Littérature scientifique sur le sujet « SLOX1 »

The tremorogenic fungal metabolite, paxilline, is widely used as a potent and relatively specific blocker of Ca2+- and voltage-activated Slo1 (or BK) K+ channels. The pH-regulated Slo3 K+ channel, a Slo1 homologue, is resistant to blockade by paxilline. Taking advantage of the marked differences in paxilline sensitivity and the homology between subunits, we have examined the paxilline sensitivity of a set of chimeric Slo1/Slo3 subunits. Paxilline sensitivity is associated with elements of the S5–P loop–S6 module of the Slo1 channel. Replacement of the Slo1 S5 segment or the second half of the P loop results in modest changes in paxilline sensitivity. Replacing the Slo1 S6 segment with the Slo3 sequence abolishes paxilline sensitivity. An increase in paxilline affinity and changes in block kinetics also result from replacing the first part of the Slo1 P loop, the so-called turret, with Slo3 sequence. The Slo1 and Slo3 S6 segments differ at 10 residues. Slo1-G311S was found to markedly reduce paxilline block. In constructs with a Slo3 S6 segment, S300G restored paxilline block, but most effectively when paired with a Slo1 P loop. Other S6 residues differing between Slo1 and Slo3 had little influence on paxilline block. The involvement of Slo1 G311 in paxilline sensitivity suggests that paxilline may occupy a position within the central cavity or access its blocking position through the central cavity. To explain the differences in paxilline sensitivity between Slo1 and Slo3, we propose that the G311/S300 position in Slo1 and Slo3 underlies a structural difference between subunits in the bend of S6, which influences the occupancy by paxilline.

Phosphatidylinositol 4,5-bisphosphate (PIP2) plays a critical role in modulating the function of numerous ion channels, including large-conductance Ca2+- and voltage-dependent K+ (BK, Slo1) channels. Slo1 BK channel complexes include four pore-forming Slo1 (α) subunits as well as various regulatory auxiliary subunits (β and γ) that are expressed in different tissues. We examined the molecular and biophysical mechanisms underlying the effects of brain-derived PIP2 on human Slo1 BK channel complexes with different subunit compositions that were heterologously expressed in human embryonic kidney cells. PIP2 inhibited macroscopic currents through Slo1 channels without auxiliary subunits and through Slo1 + γ1 complexes. In contrast, PIP2 markedly increased macroscopic currents through Slo1 + β1 and Slo1 + β4 channel complexes and failed to alter macroscopic currents through Slo1 + β2 and Slo1 + β2 Δ2–19 channel complexes. Results obtained at various membrane potentials and divalent cation concentrations suggest that PIP2 promotes opening of the ion conduction gate in all channel types, regardless of the specific subunit composition. However, in the absence of β subunits positioned near the voltage-sensor domains (VSDs), as in Slo1 and probably Slo1 + γ1, PIP2 augments the negative surface charge on the cytoplasmic side of the membrane, thereby shifting the voltage dependence of VSD-mediated activation in the positive direction. When β1 or β4 subunits occupy the space surrounding the VSDs, only the stimulatory effect of PIP2 is evident. The subunit compositions of native Slo1 BK channels differ in various cell types; thus, PIP2 may exert distinct tissue- and divalent cation–dependent modulatory influences.

To investigate the associations between soluble Lectin-like Oxidized Low-density lipoprotein receptor-1 (sLOX-1) and clinical prognosis, especially infarct volume in patients with acute atherosclerosis-related ischemic stroke. We recruited acute ischemic stroke patients within 3 days after onset. Patients were stratified into 3 groups by sLOX-1 level. Initial stroke severity was assessed using the National Institutes of Health Stroke Scale scores, and infarct volume was measured using DWI by ITK-SNAP software. The clinical prognosis was evaluated by DWI volume, clinical response at discharge, and functional outcome at 90 days. Spearman rank correlation analysis was used to examine associations between circulating sLOX-1 levels and infarct volumes. Logistic regression was used to explore the relationship between sLOX-1 levels and clinical prognosis. A total of 207 patients were included in our study. The median DWI volume in the lowest sLOX-1 tertile was 1.98 cm3, smaller than 4.26 cm3 in the highest sLOX-1 group. The Spearman rank correlation coefficient between sLOX-1 levels and DWI volume was 0.47 ( P < .01). Compared with the highest sLOX-1 tertiles, patients in the lowest sLOX-1 tertile had a higher risk of favorable functional outcome at 90 days (OR = 3.47, 95% CI, 1.21-9.96) after adjusting traditional risk factors. However, there was no difference between sLOX-1 level and clinical response at discharge. For patients with acute atherosclerosis-related ischemic stroke, circulating sLOX-1 level is correlated with DWI volume in the acute phase and favorable functional outcome at 90 days, but not with the clinical response at discharge.

