The emerging role of epigenetics in rheumatic diseases

Epigenetics is a key mechanism regulating the expression of genes. There are three main and interrelated mechanisms: DNA methylation, post-translational modification of histone proteins and non-coding RNA. Gene activation is generally associated with lower levels of DNA methylation in promoters and with distinct histone marks such as acetylation of amino acids in histones. Unlike the genetic code, the epigenome is altered by endogenous (e.g. hormonal) and environmental (e.g. diet, exercise) factors and changes with age. Recent evidence implicates epigenetic mechanisms in the pathogenesis of common rheumatic disease, including RA, OA, SLE and scleroderma. Epigenetic drift has been implicated in age-related changes in the immune system that result in the development of a pro-inflammatory status termed inflammageing, potentially increasing the risk of age-related conditions such as polymyalgia rheumatica. Therapeutic targeting of the epigenome has shown promise in animal models of rheumatic diseases. Rapid advances in computational biology and DNA sequencing technology will lead to a more comprehensive understanding of the roles of epigenetics in the pathogenesis of common rheumatic disease

Complex genetic association of 6q23 with autoimmune rheumatic conditions

In the paper by Dieguez-Gonzalez and colleagues in the present issue of Arthritis Research & Therapy, the results of a detailed genetic investigation of the recently identified rheumatoid arthritis and systemic lupus erythematosus susceptibility region at 6q23 containing the TNFAIP3 gene are reported. Their data confirm the complex nature of the association involving both the TNFAIP3 locus and a region >150 kb upstream that does not encode any known gene. These data are consistent with recent studies of systemic lupus erythematosus susceptibility confirming the presence of several independent genetic contributions to autoimmune rheumatic diseases arising from 6q23

A Calibrated Method of Massage Therapy Decreases Systolic Blood Pressure Concomitant With Changes in Heart Rate Variability in Male Rats.

ObjectiveThe purpose of this study was to develop a method for applying calibrated manual massage pressures by using commonly available, inexpensive sphygmomanometer parts and validate the use of this approach as a quantitative method of applying massage therapy to rodents.MethodsMassage pressures were monitored by using a modified neonatal blood pressure (BP) cuff attached to an aneroid gauge. Lightly anesthetized rats were stroked on the ventral abdomen for 5 minutes at pressures of 20 mm Hg and 40 mm Hg. Blood pressure was monitored noninvasively for 20 minutes following massage therapy at 5-minute intervals. Interexaminer reliability was assessed by applying 20 mm Hg and 40 mm Hg pressures to a digital scale in the presence or absence of the pressure gauge.ResultsWith the use of this method, we observed good interexaminer reliability, with intraclass coefficients of 0.989 versus 0.624 in blinded controls. In Long-Evans rats, systolic BP dropped by an average of 9.86% ± 0.27% following application of 40 mm Hg massage pressure. Similar effects were seen following 20 mm Hg pressure (6.52% ± 1.7%), although latency to effect was greater than at 40 mm Hg. Sprague-Dawley rats behaved similarly to Long-Evans rats. Low-frequency/high-frequency ratio, a widely-used index of autonomic tone in cardiovascular regulation, showed a significant increase within 5 minutes after 40 mm Hg massage pressure was applied.ConclusionsThe calibrated massage method was shown to be a reproducible method for applying massage pressures in rodents and lowering BP

The emerging role of epigenetics in rheumatic diseases

Epigenetics is a key mechanism regulating the expression of genes. There are three main and interrelated mechanisms: DNA methylation, post-translational modification of histone proteins and non-coding RNA. Gene activation is generally associated with lower levels of DNA methylation in promoters and with distinct histone marks such as acetylation of amino acids in histones. Unlike the genetic code, the epigenome is altered by endogenous (e.g. hormonal) and environmental (e.g. diet, exercise) factors and changes with age. Recent evidence implicates epigenetic mechanisms in the pathogenesis of common rheumatic disease, including RA, OA, SLE and scleroderma. Epigenetic drift has been implicated in age-related changes in the immune system that result in the development of a pro-inflammatory status termed inflammageing, potentially increasing the risk of age-related conditions such as polymyalgia rheumatica. Therapeutic targeting of the epigenome has shown promise in animal models of rheumatic diseases. Rapid advances in computational biology and DNA sequencing technology will lead to a more comprehensive understanding of the roles of epigenetics in the pathogenesis of common rheumatic diseases

