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Tumor-associated macrophages (TAM) are involved in tumor progression, metastasis, and immunosuppression. Because TAMs are highly plastic and could alter their phenotypes to proinflammatory M1 in response to environmental stimuli, reeducating TAMs has emerged as a promising approach to overcoming the challenges of solid cancer treatment. This study investigated the effect of IL9 on macrophage M1 polarization and verified its antitumor potential to retrain TAMs and promote chemokine secretion. We demonstrated that IL9 stimulated macrophage proliferation and polarized them toward the proinflammatory M1 phenotype in an IFNγ-dependent manner. Tumor-localized IL9 also polarized TAMs toward M1 in vivo and made them release CCL3/4 and CXCL9/10 to recruit antitumor immune cells, including T and natural killer cells, into the tumor microenvironment. Furthermore, peritoneal treatment with recombinant IL9 delayed the growth of macrophage-enriched B16F10 melanoma and 4T1 breast cancer in syngeneic mice, although IL9 treatment did not reduce tumor growth in the absence of macrophage enrichment. These results demonstrate the efficacy of IL9 in macrophage polarization to trigger antitumor immunity. Significance: These findings clarified the effect of IL9 on macrophage M1 polarization and verified its antitumor potential through retraining TAMs and chemokine secretion.

FACS gating strategy used for tumor-infiltrating immune cell analysis

Bodyweight change of the tumor-implanted mice in Figure 6

Generation of sorted bone marrow-derived macrophages (BMDMs)

Primers used in this study

Gating strategy to analyze the chemotactic migration of immune cells

Bodyweight change in the tumor-implanted mice in Figure 3

Treatment with IL-9 induces STAT1 and STAT3 phosphorylation in RAW 264.7 cells

Clodronate-encapsulated liposomes show cytotoxicity to BMDMs but not to B16F10 cells

IL-9 promotes M1 polarization of macrophages in vitro

Expression of IL-9R on the surface of B16F10 and 4T1 cells

Hyperpolarized proton signals in the entire structure of remdesivir are obtained due to a long-distance polarization transfer by para-hydrogen. Biological real-time reaction monitoring, by using a protein enzyme under mild conditions is carried out.

IntroductionIt is known that biological risk factors and lifestyle behaviors are important determinants of dementia. However, there has been yet to be sufficient evidence to prove that community-level social capital is one of the determinants of dementia. This retrospective cohort study is a large, long-term, population-based study that investigated the association between community-level social trust and the risk of dementia in the Republic of Korea.MethodsData came from the Korean National Health Insurance Service database. The community-level social trust values were determined by the Korean Community Health Survey. The study population consisted of 1,974,944 participants over 50 years of age and was followed up from 1 January 2012 to 31 December 2019 with a latent period of 5 years from 1 January 2012 to 31 December 2016. Cox proportional hazards regression was utilized to obtain the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the risk of dementia according to social trust quintiles.ResultsParticipants within the highest quintile of community-level social trust had a lower risk for overall dementia (aHR, 0.90; 95% CI, 0.86–0.94) and Alzheimer's disease (aHR, 0.90; 95% CI, 0.85–0.94) compared to those within the lowest quintile of community-level social trust. The alleviating trend association of high community-level social trust on dementia risk was maintained regardless of whether the participants had health examinations.ConclusionsOur findings suggest that higher community-level social trust is associated with a reduced risk of dementia. Community-level social trust is a crucial indicator of dementia and improving community-level social trust may lead to a lower risk of dementia.

