A metal-free route to PET probesPositron emission tomography (PET) is a widely used imaging technique for medical diagnostics and pharmaceutical development. As the name implies, it requires tracers ...that emit positrons, typically through labeling with fluorine or carbon radioisotopes. W. Chen et al. devised a versatile technique to incorporate radioactive fluoride into aromatic rings. The metal-free photochemical method directly substitutes aryl carbon-hydrogen bonds with 18Ffluoride and so is particularly well suited to late-stage transformation of complex molecules into tracers.Science, this issue p. 1170Positron emission tomography (PET) plays key roles in drug discovery and development, as well as medical imaging. However, there is a dearth of efficient and simple radiolabeling methods for aromatic C–H bonds, which limits advancements in PET radiotracer development. Here, we disclose a mild method for the fluorine-18 (18F)–fluorination of aromatic C–H bonds by an 18FF− salt via organic photoredox catalysis under blue light illumination. This strategy was applied to the synthesis of a wide range of 18F-labeled arenes and heteroaromatics, including pharmaceutical compounds. These products can serve as diagnostic agents or provide key information about the in vivo fate of the labeled substrates, as showcased in preliminary tracer studies in mice.
Human beige adipocytes (BAs) have potential utility for the development of therapeutics to treat diabetes and obesity-associated diseases. Although several reports have described the generation of ...beige adipocytes in vitro, their potential utility in cell therapy and drug discovery has not been reported. Here, we describe the generation of BAs from human adipose-derived stem/stromal cells (ADSCs) in serum-free medium with efficiencies >90%. Molecular profiling of beige adipocytes shows them to be similar to primary BAs isolated from human tissue. In vitro, beige adipocytes exhibit uncoupled mitochondrial respiration and cAMP-induced lipolytic activity. Following transplantation, BAs increase whole-body energy expenditure and oxygen consumption, while reducing body-weight in recipient mice. Finally, we show the therapeutic utility of BAs in a platform for high-throughput drug screening (HTS). These findings demonstrate the potential utility of BAs as a cell therapeutic and as a tool for the identification of drugs to treat metabolic diseases.
This letter proposes a cross‐domain WiFi‐based gesture recognition system (WiCross) based on a dynamically weighted multi‐label generative adversarial network. Most existing WiFi‐based gesture ...recognition systems are user, orientation, and environment sensitive, which limits the application of WiFi sensing. Compared with the influence of users and environments on WiFi sensing systems, the influence of orientation on WiFi sensing systems is more difficult to remove. To alleviate the confusion caused by the orientation more effectively, we arrange the transmitting and receiving antennas according to the characteristics of the Fresnel region. It is proposed to dynamically weight different links according to users' orientations and use a multi‐label generative adversarial network to obtain domain‐independent features. More importantly, WiCross can use domain‐independent features to classify some unknown gestures without modifying any code or dataset. Lightweight computing resource consumption allows WiCross to respond in real time. The experimental results show that WiCross can achieve an in‐domain recognition accuracy of 93.54% and a cross‐domain recognition accuracy of 93.11%.
This letter proposes and implements WiCross, a cross‐domain WiFi‐based gesture recognition system based on a dynamically weighted multi‐label generative adversarial network. WiCross removes domain information of users, orientations, and environments from the channel state information and generates domain‐independent features that can be used in common classifiers. We propose a dynamic link weights algorithm to solve the cross‐orientations problem, which achieves better performance than existing systems.
Macrophages hold great potential in cancer drug delivery because they can sense chemotactic cues and home to tumors with high efficiency. However, it remains a challenge to load large amounts of ...therapeutics into macrophages without compromising cell functions. This study reports a silica‐based drug nanocapsule approach to solve this issue. The nanocapsule consists of a drug–silica complex filling and a solid silica sheath, and it is designed to minimally release drug molecules in the early hours of cell entry. While taken up by macrophages at high rates, the nanocapsules minimally affect cell migration in the first 6–12 h, buying time for macrophages to home to tumors and release drugs in situ. In particular, it is shown that doxorubicin (Dox) as a representative drug can be loaded into macrophages up to 16.6 pg per cell using this approach. When tested in a U87MG xenograft model, intravenously (i.v.) injected Dox‐laden macrophages show comparable tumor accumulation as untreated macrophages. Therapy leads to efficient tumor growth suppression, while causing little systematic toxicity. This study suggests a new cell platform for selective drug delivery, which can be readily extended to the treatment of other types of diseases.
