An Integrative Bioorthogonal Nanoengineering Strategy for Dynamically Constructing Heterogenous Tumor Spheroids.

Although tumor models have revolutionized perspectives on cancer aetiology and treatment, current cell culture methods remain challenges in constructing organotypic tumor with in vivo-like complexity, especially native characteristics, leading to unpredictable results for in vivo responses. Herein, the bioorthogonal nanoengineering strategy (BONE) for building photothermal dynamic tumor spheroids is developed. In this process, biosynthetic machinery incorporated bioorthogonal azide reporters into cell surface glycoconjugates, followed by reacting with multivalent click ligand (ClickRod) that is composed of hyaluronic acid-functionalized gold nanorod carrying dibenzocyclooctyne moieties, resulting in rapid construction of tumor spheroids. BONE can effectively assemble different cancer cells and immune cells together to construct heterogenous tumor spheroids is identified. Particularly, ClickRod exhibited favorable photothermal activity, which precisely promoted cell activity and shaped physiological microenvironment, leading to formation of dynamic features of original tumor, such as heterogeneous cell population and pluripotency, different maturation levels, and physiological gradients. Importantly, BONE not only offered a promising platform for investigating tumorigenesis and therapeutic response, but also improved establishment of subcutaneous xenograft model under mild photo-stimulation, thereby significantly advancing cancer research. Therefore, the first bioorthogonal nanoengineering strategy for developing dynamic tumor models, which have the potential for bridging gaps between in vitro and in vivo research is presented.

Dynamic circulating tumor DNA during chemoradiotherapy predicts clinical outcomes for locally advanced non-small cell lung cancer patients.

The value of circulating tumor DNA (ctDNA) during chemoradiotherapy (CRT) remains unclear but is critical for detecting molecular residual disease (MRD). In this prospective study, we sequenced 761 blood samples from 139 patients with locally advanced non-small cell lung cancer treated with definitive radiation therapy (RT). ctDNA concentrations showed a significantly declining trend as CRT progressed at on-RT and after-RT time points versus baseline. Thirty-eight (27.3%) patients with early undetectable ctDNA at both on-RT (RT reached 40 Gy) and after-RT time points, indicating early response to CRT, had better survival outcomes for both with or without consolidation immune checkpoint inhibitors. Longitudinal undetectable MRD was found in 20.1% patients. The 2-year cancer-specific progression-free survival of these patients was 88.4%, corresponding to a potentially cured population. Further analysis revealed that pretreatment ctDNA variants serve as an essential MRD informed source. These data provide clinical insights for ctDNA-MRD detection.

Retrieving soil moisture using cosmic-ray neutron technology based on COSMIC model in the desert-oasis region.

Cosmic-ray neutron technology could estimate average soil moisture on scale of hectometers by monitoring the neutron intensity near the ground, which has been successfully applied in forest, grassland, farmland, and other ecosystems. To verify the reliability of Cosmic-ray Soil Moisture Interaction Code (COSMIC) model for retrieving mesoscale soil moisture in arid regions, we carried out soil moisture observation experiment by using the cosmic-ray neutron rover in the desert-oasis region of the middle reaches of Heihe River. The results showed that the fast neutron intensity in the desert-oasis region were 350-715 counts·(30 s)-1, and the calibrated high energy neutron intensity (Ncosmic) were (38.5±2.2) counts·(30 s)-1, which was affected by land surface characteristics. Both COSMIC model (root mean square error=0.019 g·g-1) and N0 equation (root mean square error=0.018 g·g-1) could well assess the mesoscale soil moisture, with the accuracy of soil moisture being higher considering soil lattice water. The average penetration depth was 19 cm in the oasis region and 36 cm in the desert region during the experiment. COSMIC model could be used to retrieve soil moisture by cosmic ray neutron in the desert-oasis regions, which had great potential to realize data assimilation of surface meteorological-hydrological-ecological variables by combining with land surface models.

Bioengineered Neutrophil Extinguisher Targets Cascade Immune Pathways of Macrophages for Alleviating Cytokine Storm in Pneumonia.

Cytokine storm is a common complication of COVID-19 pneumonia and has been proven to contribute to high mortality rates. However, current treatment approaches exhibit limited potential to balance immune response and overproduction of inflammatory cytokines, leading to poor therapeutic outcomes. Herein, a smart bioengineered neutrophil, Extinguisher, composed of live neutrophils encapsulating the liposome formulation of NF-κB suppressor MLN4924 and STING inhibitor H-151 (Lip@MH), is developed for alleviating the hyperinflammatory cytokine storm. Extinguisher inherits motility and chemotaxis characteristics of neutrophils, allowing for the specific delivery and sustained release of Lip@MH within inflamed tissues. Subsequently, Lip@MH effectively transports anti-inflammatory agents into macrophages and synergistically inhibits inflammatory pathways of NF-κB and STING, leading to decreased production of cytokines. In vivo studies demonstrate that Extinguisher not only selectively accumulates at the site of pneumonia caused by Pseudomonas aeruginosa-induced acute lung injury but inhibits the production of inflammatory factors through regulating NF-κB/STING signaling pathways, thereby effectively calming cytokine storm. Importantly, Extinguisher significantly improves therapeutic benefits and survival in mice with acute pneumonia. Therefore, Extinguisher represents an appropriate combination of cell therapy and immunoregulation for cytokine storm intervention and may bring insights into the treatment of COVID-19 pneumonia.