Rufinamide is new antiepileptic drugs (AED), relatively well absorbed in the lower dose range, and is currently being used in antiepileptic medications, as well as containing a triazole structure. Triazoles are heterocycles containing three nitrogen atoms in a five-membered aromatic ring. Triazole derivatives can interact with various enzymes and receptors in biological systems via diverse non-covalent interactions, thus inducing versatile biological effects. Strain-promoted azide-alkyne cycloaddition (SPAAC) is a significant method for obtaining triazoles, even under physiological conditions, in the absence of a copper catalyst. To confirm the progress of chemical reactions under biological conditions, research on reaction monitoring at low concentrations is essential. This promising strategy is gaining acceptance for applications in fields like drug development and nanoscience. We investigated the optimum Ir-catalyst and magnetic field for achieving maximum proton hyperpolarization transfer in triazole derivatives. These reactions were analyzed using signal amplification by reversible exchange (SABRE) to overcome the limitations of low sensitivity in nuclear magnetic resonance spectroscopy, when monitoring copper-free click reactions in real time. Finally, a more versatile copper-catalyzed click reaction was monitored in real time, using a 60-MHz benchtop NMR system, in order to analyze the reaction mechanism.

Objective. High disease activity of ankylosing spondylitis (AS) is associated with poor sleep quality. The purpose of this study was to identify which of the representative tools for evaluating the disease activity of AS best reflect the quality of sleep. Methods. A total of 107 AS patients were enrolled in the study and the sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Age, sex, concomitant medication, erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP) level, Beck Depression Inventory second edition (BDI-II), Bath ankylosing spondylitis disease activity index (BASDAI), ankylosing spondylitis disease activity score (ASDAS)-ESR, ASDAS-CRP, pain visual analog scale, Insomnia Severity Index (ISI), and Epworth Sleepiness Scale (ESS) were analyzed as covariates. Results. Overall, 65% (70/107) of subjects reported poor sleep quality (PSQI＞5). There was a positive correlation between the sleep quality and disease activity as measured by the BASDAI, ASDAS-ESR, and ASDAS-CRP. In addition, the BASDAI demonstrated good correlations with ISI, ESS, and BDI-II, respectively. However, only BASDAI showed reliable correlation with PSQI among the disease activity parameters of AS (adjusted odd ratio 5.36, p=0.023). Conclusion. BASDAI is the most reliable parameter of disease activity associated with the sleep quality in patients with AS. (J Rheum Dis 2021;28:143-149)

Background/Aims: We investigated the distribution of serum uric acid (SUA) lev els and estimated the prevalence of hyperuricemia and hypouricemia in the Kore an population. Methods: This cross-sectional study used data from the Korean Genome and Epi demiology Study and included 172,970 participants (58,981 men and 113,989 wom en) aged 40 to 79 years. Hypouricemia and hyperuricemia were defined as SUA level ≤ 2.0 mg/dL and > 7 mg/dL, respectively. The prevalence of hyperuricemia and hypouricemia was evaluated by age and sex. Results: The mean SUA levels were significantly higher in men than in women (5.71 ± 1.27 mg/dL vs. 4.21 ± 0.96 mg/dL, p < 0.001). The mean SUA levels and prevalence of hyperuricemia increased with age in women but not in men. The overall preva lence of hyperuricemia and that in men and women was 50.82, 133.25, and 8.17 per 1,000 persons, respectively; the overall prevalence of hypouricemia and that in men and women was 4.16, 1.10, and 5.75 per 1,000 persons, respectively. The prev alence of hypouricemia in men was similar across all age groups; however, that in women was the highest in the age group of 40 to 49 years and the lowest in the age group of 50 to 59 years. Conclusions: The distribution of SUA levels and prevalence of hyperuricemia and hypouricemia differed according to age and sex. Age and sex should be considered in studies on uric acid-related diseases.

Catalytic pyrolysis is a promising technology for the production of renewable fuels and chemicals from lignin. The yield of aromatic compounds from the catalytic pyrolysis of lignin is significantl...

In this prospective study, we aimed to determine the impact of maternal parenting and attachment on brain development in early childhood. This study...

