Chemokines play a key role in orchestrating the recruitment and positioning of myeloid cells within the tumor microenvironment. However, the tropism regulation and functions of these cells in ...hepatocellular carcinoma (HCC) are not completely understood. Herein, by scrutinizing the expression of all chemokines in HCC cell lines and tissues, we found that CCL15 was the most abundantly expressed chemokine in human HCC. Further analyses showed that CCL15 expression was regulated by genetic, epigenetic, and microenvironmental factors, and negatively correlated with patient clinical outcome. In addition to promoting tumor invasion in an autocrine manner, CCL15 specifically recruited CCR1+ cells toward HCC invasive margin, approximately 80% of which were CD14+ monocytes. Clinically, a high density of marginal CCR1+CD14+ monocytes positively correlated with CCL15 expression and was an independent index for dismal survival. Functionally, these tumor‐educated monocytes directly accelerated tumor invasion and metastasis through bursting various pro‐tumor factors and activating signal transducer and activator of transcription 1/3, extracellular signal‐regulated kinase 1/2, and v‐akt murine thymoma viral oncogene homolog signaling in HCC cells. Meanwhile, tumor‐derived CCR1+CD14+ monocytes expressed significantly higher levels of programmed cell death‐ligand 1, B7‐H3, and T‐cell immunoglobulin domain and mucin domain‐3 that may lead to immune suppression. Transcriptome sequencing confirmed that tumor‐infiltrating CCR1+CD14+ monocytes were reprogrammed to upregulate immune checkpoints, immune tolerogenic metabolic enzymes (indoleamine and arginase), inflammatory/pro‐angiogenic cytokines, matrix remodeling proteases, and inflammatory chemokines. Orthotopic animal models confirmed that CCL15‐CCR1 axis forested an inflammatory microenvironment enriched with CCR1+ monocytes and led to increased metastatic potential of HCC cells. Conclusion: A complex tumor‐promoting inflammatory microenvironment was shaped by CCL15‐CCR1 axis in human HCC. Blockade of CCL15‐CCR1 axis in HCC could be an effective anticancer therapy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Compressible supercapacitors are playing an increasingly significant role in sensors and wearable electronic devices. However, compressible supercapacitors have a limited specific capacity as well as ...lower working voltage. In this work, three-dimensional (3D) N-doped carbon foam is being explored for fabrication of a compressible supercapacitor with pseudocapacitive spinel. The fact that self-growing ZnFe2O4 on highly compressible nitrogen doped carbon foam composite electrodes can deliver significant pseudo-capacitance at negative potentials, an all-pseudocapacitive asymmetric supercapacitor device is fabricated by combining it with NiCo2O4 cathode. The composite electrodes combine the superior electrochemical and mechanical performances with maximum compressive strain of 80% and durability (cyclic strains up to 500 times under the strain of 60%). The asymmetric supercapacitor demonstrates an energy density of 11.84 Wh kg−1 (0.39 mWh cm−3) at 300 W kg−1 (10 mW cm−3), with 96.5% capacitance retention after 15 000 charge-discharge cycles at the compressive strain of 60%. Our work provides new insights for the design of compressible supercapacitors with high performance and accelerates the development of a new generation in energy storage devices with compressibility.
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•An universal method for preparing compressible electrodes is reported.•Both positive and negative electrodes can withstand up to 80% compression deformation.•An all pseudocapacitance asymmetric compressible supercapacitor was achieved.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Breast cancer is the leading cause of cancer deaths in women worldwide. EF‐24, an analog of curcumin, has been shown to possess promising anticancer effects. However, the underlying mechanism remains ...elusive. In the present study, the inhibitory effect of EF‐24 against one breast cancer cell line, MDA‐MB‐231, and its anti‐migration ability were assessed by MTT, wound healing, and Transwell assay. Furthermore, we found that EF‐24 could induce initiation of autophagy as evidenced by fluorescence and electron microscope observation. EF‐24 also induced mitochondrial apoptosis in MDA‐MB‐231 cells as detected by Hoechst 33342 staining, flow cytometry analysis, and western blot analysis. In addition, the early autophagy inhibitor 3‐MA could reduce the cleavage of PARP protein and protect cells from EF‐24‐induced apoptosis, while the autophagy inducer (rapamycin) could enhance the anticancer effect of EF‐24 in MDA‐MB‐231 cells, which suggest that EF‐24 induces crosstalk between autophagy and apoptosis, which herein participate in the antiproliferative effect of EF‐24 in breast cancer cells. Moreover, removal of EF‐24‐activated ROS with NAC significantly reversed migration ability of MDA‐MB‐231 cells, indicating that EF‐24 exerted an inhibitory effect through a ROS‐mediating pathway. These results will help to elucidate the antitumor mechanism of curcumin analogs and to explore future potential clinical applications.
