Tyrosine kinase 2 (Tyk2) is a member of the Janus family of protein tyrosine kinases (Jaks). Tyk2 associates with interferon (IFN)-α, IFN-β, interleukin (IL)-6, IL-10, IL-12, and IL-23 receptors and ...mediates their downstream signaling pathways. Based on our data using Tyk2-deficient mice and cells, Tyk2 plays crucial roles in the differentiation, maintenance, and function of T helper 1 (Th1) and Th17 cells, and its dysregulation may promote autoimmune and/or inflammatory diseases. IFN-α-induced growth inhibition of B lymphocyte progenitors is dependent on Tyk2-mediated signals to regulate death-associated protein (Daxx) nuclear localization and Daxx-promyelocytic leukemia protein interactions. Tyk2-deficient mice show impaired constitutive production of type I IFNs by macrophages under steady-state conditions. When heat-killed Cutibacterium acnes is injected intraperitoneally, Tyk2-deficient mice show less granuloma formation through enhanced prostaglandin E2 and protein kinase A activities, leading to high IL-10 production by macrophages. Thus, Tyk2 is widely involved in the immune and inflammatory response at multiple events; therefore, Tyk2 is likely to be a suitable target for treating patients with autoimmune and/or chronic inflammatory diseases. Clinical trials of Tyk2 inhibitors have shown higher response rates and improved tolerability in the treatment of patients with psoriasis and inflammatory bowel diseases. Taken together, Tyk2 inhibition has great potential for clinical application in the management of a variety of diseases.
Unidirectional SiCf/SiC-matrix composites with a pyrocarbon interface were prepared by hot-pressing SiC nano-powder via a liquid phase of sintering additives under high temperature (1900 °C) and ...applied pressure (20 MPa). The SiC reinforcing fiber volume fraction of the composites varied from 0 to 78 vol% and was found to have significant effects on densification and mechanical properties, where changes in failure mode, proportional limit stress, ultimate strength, and elastic modulus were observed. The mechanical properties were significantly enhanced with an increase in the fiber volume fraction until a moderately high fiber content was obtained, after which the ultimate strength of the composite degraded. These observations were related to the open porosity within the fiber bundles. Further, fiber strength was affected by fiber damage caused by contact with the surrounding matrix due to poor densification of the SiC nano-powder.
Pulmonary hypertension (PH) is a progressive cardiopulmonary disease characterized by pulmonary arterial remodeling. Clonal somatic mutations including JAK2V617F, the most frequent driver mutation ...among myeloproliferative neoplasms, have recently been identified in healthy individuals without hematological disorders. Here, we reveal that clonal hematopoiesis with JAK2V617F exacerbates PH and pulmonary arterial remodeling in mice. JAK2V617F-expressing neutrophils specifically accumulate in pulmonary arterial regions, accompanied by increases in neutrophil-derived elastase activity and chemokines in chronic hypoxia-exposed JAK2V617F transgenic (JAK2
) mice, as well as recipient mice transplanted with JAK2
bone marrow cells. JAK2V617F progressively upregulates Acvrl1 (encoding ALK1) during the differentiation from bone marrow stem/progenitor cells peripherally into mature neutrophils of pulmonary arterial regions. JAK2V617F-mediated STAT3 phosphorylation upregulates ALK1-Smad1/5/8 signaling. ALK1/2 inhibition completely prevents the development of PH in JAK2
mice. Finally, our prospective clinical study identified JAK2V617F-positive clonal hematopoiesis is more common in PH patients than in healthy subjects. These findings indicate that clonal hematopoiesis with JAK2V617F causally leads to PH development associated with ALK1 upregulation.
Oxide fiber-reinforced oxide matrix composites (Ox/Ox-CMCs) were fabricated by vacuum-assisted impregnation and pressureless sintering using a high-yield alumina precursor. The Ox/Ox-CMCs were ...sintered at 1100 and 1200 °C for 2 h. SEM and X-ray CT revealed that in both cases the matrix formed successfully within and between the woven fabrics. Vickers hardness of the sintered matrix was independent of the location within each composite. In a three-point bending test, a bending fracture at the tensile side occurred prior to shear fracture, suggesting that the matrix achieved good adhesion between the woven fabrics. The Ox/Ox-CMC sintered at 1100 °C showed higher tensile strength than that sintered at 1200 °C. This strength difference was attributed to their microstructures; the specimen sintered at 1100 °C showed crack deflection at the fiber/matrix interface, while that sintered at 1200 °C had a strongly adherent interface. Both composites showed notch-insensitive behavior in double-edge notch tensile tests.