A superelastic titanium alloy was subjected to uniaxial tensile deformation at room temperature. The microstructural evolution and deformation mechanisms of the superelastic titanium alloy were investigated by electron backscatter diffraction (EBSD) and X-ray diffraction (XRD). Multiple deformation mechanisms including stress-induced martensitic transformation (SIMT), dislocation slip, {332} and {112} mechanical twinning were identified with the increase in uniaxial strain. In the early stage of deformation, a SIMT from the bcc beta phase to orthorhombic martensite phase dominantly occurred. As the deformation proceeded, the phase fraction of the remained martensite which did not return to beta phase obviously increased due to dislocation slip and mechanical twinning. The kernel average misorientation (KAM) value obtained from EBSD data gradually increased with increasing the deformation, indicating that the dislocation evolution was produced by slip. This was well matched with the trend in the full width at half maximum (FWHM) value of the peak profile obtained from XRD data. In addition, the fraction of the {332} twin was lower than that of the {112} twin in the initial specimen. However, the {332} twin rapidly increased compared to the {112} twin as deformation increased. Therefore, it is confirmed that {332} twinning and dislocation slip were the dominant mechanisms during plastic deformation.

Several stomach diseases are attributed to the dysregulation of physiological function of gastric mucosal barrier by pathogens. Gastric organoids are a promising tool to develop treatment strategies for gastric infections. However, their functional features of in vivo gastric mucosal barrier and host-microbe interactions are limited due to the lack of physiological stimuli. Herein, we describe the first human stomach micro-physiological system (hsMPS) with physiologically relevant gastric mucosal defense system based on the combination of organoid and MPS technology. A fluid flow enhanced epithelial-mesenchymal interaction in the hsMPS enables functional maturation of gastric epithelial cells, which allows for the recreation of mesh-like mucus layer containing high level of mucus protective peptides and well-developed epithelial junctional complexes. Furthermore, gastroprotection mechanisms against Helicobacter pylori are successfully demonstrated in our system. Therefore, hsMPS represents a new in vitro tool for research where gastric mucosal defense mechanism is pivotal for developing therapeutic strategies.

Toll-like Receptor 3 (TLR3) initiates a potent anti-viral immune response by binding to double-stranded RNA ligands. Previous crystallographic studies showed that TLR3 forms a homodimer when bound to a 46-base pair RNA ligand. However, this short RNA fails to initiate a robust immune response. To obtain structural insights into the length dependency of TLR3 ligands, we determine the cryo-electron microscopy structure of full-length TLR3 in a complex with a synthetic RNA ligand with an average length of ~400 base pairs. In the structure, the dimeric TLR3 units are clustered along the double-stranded RNA helix in a highly organized and cooperative fashion with a uniform inter-dimer spacing of 103 angstroms. The intracellular and transmembrane domains are dispensable for the clustering because their deletion does not interfere with the cluster formation. Our structural observation suggests that ligand-induced clustering of TLR3 dimers triggers the ordered assembly of intracellular signaling adaptors and initiates a robust innate immune response.

Our experiments indicate hyperpolarized proton signals in the entire structure of remdesivir are obtained due to a long-distance polarization transfer by

Signal amplification by reversible exchange (SABRE), a parahydrogen-based hyperpolarization technique, is valuable in detecting low concentrations of chemical compounds, which facilitates the understanding of their functions at the molecular level as well as their applicability in nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI). SABRE of 1-aminoisoquinoline (1-AIQ) is significant because isoquinoline derivatives are the fundamental structures in compounds with notable biological activity and are basic organic building blocks. Through this study, we explain how SABRE is applied to hyperpolarize 1-AIQ for diverse solvent systems such as deuterated and non-deuterated solvents. We observed the amplification of individual protons of 1-AIQ at various magnetic fields. Further, we describe the polarization transfer mechanism of 1-AIQ compared to pyridine using density functional theory (DFT) calculations. This hyperpolarization technique, including the polarization transfer mechanism investigation on 1-AIQ, will provide a firm basis for the future application of the hyperpolarization study on various bio-friendly materials.