Introduction: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is involved in the pathophysiology of atherosclerosis and acute coronary syndromes (ACS). Circulating soluble LOX-1 (sLOX-1) has been linked to the risk of coronary artery disease (CAD). Our aim was to test if baseline serum sLOX-1 was associated with major adverse cardiovascular events (MACE) in patients with stable CAD. Materials and methods: This multicentre pilot study enrolled 833 stable CAD patients. All patients were followed for two years. Serum sLOX-1 concentrations were detected by enzyme-linked immunosorbent assay (ELISA). The association between sLOX-1 concentrations and MACE was assessed by logistic regression, Kaplan-Meier survival curves and Cox proportional hazards analyses. Logistic regression analysis was employed to assess the predictors of complex lesion. Results: Multivariate logistic regression analysis revealed that sLOX-1 concentration was an independent predictor of MACE (OR 2.07, 95%CI 1.52 - 2.82; P < 0.001). Kaplan-Meier cumulative survival curves showed that the incidence of MACE in patients with a high sLOX-1 concentration was significantly higher than in patients with an intermediate or low sLOX-1 concentration (P < 0.001). Soluble LOX-1 concentrations were independently correlated with coronary complex lesions (OR 2.32, 95%CI 1.81 - 2.97; P < 0.001). Conclusions: Baseline sLOX-1 concentrations were correlated with 2-year MACE in stable CAD patients. Furthermore, patients with high serum sLOX-1 concentrations had higher cumulative incidence of MACE compared to those with low serum sLOX-1 concentrations.

Although previous studies have revealed a role for the voltage-gated K+ channel α-subunit Kv1.5 ( KCNA5) in the generation of the 4-aminopyridine (4-AP)-sensitive component of delayed rectification in mouse ventricles ( IK,slow1), the phenotypic consequences of manipulating IK,slow1 expression in vivo in different (mouse) models are distinct. In these experiments, point mutations were introduced in the pore region of Kv1.5 to change the tryptophan (W) at position 461 to phenylalanine (F) to produce a nonconducting subunit, Kv1.5W461F, that is shown to function as a Kv1 subfamily-specific dominant negative (Kv1.5DN). With the use of the α-myosin heavy chain promoter to direct cardiac-specific expression, three lines of Kv1.5DN-expressing (C57BL6) transgenic mice were generated and characterized. Electrophysiological recordings from Kv1.5-DN-expressing left ventricular myocytes revealed that the micromolar 4-AP sensitive IK,slow1 is selectively eliminated. The attenuation of IK,slow1 is accompanied by increased ventricular action potential durations and marked QT prolongation. In contrast to previous findings in mice expressing a truncated (DN) Kv1.1 transgene; however, no electrical remodeling is evident in Kv1.5DN-expressing ventricular myocytes, and the (Kv1.5DN-induced) elimination of IK,slow1 does not result in spontaneous ventricular arrhythmias.

Background. Soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) may be a potential biomarker of coronary artery disease (CAD) and stroke. Objective. We aimed to investigate the association and prognostic value of elevated sLOX-1 concentrations with regard to long-term major adverse cardiovascular and cerebrovascular events (MACCEs) in patients with CAD undergoing primary percutaneous coronary intervention (PCI). Methods. A total of 1011 patients were enrolled. Serum sLOX-1 concentrations were detected by the enzyme-linked immunosorbent assay (ELISA). Patients were followed for 2 years. Multivariate Cox regression and Kaplan-Meier survival curve were explored to assess the association between sLOX-1 and MACCEs. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic efficacy of sLOX-1. Results. Two-year MACCEs were associated with serum sLOX-1 concentrations (HR 1.278, 95% CI 1.019-1.604, P=0.034), left main disease (HR 2.938, 95% CI 1.246-6.925, P=0.014), small-caliber stents used (HR 2.207, 95% CI 1.189-4.095, P=0.012), and total stent length (HR 1.057, 95% CI 1.005-1.112, P=0.030). Serum sLOX-1 concentration≥1.10 ng/ml had maximum sensitivity and specificity in predicting the occurrence of 2-year MACCEs (P<0.001). Patients with higher serum sLOX-1 concentrations showed a significantly higher incidence of MACCEs in the Kaplan-Meier curve (P<0.001). The combination of any of the risk factors identified in multiple Cox regression was associated with a stepwise increase in MACCE rate (P<0.001). Conclusions. High baseline serum sLOX-1 concentration predicts 2-year MACCEs and shows an additional prognostic value to conventional risk factors in patients after primary PCI. sLOX-1 determination might play a complementary role in the risk stratification of patients with CAD treated with PCI.