EF‐24 induces crosstalk of autophagy and apoptosis, which participate in the antiproliferative effect of EF‐24 in MDA‐MB‐231 breast cancer cells.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
We conduct numerical investigations on turbulent Rayleigh–Bénard (RB) convection modulated by oscillating filaments, where an array of active filaments is adhered to the bottom surface. Our study ...focuses on the dependence of global heat transfer, quantified by the Nusselt number (Nu), on the rigidity (B) of the active filaments under various oscillation frequencies (ω). We reveal two critical filament rigidities, Bc1 and Bc2, delineating distinct heat transfer regimes: (I) Soft regime (B<Bc1), where negligibly small filament rigidity allows for obvious bending, and Nu decreases with increasing rigidity B in this regime. (II) Elastic bending regime (Bc1<B<Bc2), where elastic bending of filament takes place, inducing swaying motion near the filament root and subsequently perturbing the boundary layers to favor thermal plumes emission. In this regime, Nu noticeably increases with rising rigidity. (III) Stiff regime (B>Bc2), characterized by minimal deformation induced by filament–fluid interaction and the saturation of heat transfer enhancement. Furthermore, we analyze the competition between bending and inertial forces experienced by the filaments through comparing their relative magnitude, from which we theoretically determine both critical rigidities Bc. Our study offers valuable insights into the intricate dynamics of active filaments in turbulent convection, advancing our understanding of heat transfer modulation in active environments with dynamically driving agents.
•Mechanism of heat transfer modulation by active filament has been elucidated.•Three heat transfer regimes are identified depending on filament rigidity.•Critical filament rigidity is determined by the competition between bending and inertial forces.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Conducting polymers with high theoretical capacitance and deformability are among the optimal candidates for compressible supercapacitor electrode materials. However, achieving both mechanical and ...electrochemical stabilities in a single electrode remains a great challenge. To address this issue, the “Polymer Chainmail” is proposed with reversible deformation capability and enhances stability because of the steric hindrance and charge compensation effect of doped anions. As a proof of concept, four common anions are selected as dopants for Poly(3,4‐ethylenedioxythiophene) (PEDOT), and their effects on the adsorption and diffusion of H+ on PEDOT are verified using density functional theory calculations. Owing to the film formation effect, the
PF6-
${{\rm{PF}}_6^- }$
doped PEDOT/nitrogen‐doped carbon foam exhibits good mechanical properties. Furthermore, the composite demonstrates excellent rate performance and stability due to suitable anion doping. This finding provides new insights into the preparation of electrochemically stable conductive polymer‐based compressible electrode materials.
After the poly(3,4‐ethylenedioxythiophene) (PEDOT) films known as “Polymer Chainmail” were modified by PF−6 anion doping, the ion adsorption and diffusion processes on the PEDOT chains were significantly optimized due to the steric hindrance and charge compensation effects, so the cycling stability (retaining 95.9 % after 20,000 cycles) and rate performance (retaining 81.1 % at 20 mA cm−3) were improved.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Photoresponsive nitric oxide (NO)‐releasing materials (NORMs) enable the spatiotemporal delivery of NO to facilitate their potential applications in physiological conditions. Here two novel ...metal–organic frameworks (MOFs)‐based photoactive NORMs achieved by the incorporation of prefunctionalized NO donors into the photosensitive Fe‐MOFs via a postmodification strategy is reported. The modified Fe‐MOFs display superior photoactivity of NO release when exposed to visible light (up to 720 nm). Significantly, the visible‐light‐driven NO release properties are further corroborated by their efficient antibacterial performance.
Two novel metal–organic frameworks‐based photoactive nitric oxide (NO)‐releasing materials, NNO@MIL‐88B and NNO@NH2‐MIL‐88B, are prepared. The NO release from NNO@MIL‐88B is activated through a photoinduced electron transfer process.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Most resistance-type humidity sensors exhibit negative humidity sensitivity, i.e., their resistance decreases with a corresponding increase in humidity. This is primarily attributed to the dominant ...role of ionic conduction in adsorbed water. In this work, a humidity sensor based on a p-type reduced graphene oxide (p-rGO) with positive humidity sensitivity is proposed. Moreover, its positive humidity sensing response is further enhanced by n-type WS
2
nanoparticles modification. The results show that both rGO and rGO/WS
2
humidity sensors have good linear response in the relative humidity (RH) range of 0% − 91.5%. The sensitivity of the rGO/WS
2
humidity sensor is 1.87 times that of rGO humidity sensor, which is mainly attributed to p–n heterojunction between rGO and WS
2
. Besides, the rGO/WS
2
humidity sensor has small humidity hysteresis (~ 3% RH) and good repeatability. This work demonstrates a humidity sensor based on rGO/WS
2
composite film and provides a facile route for fabricating humidity sensor with positive humidity sensing properties.