A Responsive Nanorobot Modulates Intracellular Zinc Homeostasis to Amplify Mitochondria-Targeted Phototherapy.

Zinc has been proven to interweave with many critical cell death pathways, and not only exhibits potent anticancer activity solely, but sensitizes cancer cells to anticancer treatment, making zinc supplementation ideal for boosting odds against malignancy. Herein, a smart nanorobot (termed as Zinger) is developed, composed of iRGD-functionalized liposome encapsulating black phosphorus nanosheet (BPNs) doped zeolite imidazole framework-8 (BPN@ZIF-8), for advancing zinc-promoted photodynamic therapy (PDT). Zinger exhibits photo-triggered sequential mitochondria-targeting ability, and can induce zinc overload-mediated mitochondrial stress, which consequently sensitized tumor to PDT through synergistically modulating reactive oxygen species (ROS) production and p53 pathway. It is identified that Zinger selectively triggered intracellular zinc overload and photodynamic effect in cancer cells, which together enhanced PDT treatment outcomes. Importantly, Zinger shows high efficacy in overcoming various treatment barriers, allowing for effectively killing cancer cells in the complex circumstances. Particularly, Zinger exhibits good tumor accumulation, penetration, and even cell uptake, and can respond to light stimulation to eliminate tumors while avoiding normal tissues, thereby prolonging survival of tumor-bearing mice. Therefore, the study provides a novel insight in the development of novel zinc-associated therapy for advancing cancer treatment approaches.

A photoactive self-healing carboxymethyl chitosan-based hydrogel for accelerated infected wound healing through simultaneously modulating multiple critical tissue repair factors.

Infected wounds cause severe medical complications and even chronic mortality, leading to persistent health burdens. Therefore, the enhancement of wound healing has been a major goal of medical researchers. Herein, a photoactive self-healing hydrogel (termed as Macropatch), composed of carboxymethyl chitosan (CMCS), tannic acid (TA) and graphitic carbon nitride g-C3N4 (GCN), was developed to promote wound healing through simultaneously modulating pathological related factors. We identified that dynamic hydrogen bond, hydrophobic interaction and crosslinking between hydrogel backbones endowed Macropatch with good self-healing capability and mechanical property, allowing for protecting the wound from further injury. In addition, Macropatch exhibited superior tissue adhesiveness and cell affinity due to numerous catechol groups of TA chains, and enabled tight wound adhesion to seal organ bleeding. Specifically, GCN endowed Macropatch with improving mechanical strength, self-healing ability and especially visible light-induced antibacterial activity, leading to a fast recovery of bacteria-infected wounds. More remarkably, benefiting from inherent and photodynamic antibacterial properties, Macropatch could prevent bacterial infections under visible light irradiation, and consequently increase the collagen synthesis and re-epithelization, accelerating bacteria-infected wound healing process. Overall, photoactive Macropatch is a safe wound dressing with the potential of overcoming challenges in infectious wound healing, and might be applied in clinical condition.

Light-Activated Chemically Reactive Fibrous Patch Revolutionizes Wound Repair Through the Prevention of Postoperative Adhesion.

A light-activated chemically reactive fibrous patch (ChemPatch) with tissue adhesion and wound healing activity was developed for preventing postoperative peritoneal adhesion. ChemPatch was constructed by an integrative electrospinning fabrication strategy, generating multifunctional PCL-NHS fibers encapsulating antioxidant curcumin and MnO2 nanoparticles. ChemPatch exhibited excellent photothermal conversion, which not only reformed the physical state to match the tissue but also improved conjugation between ChemPatch and tissues, allowing for strong attachment. Importantly, ChemPatch possessed good antioxidant and radical scavenging activity, which protected cells in an oxidative microenvironment and improved tissue regeneration. Particularly, ChemPatch acted as a multifunctional barrier and could not only promote reepithelialization and revascularization in wound defect model but simultaneously ameliorate inflammation and prevent postoperative peritoneal adhesion in a mouse cecal defect model. Thus, ChemPatch represents a dual-active bioadhesive barrier for reducing the incidence and severity of peritoneal adhesions.

Combination of Fe(OH)3 modified diatomaceous earth and qPCR for the enrichment and detection of African swine fever virus in water.

