The role of sirtuins and uncoupling proteins on vascular aging: The Northern Manhattan Study experience

aging affects all organs. arteries, in particular, are among the most affected. Vascular aging (VA) is defined as age-associated changes in function and structure of vessels. classical VA phenotypes are carotid intima-media thickness (IMT), carotid plaque (CP), and arterial stiffness (STIFF). Individuals have different predisposition to these VA phenotypes and their associated risk of cardiovascular events. some develop an early vascular aging (EVA), and others are protected and identified as having supernormal vascular aging (SUPERNOVA). the mechanisms leading to these phenotypes are not well understood. In the northern manhattan study (NOMAS), we found genetic variants in the 7 sirtuins (SIRT) and 5 uncoupling Proteins (UCP) to be differently associated with risk to developing VA phenotypes. In this article, we review the results of genetic-epidemiology studies to better understand which of the single nucleotide polymorphisms (SNPs) in SIRT and UCP are responsible for both EVA and SUPERNOVA

Monoaminergic Neuropathology in Alzheimer's disease

Acknowledgments This work was supported by The Croatian Science Foundation grant. no. IP-2014-09-9730 (“Tau protein hyperphosphorylation, aggregation, and trans-synaptic transfer in Alzheimer’s disease: cerebrospinal fluid analysis and assessment of potential neuroprotective compounds”) and European Cooperation in Science and Technology (COST) Action CM1103 (“Stucture-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain”). PRH is supported in part by NIH grant P50 AG005138.Peer reviewedPostprin

Neuronal cell lipidomics and role of cholesterol in α-synuclein binding and aggregation

α-Synuclein is an intrinsically disordered protein whose fold and multimeric state is strongly affected by its environment. The monomers of α-synuclein are enriched in the presynaptic terminals of dopaminergic neurons and seem to have a role in synaptic vesicles recycling and transmitter release. Specific cellular conditions can promote α-synuclein oligomerization which, in the end, results in neuronal death. Lipids seem to be one of these conditions as they are involved in both the native and pathogenic role of α-synuclein. This thesis aims to explore α-synuclein:lipid interaction and how binding to certain lipids may trigger or suppress oligomerization. Furthermore, it aims to establish and use lipidomic techniques for improving the state of knowledge of the lipid environment that might affect α-synuclein function and dysfunction. In Paper I we investigated how cholesterol, the most abundant lipid in mammals, affect α-synuclein affinity towards the lipid bilayer and its oligomerization properties. For this work we tested and optimized the preparation of SMA lipid nanodiscs containing cholesterol. Then, we used these nanodiscs to investigate lipid-mediated changes in fibrillation. We also determined individual amino acid affinities towards the lipid bilayer within the α-synuclein primary sequence. The results suggest the existence of two binding modes: the N-terminal and NAC binding mode. The N-terminal mode seems to be preferred in the presence of anionic lipids (like PG), and this binding leads to a delay in fibrillation onset. The NAC-binding mode seems to be promoted in the presence of lipid bilayers containing cholesterol and speed up α-synuclein oligomerization significantly. In Paper II, we focused on lipidomics methods. We established and optimized a method for lipid isolation, followed by phospholipid identification and quantification using 31P NMR. These methods were first tested on populations of a prokaryotic organism, L. innocua, which were arrested at the C/D boundary of its cell cycle. We discovered that L. innocua modulates its lipid composition, and both cardiolipin and phosphatidylethanolamine fall significantly between the B period and the C/D boundary. When we investigated how these lipid changes could affect the physical properties models of the cell membrane, we observed that the decrease of PE content seems to be compensated for by an increase of PG. In the absence of other factors, this would result in decreasing stored curvature stress, while maintaining membrane fluidity. In Paper III, we used methods established in Paper II for the lipidomic analysis of the SH-SY5Y cell line, which is a commonly used neuronal cell model for Parkinson’s disease research. We also developed an automated script for analysis of the fatty acid chain distribution of phospholipids by LC-MS/MS. We observed several deviations of lipid content from commonly used lipid models and lipid content of brain matter. The most interesting ones are a high content of PC, low content of SM and PS and absence of longer fatty acid chains, including 22:6 PS

