhesion properties is of great attraction. In nature, barnacles and mussels exhibit strong adhesion by secreting a hydroxyl-rich dopa. Inspired by their adhesion mechanism, a simple biobased MAG-PETMP (MP) adhesive was prepared from magnolol (MAG) and pentaerythritol tetra (3-mercaptopropionate) (PETMP) by a thiol–ene click chemistry reaction. MP as an adhesive exhibits high bond strength with other substrates due to hydrogen bonds formed by the abundant hydroxyl groups at the interface and shows an inherent thermosetting network structure. Since MP has a thermosetting network, it exhibits excellent thermal stability, solvent resistance, and high mechanical strength, which make the adhesive stable in a humid environment. The cross-linking degree of MP can be easily controlled by adjusting the molar ratio of MAG and PETMP. Among the synthesized samples, the elongation at break of the MP 1 formulation is 174.27%, which makes it promising for use as a flexible adhesive. Moreover, the inherent antibacterial properties of MAG enable MP to exhibit antimicrobial properties and antibacterial adhesion to some extent. This work provides a simple biomimetic strategy that could enable the application of MAG for adhesives.

ABSTRACT A normal weight porous aggregate (NWPA), with the saturated surface dry density of 2.3 g/[cm.sup.3], was prepared. Impact of NWPA on performance of mortar with water to cementitious materials [...]

The role of autophagy in cancer is context-dependent. In the present study, we aimed to investigate the regulator and underlying mechanism of autophagy. We found that a sirtuin (SIRT) family member, SIRT4, was significantly associated autophagy pathway in pancreatic ductal adenocarcinoma (PDAC). Specifically, in vitro cell culture experiments and in vivo transgenic and xenografted animal models revealed that SIRT4 could inhibit tumor growth and promote autophagy in PDAC. In terms of the mechanism, we demonstrated that SIRT4 activated the phosphorylation of p53 protein by suppressing glutamine metabolism, which was crucial in SIRT4-induced autophagy. AMPKα was implicated in the regulation of autophagy and phosphorylation of p53 mediated by SIRT4, contributing to the suppression of pancreatic tumorigenesis. Notably, the clinical significance of the SIRT4/AMPKα/p53/autophagy axis was demonstrated in human PDAC specimens. Collectively, these findings suggested that SIRT4-induced autophagy further inhibited tumorigenesis and progression of PDAC, highlighting the potential of SIRT4 as a therapeutic target for cancer.

Under the background of the 4th industrial revolution, digital twin technology has been constantly integrated with the power grid business. Power grid will build a digital twin grid covering the whole physical grid and production process. This paper first proposes the digital power grid based on digital twin. A closed-loop power grid data empowerment system is introduced to define the digital power grid based on digital twin, the three features and properties are described to enrich the digital power grid connotation. It constructs the digital power grid architecture including physical power grid, perception layer, transport layer, data layer, platform layer and application layer. The key technologies are also discussed to embody digital power grid.

Taxifolin is a natural flavonoid compound that can be isolated from onions, grapes, oranges and grapefruit. It also acts as a medicine food homology with extraordinary antioxidant and anti-inflammatory activity. This study aims to explain the protective effects and potential mechanisms of taxifolin against inflammatory reaction.

Periodontitis, a prevalent inflammatory condition in the oral cavity, is closely associated with oxidative stress‐induced tissue damage mediated by excessive reactive oxygen species (ROS) production. The jaw vascular unit (JVU), encompassing both vascular and lymphatic vessels, plays a crucial role in maintaining tissue fluid homeostasis and contributes to the pathological process in inflammatory diseases of the jaw. This study presents a novel approach for treating periodontitis through the development of an injectable thermosensitive gel (CH‐BPNs‐NBP). The gel formulation incorporates black phosphorus nanosheets (BPNs), which are notable for their ROS‐scavenging properties, and dl‐3‐n‐butylphthalide (NBP), a vasodilator that promotes lymphatic vessel function within the JVU. These results demonstrate that the designed thermosensitive gel serve as a controlled release system, delivering BPNs and NBP to the site of inflammation. CH‐BPNs‐NBP not only protects macrophages and human lymphatic endothelial cells from ROS attack but also promotes M2 polarization and lymphatic function. In in vivo studies, this work observes a significant reduction in inflammation and tissue damage, accompanied by a notable promotion of alveolar bone regeneration. This research introduces a promising therapeutic strategy for periodontitis, leveraging the unique properties of BPNs and NBP within an injectable thermosensitive gel. In this study, an injectable thermosensitive gel (CH‐BPNs‐NBP) is prepared for treating periodontitis. The designed thermosensitive gel serves as a controlled release system, delivering BPNs and NBP to the site of inflammation. CH‐BPNs‐NBP not only protects macrophages and human lymphatic endothelial cells from ROS attack but also promotes M2 polarization and lymphatic function.

