Small GTP-binding protein Rho-mediated signaling promotes proliferation of rheumatoid synovial fibroblasts

Rho is a major small GTP-binding protein that is involved in the regulation of various cell functions, including proliferation and cell migration, through activation of multiple signaling molecules in various types of cells. We studied its roles in synovial fibroblasts (SFs) in patients with rheumatoid arthritis (RA) and clarified its relevance to RA synovitis, with the following results. 1)We found that the thrombin receptor was overexpressed on RA synovial fibroblasts (RA SFs) and that thrombin induced a marked proliferation and progression of the cell cycle to the S phase in these cells. 2)We also found that thrombin efficiently activated Rho. 3)Rho activation and proliferation and the progression of the cell cycle to the S phase were completely blocked by p115RGS (an N-terminal regulator of the G-protein signaling domain of p115RhoGEF) and by the C-terminal fragments of Gα13 (an inhibitor of the interaction of receptors with G13). 4)Thrombin induced the secretion of IL-6 by RA SFs, but this action was blocked by p115RGS or Gα13. Our findings show that the actions of thrombin on the proliferation of RA SFs, cell-cycle progression to the S phase, and IL-6 secretion were mainly mediated by the G13 and RhoGEF pathways. These results suggest that p115RGS and Gα13 could be potent inhibitors of such functions. A rational design of future therapeutic strategies for RA synovitis could perhaps include the exploitation of the Rho pathway to directly reduce the growth of synovial cells

Effective Stress Analysis by Shear Strain Controllable Model and its Application to Centrifuge Shaking Model Test

Effective stress FEM which is able to control the growth of shear strains is proposed. Its validity is firstly confirmed through the simulation of undrained cyclic torsional shear tests. Then, it is applied to simulation of centrifuge shaking model tests; the experimental model consists of a caisson type quay wall and reclamation laid on the sand layer. Development of shear strain is shown to be controlled arbitrary keeping the excess porewater pressure generation unchanged through the simulation of undrained cyclic torsional shear test, which indicates that proposed model can be applicable to variety of soils with different density and fines contents. Displacement is shown to be controlled keeping excess porewater pressure generation constant in the centrifugal model, too, and good agreement is obtained between test and analysis by controlling the parameter for shear strain development

Analysis of Three-Phase Thyristor Phase Control Circuit with Series RLC Elements

An ac phase control circuit by thyristor is widely used in industry, The characteristics of the singlephase circuit with series RLC elements are numerically analyzed, and is reported the interesting phenomenon of step-up voltage without transformer. However, the performance of three phase phase control circuit with series RLC elements is not made clear. In this paper, the performance of three-phase control circuit of a balanced and an unbalanced load with series RLC elements is described. The analytical programs with each load are developed, and it is clarified that the calculated by this analytical program agree well with the measured. The calculated results, e.g. waveforms, RMS values of voltage and current, power, and power factor are illustrated and discussed the step-up phenomenon in three phase

Therapeutic Targets for Treatment of Heart Failure: Focus on GRKs and β-Arrestins Affecting βAR Signaling

Heart failure (HF) is a heart disease that is classified into two main types: HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Both types of HF lead to significant risk of mortality and morbidity. Pharmacological treatment with β-adrenergic receptor (βAR) antagonists (also called β-blockers) has been shown to reduce the overall hospitalization and mortality rates and improve the clinical outcomes in HF patients with HFrEF but not HFpEF. Although, the survival rate of patients suffering from HF continues to drop, the management of HF still faces several limitations and discrepancies highlighting the need to develop new treatment strategies. Overstimulation of the sympathetic nervous system is an adaptive neurohormonal response to acute myocardial injury and heart damage, whereas prolonged exposure to catecholamines causes defects in βAR regulation, including a reduction in the amount of βARs and an increase in βAR desensitization due to the upregulation of G protein-coupled receptor kinases (GRKs) in the heart, contributing in turn to the progression of HF. Several studies show that myocardial GRK2 activity and expression are raised in the failing heart. Furthermore, β-arrestins play a pivotal role in βAR desensitization and, interestingly, can mediate their own signal transduction without any G protein-dependent pathway involved. In this review, we provide new insight into the role of GRKs and β-arrestins on how they affect βAR signaling regarding the molecular and cellular pathophysiology of HF. Additionally, we discuss the therapeutic potential of targeting GRKs and β-arrestins for the treatment of HF

“Hook and Roll Technique” Using an Articulating Hook Cautery to Provide a Critical View during Single-incision Laparoscopic Cholecystectomy

