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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

Primers used in this study

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)

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.

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.

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.

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.

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 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.

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.

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.

Background and purpose Behavioral variant frontotemporal dementia (bvFTD) is a subtype of frontotemporal dementia, which has clinical symptoms of progressive personality and behavioral changes with deterioration of social cognition and executive functions. The pathology of bvFTD is known to be tauopathy or TDP-43 equally. We analyzed the 18F-THK5351 positron emission tomography (PET) scans, which were recently developed tau PET, in patients with clinically-diagnosed bvFTD. Methods Forty-eight participants, including participants with behavioral variant frontotemporal dementia (bvFTD, n=3), Alzheimer's disease (AD, n=21) and normal cognition (NC, n=24) who completed 3T magnetic resonance images, 18F-THK5351 PET scans, and detailed neuropsychological tests were included in the study. Voxel-wise statistical analysis and region of interest (ROI)-based analyses were performed to evaluate the retention of THK in bvFTD patients. Results In the voxel-based and ROI-based analyses, patients with bvFTD showed greater THK retention in the prefrontal, medial frontal, orbitofrontal, anterior cingulate, insula, anterior inferior temporal and striatum regions compared to NC participants. Left-right asymmetry was noted in the bvFTD patients. A patient with extrapyramidal symptoms showed much greater THK retention in the brainstem. Conclusions The distribution of THK retention in the bvFTD patients was mainly in the frontal, insula, anterior temporal, and striatum regions which are known to be the brain regions corresponding to the clinical symptoms of bvFTD. Our study suggests that 18F-THK5351 PET imaging could be a supportive tool for diagnosis of bvFTD.

Background and purpose To analyze 18F-THK5351 positron emission tomography (PET) scans of patients with clinically diagnosed nonfluent/agrammatic variant primary progressive aphasia (navPPA). Methods Thirty-one participants, including those with Alzheimer's disease (AD, n=13), navPPA (n=3), and those with normal control (NC, n=15) who completed 3 Tesla magnetic resonance imaging, 18F-THK5351 PET scans, and detailed neuropsychological tests, were included. Voxel-based and region of interest (ROI)-based analyses were performed to evaluate retention of 18F-THK5351 in navPPA patients. Results In ROI-based analysis, patients with navPPA had higher levels of THK retention in the Broca's area, bilateral inferior frontal lobes, bilateral precentral gyri, and bilateral basal ganglia. Patients with navPPA showed higher levels of THK retention in bilateral frontal lobes (mainly left side) compared than NC in voxel-wise analysis. Conclusions In our study, THK retention in navPPA patients was mainly distributed at the frontal region which was well correlated with functional-radiological distribution of navPPA. Our results suggest that tau PET imaging could be a supportive tool for diagnosis of navPPA in combination with a clinical history.

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.

Early- and late-onset Alzheimer’s disease (AD) patients often exhibit distinct features. We sought to compare overall white matter connectivity and evaluate the pathological factors (amyloid, tau, and vascular pathologies) that affect the disruption of connectivity in these two groups. A total of 50 early- and 38 late-onset AD patients, as well as age-matched cognitively normal participants, were enrolled and underwent diffusion-weighted magnetic resonance imaging to construct fractional anisotropy-weighted white matter connectivity maps. [18F]-THK5351 PET, [18F]-Flutemetamol PET, and magnetic resonance imaging were used for the evaluation of tau and related astrogliosis, amyloid, and small vessel disease markers (lacunes and white matter hyperintensities). Cluster-based statistics was performed for connectivity comparisons and correlation analysis between connectivity disruption and the pathological markers. Both patient groups exhibited significantly disrupted connectivity compared to their control counterparts with distinct patterns. Only THK retention was related to connectivity disruption in early-onset AD patients, and this disruption showed correlations with most cognitive scores, while late-onset AD patients had disrupted connectivity correlated with amyloid deposition, white matter hyperintensities, and lacunes in which only a few cognitive scores showed associations. These findings suggest that the pathogenesis of connectivity disruption and its effects on cognition are distinct between EOAD and LOAD.

Several drug candidates have been proposed and tested as the latest clinical treatment for coronavirus pneumonia (COVID-19). Chloroquine, hydroxychloroquine, ritonavir/lopinavir, and favipiravir are under trials for the treatment of this disease. The hyperpolarization technique has the ability to further provide a better understanding of the roles of these drugs at the molecular scale and in different applications in the field of nuclear magnetic resonance/magnetic resonance imaging. This technique may provide new opportunities in diagnosis and research of COVID-19. Signal amplification by reversible exchange-based hyperpolarization studies on large-sized drug candidates were carried out. We observed hyperpolarized proton signals from whole structures, due to the unprecedented long-distance polarization transfer by para-hydrogen. We also found that the optimal magnetic field for the maximum polarization transfer yield was dependent on the molecular structure. We can expect further research on the hyperpolarization of other important large molecules, isotope labeling, as well as polarization transfer on nuclei with a long spin relaxation time. A clinical perspective of these features on drug molecules can broaden the application of hyperpolarization techniques for therapeutic studies.

Signal Amplification by Reversible Exchange (SABRE), a hyperpolarization technique, has been harnessed as a powerful tool to achieve useful hyperpolarized materials by polarization transfer from parahydrogen. In this study, we systemically applied SABRE to a series of nitrile compounds, which have been rarely investigated. By performing SABRE in various magnetic fields and concentrations on nitrile compounds, we unveiled its hyperpolarization properties to maximize the spin polarization and its transfer to the next spins. Through this sequential study, we obtained a ~130-fold enhancement for several nitrile compounds, which is the highest number ever reported for the nitrile compounds. Our study revealed that the spin polarization on hydrogens decreases with longer distances from the nitrile group, and its maximum polarization is found to be approximately 70 G with 5 &mu, L of substrates in all structures. Interestingly, more branched structures in the ligand showed less effective polarization transfer mechanisms than the structural isomers of butyronitrile and isobutyronitrile. These first systematic SABRE studies on a series of nitrile compounds will provide new opportunities for further research on the hyperpolarization of various useful nitrile materials.

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...