To further enhance the mechanical properties of CO2-cured sodium-doped calcium silicate (Na2Ca2Si3O9) compacts and promote sustainable low-carbon materials, this study analyzed the subsequent hydration hardening behavior after initial carbonation curing. The compressive strength evolution, pore structure, phase composition, and microstructure were characterized through strength tests, 1H NMR, XRD, TGA, FTIR, and SEM analyses. The findings reveal that subjecting carbonated Na2Ca2Si3O9compacts to further water-saturated hydration curing enhances their hardening performance. The compressive strength of the 28 d subsequent hydration-cured samples exhibited a remarkable increase compared to the carbonated counterparts. Microscopic examination elucidates that sufficient water facilitates continuous reactions between carbonation products and unreacted Na2Ca2Si3O9, generating more prismatic pirssonite(Na2Ca(CO3)2·2 H2O), CaCO3, and (N)-C-S-H gels, leading to reduced porosity and superior compressive strength. The proposed mechanism offers insights into activating the subsequent hardening process of carbonated cementitious materials.

Intestine is a common site of adverse drug effects in clinical trials; thus, improved in vitromodels for preclinical screening of pharmaceutical compounds are sought. A planar, self-renewing human intestinal monolayer platform based on primary adult gastrointestinal stem cells, termed the 2D crypt model, has been developed to screen for the effects of various compounds on the intestinal epithelium. The 2D crypt platform is based on a standard 12-well plate format and consists of cell culture inserts with a collagen film overlaying an impermeable film patterned with an array of micron-scale holes. This two-chamber format enables a gradient of growth factors to be applied such that the tissue self-organizes into spatially segregated stem and differentiated cell compartments. The patterned monolayer mimics a gut epithelium in possessing a stem cell niche, migrating proliferative and differentiated cells. Once established, the 2D crypts replicate many aspects of in vivophysiology, including cell migration, maturation, and apoptotic cell death. The planar geometry of the system simplifies dosing, sampling, and imaging during assay. An immunofluorescence-based assay was established to quantitatively assess cell density, proliferation, migration, viability, and the abundance and localization of postmitotic lineages as a function of time. The model was used to perform a small-scale screen of compounds, including signaling molecules, endogenous hormones/cytokines, and microbial metabolites, on tissue homeostasis. Hit compounds that significantly impacted proliferation and/or differentiation were readily identified. The 2D crypt platform represents a significant innovation in the development of microphysiological systems for emulating the gut epithelium for compound screens.

Background: The globose scale (GS), Sphaerolecanium prunastri(Boyer de Fonscolombe) (Hemiptera: Coccoidea), has invaded wild apricot forests in their native range in Central Eurasia threatening the ancestral germplasm resource. Biological control efficacy of the harlequin ladybird, Harmonia axyridis(Pallas, 1773) (Coleoptera: Coccinellidae) against the globose scale was assessed in laboratory and field experiments. Results: In the laboratory, Harmonia axyridishas a high feeding capacity on GS with numbers consumed daily increasing with temperature (15, 20, 25, 30, 35 °C), reaching an upper asymptote of 160–200 scales per day. In field cage experiments, efficacy of biological control (EBC) against first instar (49–99%) and second instar nymphs (20–80%) increased with GS density. When ants were present, control efficiency was reduced by 10–15%. In open-field experiments without cages, EBC was comparatively lower regardless of duration and how H. axyridiswere released whether as adults, eggs cards or a mixture of adults and eggs cards. Conclusions: In the long term, biological control with this ladybird predator could be considered as part of an IPM program package that includes banning or delaying mowing grass and understory plants in the forests that offer pollen and nectar for natural enemies.

Capillary electrophoresis with fluorescence detection (CE-F) is a powerful method to measure enzyme activation in single cells. However, cellular enzymatic assays used in CE-F routinely utilize reporter substrates that possess a bulky fluorophore that may impact enzyme kinetics. To address these challenges, we describe a “fix and click” method utilizing an alkyne-terminated enzyme activation reporter, aldehyde-based fixation, and a click chemistry reaction to attach a fluorophore prior to analysis by single-cell CE-F. The “fix and click” strategy was utilized to investigate sphingolipid signaling in both immortalized cell lines and primary human colonic epithelial cells. When the sphingosine alkyne reporter was loaded into cells, this reporter was metabolized to ceramide (31.6 ± 3.3% peak area) without the production of sphingosine-1-phosphate. In contrast, when the reporter sphingosine fluorescein was introduced into cells, sphingosine fluorescein was converted to sphingosine-1-phosphate and downstream products (32.8 ± 5.7% peak area) without the formation of ceramide. Sphingolipid metabolism was measured in single cells from both differentiated and stem/proliferative human colonic epithelium using “fix and click” paired with CE-F to highlight the diversity of sphingosine metabolism in single cells from primary human colonic epithelium. This novel method will find widespread utility for the performance of single-cell enzyme assays by virtue of its ability to temporally and spatially separate cellular reactions with alkyne-terminated reporters, followed by the assay of enzyme activation at a later time and place.