Objective. The aim of this study was to investigate the expression level of soluble LOX-1 (sLOX-1) in the serum of non-small-cell lung cancer (NSCLC) patients and its correlation with lipid metabolism. Methods. 99 inpatients with NSCLC and 81 healthy controls were enrolled in this study. The levels of serum sLOX-1 were compared between the two groups, and the correlation of sLOX-1 with clinicopathological characteristics, blood lipid indices, and carcinoembryonic antigen was analyzed. Results. Compared with the healthy controls, sLOX-1, low-density lipoprotein, triglyceride, and carcinoembryonic antigen in the patients with NSCLC were significantly higher ( p < 0.05), while the expression level of high-density lipoprotein was lower ( p < 0.05). The expression level of sLOX-1 in the serum of patients with healthy controls was positively correlated with low-density lipoprotein (r = 0.72, p < 0.05). The levels of sLOX-1 and low-density lipoprotein in the serum of patients with NSCLC were closely related to the lymph node metastasis, distant metastasis, and TNM stage ( p < 0.05). Compared with a single index, when the sLOX-1 was combined with the CEA, its specificity increased significantly to 97.5% (AUC = 0.995, p < 0.01, 95% CI: 0.989–1.000). Conclusion. sLOX-1 and low-density lipoprotein were overexpressed in the serum of patients with NSCLC, positively correlated, and closely related to the TNM stage and metastasis. This result suggested that lipid metabolic disorders may promote the progression of NSCLC through sLOX-1, which could be a potential serological marker with diagnostic value for NSCLC.

Purpose: Patients with metabolic syndrome are at high-risk for development of atherosclerosis and cardiovascular events. Serum soluble lectin-like oxidized low-density lipoprotein receptor-1(sLOX-1) is associated with coronary artery disease (CAD) and metabolic disorders. We sought to assess whether serum sLOX-1 levels are correlated with the presence and severity of CAD in patients with metabolic syndrome (MetS) undergoing coronary angiography. Methods: Serum sLOX-1 levels were measured in 112 consecutive patients with MetS, undergoing coronary angiography for the evaluation of CAD. The severity of CAD was assessed by angiographic Gensini score system. Results: Serum sLOX-1 levels were significantly higher in MetS patients with CAD (n=69) than in those without CAD (n=43) (0.925 [range 0.137 to 1.432] ng/ml vs. 0.207 [range 0.063 to 0.774] ng/ml, P < 0.01). Multivariate logistic regression analysis revealed that serum sLOX-1 level was independently associated with the presence of CAD (odds ratio 2.489, 95% confidence interval 1.290-4.802; P < 0.01). Serum sLOX-1 levels were positively correlated with the Gensini score (ρ: 0.394, P < 0.01) after adjusting for other clinical characteristics. Conclusions: High sLOX-1 levels are associated with the presence and severity of CAD in patients with MetS. The measurement of serum sLOX-1may be potentially useful in predicting the presence and severity of CAD in patients with MetS.

In most eukaryotes, genes encoding ribosomal RNAs (rDNA) are clustered in long tandem head-to-tail repeats. Studies of Saccharomyces cerevisiae have indicated that rDNA copy number is maintained through recombination events associated with site-specific blockage of replication forks (RFs). Here, we describe two Schizosaccharomyces pombe proteins, homologs of S. cerevisiae Slx1 and Slx4, as subunits of a novel type of endonuclease that maintains rDNA copy number. The Slx1-Slx4–dependent endonuclease introduces single-strand cuts in duplex DNA on the 3′ side of junctions with single-strand DNA. Deletion of Slx1 or Rqh1 RecQ-like DNA helicase provokes rDNA contraction, whereas simultaneous elimination of Slx1-Slx4 endonuclease and Rqh1 is lethal. Slx1 associates with chromatin at two foci characteristic of the two rDNA repeat loci in S. pombe. We propose a model in which the Slx1–Slx4 complex is involved in the control of the expansion and contraction of the rDNA loci by initiating recombination events at stalled RFs.

