Expression of yeast lipid phosphatase Sac1p is regulated by phosphatidylinositol-4-phosphate

<p>Abstract</p> <p>Background</p> <p>Phosphoinositides play a central role in regulating processes at intracellular membranes. In yeast, a large number of phospholipid biosynthetic enzymes use a common mechanism for transcriptional regulation. Yet, how the expression of genes encoding lipid kinases and phosphatases is regulated remains unknown.</p> <p>Results</p> <p>Here we show that the expression of lipid phosphatase Sac1p in the yeast <it>Saccharomyces cerevisiae </it>is regulated in response to changes in phosphatidylinositol-4-phosphate (PI(4)P) concentrations. Unlike genes encoding enzymes involved in phospholipid biosynthesis, expression of the <it>SAC1 </it>gene is independent of inositol levels. We identified a novel 9-bp motif within the 5' untranslated region (5'-UTR) of <it>SAC1 </it>that is responsible for PI(4)P-mediated regulation. Upregulation of <it>SAC1 </it>promoter activity correlates with elevated levels of Sac1 protein levels.</p> <p>Conclusion</p> <p>Regulation of Sac1p expression via the concentration of its major substrate PI(4)P ensures proper maintenance of compartment-specific pools of PI(4)P.</p

Disruption of Spectrin-Like Cytoskeleton in Differentiating Keratinocytes by PKCδ Activation Is Associated with Phosphorylated Adducin

Spectrin is a central component of the cytoskeletal protein network in a variety of erythroid and non-erythroid cells. In keratinocytes, this protein has been shown to be pericytoplasmic and plasma membrane associated, but its characteristics and function have not been established in these cells. Here we demonstrate that spectrin increases dramatically in amount and is assembled into the cytoskeleton during differentiation in mouse and human keratinocytes. The spectrin-like cytoskeleton was predominantly organized in the granular and cornified layers of the epidermis and disrupted by actin filament inhibitors, but not by anti-mitotic drugs. When the cytoskeleton was disrupted PKCδ was activated by phosphorylation on Thr505. Specific inhibition of PKCδ(Thr505) activation with rottlerin prevented disruption of the spectrin-like cytoskeleton and the associated morphological changes that accompany differentiation. Rottlerin also inhibited specific phosphorylation of the PKCδ substrate adducin, a cytoskeletal protein. Furthermore, knock-down of endogenous adducin affected not only expression of adducin, but also spectrin and PKCδ, and severely disrupted organization of the spectrin-like cytoskeleton and cytoskeletal distribution of both adducin and PKCδ. These results demonstrate that organization of a spectrin-like cytoskeleton is associated with keratinocytes differentiation, and disruption of this cytoskeleton is mediated by either PKCδ(Thr505) phosphorylation associated with phosphorylated adducin or due to reduction of endogenous adducin, which normally connects and stabilizes the spectrin-actin complex

Search for gravitational waves associated with gamma-ray bursts detected by Fermi and Swift during the LIGO–Virgo run O3b

We search for gravitational-wave signals associated with gamma-ray bursts (GRBs) detected by the Fermi and Swift satellites during the second half of the third observing run of Advanced LIGO and Advanced Virgo (2019 November 1 15:00 UTC–2020 March 27 17:00 UTC). We conduct two independent searches: a generic gravitational-wave transients search to analyze 86 GRBs and an analysis to target binary mergers with at least one neutron star as short GRB progenitors for 17 events. We find no significant evidence for gravitational-wave signals associated with any of these GRBs. A weighted binomial test of the combined results finds no evidence for subthreshold gravitational-wave signals associated with this GRB ensemble either. We use several source types and signal morphologies during the searches, resulting in lower bounds on the estimated distance to each GRB. Finally, we constrain the population of low-luminosity short GRBs using results from the first to the third observing runs of Advanced LIGO and Advanced Virgo. The resulting population is in accordance with the local binary neutron star merger rate

Mid-term follow-up of aortic root remodelling compared to Bentall operation

Objectives: Aortic valve sparing with root remodelling has proven useful in cases of aortic regurgitation secondary to ascending aorta disease. An excessive rate of re-operation for recurrent aortic regurgitation after this conservative approach might compensate the prosthesis-related risk of the Bentall operation. Methods: From January 1995 to September 2000, 69 consecutive patients with aortic expansive aneurysm and concomitant aortic valve disease, were submitted to the Bentall operation (group A, n=37) in the presence of an abnormal valve, or to root remodelling (group B, n=32) in cases of secondary aortic incompetence. One patient in group A and four in group B had Marfan syndrome. The follow-up was 1021 patient-months (range, 1–68 months) in group A and 926 in group B (1–64 months). The event-free survival was calculated using the Kaplan–Meier method, and the difference between curves was evaluated using the Mantel–Cox log-rank test. Results: The operative mortality was 5% in group A and 0% in group B. One patient died at follow-up in group A and none in group B. Four patients (three Marfan) in group B were re-operated on because of recurrent aortic regurgitation. The 5-year event-free survival was 88±7% in group A and 82±8% in group B (P=0.58). Early residual aortic regurgitation remained stable over time only in patients with good early results. Conclusions: Mid-term follow-up failed to reveal statistically significant differences in the clinical outcome between remodelling and the Bentall operation. Our results support the widespread use of root remodelling, provided that an indication to this conservative approach is achieved after careful, case-by-case evaluation. A good early operative result is likely to remain stable over time

