Three-dimensional live imaging of Atoh1 reveals the dynamics of hair cell induction and organization in the developing cochlea

During cochlear development, hair cells (HCs) and supporting cells differentiate in the prosensory domain to form the organ of Corti, but how one row of inner HCs (IHCs) and three rows of outer HCs (OHCs) are organized is not well understood. Here, we investigated the process of HC induction by monitoring Atoh1 expression in cochlear explants of Atoh1-EGFP knock-in mouse embryos and showed that only the cells that express Atoh1 over a certain threshold are selected for HC fate determination. HC induction initially occurs at the medial edge of the prosensory domain to form IHCs and subsequently at the lateral edge to form OHCs, while Hedgehog signaling maintains a space between IHCs and OHCs, leading to formation of the tunnel of Corti. These results reveal dynamic Atoh1 expression in HC fate control and suggest that multi-directional signals regulate OHC induction, thereby organizing the prototype of the organ of Corti

Relationship between adhesion molecules with hs-CRP and changes therein after ARB (Valsartan) administration in patients with obstructive sleep apnea syndrome

It has been reported that a relationship exists between obstructive sleep apnea syndrome (OSAS) and cardiovascular and cerebrovascular diseases. To address this issue, we evaluated whether OSAS is associated with adhesion molecules and inflammatory signs, important indicators of atherosclerosis. Levels of high-sensitivity CRP(hs-CRP) and intercellular adhesionmolecule-1 (ICAM-1) were measured in 30 patients with ischemic heart disease, confirmed by coronary arteriography (IHD group). Twenty healthy volunteers without sleep apnea were used as controls (Group N). Sleeping respiratory information was collected using a portable sleep polygraph, together on information about oronasal flow, tracheal sound, chest respiration, and percutaneous oxygen saturation (SpO2) to obtain the apnea-hypopnea index (AHI). In the IHD group, 9 (30%) of the 30 patients showed evidence of OSAS [IHD(AHI≥40) group] and 21 did not [IHD(AHI<40) group]. The levels of hs-CRP and ICAM-1were significantly higher in the IHD group than in the N group (p<0.01). Moreover, the levels of hs-CRP and ICAM-1were significantly higher in the IHD(AHI≥40) group than in the IHD(AHI<40) group(p<0.01). However, after the administration of valsartan, angiotensin II receptor antagonists (ARB) to both IHD groups, the levels of hs-CRP and ICAM-1 decreased significantly in both groups. Moreover, a multivariate analysis revealed that the levels of hs-CRP and ICAM-1 were associated with the severity of sleep apnea. These findings suggest that, in OSAS the levels of hs-CRP and ICAM-1 are decreased and that the administration of ARB decreases the risk of atherosclerosis

A comparison of nephrotoxicity between patients with a solitary-functioning kidney and those with bilateral-functioning kidneys in cisplatin-based chemotherapy for advanced urothelial carcinoma: a Japanese retrospective multi-institutional study

BackgroundTo compare the prevalence of nephrotoxicity between patients with a solitary-functioning kidney versus those with bilateral-functioning kidneys during the administration of cisplatin-based chemotherapy for advanced urothelial carcinoma.MethodsWe retrospectively analyzed 244 advanced urothelial carcinoma patients treated with cisplatin-based chemotherapy between 2004 and 2010 at 17 institutes in Japan. The 24 h creatinine clearance, Cockcroft–Gault formula, and estimated glomerular filtration rate equation (eGFR), were compared before all chemotherapies. The urinary tract function status was determined based on the data of nephroureterectomy, hydronephrosis, and relief of upper urinary tract obstruction. A total of 244 patients were divided into four groups according to their urinary tract functioning status and eGFR results, including bilateral-functioning kidneys with pretreatment eGFR ≥60 mL/min/1.73 m2 group (n = 83, 34.0%); a solitary-functioning kidney with pretreatment eGFR ≥60 mL/min/1.73 m2 group (n = 36, 14.8%); bilateral-functioning kidneys with pretreatment eGFR  10% and 30% from baseline in the post-third-course of chemotherapy was significantly higher in patients with bilateral-functioning kidneys than in those with a solitary-functioning kidney, among patients with pretreatment eGFR  20% from baseline were significantly higher in patients with bilateral-functioning kidneys than those with a solitary-functioning kidney among patients with pretreatment eGFR < 60 mL/min/1.73 m2 (p = 0.034), whereas no significant difference was observed among patients with pretreatment eGFR ≥60 mL/min/1.73 m2.ConclusionsThe results suggest that cisplatin-based chemotherapy may have more nephrotoxicity in patients with bilateral-functioning kidneys than in those with a solitary-functioning kidney

