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BACKGROUND: Pain is a complex experience with both sensory and affective dimensions, and the affective dimension can increase the risks of chronic pain development. It is thus critical to identify factors influencing the affective dimension of pain. OBJECTIVE: This study aimed to identify the relationship between the affective dimension of pain and disorder site (primary pain source). METHODS: Study participants were recruited from patients referred for physical therapy at an orthopedic outpatient clinic. Pain quality including the affective dimension, disorder site from descriptive medical diagnosis, pain intensity, duration from pain onset, and demographic data, was collected. A multivariable logistic regression model was constructed to analyze the relationship between the affective dimension of pain and the disorder site. RESULTS: A total of 282 participants were included. Cervical and lumbar spine disorders were significantly associated with an affective dimension of pain compared to limbs disorders when adjusted for age, sex, pain intensity, and duration from the onset in the regression model. CONCLUSIONS: Regardless of duration from the onset and other confounding factors, disorder site is correlated with the affective dimension of pain. Multidimensional pain assessment is crucial when clinicians evaluate patients with cervical and lumbar spine disorders, even in the acute phase.

Group IV materials are promising candidates for highly reliable and human-friendly thin-film thermoelectric generators, used for micro-energy harvesting. In this study, we investigated the synthesis and thermoelectric applications of a Ge-based ternary alloy thin film, Ge

Argonaute (AGO) proteins use small RNAs to recognize transcripts targeted for silencing in plants and animals. Many AGOs possess an endoribonuclease activity termed RNA slicing, which catalyzes rapid turnover of target RNAs. The nuclease activity of Thermus thermophilus AGO (TtAgo)1,2 is often used as a model for RNA slicing, but how well DNA-guided slicing by this bacterial thermophile resembles RNA-guided slicing by eukaryotic AGOs is not known. We present cryo-EM structures of the Arabidopsis thaliana Argonaute10 (AtAgo10)-guide RNA complex with and without a target RNA representing a slicing substrate. Like TtAgo, AtAgo10 conformation expands in response to target binding. However, the AtAgo10-guide-target complex adopts slicing-competent and -incompetent conformations that are distinct from structures of TtAgo. AtAgo10 slicing activity is licensed by docking target (t) nucleotides t9-t13 into a surface channel containing the AGO endoribonuclease active site. A ß-hairpin, conserved in the L1 domain of eukaryotic AGOs, secures the t9-t13 segment and coordinates t9-t13 docking with extended guide-target pairing, preventing the complex from becoming trapped in slicing-incompetent conformations. Results show the mechanism for achieving RNA slicing in eukaryotes is distinct from that of bacteria and provide insights for controlling small interfering RNA (siRNA) potency.

The emergence of tyrosine kinase inhibitors as part of a front-line treatment has greatly improved the clinical outcome of the patients with Ph⁺ acute lymphoblastic leukemia (ALL). However, a portion of them still become refractory to the therapy mainly through acquiring mutations in the BCR-ABL1 gene, necessitating a novel strategy to treat tyrosine kinase inhibitor (TKI)-resistant Ph⁺ ALL cases. In this report, we show evidence that RUNX1 transcription factor stringently controls the expression of BCR-ABL1, which can strategically be targeted by our novel RUNX inhibitor, Chb-M'. Through a series of in vitro experiments, we identified that RUNX1 binds to the promoter of BCR and directly transactivates BCR-ABL1 expression in Ph⁺ ALL cell lines. These cells showed significantly reduced expression of BCR-ABL1 with suppressed proliferation upon RUNX1 knockdown. Moreover, treatment with Chb-M' consistently downregulated the expression of BCR-ABL1 in these cells and this drug was highly effective even in an imatinib-resistant Ph⁺ ALL cell line. In good agreement with these findings, forced expression of BCR-ABL1 in these cells conferred relative resistance to Chb-M'. In addition, in vivo experiments with the Ph⁺ ALL patient-derived xenograft cells showed similar results. In summary, targeting RUNX1 therapeutically in Ph⁺ ALL cells may lead to overcoming TKI resistance through the transcriptional regulation of BCR-ABL1. Chb-M' could be a novel drug for patients with TKI-resistant refractory Ph⁺ ALL.