Cadmium zinc telluride (CZT) detectors are suitable for various applications due to the good energy resolution and the simple pixilation to achieve high spatial resolution. Our group is developing a two-panel head-and-neck dedicated positron emission tomography system based on CZT detectors. Each panel will consist of 150 CZT crystals (4 $\times $ 4 $\times $ 0.5 cm3) covering an area of 20 $\times $ 15 cm2 in an edge-on configuration to achieve high detector efficiency at 511 keV. In this work, we present the design and development of a full data acquisition (DAQ) chain that enables a low noise and compact readout for each panel. The initial results of the readout circuit were quantified using a 1-kHz square wave test pulse. The pulse amplitude was chosen to generate approximately the same amount of charges as a 511-keV photon would provide in CZT. The best-case full width at half maximum (FWHM) electronic noise at 511 keV was measured to be 0.69% ± 0.16% (3.52 ± 0.81 in keV units after conversion). The FWHM electronic noise at 511 keV for a complete DAQ chain was 4.33% ± 0.30% (22.13 ± 1.53 in keV units).

Background: Fenofibrate (FNB) is a commonly used hypolipidemic agent. However, the oral bioavailability of FNB is limited by slow dissolution due to its low solubility. Thus, investigations on novel FNB formulations are necessary for their use. Objective: The objective of this study is to enhance the oral bioavailability of FNB using optimized Nanostructured Lipid Carrier (NLC) formulations. Methods: Hot homogenization followed by ultrasonication was used to prepare FNB-NLCs. These formulations were optimized using a Box-Behnken design, where the amount of FNB (X1), a ratio of solid lipid/liquid lipid (X2), and the percentage of emulsifier (X3) were set as independent variables, while the particle size (Y1), and Entrapment Efficiency (EE%) (Y2), were used as dependent factors. An in vitro dissolution test was then performed using a paddle method, while an in vivo pharmacokinetic study of FNB-NLC formulation was performed in rats. Results: FNB-NLCs were successfully prepared and optimized using a Box-Behnken design. The particle size and EE% of the FNB-NLC had less than 5% difference from predicted values. The in vitro dissolution and oral bioavailability of the FNB-NLC were both higher than those of raw FNB. Conclusion: A Box-Behnken design was successfully applied to optimize FNB-NLC formulation for the enhancement of the dissolution and bioavailability of FNB, a poorly water-soluble drug.

The goal of this project was to validate the functional relevance and utility of mucus produced by an in vitro intestinal cell culture model. This is facilitated by the need to physiologically replicate both healthy and abnormal mucus conditions from native intestinal tissue, where mucus properties have been connected to intestinal disease models. Mucus harvested from colonic cell cultures derived from healthy donors was compared to mucus collected from surgically resected, noninflamed transverse colon tissue. The rheological and biochemical properties of these mucus samples were compared using oscillational rheometry, particle-tracking microrheology, multiangle laser light scattering, refractometry, and immunohistochemical imaging. An air-liquid interface culture of primary human colonic epithelial cells generated a continuous monolayer with an attached mucus layer that displayed increasing weight percent (wt%) of solids over 1 week (1.3 ± 0.5% at 2 days vs. 2.4 ± 0.3% at 7 days). The full range of mucus concentrations (0.9–3.3%) observed during culture was comparable to that displayed by ex vivo mucus (1.3–1.9%). Bulk rheological measurements displayed similar wt%-based complex viscosities between in vitro and ex vivo mucus, with the complex viscosity of both systems increasing with wt% of solids. Particle-tracking microrheology showed higher complex viscosities for ex vivo mucus samples than in vitro mucus which was explained by a greater fraction of water present in in vitro mucus than ex vivo, i.e., in vitro mucus is more heterogeneous than ex vivo.Refractometry, multiangle laser light scattering, and immunostaining showed increased mucus complex size in ex vivo mucus compared with in vitro mucus, which may have been due to the admixture of mucus and cellular debris during ex vivo mucus collection. The air-liquid interface culture system produced intestinal mucus with similar composition and rheology to native human gut mucus, providing a platform to analyze pathological differences in intestinal mucus.

ABSTRACT To quantitatively explain the physical filling effect of aggregate micro fines (AMF), a formula was established, and the amount of free water in fresh concrete mixture can be calculated [...]