Significance and development of Urine uroplakin III mRNA measurement in vesicoureteral reflux

科学研究費補助金研究成果報告書研究種目: 基盤研究(C)研究期間: 2005～2006課題番号: 17591673研究代表者: 上仁 数義（滋賀医科大学・医学部・助手）研究分担者: 吉貴 達寛（滋賀医科大学・医学部・助教授）研究分担者: 成田 充弘（滋賀医科大学・医学部・講師）研究分担者: 影山 進（滋賀医科大学・医学部・助手）研究分担者: 坂野 祐司（滋賀医科大学・医学部・助手

Hydride-based antiperovskites with soft anionic sublattices as fast alkali ionic conductors

ソフトな陰イオンをもつ逆ペロブスカイト化合物で高速イオン伝導を達成. 京都大学プレスリリース. 2021-01-08.Most solid-state materials are composed of p-block anions, only in recent years the introduction of hydride anions (1s2) in oxides (e.g., SrVO2H, BaTi(O, H)3) has allowed the discovery of various interesting properties. Here we exploit the large polarizability of hydride anions (H–) together with chalcogenide (Ch2–) anions to construct a family of antiperovskites with soft anionic sublattices. The M3HCh antiperovskites (M = Li, Na) adopt the ideal cubic structure except orthorhombic Na3HS, despite the large variation in sizes of M and Ch. This unconventional robustness of cubic phase mainly originates from the large size-flexibility of the H– anion. Theoretical and experimental studies reveal low migration barriers for Li+/Na+ transport and high ionic conductivity, possibly promoted by a soft phonon mode associated with the rotational motion of HM6 octahedra in their cubic forms. Aliovalent substitution to create vacancies has further enhanced ionic conductivities of this series of antiperovskites, resulting in Na2.9H(Se0.9I0.1) achieving a high conductivity of ~1 × 10–4 S/cm (100 °C)

Transcriptome analysis of a dog model of congestive heart failure shows that collagen-related 2-oxoglutarate-dependent dioxygenases contribute to heart failure

Fibrosis is an important pathological mechanism in heart failure (HF) and is associated with poor prognosis. We analyzed fibrosis in HF patients using transcriptomic data. Genes differentially expressed between normal control and congestive HF (CHF) dogs included P3H1, P3H2, P3H4, P4HA2, PLOD1 and PLOD3, which belong to the 2-oxoglutarate-dependent dioxygenases (2OGD) superfamily that stabilizes collagen during fibrosis. Quantitative polymerase chain reaction analysis demonstrated 2OGD gene expression was increased in CHF samples compared with normal left ventricle (LV) samples. 2OGD gene expression was repressed in angiotensin converting enzyme inhibitor-treated samples. These genes, activated the hydroxylation of proline or lysin residues of procollagen mediated by 2-oxoglutaric acid and O2, produce succinic acid and CO2. Metabolic analysis demonstrated the concentration of succinic acid was significantly increased in CHF samples compared with normal LV samples. Fibrosis was induced in human cardiac fibroblasts by TGF-ß1 treatment. After treatment, the gene and protein expressions of 2OGD, the concentration of succinic acid, and the oxygen consumption rate were increased compared with no treatment. This is the first study to show that collagen-related 2OGD genes contribute to HF during the induction of fibrosis and might be potential therapeutic targets for fibrosis and HF

Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis.

