Physical Relation of Source I to IRc2 in the Orion KL Region

We present mid-infrared narrow-band images of the Orion BN/KL region, and N-band low-resolution spectra of IRc2 and the nearby radio source "I." The distributions of the silicate absorption strength and the color temperature have been revealed with a sub-arcsecond resolution. The detailed structure of the 7.8 micron/12.4 micron color temperature distribution was resolved in the vicinity of IRc2. A mid-infrared counterpart to source I has been detected as a large color temperature peak. The color temperature distribution shows an increasing gradient from IRc2 toward source I, and no dominant temperature peak is seen at IRc2. The spectral energy distribution of IRc2 could be fitted by a two-temperature component model, and the "warmer component" of the infrared emission from IRc2 could be reproduced by scattering of radiation from source I. IRc2 itself is not self-luminous, but is illuminated and heated by an embedded luminous young stellar object located at source I.Comment: 20 pages, 11 figures. Minor corrections had been done in the ver.2. Accepted for publication in PAS

Two-staged treatment strategy in patients with severe carotid or cerebrovascular diseases undergoing coronary artery bypass grafting.

Purpose : There is no clear consensus on how to treat patients undergoing coronary artery bypass grafting (CABG) who have severe concomitant carotidcerebral artery stenosis. The aim of this study was to evaluate our surgical results in patients with severe carotid and/or cerebrovascular disease undergoing CABG. Methods :Between October 2003 and April 2009, a total of 47 such patients were treated at our institution with the following strategies: (1) protective carotid artery stenting for severe carotid stenosis performed either before (n = 20) or after (n = 5) CABG or (2) a superficial temporal artery-middle cerebral artery anastomosis procedure followed by CABG if indicated (n = 4). Off-pump CABG was performed in 75% of the patients. Results. There were no major perioperative strokes or in-hospital deaths; however, three patients had transient ischemic attacks and two had minor strokes during the early post-CABG period. All of the patients with postoperative cerebrovascular events had had unilateral carotid artery occlusion. There were no late deaths during the follow-up period (up to 6 years, with a mean of 27 months). However, major adverse cardiocerebrovascular events (MACCE) occurred in seven patients (14.9%). The rates of freedom from MACCE at 1 and 3 years were 92% and 74%, respectively. Conclusion :It appears that our two-staged approach is safe and may reduce the risk of postoperative cerebrovascular events

頭頸部癌細胞におけるレスベラトロールのREG III発現誘導効果と癌の進展抑制・治療向上効果

Identification of reliable markers of chemo- and radiosensitivity and the key molecules that enhance the susceptibility of head and neck squamous cell carcinoma (HNSCC) to anticancer treatments is highly desirable. Previously, we have reported that regenerating gene (REG) Ⅲ expression was such a marker associated with an improved survival rate for HNSCC patients. In the present study, we investigated the stimulators for induction of REG Ⅲ expression using REG Ⅲ promoter assay in HNSCC cells transfected with REG Ⅲ promoter vector. We tested inflammatory cytokines, growth factors, polyphenols, PPARγ activator of thiazolidinediones, and histone deacetylase inhibitors, and found that 3,4',5-trihydroxy-trans-stilbene (resveratrol) significantly increased the REG Ⅲ promoter activity and the mRNA levels of REG Ⅲ in HNSCC cells. Moreover, we demonstrated the effect of resveratrol on cancer cell progression, such as cell proliferation, chemo‑ and radiosensitivity and cancer invasion of HNSCC cells. Resveratrol significantly inhibited cell growth, enhanced chemo‑ and radiosensitivity, and blocked cancer invasion of HNSCC cells. These data suggested that resveratrol could inhibit cancer progression through the REG Ⅲ expression pathway in HNSCC cells.博士（医学）・甲第682号・平成30年3月15日Copyright © Spandidos Publications 2017. All rights reserved.The Spandidos Publications link is available at " https://doi.org/10.3892/ijo.2016.3664

Evaluation of the simulator with automatic irrigation control system designed for countermeasures of internal contamination in dental unit water lines