Cell-mediated drug delivery system (CDDS) has shown great potential for cancer therapy. However, a single cell-mediated drug delivery mechanism has not generally been successful, particularly for systemic administration. To augment the antitumor therapy efficacy, herein, we propose a strategy of cell relay-delivery for the use of artificially damaging/aging erythrocytes to hitchhike on circulating monocytes/macrophages for intratumoral accumulation of anticancer drugs. This biomimetic relay-delivery strategy was derived from the manner in which circulating monocytes/macrophages in body specifically engulf damaged/senescent erythrocytes and actively transmigrate into the tumor bulk. The strategy elegantly combines the natural functions of both cells, which therefore provides a new perspective to challenge current obstacles in drug delivery. According to the strategy, we developed biotinylated erythrocyte-poly (lactic-co-glycolic acid) (PLGA) nanoparticle hybrid DDSs (bE-NPs) using avidin-biotin coupling. In such a system, biotinylated erythrocytes can mimic the natural property of damaged/senescent erythrocytes, while PLGA NPs are capable of encapsulating anticancer drugs and promoting sustained drug release. Anticancer drugs can effectively target tumor sites by two steps. First, by using biotinylated erythrocytes as the carrier, the drug-loaded PLGA NPs could be specifically phagocytized by monocytes/macrophages. Second, by taking advantage of the tumor-tropic property of monocytes/macrophages, the drug-loaded PLGA NPs could be efficiently transported into the tumor bulk. After encapsulating vincristine (VIN) as the model drug, bE-NPs exhibited the most favorable antitumor effects in vitroand in vivoby the cell relay-delivery effect. These results demonstrate that the cell relay-delivery provides a potential method for improving tumor treatment efficacy.

Aristolochic acid I (AAI) is a natural bioactive substance found in plants from the Aristolochiaceaefamily and impairs spermatogenesis. However, whether AAI-induced spermatogenesis impairment starts at the early stages of spermatogenesis has not yet been determined. Spermatogonial stem cells (SSCs) are undifferentiated spermatogonia that balance self-renewing and differentiating divisions to maintain spermatogenesis throughout adult life and are the only adult stem cells capable of passing genes onto the next generation. The objective of this study was to investigate whether AAI impairs SSCs during the early stages of spermatogenesis. After AAI treatment, we observed looser, smaller and fewer colonies, decreased cell viability, a decreased relative cell proliferation index, and increased apoptosis in SSCs in a concentration- and/or time-dependent manner. Additionally, AAI promoted apoptosis in SSCs, which was accompanied by upregulation of caspase 3, P53 and BAX expression and downregulation of Bcl-2 expression, and suppressed autophagy, which was accompanied by upregulation of P62 expression and downregulation of ATG5 and LC3B expression, in a concentration-dependent manner. Then we found that AAI impaired spermatogenesis in rats, as identified by degeneration of the seminiferous epithelium, and increased apoptosis of testicular cells. Taken together, our findings demonstrate that AAI causes damage to SSCs and implicate apoptosis and autophagy in this process. The impairment of SSCs may contribute to AAI-induced testicular impairment. Our findings provide crucial information for the human application of botanical products containing trace amounts of AAI.

Objective: Both stent grafts (SG) and drug-coated balloons (DCBs) have shown to be effective treatments for long and complex femoropopliteal (FP) lesions. However, there has not been a clinical trial comparing the 2 treatments directly. This study aims to compare the primary patency (PP) and clinical outcomes of SG and DCB for endovascular treatment of complex FP Trans-Atlantic Inter-Society Consensus (TASC) C/D lesions in patients.Methods: From July 2013 to May 2019, a retrospective study was conducted at 2 medical centers to compare the clinical outcomes of Viabahn SG and DCB angioplasty in patients with TASC C/D FP lesions. The study used overlap weighting to adjust for differences in baseline characteristics and to reduce the impact of confounding factors and selection bias between the 2 groups. The primary endpoint was PP through 24 months, and the secondary endpoints included freedom from clinical-driven target lesion revascularization (CD-TLR), all-cause of death rate, and major amputation rate.Results: A total of 161 limbs in 150 patients with TASC C/D FP lesions were treated either with Viabahn SGs (67 limbs, 65 patients) or DCBs (94 limbs, 85 patients). In the DCB group, 22 target vessels (23.4%) underwent directional atherectomy before DCB angioplasty and 37 target vessels (39.4%) underwent bail-out bare-metal stent implantation for early recoil or severe dissection. The SG group had significantly higher PP rates at both the 12 and 24 months than in the DCB group (75.8% vs 39.2%, p=0.02; 64.1% vs 31.9%, p=0.02), respectively. However, there were no significant differences between the 2 groups in terms of CD-TLR, death rate, and major amputation rate. According to the results of multivariate analysis, DCB angioplasty was the only independent predictor associated with restenosis (hazard ratio [HR]=0.264, 95% confidence interval [CI]=0.100-0.696, p=0.007).Conclusions: This study showed that SG was associated with a significantly higher PP rate in complex long FP lesions compared with DCB angioplasty. However, there was no significant difference in the freedom from CD-TLR and major amputation rate. It is important to follow the criteria for using SG strictly to avoid early restenosis, which can lead to acute thrombosis and severe limb ischemia. Closer monitoring is recommended for patients who undergo SG implantation.Clinical Impact There has no head-to-head clinical trial that compares DCB and SG in complex long FP lesions. This study showed that SG following the criteria was associated with a significantly higher PP rate compared with DCB angioplasty. Closer monitoring is recommended for patients with SG to avoid acute thrombosis. Randomized controlled trials comparing SG and DCB are necessary.