Graphic Abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The application of machine learning (ML) has shown promising results in precision medicine due to its exceptional performance in dealing with complex multidimensional data. However, using ML for ...individualized dosing of medicines is still in its early stage, meriting further exploration. A systematic review of study designs and modeling details of using ML for individualized dosing of different drugs was performed. We have summarized the status of the study populations, predictive targets, and data sources for ML modeling, the selection of ML algorithms and features, and the evaluation and validation of their predictive performance. We also used the Prediction model Risk of Bias Assessment Tool (PROBAST) to assess the risk of bias of included studies. Currently, ML can be used for both a priori and a posteriori dose selection and optimization, and it can also assist the implementation of therapeutic drug monitoring. However, studies are mainly focused on drugs with narrow therapeutic windows, predominantly immunosuppressants (N = 23, 35.9%) and anti‐infectives (N = 21, 32.8%), and there is currently only very limited attention for special populations, such as children (N = 22, 34.4%). Most studies showed poor methodological quality and a high risk of bias. The lack of external validation and clinical utility evaluation currently limits the further clinical implementation of ML for dose individualization. We therefore have proposed several ways to improve the clinical relevance of the studies and facilitate the translation of ML models into clinical practice.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Eltrombopag was approved as a first-line treatment for patients older than 2 years old with severe aplastic anemia (SAA). However, data on eltrombopag in children with different types of aplastic ...anemia (AA), especially non-severe AA (NSAA), are limited. We performed a prospective, single-arm, and observational study to investigate eltrombopag's efficacy, safety, and pharmacokinetics in children with NSAA, SAA, and very severe AA (VSAA). The efficacy and safety were assessed every 3 months. The population pharmacokinetic (PPK) model was used to depict the pharmacokinetic profile of eltrombopag. Twenty-three AA children with an average age of 7.9 (range of 3.0-14.0) years were enrolled. The response (complete and partial response) rate was 12.5%, 50.0%, and 100.0% after 3, 6, and 12 months in patients with NSAA. For patients with SAA and VSAA, these response rates were 46.7%, 61.5%, and 87.5%. Hepatotoxicity occurred in one patient. Fifty-three blood samples were used to build the PPK model. Body weight was the only covariate for apparent clearance (CL/F) and volume of distribution. The allele-T carrier of adenosine triphosphate-binding cassette transporter G2 was found to increase eltrombopag's clearance. However, when normalized by weight, the clearance between the wild-type and variant showed no statistical difference. In patients with response, children with NSAA exhibited lower area under the curve from time zero to infinity, higher CL/F, and higher weight-adjusted CL/F than those with SAA or VSAA. However, the differences were not statistically significant. The results may support further individualized treatment of eltrombopag in children with AA.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Brain ischemia compromises natural killer (NK) cell-mediated immune defenses by acting on neurogenic and intracellular pathways. Less is known about the posttranscriptional mechanisms that regulate ...NK cell activation and cytotoxicity after ischemic stroke.
Using a NanoString nCounter® miRNA array panel, we explored the microRNA (miRNA) profile of splenic NK cells in mice subjected to middle cerebral artery occlusion. Differential gene expression and function/pathway analysis were applied to investigate the main functions of predicted miRNA target genes. miR-1224 inhibitor/mimics transfection and passive transfer of NK cells were performed to confirm the impact of miR-1224 in NK cells after brain ischemia.
We observed striking dysregulation of several miRNAs in response to ischemia. Among those miRNAs, miR-1224 markedly increased 3 days after ischemic stroke. Transfection of miR-1224 mimics into NK cells resulted in suppression of NK cell activity, while an miR-1224 inhibitor enhanced NK cell activity and cytotoxicity, especially in the periphery. Passive transfer of NK cells treated with an miR-1224 inhibitor prevented the accumulation of a bacterial burden in the lungs after ischemic stroke, suggesting an enhanced immune defense of NK cells. The transcription factor Sp1, which controls cytokine/chemokine release by NK cells at the transcriptional level, is a predicted target of miR-1224. The inhibitory effect of miR-1224 on NK cell activity was blocked in Sp1 knockout mice.
These findings indicate that miR-1224 may serve as a negative regulator of NK cell activation in an Sp1-dependent manner; this mechanism may be a novel target to prevent poststroke infection specifically in the periphery and preserve immune defense in the brain.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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