Objective: The diagnostic significance of plasma soluble lectin-like oxidized low-density lipoprotein receptor-1(sLOX-1) for non-ST segment elevated myocardial infarction (NSTEMI) and ST segment elevated myocardial infarction (STEMI) were explored by this study. Methods: In this study, 107 acute NSTEMI, 223 acute STEMI and 107 healthy subjects, and hypoxic (1%02) ventricular cardiomyocytes H9c2 were used. Results: The significantly up-regulated plasma sLOX-1 levels in acute NSTEMI and STEMI patients compared to healthy subjects (p<0.001). Both male and female NSTEMI and STEMI groups had remarkably higher concentrations of plasma sLOX-1 levels than controls (p<0.001). The circulating levels of sLOX-1 expression obviously elevated in elderly aging (60-75 years) than younger aging (30-45 years) both male and female in healthy subjects as well as NSTEMI and STEMI (p<0.001). Altered levels of sLOX-1 in blood plasma revealed a significant discrimination with high sensitivity and specificity between healthy with NSTEMI and STEMI subjects with AUC= 0.916 and AUC= 0.925 respectively. Moreover, LOX-1 levls were highly released from 6hour, 12hour and 18hour hypoxic injured H9c2 cells than normoxic cell (p<0.001),reflected circulating plasma sLOX-1 in AMI patients. Conclusion: Elevated levels of plasma sLOX-1concentrations might be used as a clinical biomarker for early recognition of NSTEMI and STEMI patients. Multicenter larger scale studies are necessary before use in clinical practice. Keywords: Myocardial infarction; sLOX-1; biomarker; H9c2 cells.

Dans cette thèse nous étudions un système quantique, obtenu comme un analogue d'un système classique superintégrable perturbé au moyen de la quantification géométrique. Notre objectif est de mettre en évidence la présence des phénomènes analogues à ceux qui caractérisent la superintégrabilité classique, notamment la coexistence des mouvements réguliers et chaotiques liés aux effets des résonances ainsi que la régularité du régime non-résonant. L'analyse est effectuée par l'étude des distributions du Husimi des états quantiques sélectionnés, avec une attention particulière aux états stationnaires et à l'évolution des états cohérents. Les calculs sont effectués en utilisant les méthodes numériques et les méthodes perturbatives. Les calculs sont effectués en utilisant les méthodes numériques et les méthodes perturbatives. Bien que cette thèse devrait être considérée comme une étude préliminaire, dont l'objectif est de créer le socle des études futures, nos résultats donnent des indications intéressantes sur la dynamique quantique. Par exemple, il est démontré comment les résonancees classiques exercent une influence considérable sur le spectre du système quantique et comment il est possible, dans le comportement quantique, de trouver une trace de l'invariant adiabatique dans le régime de résonance
The abundance, among physical models, of perturbations of superintegrable Hamiltonian systems makes the understanding of their long-term dynamics an important research topic. While from the classical standpoint the situation, at least in many important cases, is well understood through the use of Nekhoroshev stability theorem and of the adiabatic invariants theory, in the quantum framework there is, on the contrary, a lack of precise results. The purpose of this thesis is to study a perturbed superintegrable quantum system, obtained from a classical counterpart by means of geometric quantization, in order to highlight the presence of indicators of superintegrability analogues to the ones that characterize the classical system, such as the coexistence of regular motions with chaotic one, due to the effects of resonances, opposed to the regularity in the non resonant regime. The analysis is carried out by studying the Husimi distributions of chosen quantum states, with particular emphasis on stationary states and evolved coherent states. The computation are performed using both numerical methods and perturbative schemes. Although this should be considered a preliminary work, the purpose of which is to lay the fundations for future investigations, the results obtained here give interesting insights into quantum dynamics. For instance, it is shown how classical resonances exert a considerable influence on the spectrum of the quantum system and how it is possible, in the quantum behaviour, to find a trace of the classical adiabatic invariance in the resonance regime
L'abbondanza, fra i modelli fisici, di perturbazioni di sistemi Hamiltoniani superintegrabili rende la comprensione della loro dinamica per tempi lunghi un importante argomento diricerca. Mentre dal punto di vista classico la situazione, perlomeno in molti case importanti, è ben compresa grazie all'uso del teorema di stabilità di Nekhoroshev e della teoria degli invariantiadiabatici, nel caso quantistico vi è, al contrario, una mancanza di risultati precisi. L'obiettivo di questa tesi è di studiare un sistema superintegrabile quantistico, ottenuto partendo da un corrispettivo classico tramite quantizzazione geometrica, al fine di evidenziare la presenza di indicatori di supertintegrabilità analoghi a quelliche caratterizzano il sistema classico, come la coesistenza di moti regolari e caotici, dovuta all'effetto delle risonanze, in contrapposizione con la regolarità nel regime non risonante. L'analisi è condotta studiando le distribuzioni di Husimi di stati quantistici scelti, con particolare enfasi posta sugli stati stazionari e sugli stati coerenti evoluti. I calcoli sono effettuati sia utilizzando tecniche numeriche che schemi perturbativi. Pur essendo da considerardi questo un lavoro preliminare, il cui compito è di porre le fondamenta per analisi future, i risultati qui ottenuti offrono interessanti spunti sulla dinamica quantistica. Per esempio è mostrato come le risonanze classiche abbiano un chiaro effeto sullo spettro del sistema quantistico, ed inoltre comesia possibile trovare una traccia, nel comportamento quantistico, dell'invarianza adiabatica classica nel regime risonante