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Sitagliptin is a dipeptidyl peptidase‐IV inhibitor for the treatment of type 2 diabetes mellitus. In the present study, a sensitive and high‐throughput quantitative method based on the direct analysis in real time tandem mass spectrometry has been developed and validated for the bioanalysis of sitagliptin in rat plasma without chromatographic separation. Sitagliptin and its internal standard retagliptin were detected in positive ion mode by multiple reaction monitoring transitions at m/z 408.2→235.0 and 465.2→260.1, respectively. The method includes a simple solid‐phase extraction sample preparation procedure, through which appropriate and reproducible analytical results within the linear concentration range of 20–2000 ng/mL have been achieved. The intra‐ and interday precisions were <10.6% and the accuracies were ranging from −8.17 to 2.60%. This method has been successfully applied to the pharmacokinetic study of sitagliptin after single intravenous administration in rats. This approach shows considerable promise of direct analysis in real time tandem mass spectrometry method in the high‐throughput bioanalysis. [ABSTRACT FROM AUTHOR]

Ferroelectrics are considered as the most promising energy-storage materials applied in advance power electronic devices due to excellent charge–discharge properties. However, the unsatisfactory energy-storage density is the paramount issue that limits their practical applications. In this work, the excellent energy-storage properties are achieved in (1-x)Na0.5Bi0.5TiO3-xSr0.7Nd0.2TiO3 ((1-x)NBT-xSNT) ferroelectric ceramics by a synergistic strategy, where SNT improves breakdown strength and enhances relaxation characteristic simultaneously. A high recoverable energy-storage density of 3.85 J cm−3 and an energy-storage efficiency of 85.3% under an applied electric field of 305 kV cm−1 are acquired in 0.5NBT-0.5SNT ceramic. Moreover, excellent temperature stability and frequency stability were also observed. The change rate of energy density is less than 10%, where the temperature and frequency in the range of 20–120 °C and 20–180 Hz, respectively. Meanwhile, an ultrahigh power density of 175 MW cm−3 together with a fast discharge time of 136 ns is realized at 250 kV cm−1. These excellent performances show that (1-x)NBT-xSNT ceramics have the potential to be used in pulsed power systems. [ABSTRACT FROM AUTHOR]

Immune response as expressed by the Drosophila Toll sequence relies on Dif, the third component in NF-kB-related factors, Along with Dorsal and Relish, Dif is present in the Toll signaling pathway, and acts downstream to induce drosomycin. Dif-impaired pathways not only result in the absence of drosomycin but defensin as well, hindering immune response.

Ferroelectric is thought to be one of the most promising energy-storage materials due to its high polarization. However, large energy loss and low breakdown strength (BDS) are the main drawbacks that hinder high energy-storage performances of ferroelectric materials. Here, excellent energy-storage performances are achieved in 0.85(0.55Na0.5Bi0.5TiO3-0.45Sr0.7La0.2TiO3)-0.15Bi(Mg2/3Nb1/3)O3 (NBT-SLT-BMN) relaxor ferroelectric ceramic by optimizing sintering temperatures, which leads to a high recoverable energy-storage density (Wrec) of 3.88 J/cm3 together with a high energy efficiency (η) of 85% at the optimal sintering temperature of 1170 °C. The microstructural analysis suggests that the softened B-O vibrations and the formation of polar nanorgeions give rise to the enhanced relaxation behavior that is responsible for the decrease of energy loss. Meanwhile, the optimal sintering temperature has an effective role in decreasing grain size, resulting in a large increase of the BDS. Moreover, the ceramic sintered at 1170 °C exhibits excellent energy-storage stability in the range of 20–180 °C and 1-125 Hz. Based on the pulse charge-discharge measurement, a high-power density of 68.47 MW/cm3 and a fast charge-discharge speed of 72 ns are acquired. These results show that the appropriate sintering temperature can optimize the microstructure and improve the energy-storage performance of ferroelectric ceramics. [ABSTRACT FROM AUTHOR]