SiC fiber oxidation is a potential factor limiting the operating temperature of SiCf/SiC composites owing to the strength degradation after oxidation. Herein, we fabricated 1-μm-diameter pillars at ...the core of the fiber cross-sectional surface after SiO2 removal to eliminate surface effects caused by external oxidation. The fiber strength significantly decreased during the first hour of oxidation in dried air at 1400 °C, but this deterioration became less pronounced after 10 h. Simultaneously, the oxidation lowered the Young’s modulus and Weibull modulus. Oxidation considerably increased the porosity and the alterations in the mechanical behavior were primarily caused by the variations in porosity. Oxidation-induced pores were frequently detected at the fiber core and were partially filled with SiO2. Compared with those of the as-received fibers, O impurities in the oxidized fiber core were significantly reduced. Thus, the fiber strength was potentially degraded by the internal oxidation reaction between residual C and O.
•SiC fibers transformed from dense to porous after oxidation.•Significant increase in porosity influenced the mechanical behavior of the fibers.•Strength of SiC fibers was evaluated by micropillar compression tests.•The strength degradation of SiC fibers was potentially caused by internal oxidation.
We have previously reported that the proanthocyanidin (PAC) fraction of blueberry leaf extract (BB‐PAC) inhibits the proliferation of HTLV‐1‐infected adult T‐cell leukemia (ATL) by inducing ...apoptosis. In the present study, we further analyzed the structure of BB‐PAC and elucidated the molecular mechanism underlying the inhibitory function of HTLV‐1‐infected and ATL cells. After hot water extraction with fractionation with methanol‐acetone, BB‐PAC was found to be concentrated in fractions 4 to 7 (Fr7). The strongest inhibition of ATL cell growth was observed with Fr7, which contained the highest BB‐PAC polymerization degree of 14. The basic structure of BB‐PAC is mainly B‐type bonds, with A‐type bonds (7.1%) and cinchonain I units as the terminal unit (6.1%). The molecular mechanism of cytotoxicity observed around Fr7 against ATL cells was the degradation of JAK1 to 3 and the dephosphorylation of STAT3/5, which occurs by proteasome‐dependent proteolysis, confirming that PAC directly binds to heat shock protein 90 (HSP90). JAK degradation was caused by proteasome‐dependent proteolysis, and we identified the direct binding of PAC to HSP90. In addition, the binding of cochaperone ATPase homolog 1 (AHA1) to HSP90, which is required for activation of the cofactor HSP90, was inhibited by BB‐PAC treatment. Therefore, BB‐PAC inhibited the formation of the HSP90/AHA1 complex and promoted the degradation of JAK protein due to HSP90 dysfunction. These results suggest that the highly polymerized PAC component from blueberry leaves has great potential as a preventive and therapeutic agent against HTLV‐1‐infected and ATL cells.
Proanthocyanidins in blueberry leaves degrade JAK protein in adult T‐cell leukemia cells by inhibiting heat shock protein 90, and inhibit JAK/STAT signaling, causing cell death.
N-myc downstream-regulated gene 2 (NDRG2), which is a tumour suppressor, is frequently lost in many types of tumours, including adult T-cell leukaemia/lymphoma (ATL). The downregulation of NDRG2 ...expression is involved in tumour progression through the aberrant phosphorylation of several important signalling molecules. We observed that the downregulation of NDRG2 induced the translocation of protein arginine methyltransferase 5 (PRMT5) from the nucleus to the cytoplasm via the increased phosphorylation of PRMT5 at Serine 335. In NDRG2low ATL, cytoplasmic PRMT5 enhanced HSP90A chaperone activity via arginine methylation, leading to tumour progression and the maintenance of oncogenic client proteins. Therefore, we examined whether the inhibition of PRMT5 activity is a drug target in NDRG2low tumours. The knockdown of PRMT5 and binding partner methylsome protein 50 (MEP50) expression significantly demonstrated the suppression of cell proliferation via the degradation of AKT and NEMO in NDRG2low ATL cells, whereas NDRG2-expressing cells did not impair the stability of client proteins. We suggest that the relationship between PRMT5/MEP50 and the downregulation of NDRG2 may exhibit a novel vulnerability and a therapeutic target. Treatment with the PRMT5-specific inhibitors CMP5 and HLCL61 was more sensitive in NDRG2low cancer cells than in NDRG2-expressing cells via the inhibition of HSP90 arginine methylation, along with the degradation of client proteins. Thus, interference with PRMT5 activity has become a feasible and effective strategy for promoting cancer vulnerability in NDRG2low ATL.