Background Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by excessive fibrosis. FcγRIIB is a low-affinity receptor for the Fc fragment of IgG. FcγRIIB is expressed on the surface of various leukocyte subsets and signals negative feedback pathways to down-regulate B-cell antigen receptor signaling. Objective The aim of the present study was to investigate the role of FcγRIIB in the development of a murine bleomycin-induced scleroderma model. Methods The experimental fibrosis model was generated by the subcutaneous injection of bleomycin into wild-type (WT) and FcγRIIB-deficient (FcγRIIB-/-) mice. We histologically assessed skin and lung fibrosis as well as inflammatory cell infiltration. Cytokine and chemokine expression levels were measured with RT-PCR. Results The severity of fibrosis in the skin and lung was significantly worse in FcγRIIB-/- mice than in WT mice. In the skin of bleomycin-treated mice, the numbers of CD8+ T cells, F4/80+ macrophages, MPO+ neutrophils, NK1.1+NK cells, and B220+ B cells were significantly higher in FcγRIIB-/- mice than in WT mice. The expression of TNF-α and IL-1β was significantly higher in FcγRIIB-/- mice than in WT mice as was the expression of ICAM-1, CXCL2, and CCL3 in the affected skin. An adoptive transfer of splenic leukocytes from FcγRIIB-/- mice into WT mice showed exacerbated skin and lung fibrosis compared to WT mice without an adoptive transfer. Conclusion These results indicate that FcγRIIB plays an inhibitory role in skin and lung fibrosis. Moreover, modulating FcγRIIB signaling has potential as a therapeutic approach for SSc.

An 83‐year‐old man with muscle involvement and interstitial lung disease (ILD) was diagnosed with anti‐OJ antibody (Ab)‐positive polymyositis (PM). He did not have Raynaud's phenomenon, heliotrope rash, Gottron's sign, fever, arthralgia, or mechanic's hand. A literature review of 21 anti‐OJ Ab‐positive patients described that the diagnoses were as follows: 10 with PM, five with dermatomyositis, five with ILD, and 1 with overlap syndrome of PM and rheumatoid arthritis. Myositis was observed in 16, ILD in 19, and skin rash in 5. Physicians need to be aware of the existence of patients with anti‐OJ Ab who have myositis and ILD.

De novo formation of the double-membrane compartment autophagosome is seeded by small vesicles carrying membrane protein autophagy-related 9 (ATG9), the function of which remains unknown. Here we find that ATG9A scrambles phospholipids of membranes in vitro. Cryo-EM structures of human ATG9A reveal a trimer with a solvated central pore, which is connected laterally to the cytosol through the cavity within each protomer. Similarities to ABC exporters suggest that ATG9A could be a transporter that uses the central pore to function. Moreover, molecular dynamics simulation suggests that the central pore opens laterally to accommodate lipid headgroups, thereby enabling lipids to flip. Mutations in the pore reduce scrambling activity and yield markedly smaller autophagosomes, indicating that lipid scrambling by ATG9A is essential for membrane expansion. We propose ATG9A acts as a membrane-embedded funnel to facilitate lipid flipping and to redistribute lipids added to the outer leaflet of ATG9 vesicles, thereby enabling growth into autophagosomes.

Aim Systemic sclerosis (SSc) is an autoimmune disease characterized by skin and lung fibrosis. Although SSc has a high mortality risk, an effective treatment for the disease has not been established yet. Mesenchymal stromal/stem cells (MSCs) are multipotential nonhematopoietic progenitor cells that have the ability to regulate immune responses. Adipose-derived stromal/stem cells (ASCs), one of the types of MSCs, have the advantage of accessibility and potent immunomodulatory effects when compared with other MSCs, such as bone marrow-derived MSCs. This study aimed to investigate the antifibrotic effect of ASCs in scleroderma mouse models, including bleomycin-induced scleroderma and sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) models. Method ASCs were intravenously administered to a bleomycin-induced scleroderma or Scl-cGVHD model on day 0. We compared the skin and lung fibrosis of scleroderma model mice between the ASC-treated group and control group. Results Administration of ASCs attenuated the skin and lung fibrosis of bleomycin-induced scleroderma and Scl-cGVHD model mice compared to that in the control mice. Immunohistochemical staining showed that ASCs suppressed the infiltration of CD4+ , CD8+ T cells and macrophages into the dermis of bleomycin model mice compared to that in control mice. In addition, ASCs attenuated the messenger RNA expression of collagen and fibrogenic cytokines, such as interleukin (IL)-6 and IL-13, in the skin of bleomycin model mice. ASCs also reduced the frequency of fibrogenic cytokine-producing CD4+ T cells and effector B cells in the spleen of bleomycin model mice. Conclusion ASCs could prove to be a potential therapeutic agent for use in patients with SSc.