Histological evaluation of surgical experiments in animal models

Introduction: The dissertation is based on six studies that focus on the application of quantitative histology in animal model experiments. It includes a presentation of virtual microscopy procedures and image field sampling strategies, mapping changes in the microscopic structure of ovine and porcine carotid segments and their comparison with human coronary arteries and internal thoracic arteries, vascularization assessment in a mouse model of lymphoma xenografts (PDX), the effect of hyperbaric oxygen therapy on type III collagen production and on vascularization in a skin wound in a Zucker Diabetic Fatty rat. Methods: The review article about virtual microscopy was focused on an example of sampling images from various areas of quantitative histology. In other studies, histologically processed sections were stained with a variety of methods for vascular wall construction, cell infiltration (orcein, picrosirius red, Verhoeff's hematoxylin and green trichrome, Gill's hematoxylin, alcian blue) and immunohistochemical antigen detection (α-smooth muscle actin, neurofilament protein, CD-31, von Willebrand factor). Using unbiased sampling and stereological methods, we quantified the area fraction of components (elastin, collagen, smooth muscle actin and chondroitin sulfate) using a stereological grid...Úvod: Dizertační práce je založena na šesti studiích, které se zaměřují na uplatnění kvantitativní histologie v hodnocení experimentů u zvířecích modelů. Zahrnuje představení postupů virtuální mikroskopie a strategií vzorkování obrazových polí, mapování změn mikroskopické struktury segmentů ovčích a prasečích krkavic a jejich porovnání s lidskými koronárními cévami a arteria thoracica interna, hodnocení vaskularizace u myšího modelu s xenografty lymfomů (PDX), vliv hyperbarické oxygenoterapie na tvorbu kolagenu typu III a na vaskularizaci v kožní ráně u Zucker Diabetic Fatty potkana. Metody: Přehledový článek o virtuální mikroskopii byl zaměřen na ukázku příkladu vzorkování snímků z různých oblastí kvantitativní histologie. V ostatních studiích byly histologicky zpracované řezy barvené škálou metod zaměřených na stavbu cévní stěny, a buněčné osídlení (orcein, pikrosiriová červeň, Verhoeffův hematoxylin a zelený trichrom, Gillův hematoxylin, alcianová modř) a imunohistochemickým průkazem antigenů (α-hladký svalový aktin, neurofilamentový protein, CD-31, von Willebrandův faktor). Pomocí nevychýleného vzorkování a stereologických metod jsme kvantifikovali plošné podíly složek (elastin, kolagen, hladkosvalový aktin a chondroitinsulfát) použitím stereologické bodové mřížky; dvourozměrnou hustotu...Ústav histologie a embryologieLékařská fakulta v PlzniFaculty of Medicine in Pilse

Systems Radiology and Personalized Medicine

Medicine has evolved into a high level of specialization using the very detailed imaging of organs. This has impressively solved a multitude of acute health-related problems linked to single-organ diseases. Many diseases and pathophysiological processes, however, involve more than one organ. An organ-based approach is challenging when considering disease prevention and caring for elderly patients, or those with systemic chronic diseases or multiple co-morbidities. In addition, medical imaging provides more than a pretty picture. Much of the data are now revealed by quantitating algorithms with or without artificial intelligence. This Special Issue on “Systems Radiology and Personalized Medicine” includes reviews and original studies that show the strengths and weaknesses of structural and functional whole-body imaging for personalized medicine

Computational socioeconomics

Uncovering the structure of socioeconomic systems and timely estimation of socioeconomic status are significant for economic development. The understanding of socioeconomic processes provides foundations to quantify global economic development, to map regional industrial structure, and to infer individual socioeconomic status. In this review, we will make a brief manifesto about a new interdisciplinary research field named Computational Socioeconomics, followed by detailed introduction about data resources, computational tools, data-driven methods, theoretical models and novel applications at multiple resolutions, including the quantification of global economic inequality and complexity, the map of regional industrial structure and urban perception, the estimation of individual socioeconomic status and demographic, and the real-time monitoring of emergent events. This review, together with pioneering works we have highlighted, will draw increasing interdisciplinary attentions and induce a methodological shift in future socioeconomic studies