Environ Mol Mutagen

Epigenetic changes such as DNA methylation may be a molecular mechanism through which environmental exposures affect health. Methylation of Alu and long interspersed nucleotide elements (LINE-1) is a well-established measure of DNA methylation often used in epidemiologic studies. Yet, few studies have examined the effects of host factors on LINE-1 and Alu methylation in children. We characterized the relationship of age, sex, and prenatal exposure to persistent organic pollutants (POPs), dichlorodiphenyl trichloroethane (DDT), dichlorodiphenyldichloroethylene (DDE), and polybrominated diphenyl ethers (PBDEs), with DNA methylation in a birth cohort of Mexican-American children participating in the CHAMACOS study. We measured Alu and LINE-1 methylation by pyrosequencing bisulfite-treated DNA isolated from whole blood samples collected from newborns and nine-year old children (n\ue2\u20ac\u2030=\ue2\u20ac\u2030358). POPs were measured in maternal serum during late pregnancy. Levels of DNA methylation were lower in nine-year olds compared to newborns and were higher in boys compared to girls. Higher prenatal DDT/E exposure was associated with lower Alu methylation at birth, particularly after adjusting for cell type composition (P\ue2\u20ac\u2030=\ue2\u20ac\u20300.02 for o,p' -DDT). Associations of POPs with LINE-1 methylation were only identified after examining the co-exposure of DDT/E with PBDEs simultaneously. Our data suggest that repeat element methylation can be an informative marker of epigenetic differences by age and sex and that prenatal exposure to POPs may be linked to hypomethylation in fetal blood. Accounting for co-exposure to different types of chemicals and adjusting for blood cell types may increase sensitivity of epigenetic analyses for epidemiological studies.P01 ES009605/ES/NIEHS NIH HHS/United StatesP01 ES009605/ES/NIEHS NIH HHS/United StatesR01 ES015572/ES/NIEHS NIH HHS/United StatesR01 OH007400/OH/NIOSH CDC HHS/United States2015-04-27T00:00:00

Microscopic dynamics in liquid metals: the experimental point of view

The experimental results relevant for the understanding of the microscopic dynamics in liquid metals are reviewed, with special regards to the ones achieved in the last two decades. Inelastic Neutron Scattering played a major role since the development of neutron facilities in the sixties. The last ten years, however, saw the development of third generation radiation sources, which opened the possibility of performing Inelastic Scattering with X rays, thus disclosing previously unaccessible energy-momentum regions. The purely coherent response of X rays, moreover, combined with the mixed coherent/incoherent response typical of neutron scattering, provides enormous potentialities to disentangle aspects related to the collectivity of motion from the single particle dynamics. If the last twenty years saw major experimental developments, on the theoretical side fresh ideas came up to the side of the most traditional and established theories. Beside the raw experimental results, therefore, we review models and theoretical approaches for the description of microscopic dynamics over different length-scales, from the hydrodynamic region down to the single particle regime, walking the perilous and sometimes uncharted path of the generalized hydrodynamics extension. Approaches peculiar of conductive systems, based on the ionic plasma theory, are also considered, as well as kinetic and mode coupling theory applied to hard sphere systems, which turn out to mimic with remarkable detail the atomic dynamics of liquid metals. Finally, cutting edges issues and open problems, such as the ultimate origin of the anomalous acoustic dispersion or the relevance of transport properties of a conductive systems in ruling the ionic dynamic structure factor are discussed.Comment: 53 pages, 41 figures, to appear in "The Review of Modern Physics". Tentatively scheduled for July issu

A multi-element psychosocial intervention for early psychosis (GET UP PIANO TRIAL) conducted in a catchment area of 10 million inhabitants: study protocol for a pragmatic cluster randomized controlled trial

Multi-element interventions for first-episode psychosis (FEP) are promising, but have mostly been conducted in non-epidemiologically representative samples, thereby raising the risk of underestimating the complexities involved in treating FEP in 'real-world' services

