How host cells recognize many kinds of RNA and DNA viruses and initiate innate antiviral responses against them has not yet been fully elucidated. Over the past decade, investigations into the ...mechanisms underlying these antiviral responses have focused extensively on immune surveillance sensors that recognize virus‐derived components (such as lipids, sugars and nucleic acids). The findings of these studies have suggested that antiviral responses are mediated by cytosolic or intracellular compartment sensors and their adaptor molecules (e.g., TLR, myeloid differentiation primary response 88, retinoic acid inducible gene‐I, IFN‐β promoter stimulator‐1, cyclic GMP‐AMP synthase and stimulator of IFN genes axis) for the primary sensing of virus‐derived nucleic acids, leading to production of type I IFNs, pro‐inflammatory cytokines and chemokines by the host cells. Thus, host cells have evolved an elaborate host defense machinery to recognize and eliminate virus infections. In turn, to achieve sustained viral infection and induce pathogenesis, viruses have also evolved several counteracting strategies for achieving immune escape by targeting immune sensors, adaptor molecules, intracellular kinases and transcription factors. In this review, we discuss recent discoveries concerning the role of the cytosolic nucleic acid‐sensing immune response in viral recognition and control of viral infection. In addition, we consider the regulatory machinery of the cytosolic nucleic acid‐sensing immune response because these immune surveillance systems must be tightly regulated to prevent aberrant immune responses to self and non‐self‐nucleic acids.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Highly dispersed Ru nanoparticles loaded on a TiO2 support (Ru/TiO2(B)), which affects the hydrogenation of CO2 to CH4 (methanation), were prepared by employing a "dry" modification method using a ...barrel-sputtering instrument. The loaded Ru nanoparticles exhibited a narrow particle-size distribution with a mean diameter of ca. 2.5 nm. Methanation of CO2 on the Ru/TiO2(B) catalyst produced a 100% yield at ca. 160 degreeC, which is more than 200 degreeC below that required for Ru/TiO2 prepared by a conventional "wet" impregnation method. In addition, the methanation reaction over Ru/TiO2(B) proceeded at temperatures as low as room temperature with a reaction rate of 0.04 small micromol min-1 g-1.
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IJS, KILJ, NUK, UL, UM, UPUK
Programmed death‐ligand 1 (PD‐L1) is an immune modulator that promotes immunosuppression by binding to programmed death‐1 of T‐lymphocytes. Although tumor cell PD‐L1 expression has been shown to be ...associated with the clinical response to anti–PD‐L1 antibodies, its concise regulatory mechanisms remain elusive. In this study, we evaluated the associations of tumor PD‐L1 expression and immune cell infiltrating patterns in 146 cases of early lung adenocarcinoma (AC) to investigate the possible extrinsic regulation of tumor PD‐L1 by immune cells. Using immunohistochemistry, cell surface PD‐L1 expression in tumor cells was observed in 18.5% of stage 0‐IA lung AC patients. Tumor PD‐L1 positivity was significantly associated with stromal invasion, which was accompanied by increased tumor‐associated macrophages (TAM), CD8+ cytotoxic T cells and FoxP3+ regulatory T cells. Among these immune cells, TAM and CD8+ T cells significantly accumulated in PD‐L1‐positive carcinoma cell areas, which showed a tumor cell nest‐infiltrating pattern. Although CD8+ T cells are known to induce tumor PD‐L1 expression via interferon‐ɣ production, the increased TAM within tumors were also associated with tumor cell PD‐L1 positivity, independently of CD8+ T cell infiltration. Our in vitro experiments revealed that PD‐L1 expression in lung cancer cell lines was significantly upregulated by co–culture with M2‐differentiated macrophages; expression of PD‐L1 was reduced to baseline levels following treatment with a transforming growth factor‐β inhibitor. These results demonstrated that tumor‐infiltrating TAM are extrinsic regulators of tumor PD‐L1 expression, indicating that combination therapy targeting both tumor PD‐L1 and stromal TAM might be a possible strategy for effective treatment of lung cancer.
In this study, we showed that tumor‐associated macrophage (TAM) infiltration was an additional factor related to tumor programmed death‐ligand 1 (PD‐L1) expression in early lung adenocarcinoma. Our in vitro experiments demonstrated that M2‐differentiated macrophages facilitated tumor PD‐L1 expression through transforming growth factor‐β. These results suggested that TAM were extrinsic regulators of tumor PD‐L1 expression and could serve as potential therapeutic targets.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
•CO2 methanation reaction on Ru/TiO2 catalyst was analyzed by DFT analysis.•The overall potential energy diagram of methanation reaction was obtained.•CO hydrogenation and CH4 formation have high ...reaction energy barrier.•These energy barriers decreased in comparison with that on bulk Ru surface.•The size and structure of Ru cluster affected the catalytic activity of Ru/TiO2.
