Variable Neighborhood Search for Solving the Capacitated Single Allocation Hub Location Problem

In this paper a Variable Neighborhood Search (VNS) algorithm for solving the Capacitated Single Allocation Hub Location Problem (CSAHLP) is presented. CSAHLP consists of two subproblems; the first is choosing a set of hubs from all nodes in a network, while the other comprises finding the optimal allocation of non-hubs to hubs when a set of hubs is already known. The VNS algorithm was used for the first subproblem, while the CPLEX solver was used for the second. Computational results demonstrate that the proposed algorithm has reached optimal solutions on all 20 test instances for which optimal solutions are known, and this in short computational time

From Neolithic to Copper Age: two tales of change in the Carpathian Basin

A review of two volumes - Florin Drașovean & Wolfram Schier (ed.). 2020. Uivar“Gomila”:a prehistoric tell settlement in the Romanian Banat.Vol.I: site, architecture, stratigraphy and dating and William A.Parkinson, Attila Gyucha & Richard W. Yerkes(ed.). 2021.Bikeri: two Copper Age villages on the Great Hungarian Plai

Modulation of c-Jun N-terminal kinase signaling and specific glucocorticoid receptor phosphorylation in the treatment of major depression

Glucocorticoid resistance is a common finding in major depressive disorder. Increased glucocorticoid receptor (GR) phosphorylation at serine 226 is associated with increased glucocorticoid resistance. Previously we have demonstrated that depressed patients exhibit higher levels of GR phosphorylated at serine 226 compared to healthy controls. The enzyme that is involved in this specific GR phosphorylation is c-Jun N-terminal kinase (JNK). We propose that modulation of glucocorticoid phosphorylation at serine 226, by targeting JNK signaling pathway, could be a potential strategy for antidepressant treatment. We base this assumption on the results of previous research that examined GR phosphorylation and JNK signaling in animal models and human studies. We also discuss the potential challenges in targeting JNK signaling pathway in depression. (C) 2015 Elsevier Ltd. All rights reserved

Accumulation of Cytoplasmic Glucocorticoid Receptor Is Related to Elevation of FKBP5 in Lymphocytes of Depressed Patients

We have previously shown that patients with the major depressive disorder (MDD) exhibited elevated phosphorylation of the lymphocyte glucocorticoid receptor (GR) at serine 226 (S226). Here, we further analyse potential alterations of GR signalization in lymphocytes of MDD patients, i.e. the cytoplasmic/nuclear distribution of GR, levels of FK506-binding protein 5 (FKBP5) and glucocorticoid-induced leucine zipper (GILZ). The FKBP5 acts as an important regulator of GR activation, by decreasing ligand binding and impeding translocation of the receptor to the nucleus, while GILZ mediates glucocorticoid anti-inflammatory effects. Our result showed that the depressed patients had significantly higher GR levels in the cytoplasm compared to controls, which was accompanied by higher FKBP5 levels. Linear regression model demonstrated significantly higher correlation between FKBP5 and cytoplasmic GR than the presence of MDD itself or phosphorylation of nuclear GR at S226. There were no differences in the levels of GILZ isoforms. Therefore, the results suggest that accumulation of the GR in cytoplasm is related to the elevation of FKBP5, adding one more step in understanding altered GR signalling in lymphocytes, and potentially brain tissue, of MDD patients

Pharmacological Modulation of Hpa Axis in Depression - New Avenues for Potential Therapeutic Benefits

One of the most consistent biological findings in major depression (MDD) is the altered activity of the hypothalamic-pituitary-adrenal (HPA) axis. It is not surprising that glucocorticoid receptor (GR), the common mechanism for stress-related changes in brain function, is a potential target of antidepressant drugs and therapies. All effective antidepressant treatments should trigger and maintain GR-related cellular processes necessary for recovery from MDD. Classic antidepressants act indirectly, by affecting the dynamic interplay between serotonin neurotransmission and HPA. On the other hand, certain compounds acting at supra-hypothalamic, HPA axis, glucocorticoid receptors, and post-receptor levels are being considered as new therapeutic options with the potential to modulate the aforementioned system in affective disorders directly. Different classes of drugs pharmacologically modify the HPA axis. This article summarizes the efficacy of classic antidepressants, as well as drugs classified as antiglucocorticoids (GR agonists, GR antagonists, dehydroepiandrosterone-DHEA, steroid synthesis inhibitors drugs, etc) in their capacity to heal glucocorticoid-mediated damage in depression. New avenues investigating the potential therapeutic benefits of antiglucocorticoids in affective disorders are at the proof-of-concept stage and future developments in this area deserve the full attention of psychiatrists and neuroscientists, as the current pharmacological treatment of MDD is far from perfect