The effect of high electric current density on the sintering of Ag wires manufactured by screen printing is evaluated through electrical resistivity analysis and microstructure observation. Different forms (continuous and pulsed) of electric current with different current densities are applied to the specimens. Conventional heat treatment is also performed as a control group to examine the athermal effect of electropulsing treatment. Compared to the conventional heat treatment, the resistivity is reduced more under the electropulsing treatment with continuous current for the same temperature and treatment time. Also, the process time of electropulsing treatment can be reduced by applying a pulse form of high density current instead of continuous current without losing the benefit of enhanced reduction of resistivity. The microstructural observations obtained from high angle annular dark field scanning transmission electron microscope and a digital precession instrument clearly show that necking connecting the crystals is formed more firmly under electric current. In addition, the temperature change of Ag wire and substrate is calculated according to the change of the resistivity when the electric current is applied to confirm the reliability.

The tandem acylation reactions of 2-quinolylzincates under one-pot reaction conditions facilitated the formation of biologically active (Z)-3-alkylidenephthalides and multifunctionalized quinoline derivatives at specific positions. The reactions of these zincates with allyl iodide produced three different types of temperature- and alkyl-ligand-dependent C-2 homologated quinolines. The reaction mechanisms for the formation of the presented products from 2-quinolylzincates are also proposed in detail.

Higd-1a/HIMP1-a/HIG1, a mitochondrial inner membrane protein, promotes cell survival under low glucose and hypoxic conditions. We previously reported that it interacts with Opa1, a factor involved in mitochondrial fusion, to regulate mitochondrial homeostasis. In the present study, we found that depletion of Higd-1a inhibited the proliferation of pancreatic cancer cells in vitro and in mice xenografts. Higd-1a knockdown did not itself lead to cell death but it caused cell cycle arrest through induction of p27KIP1 and hypo-phosphorylation of RB protein. Knockdown of Higd-1a also induced cellular senescence as shown by increased granularity and SA-β-galactosidase activity. We further showed that the mitochondrial stress induced by Higd-1a led to reduced ERK phosphorylation. Inhibition of the ERK pathway with U0126 induced p27KIP1 expression in the pancreatic cancer cells, confirming that the cell cycle retardation was the result of inhibition of the ERK pathway. Array analysis of human pancreatic cancers revealed that expression of Higd-1a was significantly elevated in pancreatic cancer tissues compared to normal tissue. Collectively, our results demonstrate that Higd-1a plays an important role in the proliferation of pancreatic cancer cells by regulating the pERK/p27KIP1/pRB signaling pathway.

The efficacy and safety of febuxostat in patients with stage 4-5 chronic kidney disease (CKD) remains unclear. We evaluated the urate-lowering efficacy and renal safety of febuxostat in patients with stage 4-5 CKD not yet on dialysis, through a meta-analysis of observational studies.We performed a systematic search in PubMed, Ovid MEDLINE, Embase, and the Cochrane Library databases for observational studies of patients with advanced CKD starting febuxostat. Articles describing changes in serum urate levels and/or renal function assessed by the estimated glomerular filtration rate (eGFR) were included.Among 148 retrieved studies, five relevant observational studies with 327 patients were included in the meta-analysis. Febuxostat was administered daily at 10-120 mg for 3-12 months. Serum urate reduced in response to febuxostat (weighted mean difference, -1.85 mg/dL; 95% CI, -2.04--1.67 mg/dL; IOverall, febuxostat has acceptable urate-lowering efficacy and renal safety in patients with hyperuricemia and stage 4-5 CKD who are not yet on dialysis.