Macrophages are exploited as a vehicle to deliver therapeutics to tumors. This is achieved by a silica‐based nanocapsule that can be engulfed by macrophages by large quantities but minimally release its payloads in the early hours of cell entry. This property buys time for macrophages to migrate to tumors to selectively kill cancer cells while causing minimal systemic toxicity.
Ceramides, the core of the sphingolipid metabolism, draw wide attention as tumor suppressor, and act directly on mitochondria to trigger apoptotic cell death. Ceramide-based therapies are being ...developed by using promote ceramide generating agents. The ceramide metabolism balance is regulated by multifaceted factors in cancer development. Ceramide metabolic enzymes can increase the elimination of ceramide and counteract the anti-tumor effects of ceramide. However, recent research showed that these metabolic enzymes were highly expressed in several cancers. Especially ceramide glycosyltransferases, they catalyze ceramide glycosylation and synthesis the skeleton of glycosphingolipids (GSLs), play an important role in regulating tumor progression and have a significant correlation with the poor prognosis of cancer patients. To further understand the biological characteristics of ceramide metabolism in tumor, this review focuses on the role of ceramide glycosylation and related enzymes in cancer signaling and therapy. Besides, the research on multidrug resistance and potential inhibitors of ceramide glycosyltransferases are also discussed. Advance study on the structure of ceramide glycosyltransferases and ceramide glycosylation signaling pathway will open the path to new therapies and treatments.
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•The abnormality of GSLs is a common phenotype in cancer cells.•Ceramide glycosyltransferases can be used as therapeutic targets for cancer.•Ceramide glycosylation is closely related to drug resistance.•The inhibitors of ceramide glycosyltransferases are worth further research in the treatment of cancer.
Autophagy is a conserved process that delivers cytosolic substances to the lysosome for degradation, but its direct role in the regulation of antiviral innate immunity remains poorly understood. ...Here, through high-throughput screening, we discovered that CCDC50 functions as a previously unknown autophagy receptor that negatively regulates the type I interferon (IFN) signaling pathway initiated by RIG-I-like receptors (RLRs), the sensors for RNA viruses. The expression of CCDC50 is enhanced by viral infection, and CCDC50 specifically recognizes K63-polyubiquitinated RLRs, thus delivering the activated RIG-I/MDA5 for autophagic degradation. The association of CCDC50 with phagophore membrane protein LC3 is confirmed by crystal structure analysis. In contrast to other known autophagic cargo receptors that associate with either the LIR-docking site (LDS) or the UIM-docking site (UDS) of LC3, CCDC50 can bind to both LDS and UDS, representing a new type of cargo receptor. In mouse models with RNA virus infection, CCDC50 deficiency reduces the autophagic degradation of RIG-I/MDA5 and promotes type I IFN responses, resulting in enhanced viral resistance and improved survival rates. These results reveal a new link between autophagy and antiviral innate immune responses and provide additional insights into the regulatory mechanisms of RLR-mediated antiviral signaling.
Nasopharyngeal carcinoma (NPC) is a common head and neck malignant with a high incidence in Southern China. Genetic aberrations play a vital role in the pathogenesis, progression and prognosis of ...NPC. In the present study, we elucidated the underlying mechanism of FAS-AS1 and its genetic variation rs6586163 in NPC. We demonstrated that FAS-AS1 rs6586163 variant genotype carriers were associated with lower risk of NPC (CC vs. AA, OR = 0.645, P = 0.006) and better overall survival (AC + CC vs. AA, HR = 0.667, P = 0.030). Mechanically, rs6586163 increased the transcriptional activity of FAS-AS1 and contributed to ectopic overexpression of FAS-AS1 in NPC. rs6586163 also exhibited an eQTL trait and the genes affected by rs6586163 were enriched in apoptosis related signaling pathway. FAS-AS1 was downregulated in NPC tissues and over-expression of FAS-AS1 was associated with early clinical stage and better short-term treatment efficacy for NPC patients. Overexpression of FAS-AS1 inhibited NPC cell viability and promoted cell apoptosis. GSEA analysis of RNA-seq data suggested FAS-AS1 participate in mitochondria regulation and mRNA alternative splicing. Transmission electron microscopic examination verified that the mitochondria was swelled, the mitochondrial cristae was fragmented or disappeared, and their structures were destroyed in FAS-AS1 overexpressed cells. Furthermore, we identified HSP90AA1, CS, BCL2L1, SOD2 and PPARGC1A as the top 5 hub genes of FAS-AS1 regulated genes involved in mitochondria function. We also proved FAS-AS1 could affect Fas splicing isoform sFas/mFas expression ratio, and apoptotic protein expression, thus leading to increased apoptosis. Our study provided the first evidence that FAS-AS1 and its genetic polymorphism rs6586163 triggered apoptosis in NPC, which might have a potential as new biomarkers for NPC susceptibility and prognosis.