The phosphorylation of pyruvate dehydrogenase (PDH) by pyruvate dehydrogenase kinase (PDK) 4 inhibits its ability to induce a glycolytic shift. PDK4 expression is upregulated in various types of human cancer. Because PDK4 regulation is critical for metabolic changes in cancer cells, it is an attractive target for cancer therapy given its ability to shift glucose metabolism. It was previously shown that a novel PDK4 inhibitor, cryptotanshinone (CPT), suppressed the three‑dimensional (3D)‑spheroid formation of pancreatic and colorectal cancer cells. In the present study, the effects of CPT on the invasiveness of bladder cancer cells were investigated. CPT significantly suppressed the invasiveness and 3D‑spheroid formation of T24 and J82 bladder cancer cells. CPT also suppressed the phosphorylation of PDH and β‑catenin, as well as the expression of N‑cadherin, which are all critical for inducing epithelial‑mesenchymal transition (EMT). The knockdown of β‑catenin or PDK4 using specific small interfering RNAs suppressed N‑cadherin expression and invasiveness in T24 cells. An mTOR inhibitor also suppressed the phosphorylation of β‑catenin and N‑cadherin expression. Furthermore, CPT injection significantly suppressed pancreatic tumor growth and peritoneal dissemination of highly metastatic SUIT‑2 pancreatic cancer cells in a mouse orthotopic pancreatic cancer model, without evident toxicity. Moreover, immunohistochemistry analyses demonstrated decreased β‑catenin expression in CPT‑treated pancreatic tumors compared with control tumors. Taken together, these results indicate that CPT reduced the invasiveness and metastasis of bladder cancer cells by suppressing EMT via the mTOR/β‑catenin/N‑cadherin pathway

The usefulness of re-attachability of anti-adhesive cross-linked gelatin film and the required physical and biological properties.

Background:To overcome the unfavorable issues associated with conventional anti-adhesive HA/CMC film, we developed an anti-adhesive thermally cross-linked gelatin film.Objective:We tried to clarify the re-attachability of the film and the required properties concerning the film thickness, stiffness and anti-adhesion effect.Methods:To determine the optimal thickness, 5 kinds of the thickness of gelatin film and the conventional film were analyzed by the tensile test, shearing test, buckling test and tissue injury test. Finally, using the optimal film thickness, we tried to clarify the anti-adhesion effect of the reattached film.Results:The tensile and shearing test showed gelatin films ≥30 μm thick had greater tensile strength and a smaller number of film fractures, than the conventional film. The buckling and tissue injury test showed gelatin films ≥60 μm thick had higher buckling strength and worse injury scores than the conventional film. The anti-adhesive effect of re-attached gelatin film using optimal thickness (30-40 μm) found the anti-adhesion score was significantly better than that of the control.Conclusions:Provided it has an optimal thickness, gelatin film can be reattached with enough physical strength not to tear, safety stiffness not to induce tissue injury, and a sufficient anti-adhesion effect

Effects of Fiber Diameter and Spacing Size of an Artificial Scaffold on the In Vivo Cellular Response and Tissue Remodeling.

By mimicking the extracellular matrix, nonwoven fabrics can function as scaffolds for tissue engineering application ideally, and they have been characterized regarding their fiber diameter and fiber spacing (spacing size) in vitro. We chronologically examined the in vivo effects of these fabrics on the cellular response and tissue remodeling. Four types of nonwoven polyglycolic acid fabrics (Fabric-0.7, Fabric-0.9, Fabric-3, and Fabric-16 with fiber diameters of 0.7, 0.9, 3.0, and 16.2 μm and spacing sizes of 2.0, 19.3, 19.0, and 825.4 μm, respectively) were implanted into the rat dorsum and subjected to histologic and immunohistochemical analyses from day 3 to 70. With Fabric-0.7, inflammatory cells (mainly M1 macrophages) and myofibroblasts with collagen type III accumulated mainly on the surface of the fabric and did not infiltrate inside the fabric initially, likely due to the narrow fiber space. Massive formation of collagen type I then appeared with the degradation of the fabrics, and finally, the remodeled tissue turned into a dense scar. With Fabric-0.9 and Fabric-3, inflammatory cells (predominantly M2 macrophages) were seen in all layers of the fabric initially. A mild increase in collagen type I was then seen, with few myofibroblasts, and the remodeled tissue ultimately showed a relatively little scar with an adequate thickness of the tissue induced by the fabrics. With Fabric-16, inflammatory cells (predominantly M1 macrophages) infiltrated into all layers of the fabric initially along with many myofibroblasts, especially in the hole. Lately, massive formation of collagen type I was noted due to the slow degradation of the fabric, with the shrinking of the fabric substantially, and the remodeled tissue finally turned to a dense scar. These findings suggest that optimizing the spacing size as well as the fiber diameter of artificial scaffolds may control the cellular response and tissue remodeling and facilitate favorable tissue regeneration without scar formation