Randomized Trial Of Weight Loss On Ghrelin Levels Among Breast Cancer Survivors

Purpose: Obesity is associated with increased breast cancer risk and mortality. Ghrelin is a hormone that participates in a negative feedback loop to regulate body weight. Understanding the impact of an individualized, sustainable, dietary and exercise weight-loss intervention on circulating ghrelin levels could provide insight on weight control mechanisms among overweight and obese breast cancer survivors. Methods: The Lifestyle, Exercise, and Nutrition (LEAN) randomized controlled trial was a 6-month weight loss trial conducted to examine the effect of a weight loss intervention versus usual care on outcomes in 151 breast cancer survivors with BMI ≥ 25 kg/m2. Fasting blood samples were collected at baseline and 6-months and ghrelin was measured using enzyme-linked immunosorbent assays (ELISA). Pearson correlation coefficients were used to examine baseline associations and general linear models and least square means were used to compare changes in ghrelin levels from baseline to 6-months between randomization groups. Results: Ghrelin measurements from 128 women were analyzed. At baseline, there was a significant positive correlation between circulating ghrelin and age (r=0.28, p Conclusion: These findings support that greater weight loss, achieved through a sustainable diet and exercise intervention, is associated with increased circulating ghrelin levels in overweight or obese breast cancer survivors. Further research is warranted to explore whether this change might affect long-term maintenance of weight loss as well as to further understand the role ghrelin may play in breast cancer recurrence and mortality

GIS Technology Application in Railway Transport System

U radu je analizirana upotreba geografskog informacijskog sustava (GIS) na aspekte željezničkoga prometa. GIS predstavlja programski sustav kojim se prikupljaju, a zatim i koriste geoprostorni podaci kako bi se riješili problemi prometnog sustava. Na početku rada su iznesene značajke željezničkog prometnog sustava koje je moguće predstaviti korištenjem GIS tehnologije. Definirano je šta je GIS tehnologija, te potrebni ulazni podaci s obzirom da geoprostorne analize uglavnom ovise o raspoloživim podacima. Posebno je obrađen modul za analiziranje prometnih mreža (eng. Network Analyst) i na kraju je dana primjena GIS tehnologije na željeznički prometni sustav.In this work the use of geographic information system (GIS) in the aspects of railway traffic is analyzed. The GIS represents the software system that collects, and then uses geospatial data to solve traffic system problems. At the beginning of the work, the features of the railway traffic system, using GIS technology are presented. It is defined what GIS technology is, and the necessary input data as geospatial analysis depends largely on the available data. Particularly elaborated was the module for analysis traffic network's „Network Analyst“, and at the end was given application of GIS technology to the railway traffic syste

Train and Traffic Control System in Podsused Tvornica Railway Station

U radu je analiziran tehnološki proces i postojeći sustav osiguranja željezničkog prometa u kolodvoru Podsused Tvornica.Kolodvor Podsused Tvornica je međukolodvor na pruzi M101 (DG - Savski Marof – Zagreb Glavni kolodvor) te se nalazi između Zagreb Zapadnog kolodvora i kolodvora Zaprešić. Osiguranje željezničkog prometa u tom kolodvorskom području provodi se pomoću elektro-relejnog signalno – sigurnosnog uređaja tipa Sp-Dr-L 30 „Lorenz“ pri čemu prometnik vlakova u svom uredu pomoću komandnog stola osigurava vlakovne i manevarske putove vožnje.In this work technological process and the existing train and traffic control system in the PodsusedTvornica railway station is analyzed.PodsusedTvornica is an interstation located on the railway line M101 (DG - SavskiMarof – Zagreb Glavnikolodvor) between railway stations Zagreb Zapadni and Zapresić. In the station area train control processes are carried out by the relay interlocking system Sp Dr L-30 "Lorenz" where the station dispatcher in his office by using the operation table provides train and shunting routes

GIS Technology Application in Railway Transport System

U radu je analizirana upotreba geografskog informacijskog sustava (GIS) na aspekte željezničkoga prometa. GIS predstavlja programski sustav kojim se prikupljaju, a zatim i koriste geoprostorni podaci kako bi se riješili problemi prometnog sustava. Na početku rada su iznesene značajke željezničkog prometnog sustava koje je moguće predstaviti korištenjem GIS tehnologije. Definirano je šta je GIS tehnologija, te potrebni ulazni podaci s obzirom da geoprostorne analize uglavnom ovise o raspoloživim podacima. Posebno je obrađen modul za analiziranje prometnih mreža (eng. Network Analyst) i na kraju je dana primjena GIS tehnologije na željeznički prometni sustav.In this work the use of geographic information system (GIS) in the aspects of railway traffic is analyzed. The GIS represents the software system that collects, and then uses geospatial data to solve traffic system problems. At the beginning of the work, the features of the railway traffic system, using GIS technology are presented. It is defined what GIS technology is, and the necessary input data as geospatial analysis depends largely on the available data. Particularly elaborated was the module for analysis traffic network's „Network Analyst“, and at the end was given application of GIS technology to the railway traffic syste

