A Hierarchical Bayesian Model for Frame Representation

In many signal processing problems, it may be fruitful to represent the signal under study in a frame. If a probabilistic approach is adopted, it becomes then necessary to estimate the hyper-parameters characterizing the probability distribution of the frame coefficients. This problem is difficult since in general the frame synthesis operator is not bijective. Consequently, the frame coefficients are not directly observable. This paper introduces a hierarchical Bayesian model for frame representation. The posterior distribution of the frame coefficients and model hyper-parameters is derived. Hybrid Markov Chain Monte Carlo algorithms are subsequently proposed to sample from this posterior distribution. The generated samples are then exploited to estimate the hyper-parameters and the frame coefficients of the target signal. Validation experiments show that the proposed algorithms provide an accurate estimation of the frame coefficients and hyper-parameters. Application to practical problems of image denoising show the impact of the resulting Bayesian estimation on the recovered signal quality

Bronchodilation induced by PGE2 is impaired in Group-III pulmonary hypertension

BACKGROUND AND PURPOSE: In patients with pulmonary hypertension (PH) associated with lung disease and/or hypoxia (Group III), a reduction of pulmonary vascular tone and tissue hypoxia are considered therapeutically beneficial. Prostaglandin (PG) E2 and PGI2 induce potent relaxation of human bronchi from non-PH (control) patients via EP4 and IP receptors, respectively. However, the effects of PGE2 /PGI2 and their mimetics on human bronchi from PH-patients are unknown. Our aim was to compare the relaxant effects of several PGI2 -mimetics approved for treating PH-Group I with several PGE2 -mimetics in bronchial preparations derived from PH-Group III and control patients. EXPERIMENTAL APPROACH: Using an organ bath system, the tone of bronchial muscle was investigated in tissue from either control or PH-Group III patients. Expression of prostanoid receptors were analyzed by Western blot and real-time PCR and endogenous PGE2 , PGI2 and cAMP levels were determined by ELISA. KEY RESULTS: Maximal relaxations induced by different EP4 agonists (PGE2 , L-902688, ONO-AE1-329) were significantly decreased in human bronchi from PH-patients versus controls. In contrast, the maximal relaxations produced by PGI2 -mimetics (iloprost, treprostinil, beraprost) were similar for both groups of patients. Both EP4 and IP receptor protein and mRNA expressions were significantly lower in human bronchi from PH-patients. cAMP levels significantly correlated with PGI2 but not with PGE2 levels. CONCLUSION AND IMPLICATIONS: This study shows that PGI2 -mimetics have preserved maximal bronchodilation in PH-Group III patients. The decreased bronchodilation induced by EP4 agonists suggests that restoration of EP4 expression in airways of PH-patients with respiratory diseases could bring additional therapeutic benefit

The accumulation of assembly intermediates of the mitochondrial complex I matrix arm is reduced by limiting glucose uptake in a neuronal-like model of MELAS syndrome

Ketogenic diet (KD) which combined carbohydrate restriction and the addition of ketone bodies has emerged as an alternative metabolic intervention used as an anticonvulsant therapy or to treat different types of neurological or mitochondrial disorders including MELAS syndrome. MELAS syndrome is a severe mitochondrial disease mainly due to the m.3243A > G mitochondrial DNA mutation. The broad success of KD is due to multiple beneficial mechanisms with distinct effects of very low carbohydrates and ketones. To evaluate the metabolic part of carbohydrate restriction, transmitochondrial neuronal-like cybrid cells carrying the m.3243A > G mutation, shown to be associated with a severe complex I deficiency was exposed during 3 weeks to glucose restriction. Mitochondrial enzyme defects were combined with an accumulation of complex I (CI) matrix intermediates in the untreated mutant cells, leading to a drastic reduction in CI driven respiration. The severe reduction of CI was also paralleled in post-mortem brain tissue of a MELAS patient carrying high mutant load. Importantly, lowering significantly glucose concentration in cell culture improved CI assembly with a significant reduction of matrix assembly intermediates and respiration capacities were restored in a sequential manner. In addition, OXPHOS protein expression and mitochondrial DNA copy number were significantly increased in mutant cells exposed to glucose restriction. The accumulation of CI matrix intermediates appeared as a hallmark of MELAS pathophysiology highlighting a critical pathophysiological mechanism involving CI disassembly, which can be alleviated by lowering glucose fuelling and the induction of mitochondrial biogenesis, emphasizing the usefulness of metabolic interventions in MELAS syndrome

Prostanoid EP₂ Receptors Are Up-Regulated in Human Pulmonary Arterial Hypertension: A Key Anti-Proliferative Target for Treprostinil in Smooth Muscle Cells