application/pdf, Welding International. 2021, 33 (Issue 1-3 (2019)), P.1-16

Active S1PR3 structure reveals the unique ligand-binding mode and signaling selectivity switching mechanism., Sphingosine-1-phosphate (S1P) regulates numerous important physiological functions, including immune response and vascular integrity, via its cognate receptors (S1PR1 to S1PR5); however, it remains unclear how S1P activates S1PRs upon binding. Here, we determined the crystal structure of the active human S1PR3 in complex with its natural agonist S1P at 3.2-Å resolution. S1P exhibits an unbent conformation in the long tunnel, which penetrates through the receptor obliquely. Compared with the inactive S1PR1 structure, four residues surrounding the alkyl tail of S1P (the “quartet core”) exhibit orchestrating rotamer changes that accommodate the moiety, thereby inducing an active conformation. In addition, we reveal that the quartet core determines G protein selectivity of S1PR3. These results offer insight into the structural basis of activation and biased signaling in G protein–coupled receptors and will help the design of biased ligands for optimized therapeutics.

In recent years, ship hulls have become larger. And the welding has become more important technology in ship building. In other word, welding has become more important technology in shipbuilding. In Japanese shipbuilding, multiple electrode butt welding has been performed with large current and high speed to increase construction efficiency. However, the multiple electrode welding method may cause a hot cracking. X-ray or ultra sonic wave inspection and repair welding are necessary due to the generation of hot cracking. These will increase the production cost. Therefore, it is important to prevent hot cracking. It is known that hot cracking is generated by both metallurgical and mechanical factors. The authors propose a new evaluation method of hot cracking based on the modeling of both mechanical and metallurgical behaviors. In the developed method, from the metallurgical point of view, solidification growth direction is determined from the temperature gradient obtained by the heat conduction analysis to predict the position of hot cracking. Moreover, from the mechanical point of view, the possibility of the generation of hot cracking is assessed using plastic strain increment in Brittleness Temperature Range (BTR). In order to show the validity of the developed method, the developed method is applied to the analysis of hot cracking on automatic tandem butt welding through the comparison with experimental results. As a result, it is demonstrated that the hot cracking can be evaluated by using the developed method.

Although the function of Runt-related (RUNX) transcription factors has been well characterized in leukemogenesis and regarded as an ideal target in antileukemia strategies, the effect of RUNX-inhibition therapy on bone marrow niche cells andr its impact on the engraftment of acute myeloid leukemia (AML) cells have largely been unknown. Here, we provide evidence suggesting the possible involvement of RUNX transcription factors in the transactivation of E-selectin, a member of selectin family of cell adhesion molecules, on the vascular endothelial cells of the mice bone marrow niche. In our experiments, gene switch-mediated silencing of RUNX downregulated E-selectin expression in the vascular niche and negatively controlled the engraftment of AML cells in the bone marrow, extending the overall survival of leukemic mice. Our work identified the novel role of RUNX family genes in the vascular niche and showed that the vascular niche, a home for AML cells, could be strategically targeted with RUNX-silencing antileukemia therapies. Considering the excellent efficacy of RUNX-inhibition therapy on AML cells themselves as we have previously reported, this strategy potentially targets AML cells both directly and indirectly, thus providing a better chance of cure for poor-prognostic AML patients., 骨髄微少環境を制御する新手法で白血病の延命効果を確認 --白血病治療に新しいコンセプトを提示--. 京都大学プレスリリース. 2018-04-06.