Simple Summary Interleukin (IL) 15 is a proinflammatory cytokine and is well-known as an efficacious cytokine for cancer immunotherapy. Interestingly, the IL-15:IL-15Rα complex, a self-assembling form of IL-15 and its soluble receptor α (IL-15Rα), has shown greater antitumor activity than IL-15 itself. However, the development of a suitable multigene delivery system is needed for further applications of IL-15:IL-15Rα. Baculovirus, an arthropod-specific virus, is known for its adjuvant effect in cancer therapy. Here, we investigated the potential of the BacMam virus, a modified baculovirus for gene delivery into mammalian cells, as a novel multigene delivery system to generate a cell-based cancer vaccine secreting the self-assembling IL-15:IL-15Rα complex. Vaccination with a BacMam-based IL-15:IL-15Rα cancer vaccine triggered antitumor immune responses in a tumor antigen-specific manner. Our findings indicate that the BacMam system is a safe and effective method to produce protective and therapeutic cancer vaccines. Abstract This study reports the use of the BacMam system to deliver and express self-assembling IL-15 and IL-15Rα genes to murine B16F10 melanoma and CT26 colon cancer cells. BacMam-based IL-15 and IL-15Rα were well-expressed and assembled to form the biologically functional IL-15:IL-15Rα complex. Immunization with this IL-15:IL-15Rα cancer vaccine delayed tumor growth in mice by inducing effector memory CD4+ and CD8+ cells and effector NK cells which are tumor-infiltrating. It caused strong antitumor immune responses of CD8+ effector cells in a tumor-antigen specific manner both in vitro and in vivo and significantly attenuated Treg cells which a control virus-infected cancer vaccine could induce. Post-treatment with this cancer vaccine after a live cancer cell injection also prominently delayed the growth of the tumor. Collectively, we demonstrate a vaccine platform consisting of BacMam virus-infected B16F10 or CT26 cancer cells that secrete IL-15:IL-15Rα. This study is the first demonstration of a functionally competent soluble IL-15:IL-15Rα complex-related cancer vaccine using a baculovirus system and advocates that the BacMam system can be used as a secure and rapid method of producing a protective and therapeutic cancer vaccine.

Signal amplification by reversible exchange (SABRE) is an effective NMR hyperpolarization technique for signal enhancement using para-hydrogen on iridium catalysts. To date, monodentate chelating nitrogen analogs have been predominantly used as substrates for SABRE because of the limited chelating sites of the Ir-catalyst with different molecular orientations. Herein, for the first time, the use of a tridentate chelating ligand (BPEA) containing pyridine moieties and a secondary amine as a SABRE substrate is demonstrated. For the optimization of the tridentate chelating ligand, alkyl chain lengths were varied with the optimization of the external magnetic field and concentrations of three different ligands. Because many chemically multidentate complexes present in nature have scarcely been studied as SABRE substrates, this optimized tridentate chelating ligand structure with the SABRE catalyst and its polarization transfer from para-hydrogen will broaden the scope of hyperpolarizable substrates and help in the investigation of chelating structures for future applications.

Currently, signal amplification by reversible exchange (SABRE) using para-hydrogen is an attractive method of hyperpolarization for overcoming the sensitivity problems of nuclear magnetic resonance...

In the present study, the tensile deformation behavior of transformation-induced plasticity (TRIP)-aided steel under pulsed electric current is investigated. When a pulsed electric current is applied to the specimen during entire tensile deformation, a significant reduction of elongation is observed. The reason is that the mechanically induced martensitic transformation (MIMT) effect does not work properly as the stability of retained austenite phase increases due to temperature rise by the applied electric current. To improve the ductility of the TRIP-aided steel, the pulsing pattern of electric current is modified to apply the electric current only in the early stage of deformation immediately before the phase transformation of retained austenite phase begins to take place. As a result, the elongation is significantly increased by delaying the MIMT effect and making it work properly in the latter stage of deformation. Also, the electrically-induced annealing effect, which occurs in the early stage of deformation where a dislocation plasticity occurs dominantly, contributes to the improvement of elongation. The modified pulsing pattern suggested in the present study provides an easy-to-implement technique to improve the formability of the TRIP-aided steel.