Organoid culture has had a significant impact on in vitrostudies of the intestinal epithelium; however, the exquisite architecture, luminal accessibility, and lineage compartmentalization found in vivohas not been recapitulated in the organoid systems. We have used a microengineered platform with suitable extracellular matrix contacts and stiffness to generate a self-renewing mouse colonic epithelium that replicates key architectural and physiological functions found in vivo, including a surface lined with polarized crypts. Chemical gradients applied to the basal–luminal axis compartmentalized the stem/progenitor cells and promoted appropriate lineage differentiation along the in vitrocrypt axis so that the tissue possessed a crypt stem cell niche as well as a layer of differentiated cells covering the luminal surface. This new approach combining microengineered scaffolds, native chemical gradients, and biophysical cues to control primary epithelium ex vivocan serve as a highly functional and physiologically relevant in vitrotissue model.

The issue of bacterial infectious diseases remains a significant concern worldwide, particularly due to the misuse of antibiotics, which has caused the emergence of antibiotic-resistant strains. Fortunately, the rapid development of nanomaterials has propelled significant progress in antimicrobial therapy, offering promising solutions. Among them, the utilization of nanoenzyme-based chemodynamic therapy (CDT) has become a highly hopeful approach to combating bacterial infectious diseases. Nevertheless, the application of CDT appears to be facing certain constraints for its low efficiency in the Fenton reaction at the infected site. In this study, we have successfully synthesized a versatile nanozyme, which was a composite of molybdenum sulfide (MoS2) and iron sulfide (FeS2), through the hydrothermal method. The results showed that iron/molybdenum sulfide nanozymes (Fe/Mo SNZs) with desirable peroxidase (POD) mimic activity can generate cytotoxic reactive oxygen species (ROS) by successfully triggering the Fenton reaction. The presence of MoS2significantly accelerates the conversion of Fe2+/Fe3+through a cocatalytic reaction that involves the participation of redox pairs of Mo4+/Mo6+, thereby enhancing the efficiency of CDT. Additionally, based on the excellent photothermal performance of Fe/Mo SNZs, a near-infrared (NIR) laser was used to induce localized temperature elevation for photothermal therapy (PTT) and enhance the POD-like nanoenzymatic activity. Notably, both in vitroand in vivoresults demonstrated that Fe/Mo SNZs with good broad-spectrum antibacterial properties can help eradicate Gram-negative bacteria like Escherichia coliand Gram-positive bacteria like Staphylococcus aureus. The most exciting thing is that the synergistic PTT/CDT exhibited astonishing antibacterial ability and can achieve complete elimination of bacteria, which promoted wound healing after infection. Overall, this study presents a synergistic PTT/CDT strategy to address antibiotic resistance, providing avenues and directions for enhancing the efficacy of wound healing treatments and offering promising prospects for further clinical use in the near future.

Sepsis was redefined as life‐threatening organ dysfunction caused by a dysregulated host response to infection in 2016. One of its most common causes is Staphylococcus aureus, especially methicillin‐resistant Staphylococcus aureus(MRSA), which leads to a significant increase in morbidity and mortality. Therefore, innovative and effective approaches to combat MRSA infection are urgently needed. Recently, host‐directed therapy (HDT) has become a new strategy in the treatment of infectious diseases, especially those caused by antibiotic‐resistant bacteria. Baicalin (BAI) is the predominant flavonoid and bioactive compound isolated from the roots of Radix Scutellariae(Huang Qin), a kind of traditional Chinese medicine. It has been reported that BAI exhibits multiple biological properties such as anti‐oxidant, antitumor, and anti‐inflammatory activities. However, the therapeutic role of BAI in MRSA infection is still unknown. In this study, it is found that BAI treatment inhibited the production of IL‐6, TNF‐α, and other cytokines from MRSA‐ or bacterial mimics‐stimulated Mϕs and dendritic cells (DCs). BAI played an anti‐inflammatory role by inhibiting the activation of ERK, JNK MAPK, and NF‐κB pathways. Moreover, the serum level of TNF‐α was decreased, whereas IL‐10 was increased, in mice injected with MRSA. Furthermore, the bacterial load in livers and kidneys were further decreased by the combination of BAI and vancomycin (VAN), which might account for the amelioration of tissue damage. BAI reduced the high mortality rate caused by MRSA infection. Collectively, the results suggested that BAI may be a viable candidate of HDT strategy against severe sepsis caused by antibiotic‐resistant bacteria such as MRSA. Baicalin is a drug candidate for host‐directed therapy (HDT) in severe infection caused by methicillin‐resistant Staphylococcus aureus.