We describe a new simple and easy technique called the "Hook and roll technique" (HRT) that uses an articulating hook cautery to provide a critical view during single incision laparoscopic cholecystectomy (SILC). A 2-cm incision is made at the umbilicus to insert three 5-mm trocars or a multichannel port. After dissection of the serosa of the dorsal and ventral sides of the gall bladder, including Calot's triangle, the angled tip of the hook cautery is inserted between the cystic artery and duct with its tip placed dorsally. The tip is then rotated in a clockwise manner to avoid bile duct injury, allowing the connective tissue between them to be hooked, coagulated and cut. This procedure is repeated several times, followed by dissection between the cystic artery and the liver bed to achieve a critical view. From December 2008 to May 2011, 121 patients underwent SILC using HRT in our hospital without any serious complications. This technique is suitable for SILC, as it is consists of simple procedures that can be performed safely and easily, even by left hand in a cross-over approach, and it allows complete dissection of Calot's triangle to achieve a critical view without using any dissector under dangerous in-line viewing

0365: Non-peptidic prokineticin receptor 1 agonist as a novel cardioprotective therapeutic

ObjectiveProkineticins are potent angiogenic peptides that bind to two G protein-coupled receptors to initiate their biological effects. We previously have shown that prokineticin receptor-1 (PKR1) signaling contributes to cardiomyocyte survival or repair in myocardial infarction. Here, we discovered the first non-peptidic PKR1 agonists and examined their effects in mice model of heart diseases.Methods and resultsHerein we identify a selective PKR1 agonist both in vitro and in vivo, utilizing GPCR structure-based virtual screening approach. High Throughput Docking was carried out by GOLD using homology model of PKR1. Asinex gold collection 3D chemical databese (250,000 compounds) was screened by the docking protocol. We provided a strategy with a high potential for in silico identifying one agonist hit. We present here IS20, the first synthetic PKR1 agonist that induces angiogenesis in the presence of PKR1 on the endothelial cells seeded on matrigel. IS20 reduced doxorubicin cytotoxicity in H9C2 cells. IS20 promotes mouse epicardial progenitor cell differentiation into endothelial cells. In vivo IS20 activates Akt in mice heart. IS20 treatment of mice after coronary ligation reduces mortality by 30%.ConclusionThis study identifies a non-peptidic PKR1 agonist as therapeutic target holding promise for treatment of heart diseases

Purinergic P2Y(6) receptors heterodimerize with angiotensin AT1 receptors to promote angiotensin II-induced hypertension

The angiotensin (Ang) type 1 receptor (AT1R) promotes functional and structural integrity of the arterial wall to contribute to vascular homeostasis, but this receptor also promotes hypertension. In our investigation of how Ang II signals are converted by the AT1R from physiological to pathological outputs, we found that the purinergic P2Y6 receptor (P2Y6R), an inflammation-inducible G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor (GPCR), promoted Ang II–induced hypertension in mice. In mice, deletion of P2Y6R attenuated Ang II–induced increase in blood pressure, vascular remodeling, oxidative stress, and endothelial dysfunction. AT1R and P2Y6R formed stable heterodimers, which enhanced G protein–dependent vascular hypertrophy but reduced β-arrestin–dependent AT1R internalization. Pharmacological disruption of AT1R-P2Y6R heterodimers by the P2Y6R antagonist MRS2578 suppressed Ang II–induced hypertension in mice. Furthermore, P2Y6R abundance increased with age in vascular smooth muscle cells. The increased abundance of P2Y6R converted AT1R-stimulated signaling in vascular smooth muscle cells from β-arrestin–dependent proliferation to G protein–dependent hypertrophy. These results suggest that increased formation of AT1R-P2Y6R heterodimers with age may increase the likelihood of hypertension induced by Ang II

Laparoscopic repair of an abdominal incisional hernia above the pubis

　　Laparoscopic repair of a suprapubic hernia typically carries a high risk of recurrence, because fixation of the mesh in the peripubic area is difficult. We herein report a patient undergoing laparoscopic repair of a suprapubic hernia, along with a description of the surgical techniques employed. 　A 78-year-old woman visited our hospital with a chief complaint of swelling at the median hypogastric incision site after surgery for an ovarian cyst performed at age 25 years. Laparoscopic examination revealed the hernia orifice to be 3.5×3.0 cm in size and that the distance between the caudal margin of the hernia orifice and the pubis was 2.5 cm. Parietex composite mesh was used for fixation through all layers of the abdominal wall with non-absorbable sutures and tack fixation. On the pubic side, after the pubis had been exposed by separating it from the bladder, we performed mesh fixation through all layers of the abdominal wall immediately above the pubis with the sutures placed inside the mesh, combined with tack mesh fixation directly to the pubis. This procedure enabled definite fixation of the mesh. Six days after surgery, she was discharged without complications. To date, two years and five months after surgery, no recurrence has been observed

Study on Coupling Beams Using Low Yield Point Steel : Part 2 Evaluation of Test Results

日本建築学会大会学術講演梗概集（北陸）2002年8月rights:日本建築学会　rights: 本文データは学協会の許諾に基づきCiNiiから複製したものである　relation: isVersionOf: http://ci.nii.ac.jp/naid/11000374217