The methanation reaction of CO2 on a Ru nanoparticle supported on TiO2 catalyst has been investigated by density functional theory (DFT) using the generalized gradient approximation with periodic boundary conditions. Two plausible reaction paths were found for the transformation of CO2 to CH4 on TiO2-supported Ru nanoparticles. The origin of the high activity of the catalyst is discussed based on the overall reaction energy diagram obtained from DFT calculations. The CO2 is readily and stably adsorbed on Ru cluster at moderate temperature as compared with that on bulk Ru surface. It is due to the difference of the Ru structure between the Ru nanoparticle and the bulk Ru surface. The elementary reactions of the hydrogenation of adsorbed CO and of the production of CH4 are possible to become the rate-determining steps over the methanation reaction, because these two reactions have a higher potential energy barrier than that of other elementary reactions in the overall reaction path. These potential energy barriers for the hydrogenation of CO and the production of CH4 on TiO2-supported Ru nanoparticles were lower than those on bulk Ru surface, which explains the high activity of the Ru nanoparticle-loaded TiO2 catalyst. The lowering of these potential energy barriers can be caused by weak charge transfer between Ru atoms and adsorbed species on the TiO2-supported Ru nanoparticles. As the results, the catalytic activity of the Ru nanoparticles supported on TiO2 catalyst is characterized by the structure of Ru nanoparticles and by the weak charge transfer between Ru atoms and adsorbed species.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
High-fat diet (HFD)-induced obesity is a primary risk factor for serious health problems. Although much research has been performed at the genomic level, lipidomic studies were limited. In this ...study, we aim to obtain a comprehensive profile of circulating plasma lipids, which are altered in rodent rat obesity by untargeted liquid chromatography–mass spectrometry. Rats fed with HFD for 8 weeks had increased body weight, liver and adipose tissue weight. The analysis results revealed that polyunsaturated fatty acids (PUFAs) and their corresponding phosphatidylcholine, phosphatidylinositol, and phosphatidylserine were significantly decreased in rats fed with HFD. In contrast, less unsaturated and ether type phosphatidylglycerols were increased. The triacylglycerides (TAGs) having saturated FA were increased in the HFD condition, whereas TAGs having PUFA were decreased. The levels of many plasma lipids were altered, and interestingly PUFA derived lipids were negatively associated with obesity. This signifies the importance of a PUFAs enriched diet to overwhelm obesity associated diseases.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In mammals, cytosolic detection of nucleic acids is critical in initiating innate antiviral responses against invading pathogens (like bacteria, viruses, fungi and parasites). These programs are ...mediated by multiple cytosolic and endosomal sensors and adaptor molecules (c-GAS/STING axis and TLR9/MyD88 axis, respectively) and lead to the production of type I interferons (IFNs), pro-inflammatory cytokines, and chemokines. While the identity and role of multiple pattern recognition receptors (PRRs) have been elucidated, such immune surveillance systems must be tightly regulated to limit collateral damage and prevent aberrant responses to self- and non-self-nucleic acids. In this review, we discuss recent advances in our understanding of how cytosolic sensing of DNA is controlled during inflammatory immune responses.
Our group has conducted extensive basic and preclinical studies of the use of human induced pluripotent cell (iPSC)-derived neural stem/progenitor cell (hiPSC-NS/PC) grafts in models of spinal cord ...injury (SCI). Evidence from animal experiments suggests this approach is safe and effective. We are preparing to initiate a first-in-human clinical study of hiPSC-NS/PC transplantation in subacute SCI.
NS/PCs were prepared at a Good Manufacturing Practice-grade cell processing facility at Osaka National Hospital using a clinical-grade integration-free hiPSC line established by the iPSC Stock Project organized by the Kyoto University Center for iPS Cell Research and Application. After performing all quality checks, the long-term safety and efficacy of cells were confirmed using immunodeficient mouse models.