Enteroendocrine (EE) cells within the intestinal epithelium produce a range of hormones that have key roles in modulating satiety and feeding behavior in humans. The regulation of hormone release from EE cells as a potential therapeutic strategy to treat metabolic disorders is highly sought after by the pharmaceutical industry. However, functional studies are limited by the scarcity of EE cells (or surrogates) in both in vivoand in vitrosystems. Enterochromaffin (EC) cells are a subtype of EE cells that produce serotonin (5HT). Here, we explored simple strategies to enrich EC cells in in vitromonolayer systems derived from human primary intestinal stem cells. During differentiation of the monolayers, the EC cell lineage was significantly altered by both the culture method [air–liquid interface (ALI) vssubmerged] and the presence of vasoactive intestinal peptide (VIP). Compared with traditional submerged cultures without VIP, VIP-assisted ALI culture significantly boosted the number of EC cells and their 5HT secretion by up to 430 and 390%, respectively. The method also increased the numbers of other subtypes of EE cells such as L cells. Additionally, this method generated monolayers with enhanced barrier integrity, so that directional (basal or apical) 5HT secretion was measurable. For all donor tissues, the enriched EC cells improved the signal-to-background ratio and reliability of 5HT release assays. The enhancement in the 5HT secretion behavior was consistent over time from a single donor, but significant variation in the amount of secreted 5HT was present among tissues derived from five different donors. To demonstrate the utility of the EC-enriched monolayer system, 13 types of pungent food ingredients were screened for their ability to stimulate 5HT secretion. Curcumin found in the spice turmeric derived from the Curcuma longaplant was found to be the most potent secretagogue. This EC-enriched cell monolayer platform can provide a valuable analytical tool for the high-throughput screening of nutrients and gut microbial components that alter the secretion of 5HT.

Design parameters for microphysiological systems (MPSs) are driven by the need for new tools to answer questions focusing on human physiology in a robust and reliable manner. Within this perspective, engineering benchmarks and principles are identified to guide the construction of new devices in the MPS field, with emphasis placed on the design principles common to all tissues and those unique to a subset of tissues. Leading organ replica technologies that recapitulate various functions of the brain, heart, intestine, and lung are highlighted as examples that meet the identified benchmarks and standards, with current barriers for large-scale production and commercialization discussed. To reach their full potential and achieve widespread use, MPSs will have to be recognized officially by government agencies, and toward this end, considerations of the MPS as a potential regulatory tool are presented.

Building scaffolds with heterogeneous and reconfigurable mechanical properties has been recognized as the key to recapitulating the natural extracellular microenvironments for in vitrocell incubation systems. However, in situchanging and tracking of the mechanical change of cell scaffolds are still challenging. In this paper we developed a novel strategy to solve this problem. We show a convenient method for tracking the hardness of cell scaffolds in a non-invasive manner viatheir color change. This is achieved by introducing colloidal crystal features into a photo-reconfigurable hydrogel, which leads to a smart hydrogel scaffold with dynamically adjustable and in situmonitorable mechanical properties. The stiffness of the hydrogel can be spatiotemporally and dynamically manipulated by light; meanwhile, its changes can be in siturecognized by analyzing the hydrogel color. This allows real-time control and investigation of the extracellular stiffness in cell incubation systems in a non-invasive fashion. In addition, the cell–matrix interactions on this smart scaffold can be easily understood owing to the simultaneous observation of cell morphology and matrix stiffness under a microscope. We also show that such a hydrogel could be used as a user-designable microarray for cell culture applications.

Biochemical gradients across the intestinal epithelium play a major role in governing intestinal stem cell compartmentalization, differentiation dynamics, and organ-level self-renewal. However, scalable platforms that recapitulate the architecture and gradients present in vivo are absent. We present a platform in which individually addressable arrays of chemical gradients along the intestinal crypt long axis can be generated, enabling scalable culture of primary in vitro colonic epithelial replicas. The platform utilizes standardized well plate spacing, maintains access to basal and luminal compartments, and relies on a photopatterned porous membrane to act as diffusion windows while supporting the in vitro crypts. Simultaneous fabrication of 3875 crypts over a single membrane was developed. Growth factor gradients were modeled and then experimentally optimized to promote long-term health and self-renewal of the crypts which were assayed in situ by confocal fluorescence microscopy. The cultured in vitro crypt arrays successfully recapitulated the architecture and luminal-to-basal phenotypic polarity observed in vivo. Furthermore, known signaling regulators (e.g., butyrate and DAPT) produced measurable and predictable effects on the organized cell compartments, each decreasing crypt proliferation in the basal regions to negligible values. This platform is readily adaptable to the screening of tissue from individual patients to assay the impact of food and bacterial metabolites and/or drugs on colonic crypt dynamics. Importantly, the cassette is compatible with a wide range of sensing/detection modalities, and the developed fabrication methods should find applications for other cell and tissue types.