The prevention of nosocomial infections is an imperative task. The dental chair unit (DCU) is an indispensable device used in dental treatment. However, it is known that the dental unit water line (DUWL) can become contaminated with biofilm, consisting mainly of heterotrophic bacteria (HB). Recently, the International Organization for Standardization specified the methods for testing DUWL contamination management. On these grounds, a simulator reproducing DUWL was prepared to standardize the examination method of the DUWL contamination. Objectives To evaluate the reproducibility of the DUWL simulator, monitor the DUWL contamination states, and test the efficacy of a commercial decontaminant for DUWL. Methods The DUWL simulator was assembled by a DCU manufacturing company. The simulator's DUWL was filled with tap water (TW), and left for approximately one year. Neutral electrolyzed water (NEW) was used as a decontaminant for DUWL. Both TW and NEW were passed through DUWL in a timely manner simulating daily dental treatment. Water was sampled from the air turbine hand piece weekly for 4 weeks and used for HB culture. Contamination status was evaluated by measuring bacterial adenosine triphosphate release and by culturing on Reasoner's 2A medium. Results The DUWL released contaminated water had a bacterial count of over 6 × 104 cfu/mL. After passing NEW through DUWL for 1 week, the count drastically decreased to its basal level and remained steady for 4 weeks. However, TW showed no effect on DUWL decontamination throughout the examination periods. Conclusions The DUWL simulator could be useful to examine the efficacy of the decontaminant for DUWL and development of new methods in DUWL contamination management

Artificial Intelligence, Robots, and Philosophy

This book is a collection of all the papers published in the special issue “Artificial Intelligence, Robots, and Philosophy,” Journal of Philosophy of Life, Vol.13, No.1, 2023, pp.1-146. The authors discuss a variety of topics such as science fiction and space ethics, the philosophy of artificial intelligence, the ethics of autonomous agents, and virtuous robots. Through their discussions, readers are able to think deeply about the essence of modern technology and the future of humanity. All papers were invited and completed in spring 2020, though because of the Covid-19 pandemic and other problems, the publication was delayed until this year. I apologize to the authors and potential readers for the delay. I hope that readers will enjoy these arguments on digital technology and its relationship with philosophy. *** Contents*** Introduction : Descartes and Artificial Intelligence; Masahiro Morioka*** Isaac Asimov and the Current State of Space Science Fiction : In the Light of Space Ethics; Shin-ichiro Inaba*** Artificial Intelligence and Contemporary Philosophy : Heidegger, Jonas, and Slime Mold; Masahiro Morioka*** Implications of Automating Science : The Possibility of Artificial Creativity and the Future of Science; Makoto Kureha*** Why Autonomous Agents Should Not Be Built for War; István Zoltán Zárdai*** Wheat and Pepper : Interactions Between Technology and Humans; Minao Kukita*** Clockwork Courage : A Defense of Virtuous Robots; Shimpei Okamoto*** Reconstructing Agency from Choice; Yuko Murakami*** Gushing Prose : Will Machines Ever be Able to Translate as Badly as Humans?; Rossa Ó Muireartaigh**

Novel Calcium-Binding Ablating Mutations Induce Constitutive RET Activity and Drive Tumorigenesis

がんゲノム医療のさらなる拡大へ向けた一歩 --コンピュータ解析で意義不明変異のなかに治療標的となる新たな遺伝子変異を発見--. 京都大学プレスリリース. 2022-09-29.Distinguishing oncogenic mutations from variants of unknown significance (VUS) is critical for precision cancer medicine. Here, computational modeling of 71, 756 RET variants for positive selection together with functional assays of 110 representative variants identified a three-dimensional cluster of VUSs carried by multiple human cancers that cause amino acid substitutions in the calmodulin-like motif (CaLM) of RET. Molecular dynamics simulations indicated that CaLM mutations decrease interactions between Ca²⁺ and its surrounding residues and induce conformational distortion of the RET cysteine-rich domain containing the CaLM. RET-CaLM mutations caused ligand-independent constitutive activation of RET kinase by homodimerization mediated by illegitimate disulfide bond formation. RET-CaLM mutants possessed oncogenic and tumorigenic activities that could be suppressed by tyrosine kinase inhibitors targeting RET. This study identifies calcium-binding ablating mutations as a novel type of oncogenic mutation of RET and indicates that in silico–driven annotation of VUSs of druggable oncogenes is a promising strategy to identify targetable driver mutations

Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice

金沢大学医薬保健研究域医学系Vascular complications arising from multiple environmental and genetic factors are responsible for many of the disabilities and short life expectancy associated with diabetes mellitus. Here we provide the first direct in vivo evidence that interactions between advanced glycation end products (AGEs; nonenzymatically glycosylated protein derivatives formed during prolonged hyperglycemic exposure) and their receptor, RAGE, lead to diabetic vascular derangement. We created transgenic mice that overexpress human RAGE in vascular cells and crossbred them with another transgenic line that develops insulin-dependent diabetes shortly after birth. The resultant double transgenic mice exhibited increased hemoglobin A1c and serum AGE levels, as did the diabetic controls. The double transgenic mice demonstrated enlargement of the kidney, glomerular hypertrophy, increased albuminuria, mesangial expansion, advanced glomerulosclerosis, and increased serum creatinine compared with diabetic littermates lacking the RAGE transgene. To our knowledge, the development of this double transgenic mouse provides the first animal model that exhibits the renal changes seen in humans. Furthermore, the phenotypes of advanced diabetic nephropathy were prevented by administering an AGE inhibitor, (±)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide (OPB-9195), thus establishing the AGE-RAGE system as a promising target for overcoming this aspect of diabetic pathogenesis

Efficacy and safety of micafungin in empiric and D-index-guided early antifungal therapy for febrile neutropenia ; A subgroup analysis of the CEDMIC trial

Objectives: The D-index is defined as the area over the neutrophil curve during neutropenia. The CEDMIC trial confirmed the noninferiority of D-index-guided early antifungal therapy (DET) using micafungin to empirical antifungal therapy (EAT). In this study, we evaluated the efficacy and safety of micafungin in these settings. Methods: From the CEDMIC trial, we extracted 67 and 113 patients who received micafungin in the DET and EAT groups, respectively. Treatment success was defined as the fulfilment of all components of a five-part composite end point. Fever resolution was evaluated at seven days after the completion of therapy. Results: The proportion of high-risk treatments including induction chemotherapy for acute leukemia and allogeneic hematopoietic stem cell transplantation was significantly higher in the DET group than in the EAT group (82.1% vs. 52.2%). The efficacy of micafungin was 68.7% (95%CI: 56.2–79.4) and 79.6% (71.0–86.6) in the DET and EAT groups, respectively. When we focused on high-risk treatments, the efficacy was 69.1% (55.2–80.9%) and 78.0% (65.3–87.7%), respectively (P = 0.30). There was no significant difference in any of the 5 components between the two groups. Conclusions: The efficacy of micafungin in patients undergoing high-risk treatment was not strongly impaired in DET compared to that in EAT

Mechanical guidance of self-condensation patterns of differentiating progeny

Spatially controlled self-organization represents a major challenge for organoid engineering. We have developed a mechanically patterned hydrogel for controlling self-condensation process to generate multi-cellular organoids. We first found that local stiffening with intrinsic mechanical gradient (IG > 0.008) induced single condensates of mesenchymal myoblasts, whereas the local softening led to stochastic aggregation. Besides, we revealed the cellular mechanism of two-step self-condensation: (1) cellular adhesion and migration at the mechanical boundary and (2) cell-cell contraction driven by intercellular actin-myosin networks. Finally, human pluripotent stem cell-derived hepatic progenitors with mesenchymal/endothelial cells (i.e., liver bud organoids) experienced collective migration toward locally stiffened regions generating condensates of the concave to spherical shapes. The underlying mechanism can be explained by force competition of cell-cell and cell-hydrogel biomechanical interactions between stiff and soft regions. These insights will facilitate the rational design of culture substrates inducing symmetry breaking in self-condensation of differentiating progeny toward future organoid engineering.Matsuzaki T., Shimokawa Y., Koike H., et al. Mechanical guidance of self-condensation patterns of differentiating progeny. iScience 25, 105109 (2022); https://doi.org/10.1016/j.isci.2022.105109

Preparation of mechanically patterned hydrogels for controlling the self-condensation of cells

Synthetic protocols providing mechanical patterns to culture substrate are essential to control the self-condensation of cells for organoid engineering. Here, we present a protocol for preparing hydrogels with mechanical patterns. We describe steps for hydrogel synthesis, mechanical evaluation of the substrate, and time-lapse imaging of cell self-organization. This protocol will facilitate the rational design of culture substrates with mechanical patterns for the engineering of various functional organoids. For complete details on the use and execution of this protocol, please refer to Takebe et al. (2015) and Matsuzaki et al. (2014, 2022).Matsuzaki T., Kawano Y., Horikiri M., et al. Preparation of mechanically patterned hydrogels for controlling the self-condensation of cells. STAR Protocols 4, 102471 (2023); https://doi.org/10.1016/j.xpro.2023.102471