Abstract With the gradual shift of coal mining to the western coal mining region of China, floor heave in weakly cemented mudstone roadways has become an issue affecting the safety and efficiency of ...coal mine production. Additionally, different mining rates can lead to fluctuating support stresses on the roof and floor of weakly cemented mudstone roadways. Therefore, obtaining a comprehensive understanding of the mechanical properties of weakly cemented mudstone at different loading rates is conducive to improving the issue of floor heave in such roadways and provides a theoretical basis for further study. In this context, a series of uniaxial mechanical tests with concurrent acoustic emission monitoring were conducted on specimens of weakly cemented mudstone under various loading rates (0.005, 0.01, 0.05, and 0.1 mm/s). The stress‒strain and acoustic emission response curves were obtained to effectively characterize the strength, deformation, damage, macroscale instability, and crack propagation characteristics of the mudstone under the influence of loading rate effects. The research results support the following findings: (1) With increasing loading rate, the peak strength and elastic modulus of weakly cemented mudstone significantly increase, while the peak axial strain and peak radial deformation significantly decrease. (2) With increasing loading rate, the stress required to trigger the expansion of weakly cemented mudstone gradually increases, and a significant power-law relationship arises between the strain of the mudstone at the start of expansion and the loading rate. (3) With increasing loading rate, the acoustic emission ringing count of weakly cemented mudstone increases: The failure of weakly cemented mudstone changes from small-range progressive failure to sudden failure, and the failure mode transitions from shear failure to tensile‒shear composite failure. (4) The studied mudstone damage variables increase with increasing loading rate, following an approximate exponential function. The conclusions obtained in this work can provide a theoretical basis for the evolution mechanism and control of floor heave in deep roadway mining.
Peanut (Arachis hypogaea), a vital oil and food crop globally, is susceptible to web blotch which is a significant foliar disease caused by Phoma arachidicola Marasas Pauer&Boerema leading to ...substantial yield losses in peanut production. Calcium treatment has been found to enhance plant resistance against pathogens. This study investigates the impact of exogenous calcium on peanut resistance to web blotch and explores its mechanisms. Greenhouse experiments revealed that exogenous calcium treatment effectively enhanced resistance to peanut web blotch. Specifically, amino acid calcium and sugar alcohol calcium solutions demonstrated the best induced resistance effects, achieving reduction rates of 61.54% and 60% in Baisha1016, and 53.94% and 50% in Luhua11, respectively. All exogenous calcium treatments reduced malondialdehyde (MDA) and relative electrical conductivity (REC) levels in peanut leaves, mitigating pathogen-induced cell membrane damage. Exogenous calcium supplementation led to elevated hydrogen peroxide (H.sub.2O.sub.2) content and superoxide anion (O.sub.2.sup.*-) production in peanut leaves, facilitating the accumulation of reactive oxygen species (ROS) crucial for plant defense responses. Amino acid calcium and sugar alcohol calcium treatments significantly boosted activities of peroxidase (POD), superoxide dismutase (SOD), catalase (CAT), and ascorbate peroxidase (APX) in peanut leaves. Activation of these antioxidant enzymes effectively scavenged excess ROS, maintaining ROS balance and mitigating cellular damage. In summary, exogenous calcium treatment triggered ROS production, which was subsequently eliminated by the activation of antioxidant enzymes, thereby reducing cell membrane damage and inducing defense responses against peanut web blotch.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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