Conventional drug delivery systems for natural clay materials still face critical challenges in their practical application, including multiple bacterial infections, combined infection of bacteria and fungi, and low sterilization efficiency. In this work, we address these challenges using the multifunctional montmorillonite nanosheet-based (MMT-based) drug nanoplatform, which involves the antibiotic 5-fluorocytosine (5-FC), antibacterial metal copper ions, and quaternized chitosan (QCS). Composite material QCS/MMT/5-FCCu can can strongly inhibit Staphylococcus aureus(a typical Gram-positive bacterium), Escherichia coli(a typical Gram-negative bacterium), and Candida albicans(a fungus) because 5-FC coordinates with copper ions in situand due to the deposition of QCS. The subsequent drug release behavior of 5-FCCu was studied, and the results show an initial high concentration kills microorganisms and long-acting sustained release inhibition. Moreover, in vivowound experiments and toxicity experiments show the promotion of wound healing and excellent biocompatibility. As a demonstration of the utility of the latter, we have shown that the MMT-based smart platform can be used for the treatment of mixed infections of wounds.

Environmentally friendly pesticide delivery systems have drawn extensive attention in recent years, and they show great promise in sustainable development of agriculture. We herein report a multifunctional nanoplatform, carboxymethyl chitosan modified carbon nanoparticles (CMC@CNP), as the carrier for emamectin benzoate (EB, a widely used insecticide), and investigate its sustainable antipest activity. EB was loaded on CMC@CNP nanocarrier via simple physisorption process, with a high loading ratio of 55.56%. The EB@CMC@CNP nanoformulation showed improved solubility and dispersion stability in aqueous solution, which is of vital importance to its practical application. Different from free EB, EB@CMC@CNP exhibited pH-responsive controlled release performance, leading to sustained and steady EB release and prolonged persistence time. In addition, the significantly enhanced anti-UV property of EB@CMC@CNP further ensured its antipest activity. Therefore, EB@CMC@CNP exhibited superior pest control performance than free EB. In consideration of its low cost, easy preparation, free of organic solution, and enhanced bioactivity, we expect, CMC@CNP will have a brilliant future in pest control and green agriculture.

Background: The local anesthetic drugs, especially ropivacaine, were considered favorable analgesia for postoperative management because of their effective local pain relief and low adverse effects. However, the short half-life and the resulting in bolus doses lead to the indistinctive improvement of these drugs in postoperative pain relief. Therefore, the ropivacaine microspheres with sustained release and low initial burst release were anticipated. Methods: Three methods including oil in water (O/W), water in oil in water (W/O/W), and solid in oil in water (S/O/W) emulsion solvent evaporation method were used to optimize the ropivacaine loaded PLGA microspheres. The microspheres were evaluated both in vitro and in rats. The in vitro-in vivo correlation (IVIVC) was also investigated. Results: The microspheres prepared by O/W method showed more satisfactory properties and the microspheres used for evaluation were prepared by O/W method. The particle size, drug loading, encapsulation efficiency and burst release were 11.19±1.24 μm, 28.37±1.15%, 98.15±3.98%, and 10.96±5.37% for microspheres with PLGA of 12 kDa, and 6.64±0.61 μm, 19.62±0.89%, 92.74±4.21%, and 18.42±5.12% for microspheres with PLGA of 8 kDa, respectively. These microspheres were also injected into rats by subcutaneous, intramuscular and intraperitoneal route, respectively. It was indicated that the detectable concentration of ropivacaine could last for at least 20 days for both kinds of microspheres in spite of injection routes. The low burst releases at 1 d were also manifested in rats and they were 6.62%, 6.99%, 6.48% for the microspheres with PLGA of 12 kDa, and 4.72%, 4.33%, 4.48% for the microspheres with PLGA of 8 kDa by intraperitoneal, intramuscular and subcutaneous route, respectively. A linear relationship between the in vitro release and the in vivo adsorption of ropivacaine from microspheres was also established. Conclusion: The ropivacaine microspheres with sustained release and low burst release were acquired, which indicated that the postoperative pain relief might last longer and the side effects might get lower. Therefore, the ropivacaine microspheres prepared in this paper have great potential for clinical use.

Paper, with advantages of low-cost, easy fabrication and disposal, flexibility and renewability, is a suitable substrate material for various applications. Functionalization and patterning on paper substrates are commonly required in many applications. Although many methods have been developed to achieve this, they typically suffer from some drawbacks such as time-consuming process, specific device dependence, lack of flexibility, low patterning resolution, and so forth. Herein, we present a general and fast method to functionalize paper sheets and create patterns. The whole modification process can be completed in 10 min and can be applied on various types of paper substrates and other natural materials such as natural fabrics. By our method, many commonly used functional groups can be covalently attached and patterned on paper substrates, while the characteristic features of the original paper substrates, for example, color, transparency, and conductivity, can be perfectly retained after modification to allow these properties to be incorporated into the resultant materials. High-resolution patterns can be created on paper by applying a photomask during the modification or controlling the time of modification to precisely control the functionality at any area on the obtained paper substrates. We also show the potential applications of our method in the fabrication of superhydrophobic coatings and biomaterials.