THE INTERPLAY BETWEEN TH17 AND TREGS: A NEW IMMUNOSUPPRESSIVE INSIGHT IN CHRONIC LYMPHOCYTIC LEUKEMIA

THE INTERPLAY BETWEEN TH17 AND TREGS: A NEW IMMUNOSUPPRESSIVE INSIGHT IN CHRONIC LYMPHOCYTIC LEUKEMI

Residual aortic valve regurgitation after aortic root remodeling without a direct annuloplasty

Background. Aortic insufficiency secondary to degenerative aneurysms of the ascending aorta can be surgically treated with replacement of the valve or with remodeling of the aortic root. Methods. In 15 patients who underwent aortic root remodeling from January 1994 to December 1996, we evaluated the postoperative aortic regurgitation and correlated it with several anatomic and functional variables. Operative success was defined as a residual aortic regurgitation less than or equal to 1 on a scale of 0 to 4. Results. Root dimensions and aortic incompetence decreased significantly after the operation (p < 0.0001). The difference between preoperative and postoperative root diameters (p = 0.0006) and the presence of Marfan's syndrome (p < 0.0001) were independently predictive of persisting significant aortic insufficiency. Operative success was obtained in patients with a difference between preoperative and postoperative root diameters smaller than 30 mm. Conclusions. Aortic root remodeling is effective in reducing aortic regurgitation. Severe aortic root dilatation may result in excessive geometric alteration, leading to suboptimal results. The choice of a larger graft contributes to avoiding excessive geometric constraint of a profoundly diseased aortic root. Indication to undergo root remodeling should be evaluated cautiously in patients with Marfan's syndrome. (Ann Thorac Surg 1998;66:1269-72

Regression of left ventricular hypertrophy after aortic valve replacement for aortic stenosis with different valve substitutes

Objective: Stentless biologic aortic valves are less obstructive than stented biologic or mechanical valves. Their superior hemodynamic performances are expected to reflect in better regression of left ventricular hypertrophy. We compared the regression of left ventricular hypertrophy in 3 groups of patients undergoing aortic valve replacement for severe aortic stenosis. Group I (10 patients) received stentless biologic aortic valves, group II (10 patients) received stented biologic aortic valves, and group III (10 patients received bileaflet mechanical aortic valves. Methods: Echocardiographic evaluations were performed before the operation and after I Seal; and the results were compared with those of a control group. Left ventricular diameters and function, left ventricular mall thickness, and left ventricular mass were assessed by echocardiography. Results: Group I patients had a significantly lower maximum and mean transprosthetic gl adient than the other valve groups (P =.001), One year after operation there was a significant reduction in left. ventricular mass for all patient groups (P<.01), hut mass did not reach normal values (P =.05). Although the rate of regression in the interventricular septum and posterior wall thickness differed slightly among groups, their values at follow-up were comparable and still higher than control values (P =.002), The ratio between interventricular septum and posterior wall and the ratio between wall thickness and chamber radius did not change significantly at follow-up, Conclusions: Because the number of patients was relatively small, we could not use Left ventricular mass regression after 1 Scar to distinguish among patients undergoing aortic valve replacement for aortic stenosis by means of valve prostheses with different hemodynamic performances

Temporal Sequenze and spatial distribution of ischemic changes during dipyridamole stress test - the key role of microvascular disfunction

Background: It is accepted that, in patients with epicardial coronary atherosclerosis, ischaemia produces a time sequence of events in myocardial regions supplied by stenotic branches characterised by regional wall motion abnormalities (WMA) followed by electrocardiographic changes and angina. Yet, the evidence indicates that patients with coronary atherosclerosis present a diffuse impairment of distal coronary vessels even in remote myocardial regions supplied by non-stenotic branches. Thus, temporal sequence of ischaemic events and the distribution of WMA may be influenced by microcirculatory dysfunction. Methods and Results: The study population consisted of 21 patients with stable angina and isolated stenosis of left anterior descending coronary artery (LAD). Patients underwent electrocardiographic and echocardiographic monitoring during dipyridamole infusion (DIP). During DIP, 14 patients exhibited both echocardiographic abnormalities and electrocardiographic changes and/or angina. In 8 patients (57 %) echocardiographic abnormalities represented the first ischaemic event; in the remaining 6 patients (43 %) the first ischaemic event was represented by electrocardiographic changes and/or angina. WMA appeared in LAD-dependent territories in 4 of 15 patients (27 %), in non-LAD-dependent territories in 5 patients (33 %), in both LAD and non-LAD-dependent territories in the 6 remaining patients (40 %). The mean percentage of abnormal segments and the mean WMA score were similar among the 3 groups (p = 0.8 and p = 0.47). Conclusions: In patients with stable angina, the mechanisms of myocardial ischaemia are determined by a complex interplay between epicardial obstructions and microvascular dysfunction. This evidence underscores the need in individual patients of a tailored treatment based on the main mechanisms of myocardial ischaemia