Purpose: In vivo imaging of programmed death ligand 1 (PD-L1) during immunotherapy could potentially monitor changing PD-L1 expression and PD-L1 expression heterogeneity within and across tumors. Some protein constructs can be used for same-day positron emission tomography (PET) imaging. Previously, we evaluated the PD-L1-targeting Affibody molecule [18F]AlF-NOTA-ZPD-L1_1 as a PET tracer in a mouse tumor model of human PD-L1 expression. In this study, we evaluated the affinity-matured Affibody molecule ZPD-L1_4, to determine if improved affinity for PD-L1 resulted in increased in vivo targeting of PD-L1. Procedures: ZPD-L1_4 was conjugated with NOTA and radiolabeled with either [18F]AlF or 68Ga. [18F]AlF-NOTA-ZPD-L1_4 and [68Ga]NOTA-ZPD-L1_4 were evaluated in immunocompromised mice with LOX (PD-L1+) and SUDHL6 (PD-L1-) tumors with PET and ex vivo biodistribution measurements. In addition, whole-body PET studies were performed in rhesus monkeys to predict human biodistribution in a model with tracer binding to endogenous PD-L1, and to calculate absorbed radiation doses. Results: Ex vivo biodistribution measurements showed that both tracers had > 25 fold higher accumulation in LOX tumors than SUDHL6 ([18F]AlF-NOTA-ZPD-L1_4: LOX: 8.7 ± 0.7 %ID/g (N = 4) SUDHL6: 0.2 ± 0.01 %ID/g (N = 6), [68Ga]NOTA-ZPD-L1_4: LOX: 15.8 ± 1.0 %ID/g (N = 6) SUDHL6: 0.6 ± 0.1 %ID/g (N = 6)), considerably higher than ZPD-L1_1. In rhesus monkeys, both PET tracers showed fast clearance through kidneys and low background signal in the liver ([18F]AlF-NOTA-ZPD-L1_4: 1.26 ± 0.13 SUV, [68Ga]NOTA-ZPD-L1_4: 1.11 ± 0.06 SUV). PD-L1-expressing lymph nodes were visible in PET images, indicating in vivo PD-L1 targeting. Dosimetry estimates suggest that both PET tracers can be used for repeated clinical studies, although high kidney accumulation may limit allowable radioactive doses. Conclusions: [18F]AlF-NOTA-ZPD-L1_4 and [68Ga]NOTA-ZPD-L1_4 are promising candidates for same-day clinical PD-L1 PET imaging, warranting clinical evaluation. The ability to use either [18F] or [68Ga] may expand access to clinical sites. [ABSTRACT FROM AUTHOR]

Binary SiO 2 -CaO mesoporous bioactive glass nanoparticles (MBGNs) are multifunctional biomaterials able to promote osteogenic, angiogenic, and immunomodulatory activities. MBGNs have been applied in a variety of tissue regeneration strategies. However, MBGNs lack strong antibacterial activity and current strategies (loading of antibacterial ions or antibiotics) toward enhanced antibacterial activity may cause cytotoxicity or antibiotic resistance. Here we engineered MBGNs using bacteriophages (phages) to enhance the antibacterial activity. Salmonella Typhimurium (S. T) phage PFPV25.1 that can infect Salmonella enterica serovar Typhimurium strain LT2 was used as a model phage to engineer MBGNs. MBGNs were first modified with amine groups to enhance the affinity between phages and MBGNs surfaces. Afterward, the physicochemical and antibacterial activity of phage-engineered MBGNs was evaluated. The results showed that S. T phage PFPV25.1 was successfully bound onto MBGNs surfaces without losing their bioactivity. A higher quantity of phages could be bounded onto amine-functionalized MBGNs than onto non-functionalized MBGNs. Phages on amine-functionalized MBGNs exhibited higher antibacterial activity. The stability test showed that phages could remain on amine-functionalized MBGNs for over 28 days. This work provides valuable information on developing phage-modified MBGNs as a new and effective antibacterial system for biomedical applications. [Display omitted] ● Bacteriophages bonded onto the surface of modified MBGNs through electrostatic force. ● Bacteriophages exclusively infect bacteria with high specificity. ● Bacteriophages can potentially address the antibiotic resistance issue. ● Bacteriophages provide an "antibiotic-free" strategy to combat bacterial infection. [ABSTRACT FROM AUTHOR]

Cytokine release syndrome (CRS) is a major cause of the multi-organ injury and fatal outcome induced by SARS-CoV-2 infection in severe COVID-19 patients. Metabolism can modulate the immune responses against infectious diseases, yet our understanding remains limited on how host metabolism correlates with inflammatory responses and affects cytokine release in COVID-19 patients. Here we perform both metabolomics and cytokine/chemokine profiling on serum samples from healthy controls, mild and severe COVID-19 patients, and delineate their global metabolic and immune response landscape. Correlation analyses show tight associations between metabolites and proinflammatory cytokines/chemokines, such as IL-6, M-CSF, IL-1α, IL-1β, and imply a potential regulatory crosstalk between arginine, tryptophan, purine metabolism and hyperinflammation. Importantly, we also demonstrate that targeting metabolism markedly modulates the proinflammatory cytokines release by peripheral blood mononuclear cells isolated from SARS-CoV-2-infected rhesus macaques ex vivo, hinting that exploiting metabolic alterations may be a potential strategy for treating fatal CRS in COVID-19. Metabolism changes can modulate immune responses in many contexts, and vice versa. Here the authors associate metabolomic, as well as cytokine and chemokine, data from stratified COVID-19 patients to find that arginine, tryptophan and purine metabolic pathways correlate with hyperproliferation, thus hinting at potential therapeutic targets for severe COVID-19 patients. [ABSTRACT FROM AUTHOR]