The forthcoming clinical study uses an open-label, single-arm design. The initial follow-up period is 1 year. The primary objective is to assess the safety of hiPSC-NS/PC transplantation in patients with subacute SCI. The secondary objective is to obtain preliminary evidence of its impact on neurological function and quality-of-life outcomes. Four patients with C3/4-Th10 level, complete subacute (within 24 days post-injury) SCI will be recruited. After obtaining consent, cryopreserved cells will be thawed and prepared following a multi-step process including treatment with a γ-secretase inhibitor to promote cell differentiation. A total of 2 × 106 cells will be transplanted into the injured spinal cord parenchyma 14–28 days post-injury. Patients will also receive transient immunosuppression. This study protocol has been reviewed and approved by the Certified Committee for Regenerative Medicine and the Japanese Ministry of Health, Labor and Welfare (University Hospital Medical Information Network Clinical Trials Registry UMIN-CTR number, UMIN000035074; Japan Registry of Clinical Trials jRCT number, jRCTa031190228).
We plan to start recruiting a patient as soon as the COVID-19 epidemic subsides. The primary focus of this clinical study is safety, and the number of transplanted cells may be too low to confirm efficacy. After confirming safety, a dose-escalation study is planned.
•A first-in-human clinical study for spinal cord injury using iPSC-derived cells is about to begin.•The primary objective is to assess the safety of human iPSC-derived neural stem/progenitor cells.•Further clinical trials are expected to be conducted to statistically assess efficacy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The rational design of high-temperature endurable Cu-based catalysts is a long-sought goal since they are suffering from significant sintering. Establishing a barrier on the metal surface by the ...classical strong metal-support interaction (SMSI) is supposed to be an efficient way for immobilizing nanoparticles. However, Cu particles were regarded as impossible to form classical SMSI before irreversible sintering. Herein, we fabricate the SMSI between sputtering reconstructed Cu and flame-made LaTiO
support at a mild reduction temperature, exhibiting an ultra-stable performance for more than 500 h at 600 °C. The sintering of Cu nanoparticles is effectively suppressed even at as high as 800 °C. The critical factors to success are reconstructing the electronic structure of Cu atoms in parallel with enhancing the support reducibility, which makes them adjustable by sputtering power or decorated supports. This strategy will extremely broaden the applications of Cu-based catalysts at more severe conditions and shed light on establishing SMSI on other metals.
How the cell recognizes cytosolic DNA including DNA-based microbes to trigger host-defense-related gene activation remains to be fully resolved. Here, we demonstrate that STING (stimulator of ...interferon genes), an endoplasmic reticulum translocon-associated transmembrane protein, acts to detect cytoplasmic DNA species. STING homodimers were able to complex with self- (apoptotic, necrotic) or pathogen-related ssDNA and dsDNA and were indispensible for HSV-1-mediated transcriptional activation of a wide array of innate immune and proinflammatory genes in addition to type I IFN. Our data indicate that STING instigates cytoplasmic DNA-mediated cellular defense gene transcription and facilitates adoptive responses that are required for protection of the host. In contrast, chronic STING activation may manifest inflammatory responses and possibly autoimmune disease triggered by self-DNA.
► Activation of cytosolic DNA signaling by STING
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Objectives To assess the effectiveness of adaptive iterative dose reduction (AIDR) and AIDR 3D in improving the image quality in low-dose chest CT (LDCT). Materials and methods Fifty ...patients underwent standard-dose chest CT (SDCT) and LDCT simultaneously, performed under automatic exposure control with noise index of 19 and 38 (for a 2-mm slice thickness), respectively. The SDCT images were reconstructed with filtered back projection (SDCT-FBP images), and the LDCT images with FBP, AIDR and AIDR 3D (LDCT-FBP, LDCT-AIDR and LDCT-AIDR 3D images, respectively). On all the 200 lung and 200 mediastinal image series, objective image noise and signal-to-noise ratio (SNR) were measured in several regions, and two blinded radiologists independently assessed the subjective image quality. Wilcoxon's signed rank sum test with Bonferroni's correction was used for the statistical analyses. Results The mean dose reduction in LDCT was 64.2% as compared with the dose in SDCT. LDCT-AIDR 3D images showed significantly reduced objective noise and significantly increased SNR in all regions as compared to the SDCT-FBP, LDCT-FBP and LDCT-AIDR images (all, P ≤ 0.003). In all assessments of the image quality, LDCT-AIDR 3D images were superior to LDCT-AIDR and LDCT-FBP images. The overall diagnostic acceptability of both the lung and mediastinal LDCT-AIDR 3D images was comparable to that of the lung and mediastinal SDCT-FBP images. Conclusions AIDR 3D is superior to AIDR. Intra-individual comparisons between SDCT and LDCT suggest that AIDR 3D allows a 64.2% reduction of the radiation dose as compared to SDCT, by substantially reducing the objective image noise and increasing the SNR, while maintaining the overall diagnostic acceptability.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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