Glioma is a fatal disease with limited treatment options and very short survival. Although chemotherapy is one of the most important strategies in glioma treatment, it remains extremely clinically challenging largely due to the blood–brain barrier (BBB) and the blood–brain tumor barrier (BBTB). Thus, the development of nanoparticles with both BBB and BBTB penetrability, as well as glioma-targeting feature, is extremely important for the therapy of glioma. New findings in nanomedicine are promoting the development of novel biomaterials. Herein, we designed a red blood cell membrane-coated solid lipid nanoparticle (RBCSLN)-based nanocarrier dual-modified with T7 and NGR peptide (T7/NGR-RBCSLNs) to accomplish these objectives. As a new kind of biomimetic nanovessels, RBCSLNs preserve the complex biological functions of natural cell membranes while possessing physicochemical properties that are needed for efficient drug delivery. T7 is a ligand of transferrin receptors with seven peptides that is able to circumvent the BBB and target to glioma. NGR is a peptide ligand of CD13 that is overexpressed during angiogenesis, representing an excellent glioma-homing property. After encapsulating vinca alkaloid vincristine as the model drug, T7/NGR-RBCSLNs exhibited the most favorable antiglioma effects in vitro and in vivo by combining the dual-targeting delivery effect. The results demonstrate that dual-modified biomimetic nanoparticles provide a potential method to improve drug delivery to the brain, hence increasing glioma therapy efficacy.

Animal models are frequently used for in vitro physiologic and drug transport studies of the colon, but there exists significant pressure to improve assay throughput as well as to achieve tighter control of experimental variables than can be achieved with animals. Thus, development of a primary in vitro colonic epithelium cultured as high resistance with transport protein expression and functional behavior similar to that of a native colonic would be of enormous value for pharmaceutical research. A collagen scaffold, in which the degree of collagen cross-linking was present as a gradient, was developed to support the proliferation of primary colonic cells. The gradient of cross-linking created a gradient in stiffness across the scaffold, enabling the scaffold to resist deformation by cells. mRNA expression and quantitative proteomic mass spectrometry of cells growing on these surfaces as a monolayer suggested that the transporters present were similar to those in vivo. Confluent monolayers acted as a barrier to small molecules so that drug transport studies were readily performed. Transport function was evaluated using atenolol (a substrate for passive paracellular transport), propranolol (a substrate for passive transcellular transport), rhodamine 123 (Rh123, a substrate for P-glycoprotein), and riboflavin (a substrate for solute carrier transporters). Atenolol was poorly transported with an apparent permeability (Papp) of <5 × 10–7cm s–1, while propranolol demonstrated a Pappof 9.69 × 10–6cm s–1. Rh123 was transported in a luminal direction (Papp,efflux/Papp,influx= 7) and was blocked by verapamil, a known inhibitor of P-glycoprotein. Riboflavin was transported in a basal direction, and saturation of the transporter was observed at high riboflavin concentrations as occurs in vivo. It is anticipated that this platform of primary colonic epithelium will find utility in drug development and physiological studies, since the tissue possesses high integrity and active transporters and metabolism similar to that in vivo.

In vitro models of the human intestinal epithelium derived from primary stem cells are much needed for the study of intestinal immunology in health and disease. Here, we describe an intestinal monolayer cultured on a porous membrane with accessible basal and apical surfaces for assay of intestinal cytokine production in response to stimuli. The system was composed of a differentiated, confluent epithelial monolayer derived from human primary stem cells obtained from small or large intestine. Interleukin 8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1) were the most abundant inflammatory cytokines produced by the intestinal epithelium. The epithelium from all five tested regions of the intestine preferentially secreted into the apical reservoir of the monolayer, with a 26-fold greater concentration of IL-8 present in the apical reservoir of the colonic monolayer relative to that in the basal reservoir. Upon application of tumor-necrosis factor α (TNF-α) to the basal surface of the colonic monolayer, the IL-8 concentration significantly increased in the basal, but not the apical, reservoir. A dose-dependent elevation of IL-8 in the basal reservoir was observed for TNF-α-stimulation of the monolayer but not for an organoid-based platform. To demonstrate the utility of the monolayer system, 88 types of dietary metabolites or compounds were screened for their ability to modulate IL-8 production in the basal reservoir of the intestinal monolayer in the absence or presence of TNF-α. No dietary metabolite or compound caused an increase in IL-8 in the basal reservoir in the absence of TNF-α. After addition of TNF-α to the monolayer, two compounds (butyrate and gallic acid) suppressed IL-8 production, suggesting their potential anti-inflammatory effects, whereas the dietary factor forskolin significantly increased IL-8 production. These results demonstrate that the described human-intestinal-monolayer platform has the potential for assays and screening of metabolites and compounds that alter the inflammatory response of the intestine.