PHARMACOLOGICAL MODULATION OF HPA AXIS IN DEPRESSION – NEW AVENUES FOR POTENTIAL THERAPEUTIC BENEFITS

One of the most consistent biological findings in major depression (MDD) is the altered activity of the hypothalamic-pituitaryadrenal (HPA) axis. It is not surprising that glucocorticoid receptor (GR), the common mechanism for stress-related changes in brain function, is a potential target of antidepressant drugs and therapies. All effective antidepressant treatments should trigger and maintain GR-related cellular processes necessary for recovery from MDD. Classic antidepressants act indirectly, by affecting the dynamic interplay between serotonin neurotransmission and HPA. On the other hand, certain compounds acting at suprahypothalamic, HPA axis, glucocorticoid receptors, and post-receptor levels are being considered as new therapeutic options with the potential to modulate the aforementioned system in affective disorders directly. Different classes of drugs pharmacologically modify the HPA axis. This article summarizes the efficacy of classic antidepressants, as well as drugs classified as "antiglucocorticoids" (GR agonists, GR antagonists, dehydroepiandrosterone- DHEA, steroid synthesis inhibitors drugs, etc) in their capacity to heal glucocorticoid-mediated damage in depression. New avenues investigating the potential therapeutic benefits of antiglucocorticoids in affective disorders are at the proof-of-concept stage and future developments in this area deserve the full attention of psychiatrists and neuroscientists, as the current pharmacological treatment of MDD is far from perfect

Emerging roles of A-kinase anchoring proteins in cardiovascular pathophysiology

Heart and blood vessels ensure adequate perfusion of peripheral organs with blood and nutrients. Alteration of the homeostatic functions of the cardiovascular system can cause hypertension, atherosclerosis, and coronary artery disease leading to heart injury and failure. A-kinase anchoring proteins (AKAPs) constitute a family of scaffolding proteins that are crucially involved in modulating the function of the cardiovascular system both under physiological and pathological conditions. AKAPs assemble multifunctional signaling complexes that ensure correct targeting of the cAMP-dependent protein kinase (PKA) as well as other signaling enzymes to precise subcellular compartments. This allows local regulation of specific effector proteins that control the function of vascular and cardiac cells. This review will focus on recent advances illustrating the role of AKAPs in cardiovascular pathophysiology. The accent will be mainly placed on the molecular events linked to the control of vascular integrity and blood pressure as well as on the cardiac remodeling process associated with heart failure. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel

The influence of interactive learning materials on solving tasks that require different types of mathematical reasoning

The purpose of this study is to analyse the effects of the Interactive Learning Materials Triangle (iLMT) on the learning and knowledge retention of 12-year- old students. The iLMT is a digital version of the standard school learning materials in Serbia, and is characterized by a high degree of interactivity and immediate feedback during the learning process. We conducted an experiment to explore whether iLMT influences student success in solving mathematical tasks that require different types of mathematical reasoning. Based on previous extensive research by Lithner, 4 types of tasks are discussed: high relatedness answer, high relatedness algorithm, local low relatedness, and global low relatedness. The study involved 633 students and 13 teachers of mathematics, equally distributed in control and test groups. The main findings indicate that student success on a knowledge test for high relatedness answer and local low relatedness tasks for the test group was significantly higher than for the control group. On the knowledge retention test, students in the test group outperformed students in the control group at high relatedness algorithm and local low relatedness tasks. Our results also suggest that, even when learning materials are carefully digitalized with the use of available technological advantages, student success in global low relatedness tasks may still be lacking

The influence of interactive learning materials on solving tasks that require different types of mathematical reasoning

The purpose of this study is to analyse the effects of the Interactive Learning Materials Triangle (iLMT) on the learning and knowledge retention of 12-year- old students. The iLMT is a digital version of the standard school learning materials in Serbia, and is characterized by a high degree of interactivity and immediate feedback during the learning process. We conducted an experiment to explore whether iLMT influences student success in solving mathematical tasks that require different types of mathematical reasoning. Based on previous extensive research by Lithner, 4 types of tasks are discussed: high relatedness answer, high relatedness algorithm, local low relatedness, and global low relatedness. The study involved 633 students and 13 teachers of mathematics, equally distributed in control and test groups. The main findings indicate that student success on a knowledge test for high relatedness answer and local low relatedness tasks for the test group was significantly higher than for the control group. On the knowledge retention test, students in the test group outperformed students in the control group at high relatedness algorithm and local low relatedness tasks. Our results also suggest that, even when learning materials are carefully digitalized with the use of available technological advantages, student success in global low relatedness tasks may still be lacking