Silicon carbide (SiC) porous-matrix composites lacking a fiber/matrix interface and incorporating continuous unidirectional SiC fibers as reinforcements were developed using sandwiched layers with ...non-infiltration fiber bundles and a porous matrix in a laminate to achieve crack deflection. Excellent control of the porosity was achieved by varying the amount of carbon powder added. The matrix porosity was characterized in terms of its microstructure and mechanical properties. The SiC porous-matrix composite with an open porosity of 22%, which was formed with 40 vol% carbon powder, had a flexural strength of 253 ± 31 MPa and exhibited non-brittle fracture behavior up to a stress maximum, followed by a gradual depletion of the fracture energy, decreasing the stress on continued deformation. Significant changes in the mechanical properties, such as the flexural strength and fracture energy, of the fabricated SiC porous-matrix composite were not observed following exposure to air at high temperature (up to 1100 °C).
Tyrosine kinase 2 (TYK2), a member of the JAK family, has attracted attention as a potential therapeutic target for autoimmune diseases. However, the role of TYK2 in CD8
T cells and autoimmune type 1 ...diabetes (T1D) is poorly understood. In this study, we generate Tyk2 gene knockout non-obese diabetes (NOD) mice and demonstrate that the loss of Tyk2 inhibits the development of autoreactive CD8
T-BET
cytotoxic T lymphocytes (CTLs) by impairing IL-12 signaling in CD8
T cells and the CD8
resident dendritic cell-driven cross-priming of CTLs in the pancreatic lymph node (PLN). Tyk2-deficient CTLs display reduced cytotoxicity. Increased inflammatory responses in β-cells with aging are dampened by Tyk2 deficiency. Furthermore, treatment with BMS-986165, a selective TYK2 inhibitor, inhibits the expansion of T-BET
CTLs, inflammation in β-cells and the onset of autoimmune T1D in NOD mice. Thus, our study reveals the diverse roles of TYK2 in driving the pathogenesis of T1D.
EZH2 is a component of polycomb repressive complex 2 (PRC2) and functions as an H3K27 methyltransferase. Loss-of-function mutations in EZH2 are associated with poorer outcomes in patients with ...myeloproliferative neoplasms (MPNs), particularly those with primary myelofibrosis (MF PMF). To determine how EZH2 insufficiency is involved in the pathogenesis of PMF, we generated mice compound for an Ezh2 conditional deletion and activating mutation in JAK2 (JAK2V617F) present in patients with PMF. The deletion of Ezh2 in JAK2(V617F) mice markedly promoted the development of MF, indicating a tumor suppressor function for EZH2 in PMF. The loss of Ezh2 in JAK2(V617F) hematopoietic cells caused significant reductions in H3K27 trimethylation (H3K27me3) levels, resulting in an epigenetic switch to H3K27 acetylation (H3K27ac). These epigenetic switches were closely associated with the activation of PRC2 target genes including Hmga2, an oncogene implicated in the pathogenesis of PMF. The treatment of JAK2(V617F)/Ezh2-null mice with a bromodomain inhibitor significantly attenuated H3K27ac levels at the promoter regions of PRC2 targets and down-regulated their expression, leading to the abrogation of MF-initiating cells. Therefore, an EZH2 insufficiency not only cooperated with active JAK2 to induce MF, but also conferred an oncogenic addiction to the H3K27ac modification in MF-initiating cells that was capable of being restored by bromodomain inhibition.
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