The eukaryotic initiation factor 2 kinase GCN2 protects against hepatotoxicity during asparaginase treatment

Asparaginase is an important drug in the treatment regimen for acute lymphoblastic leukemia. Asparaginase depletes circulating asparagine and glutamine, activating an amino acid stress response (AAR) involving phosphorylation of eukaryotic initiation factor 2 (eIF2) by general control nonderepressible kinase 2 (GCN2). We hypothesized that GCN2 functions to mitigate hepatic stress during asparaginase therapy by activating the AAR. To test this idea, C57BL/6J wild-type mice (Gcn2(+/+)) and those deleted for Gcn2 (Gcn2(-/-)) were injected with asparaginase or saline excipient one time daily for 1 or 6 days. In liver, increased phosphorylation of eIF2 and mRNA expression of AAR target genes activating transcription factor 4, asparagine synthetase, eIF4E-binding protein 1, and CAAT enhancer-binding protein homologous protein were significantly blunted or blocked in the liver of Gcn2(-/-) mice. Loss of AAR during asparaginase coincided with increases in mammalian target of rapamycin signaling, hepatic triglyceride accumulation, and DNA damage in association with genetic markers of oxidative stress (glutathione peroxidase) and inflammation (tumor necrosis factor alpha-α). Although asparaginase depleted circulating asparagine in both Gcn2(+/+) and Gcn2(-/-) mice, all other amino acids, including plasma glutamine, were elevated in the plasma of Gcn2(-/-) mice. This study shows that loss of GCN2 promotes oxidative stress and inflammatory-mediated DNA damage during asparaginase therapy, suggesting that patients with reduced or dysfunctional AAR may be at risk of developing hepatic complications during asparaginase treatment

Warfare, Demography & Anthropogenic Transformation at Angel Mounds State Historic Site

poster abstractRecent investigations by the Department of Anthropology (IU School of Liberal Arts) and the Glenn A. Black Laboratory of Archaeology (IU-Bloomington) at Angel Mounds have greatly enhanced our understanding of this Mississippian period (AD 1050-1450) village located on the Ohio River in southwestern Indiana. During this timeframe, the Ohio Valley and adjoining regions witnessed an evolution in social complexity with the emergence of small-scale polities, population aggregation in fortified towns, and associated earthwork construction. Angel Mounds was established, grew in prominence, and was eventually abandoned. However, until recently, absolute ages from the site were sparse and the chronology of the town’s settlement, growth and abandonment was poorly understood. Similarly, chronological models for earthwork and fortification construction were non-existent. Our research has revealed that Angel Mounds began as a ceremonial center between AD 1100 and 1300 with few occupants. The residential population at Angel Mounds grew precipitously after AD 1300. By AD 1400, we estimate that as many as 1,000 people lived at Angel Mounds. Concurrently, a series of fortifications were erected at the site to protect the inhabitants from neighboring polities. Meanwhile, earthworks on site were “capped” and abandoned soon thereafter, which may reflect the sociopolitical disintegration of Angel Mounds. Depending on the type of agricultural production and environmental change with the onset of the Little Ice Age, these patterns have important implications for settlement longevities, the historical ecology of land-use, and population estimates in the Eastern Woodlands of North America by AD 1500. With support from the Nation Science Foundation, the next three years of investigations at Angel Mounds will continue to focus on population dynamics, earthwork construction and use, anthropogenic transformation of the landscape, and environmental change during the Medieval Warm and Little Ice Age

General Algorithm For Improved Lattice Actions on Parallel Computing Architectures

Quantum field theories underlie all of our understanding of the fundamental forces of nature. The are relatively few first principles approaches to the study of quantum field theories [such as quantum chromodynamics (QCD) relevant to the strong interaction] away from the perturbative (i.e., weak-coupling) regime. Currently the most common method is the use of Monte Carlo methods on a hypercubic space-time lattice. These methods consume enormous computing power for large lattices and it is essential that increasingly efficient algorithms be developed to perform standard tasks in these lattice calculations. Here we present a general algorithm for QCD that allows one to put any planar improved gluonic lattice action onto a parallel computing architecture. High performance masks for specific actions (including non-planar actions) are also presented. These algorithms have been successfully employed by us in a variety of lattice QCD calculations using improved lattice actions on a 128 node Thinking Machines CM-5. {\underline{Keywords}}: quantum field theory; quantum chromodynamics; improved actions; parallel computing algorithms