Prostacyclins are extensively used to treat pulmonary arterial hypertension (PAH), a life-threatening disease involving the progressive thickening of small pulmonary arteries. Although these agents are considered to act therapeutically via the prostanoid IP receptor, treprostinil is the only prostacyclin mimetic that potently binds to the prostanoid EP₂ receptor, the role of which is unknown in PAH. We hypothesised that EP₂ receptors contribute to the anti-proliferative effects of treprostinil in human pulmonary arterial smooth muscle cells (PASMCs), contrasting with selexipag, a non-prostanoid selective IP agonist. Human PASMCs from PAH patients were used to assess prostanoid receptor expression, cell proliferation, and cyclic adenosine monophosphate (cAMP) levels following the addition of agonists, antagonists or EP₂ receptor small interfering RNAs (siRNAs). Immunohistochemical staining was performed in lung sections from control and PAH patients. We demonstrate using selective IP (RO1138452) and EP₂ (PF-04418948) antagonists that the anti-proliferative actions of treprostinil depend largely on EP₂ receptors rather than IP receptors, unlike MRE-269 (selexipag-active metabolite). Likewise, EP₂ receptor knockdown selectively reduced the functional responses to treprostinil but not MRE-269. Furthermore, EP₂ receptor levels were enhanced in human PASMCs and in lung sections from PAH patients compared to controls. Thus, EP₂ receptors represent a novel therapeutic target for treprostinil, highlighting key pharmacological differences between prostacyclin mimetics used in PAH

No evidence for circulating HuD-specific CD8+ T cells in patients with paraneoplastic neurological syndromes and Hu antibodies

Aim: In paraneoplastic neurological syndromes (PNS) associated with small cell lung cancer (SCLC) and Hu antibodies (Hu-PNS), Hu antigens expressed by the tumour hypothetically trigger an immune response that also reacts with Hu antigens in the nervous system, resulting in tumour suppression and neuronal damage. To gain more insight into the hypothesized CD8+T cell-mediated immune pathogenesis of these syndromes, we searched for circulating HuD-specific CD8+T cells in a large cohort of Hu-PNS patients and controls. Patients and methods: Blood was tested from 43 Hu-PNS patients, 31 Hu antibody negativ

Identification of an autoantibody panel to separate lung cancer from smokers and nonsmokers

<p>Abstract</p> <p>Background</p> <p>Sera from lung cancer patients contain autoantibodies that react with tumor associated antigens (TAAs) that reflect genetic over-expression, mutation, or other anomalies of cell cycle, growth, signaling, and metabolism pathways.</p> <p>Methods</p> <p>We performed immunoassays to detect autoantibodies to ten tumor associated antigens (TAAs) selected on the basis of previous studies showing that they had preferential specificity for certain cancers. Sera examined were from lung cancer patients (22); smokers with ground-glass opacities (GGOs) (46), benign solid nodules (55), or normal CTs (35); and normal non-smokers (36). Logistic regression models based on the antibody biomarker levels among the high risk and lung cancer groups were developed to identify the combinations of biomarkers that predict lung cancer in these cohorts.</p> <p>Results</p> <p>Statistically significant differences in the distributions of each of the biomarkers were identified among all five groups. Using Receiver Operating Characteristic (ROC) curves based on age, c-myc, Cyclin A, Cyclin B1, Cyclin D1, CDK2, and survivin, we obtained a sensitivity = 81% and specificity = 97% for the classification of cancer vs smokers(no nodules, solid nodules, or GGO) and correctly predicted 31/36 healthy controls as noncancer.</p> <p>Conclusion</p> <p>A pattern of autoantibody reactivity to TAAs may distinguish patients with lung cancer versus smokers with normal CTs, stable solid nodules, ground glass opacities, or normal healthy never smokers.</p

Granular Flow in Silo Discharge: Discrete Element Method Simulations and Model Assessment

Discharge dynamics of granular particles from a flat-bottomed silo is studied using both continuum modeling and three-dimensional (3D) discrete element method (DEM) simulations. Using DEM, the influence of microscopic parameters (interparticle friction coefficient, particle–wall friction coefficient and particle coefficient of restitution) and system parameters (orifice width) on the discharge rate is quantified. The spatial extent of different regimes (quasi-static, intermediate and inertial) of granular rheology are quantified using a regime map previously established from DEM data of homogeneously sheared granular flow. It is shown that all three regimes of granular rheology coexist during silo discharge, and the intermediate regime plays a significant role in discharge dynamics. A quantitative comparison between results of continuum and DEM simulations is performed by computing discharge rates, solid velocities, and solid stresses for a three-dimensional (3D) flat-bottomed silo. It is found that the three constitutive models investigated in this study overpredict the discharge rate when compared to DEM data. Contour plots of the error in solid stress prediction are compared with the spatial extent of different regimes of granular rheology to deduce that it is inaccurate modeling of the intermediate regime that is responsible for overprediction of the discharge rate