Water is one of the primary vectors for African swine fever virus (ASFV) transmission among swine herds. However, the low concentrations of ASFV in water represent a challenge for the detection of the virus by conventional PCR methods, and enrichment of the virus would increase the test sensitivity. In this study, aiming to enrich ASFV in water quickly and efficiently, a rapid and efficient water-borne virus enrichment system (MDEF, modified diatomaceous earth by ferric hydroxide colloid) was used to enrich ASFV in water. After enrichment by MDEF, conventional real-time PCR (qPCR) was used for ASFV detection. ASFV were inactivated and diluted in 10 L of water, of which 4 mL were collected after 60 min treatment using the MDEF system. Two thousand five hundred times reduction of the sample volume was achieved after enrichment. A high adsorption rate of about 99.99 (±0.01)% and a high recovery rate of 64.01 (±10.20)% to 179.65 (±25.53)% was achieved by using 1g modified diatomaceous earth for 10 L ASFV contaminated water. The limit of qPCR detection of ASFV decreased to 1 × 10-1.11 GU ml-1 (genomic units per milliliter) from 1 × 102.71 GU ml-1 after concentrating the spiked water from 10 L to 4 ml. Preliminary application of MDEF allowed successful detection of African swine fever virus (ASFV), porcine circovirus type 2 (PCV2), and pseudorabies virus (PRV) in sewage. Thus, the combination of modified diatomaceous earth and real-time PCR is a promising strategy for the detection of viruses in water.

Properties of PEDOT nanowire/Te nanowire nanocomposites and fabrication of a flexible thermoelectric generator.

Light-weight, mechanically flexible, transparent thermoelectric devices are promising as portable, and easy-to-integrate energy sources. Poly(3,4-ethylenedioxythiophene) nanowires (PEDOT NWs) possessing high electrical conductivity were synthesized by a facile self-assembled micellar soft-template method. And then, Te nanowires (Te NWs) with high Seebeck coefficient were easily synthesized by the solution process and then added as an inorganic filler to form the PEDOT NW/Te NW nanocomposite films via a simple and convenient vacuum filtration method. The thermoelectric (TE) properties of the nanocomposites were characterized in this research. A maximum power factor of 58.03 µW m-1 K-2 is obtained from the film containing 90 wt% Te NWs at room temperature, which is dozens of times that of the pure PEDOT NW film. This work uses the as-prepared PEDOT NWs/Te NW (90 wt%) nanocomposite film to fabricate a flexible thermoelectric generator and an output voltage of 2.8 mV was generated at a temperature difference of 13.5 K between the environment and human body.

RNAactDrug: a comprehensive database of RNAs associated with drug sensitivity from multi-omics data.

Drug sensitivity has always been at the core of individualized cancer chemotherapy. However, we have been overwhelmed by large-scale pharmacogenomic data in the era of next-generation sequencing technology, which makes it increasingly challenging for researchers, especially those without bioinformatic experience, to perform data integration, exploration and analysis. To bridge this gap, we developed RNAactDrug, a comprehensive database of RNAs associated with drug sensitivity from multi-omics data, which allows users to explore drug sensitivity and RNA molecule associations directly. It provides association data between drug sensitivity and RNA molecules including mRNAs, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) at four molecular levels (expression, copy number variation, mutation and methylation) from integrated analysis of three large-scale pharmacogenomic databases (GDSC, CellMiner and CCLE). RNAactDrug currently stores more than 4 924 200 associations of RNA molecules and drug sensitivity at four molecular levels covering more than 19 770 mRNAs, 11 119 lncRNAs, 438 miRNAs and 4155 drugs. A user-friendly interface enriched with various browsing sections augmented with advance search facility for querying the database is offered for users retrieving. RNAactDrug provides a comprehensive resource for RNA molecules acting in drug sensitivity, and it could be used to prioritize drug sensitivity-related RNA molecules, further promoting the identification of clinically actionable biomarkers in drug sensitivity and drug development more cost-efficiently by making this knowledge accessible to both basic researchers and clinical practitioners. Database URL: http://bio-bigdata.hrbmu.edu.cn/RNAactDrug.

Arecoline inhibits the growth of 3T3-L1 preadipocytes via AMP-activated protein kinase and reactive oxygen species pathways.

The present study was designed to investigate the pathways involved in the effect of betel nut arecoline on cell viability in 3T3-L1 preadipocytes. Arecoline, but not arecaidine or guvacine, inhibited preadipocyte viability in a concentration- and time-dependent manner. Arecoline arrested preadipocyte growth in the G2/M phase of the cell cycle; decreased the total levels of cyclin-dependent kinase 1 (CDK1), p21, and p27 proteins; increased p53 and cyclin B1 protein levels; and had no effect on CDK2 protein levels. These results suggested that arecoline selectively affected a particular CDK subfamily. Arecoline inhibited AMP-activated protein kinase (AMPK) activity; conversely, the AMPK activator, AICAR, blocked the arecoline-induced inhibition of cell viability. Pre-treatment with the antioxidant, N-acetylcysteine, prevented the actions of arecoline on cell viability, G2/M growth arrest, reactive oxygen species (ROS) production, and the levels of CDK1, p21, p27, p53, cyclin B1, and phospho-AMPK proteins. These AMPK- and ROS-dependent effects of arecoline on preadipocyte growth may be related to the mechanism underlying the modulatory effect of arecoline on body weight.