Chronology of a Fortified Mississippian Village in the Central Illinois River Valley

Geophysical survey and excavations from 2010–2016 at Lawrenz Gun Club (11CS4), a late pre-Columbian village located in the central Illinois River valley in Illinois, identified 10 mounds, a central plaza, and dozens of structures enclosed within a stout 10 hectare bastioned palisade. Nineteen radiocarbon (14C) measurements were taken from single entities of wood charcoal, short-lived plants, and animal bones. A site chronology has been constructed using a Bayesian approach that considers the stratigraphic contexts and feature formation processes. The village was host to hundreds of years of continuous human activity during the Mississippi Period. Mississippian activity at the site is estimated to have begun in cal AD 990–1165 (95% probability), ended in cal AD 1295–1450 (95% probability), and lasted 150–420 yr (95% probability) in the primary Bayesian model with similar results obtained in two alternative models. The palisade is estimated to have been constructed in cal AD 1150–1230 (95% probability) and was continuously repaired and rebuilt for 15–125 yr (95% probability), probably for 40–85 yr (68% probability). Comparison to other studies demonstrates that the bastioned palisade at Lawrenz was one of the earliest constructed in the midcontinental United States

Synthesis and Characterization of Pyridine-Armed Reinforced Macrocycles and Their Transition Metal Complexes as Potential Oxidation Catalysts

Oxidation catalysts stable in aqueous solution under both harsh pH\u27s and at high temperature would be environmentally friendly alternatives to current technologies. Transition metal complexes of tetraazamacrocycles reinforced with additional ethylene bridges have produced such oxidation catalysts. A controlling aspect of the usefulness of any metal catalyst is its set of oxidation and reduction potentials. Reversible redox processes that bracket a potential window within which useful oxidation of substrate molecules can occur are desirable. Though quite robust, and exhibiting reversible electrochemistry, some reinforced macrocycle complexes are not useful catalysts because their redox potentials are not in a desired potential range. An established method of modifying the electrochemical properties of a transition metal complex is to modify the ligand, which subsequently modifies the properties of its complexed metal ion. We wished to determine if the addition of pyridine pendant arms to the known reinforced macrocycle ligands would result in beneficial shifts in the redox potentials of their transition metal complexes. The resulting ligands must allow at least one open coordination site on the bound metal ion for oxidant and/or substrate binding. We have synthesized and characterized both cross-bridged and side-bridged cyclen and cyclam tetraazamacrocycles with pyridine pendant arms. Cobalt, nickel, copper, and zinc complexes were made. The synthesis and characterization of the ligands and the synthesis and characterization of their complexes will be presented

GeneLink: a database to facilitate genetic studies of complex traits

BACKGROUND: In contrast to gene-mapping studies of simple Mendelian disorders, genetic analyses of complex traits are far more challenging, and high quality data management systems are often critical to the success of these projects. To minimize the difficulties inherent in complex trait studies, we have developed GeneLink, a Web-accessible, password-protected Sybase database. RESULTS: GeneLink is a powerful tool for complex trait mapping, enabling genotypic data to be easily merged with pedigree and extensive phenotypic data. Specifically designed to facilitate large-scale (multi-center) genetic linkage or association studies, GeneLink securely and efficiently handles large amounts of data and provides additional features to facilitate data analysis by existing software packages and quality control. These include the ability to download chromosome-specific data files containing marker data in map order in various formats appropriate for downstream analyses (e.g., GAS and LINKAGE). Furthermore, an unlimited number of phenotypes (either qualitative or quantitative) can be stored and analyzed. Finally, GeneLink generates several quality assurance reports, including genotyping success rates of specified DNA samples or success and heterozygosity rates for specified markers. CONCLUSIONS: GeneLink has already proven an invaluable tool for complex trait mapping studies and is discussed primarily in the context of our large, multi-center study of hereditary prostate cancer (HPC). GeneLink is freely available at