How the headpiece hinge angle is opened: new insights into the dynamics of integrin activation

How the integrin head transitions to the high-affinity conformation is debated. Although experiments link activation with the opening of the hinge angle between the βA and hybrid domains in the ligand-binding headpiece, this hinge is closed in the liganded αvβ3 integrin crystal structure. We replaced the RGD peptide ligand of this structure with the 10th type III fibronectin module (FnIII10) and discovered through molecular dynamics (MD) equilibrations that when the conformational constraints of the leg domains are lifted, the βA/hybrid hinge opens spontaneously. Together with additional equilibrations on the same nanosecond timescale in which small structural variations impeded hinge-angle opening, these simulations allowed us to identify the allosteric pathway along which ligand-induced strain propagates via elastic distortions of the α1 helix to the βA/hybrid domain hinge. Finally, we show with steered MD how force accelerates hinge-angle opening along the same allosteric pathway. Together with available experimental data, these predictions provide a novel framework for understanding integrin activation

Conformational Stability Analyses of Alpha Subunit I Domain of LFA-1 and Mac-1

β2 integrin of lymphocyte function-associated antigen-1 (LFA-1) or macrophage-1 antigen (Mac-1) binds to their common ligand of intercellular adhesion molecule-1 (ICAM-1) and mediates leukocyte-endothelial cell (EC) adhesions in inflammation cascade. Although the two integrins are known to have distinct functions, the corresponding micro-structural bases remain unclear. Here (steered-)molecular dynamics simulations were employed to elucidate the conformational stability of α subunit I domains of LFA-1 and Mac-1 in different affinity states and relevant I domain-ICAM-1 interaction features. Compared with low affinity (LA) Mac-1, the LA LFA-1 I domain was unstable in the presence or absence of ICAM-1 ligand, stemming from diverse orientations of its α7-helix with different motifs of zipper-like hydrophobic junction between α1- and α7-helices. Meanwhile, spontaneous transition of LFA-1 I domain from LA state to intermediate affinity (IA) state was first visualized. All the LA, IA, and high affinity (HA) states of LFA-1 I domain and HA Mac-1 I domain were able to bind to ICAM-1 ligand effectively, while LA Mac-1 I domain was unfavorable for binding ligand presumably due to the specific orientation of S144 side-chain that capped the MIDAS ion. These results furthered our understanding in correlating the structural bases with their functions of LFA-1 and Mac-1 integrins from the viewpoint of I domain conformational stability and of the characteristics of I domain-ICAM-1 interactions

Demonstration of catch bonds between an integrin and its ligand

Binding of integrins to ligands provides anchorage and signals for the cell, making them prime candidates for mechanosensing molecules. How force regulates integrin–ligand dissociation is unclear. We used atomic force microscopy to measure the force-dependent lifetimes of single bonds between a fibronectin fragment and an integrin α5β1-Fc fusion protein or membrane α5β1. Force prolonged bond lifetimes in the 10–30-pN range, a counterintuitive behavior called catch bonds. Changing cations from Ca2+/Mg2+ to Mg2+/EGTA and to Mn2+ caused longer lifetime in the same 10–30-pN catch bond region. A truncated α5β1 construct containing the headpiece but not the legs formed longer-lived catch bonds that were not affected by cation changes at forces <30 pN. Binding of monoclonal antibodies that induce the active conformation of the integrin headpiece shifted catch bonds to a lower force range. Thus, catch bond formation appears to involve force-assisted activation of the headpiece but not integrin extension

Syndecan-4 phosphorylation is a control point for integrin recycling

Precise spatiotemporal coordination of integrin adhesion complex dynamics is essential for efficient cell migration. For cells adherent to fibronectin, differential engagement of α5β1 and αVβ3 integrins is used to elicit changes in adhesion complex stability, mechanosensation, matrix assembly, and migration, but the mechanisms responsible for receptor regulation have remained largely obscure. We identify phosphorylation of the membrane-intercalated proteoglycan syndecan-4 as an essential switch controlling integrin recycling. Src phosphorylates syndecan-4 and, by driving syntenin binding, leads to suppression of Arf6 activity and recycling of αVβ3 to the plasma membrane at the expense of α5β1. The resultant elevation in αVβ3 engagement promotes stabilization of focal adhesions. Conversely, abrogation of syndecan-4 phosphorylation drives surface expression of α5β1, destabilizes adhesion complexes, and disrupts cell migration. These data identify the dynamic spatiotemporal regulation of Src-mediated syndecan-4 phosphorylation as an essential switch controlling integrin trafficking and adhesion dynamics to promote efficient cell migration