Plutonium has potential applications in energy production in well-controlled nuclear reactors. Since nuclear power plants have great merit as environmentally friendly energy sources with a recyclable system, a recycling system for extracting Pu from spent fuels using suitable extractants has been proposed. Pu leakage is a potential environmental hazard, hence the need for chemical sensor development. Both extractants and chemical sensors involve metal–ligand interactions and to develop efficient extractants and chemical sensors, structural information about Pu ligands must be obtained by quantum calculations. Herein, six representative nitrogen tridentate ligands were introduced, and their binding stabilities were evaluated. The tridentate L6, which contains tri-pyridine chelate with benzene connectors, showed the highest binding energies for Pu(IV) and PuO2(VI) in water. Analysis based on the quantum theory of atoms in molecular analysis, including natural population analysis and electron density studies, provided insight into the bonding characteristics for each structure. We propose that differences in ionic bonding characteristics account for the Pu-ligand stability differences. These results form a basis for designing novel extractants and organic Pu sensors.

In this study, the effects of sucrose on nutritional and functional composition as well as antioxidant activities in buckwheat sprouts during germination were investigated. Treatment with 1%, 2%, or 3% sucrose resulted in an increase in the amount of vitamins, four C-glycosylflavones, and rutin. Tocopherols and β-carotene in sprouts treated with 1%, 2%, and 3% sucrose were increased in a dose-dependent manner. Similarly, the sum of individual flavonoid was 1.35, 1.29, and 1.60 times higher than that of control sprouts. Sucrose treatment increased tyrosine and phenylalanine ammonia-lyase activities resulting in an increase in the flavonoid content. Moreover, treatment of HepG2 cells with buckwheat sprouts ameliorated oxidative damages by modulating reactive oxygen species production, malondialdehyde generation, and antioxidant enzyme activities. These results suggest that sucrose treatment could improve the nutritional composition and antioxidant effects of germinating buckwheat sprouts.

BACKGROUND Semantic variant primary progressive aphasia (svPPA) has been associated with a variety of proteinopathies, mainly transactive response DNA-binding protein, but also with tau and β-amyloid. Recently selective tau tracers for positron emission tomography (PET) have been developed to determine the presence of cerebral tau deposits in vivo. Here, we investigated the topographical distribution of THK5351 in svPPA patients. MATERIALS AND METHODS Five svPPA patients, 14 Alzheimer's disease patients, and 15 age-matched normal controls underwent [F]-THK5351 PET scans, magnetic resonance imaging, and detailed neuropsychological tests. [F]-fluorodeoxyglucose PET was obtained in 3 svPPA patients, whereas the remaining 2 underwent amyloid PET using [F]-flutemetamol. Tau distribution among the 3 groups was compared using regions of interest-based and voxel-based statistical analyses. RESULTS In svPPA patients, [F]-THK5351 retention was elevated in the anteroinferior and lateral temporal cortices compared with the normal controls group (left>right), and in the left inferior and temporal polar region compared with Alzheimer's disease patients. [F]-THK5351 retention inversely correlated with glucose metabolism, whereas regional THK retention correlated with clinical severity. [F]-flutemetamol scans were negative for β-amyloid. CONCLUSIONS These findings show that [F]-THK5351 retention may be detected in cortical regions correlating with svPPA pathology.

An empirical expression describing the electroplastic deformation behavior is suggested based on the Johnson-Cook (JC) model by adding several functions to consider both thermal and athermal electric current effects. Tensile deformation behaviors are carried out for an AZ31 magnesium alloy and an Al-Mg-Si alloy under pulsed electric current at various current densities with a fixed duration of electric current. To describe the flow curves under electric current, a modified JC model is proposed to take the electric current effect into account. Phenomenological descriptions of the adopted parameters in the equation are made. The modified JC model suggested in the present study is capable of describing the tensile deformation behaviors under pulsed electric current reasonably well.