Ypk1/Ypk2 kinases maintain Rho1 at the plasma membrane by flippase-dependent lipid remodelling after membrane stresses

The plasma membrane (PM) is frequently challenged by mechanical stresses. In budding yeast, TORC2-Ypk1/Ypk2 kinase cascade plays a critical role in PM stress responses by reorganizing the actin cytoskeleton via Rho1 GTPase. However, the molecular mechanism by which TORC2-Ypk1/Ypk2 regulates Rho1 is not well defined. Here, we found that Ypk1/Ypk2 maintain PM localization of Rho1 under PM stress via spatial reorganization of the lipids including phosphatidylserine (PS). Genetic evidence suggests that this process is mediated by the Lem3-containing lipid flippase. We propose that TORC2-Ypk1/Ypk2-Lem3 axis-mediated lipid remodelling is a backup mechanism for PM anchoring of Rho1 after PM stress-induced acute degradation of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), which is responsible for Rho1 localization in a normal condition. Since all the signaling molecules studied here are conserved in higher eukaryotes, our findings may represent a general mechanism to cope with PM stress

Autosynchronized systolic unloading during left ventricular assist with a centrifugal pump

AbstractObjectives: The purpose of this study was to investigate how the inflow cannulation site of the left ventricular assist system with a centrifugal pump would influence cardiac function on failing heart models. Methods: In 10 sheep, a left ventricular assist system was instituted by an outflow cannula in the descending aorta, two inflow cannulas in the left atrium and the left ventricle, and connecting those cannulas to a magnetically suspended centrifugal pump. A conductance catheter and a tipped micromanometer for monitoring the pressure-volume loop were also inserted into the left ventricle. Myocardial oxygen consumption was directly measured. Heart failure was induced by injection of microspheres into the left main coronary artery. The assist rate was varied from 0% to 100% at each inflow cannulation site. Results: The pump flow with left ventricular cannulation increased during the systolic phase and decreased during the diastolic phase, whereas it was constant with left atrial cannulation. Ejection fraction with left atrial cannulation decreased as the assist rate increased, whereas that with left ventricular cannulation was maintained up to 75% assist. The external work with left atrial cannulation decreased gradually as the assist rate increased, whereas the external work with left ventricular cannulation did not decrease until the assist rate reached 75%. The myocardial oxygen consumption in both cannulations decreased proportionally as the assist rate increased; they were significantly less with left ventricular cannulation at the 100% assist rate than with left atrial cannulation. Conclusion: Left ventricular cannulation during left ventricular assistance maintains ejection fraction and effectively reduces oxygen consumption.J Thorac Cardiovasc Surg 2003;125:353-6

Risk factors for excessive postoperative exo-drift after unilateral lateral rectus muscle recession and medial rectus muscle resection for intermittent exotropia

Background: To detect significant factors associated with excessive postoperative exo-drift in young patients with intermittent exotropia who had undergone unilateral lateral rectus muscle recession and medial rectus muscle resection. Methods: We retrospectively examined the records of 64 consecutive patients Results: Younger patients (P = 0.007), and those with larger preoperative exo-deviation at distance (P = 0.033), a lower incidence of peripheral fusion at distance (P = 0.021) or a greater postoperative initial eso-deviation (P = 0.001), were significantly more likely to have an excessive postoperative exo-drift (> 20 prism diopters). Univariate analysis revealed significant associations between excessive postoperative exo-drift and age at surgery (P = 0.004), preoperative exo-deviation at distance (P = 0.017) and postoperative initial eso-deviation at distance (P Conclusions: Postoperative exodrift in unilateral RR is predicted by the initial postoperative eso-deviation, which may offset the overcorrection. However, the exo-drift is greater in cases with a large preoperative exo-deviation and/or at a younger age, and should be followed carefully

Formulas to Estimate Appropriate Surgical Amounts of Unilateral Recession-Resection in Intermittent Exotropia with Distance-Near Disparity

The purpose of this study was to derive new formulas to provide an optimal surgical procedure and optimal amount of recession-resection (RR) surgery in intermittent exotropia (IXT) with a disparity in angle of deviation depending on the fixation distance. The records of 117 consecutive patients with IXT who underwent RR surgery between March 2008 and December 2011 at Okayama University Hospital were retrospectively examined. Multivariable linear regression analysis was performed using the observed corrective angle of deviation at distance or near fixation as the dependent variable, and amounts of lateral rectus muscle (LR) recession (mm) and medial rectus muscle (MR) resection, and age at surgery (years) as independent variables. Two simultaneous formulas were derived: corrective angle of deviation at distance fixation (°)=1.8×recession (mm)+1.6× resection (mm)+0.15×age (years)–6.6, and corrective angle at near fixation (°)=1.5×recession (mm)+1.7× resection (mm)+0.18×age (years)–3.8. Comparisons of coefficient values of the formulas between distance and near fixation revealed that LR recession was more affected by the corrective angle in distance than near fixation. MR resection was more affected at near than distance fixation. We found that our new formulas estimated the appropriate amount of unilateral RR surgery

Thrombolysis with Low-Dose Tissue Plasminogen Activator 3–4.5 h After Acute Ischemic Stroke in Five Hospital Groups in Japan

Clinical data from Japan on the safety and real-world outcomes of alteplase (tPA) thrombolysis in the extended therapeutic window are lacking. The aim of this study was to assess the safety and real-world outcomes of tPA administered within 3-4.5 h of stroke onset. The study comprised consecutive acute ischemic stroke patients (n = 177) admitted across five hospitals between September 2012 and August 2014. Patients received intravenous tPA within <3 or 3-4.5 h of stroke onset. Endovascular therapy was used for tPA-refractory patients. In the 3-4.5 h subgroup (31.6 % of patients), tPA was started 85 min later than the <3 h group (220 vs. 135 min, respectively). However, outcome measures were not significantly different between the <3 and 3-4.5 h subgroups for recanalization rate (67.8 vs. 57.1 %), symptomatic intracerebral hemorrhage (2.5 vs. 3.6 %), modified Rankin Scale score of 0-1 at 3 months (36.0 vs. 23.4 %), and mortality (6.9 vs. 8.3 %). We present data from 2005 to 2012 using a therapeutic window <3 h showing comparable results. tPA following endovascular therapy with recanalization might be superior to tPA only with recanalization (81.0 vs. 59.1 %). Compared with administration within 3 h of ischemic stroke onset, tPA administration within 3-4.5 h of ischemic stroke onset in real-world stroke emergency settings at multiple sites in Japan is as safe and has the same outcomes