Heart Valve Replacements with Regenerative Capacity

The incidence of severe valvular dysfunctions (e.g., stenosis and insufficiency) is increasing, leading to over 300,000 valves implanted worldwide yearly. Clinically used heart valve replacements lack the capacity to grow, inherently requiring repetitive and high-risk surgical interventions during childhood. The aim of this review is to present how different tissue engineering strategies can overcome these limitations, providing innovative valve replacements that proved to be able to integrate and remodel in pre-clinical experiments and to have promising results in clinical studies. Upon description of the different types of heart valve tissue engineering (e.g., in vitro, in situ, in vivo, and the pre-seeding approach) we focus on the clinical translation of this technology. In particular, we will deepen the many technical, clinical, and regulatory aspects that need to be solved to endure the clinical adaptation and the commercialization of these promising regenerative valves

Translational cardiac stem cell therapy: advancing from first-generation to next-generation cell types

Acute myocardial infarction and chronic heart failure rank among the major causes of morbidity and mortality worldwide. Except for heart transplantation, current therapy options only treat the symptoms but do not cure the disease. Stem cell-based therapies represent a possible paradigm shift for cardiac repair. However, most of the first-generation approaches displayed heterogeneous clinical outcomes regarding efficacy. Stemming from the desire to closely match the target organ, second-generation cell types were introduced and rapidly moved from bench to bedside. Unfortunately, debates remain around the benefit of stem cell therapy, optimal trial design parameters, and the ideal cell type. Aiming at highlighting controversies, this article provides a critical overview of the translation of first-generation and second-generation cell types. It further emphasizes the importance of understanding the mechanisms of cardiac repair and the lessons learned from first-generation trials, in order to improve cell-based therapies and to potentially finally implement cell-free therapies

Abstract 307: Quantitative Characterization of the Contractile Architecture of Human Stem Cell Derived Cardiomyocytes

Human induced pluripotent stem cell derived cardiomyocytes (hiCMs) exhibit a fetal phenotype, but tools to quantify their relative immaturity are scarce. We reasoned that, during myocyte specification, cells progress through myofibrillogenesis as force-generating units, known as sarcomeres, self-assemble along the cell cytoskeleton. Therefore, we developed image processing techniques to quantitatively score myocyte structural phenotypes by the increasing degree of organization and alignment that sarcomeres acquire during myofibrillogenesis. Since this is a highly conserved process, quantifications obtained from α-actinin immunostains in rodent and hiCMs can be compared. Utilizing these metrics we quantitatively showed that hiCMs patterned on square fibronectin islands had significantly under-developed contractile architecture, in agreement with the qualitative observation that these cells retain a more migratory cytoskeleton. Furthermore, we trained thee independent machine learning algorithms on over 100 α-actin immunostains from engineered primary cardiac tissues at 6, 24 and 48 hours after seeding. These preparations were taken to represent differentiated, immature and mature structural architectures, respectively. After training,[[Unable to Display Character: ]]α-actinin immunostains of hiPS-derived cardiac tissues were unbiasedly analyzed by these classifiers. The results indicated that ~30% of cells exhibited cytoskeletal architectures similar to those of mature myocytes and that treatment with commercially available small molecules influence hiCM structural maturation. In conclusion, we provided metrics to assess the organization of the contractile cytoskeleton in primary and stem cell-derived cardiomyocytes and to unbiasedly quantify their maturation

Organ chips: quality assurance systems in regenerative medicine

A class of novel therapies leverages regenerative cell types in disease microenvironments. This complex interplay challenges established good manufacturing practices, as standards and analytical tools to measure regenerative potency are missing. That is, we can build the product right, but we do not know if we are building the right product. Here, we suggest that organ‐chips, biomimetic in vitro phenotyping platforms, can serve as key quality assurance systems in regenerative medicine

Emerging strategies in 3D printed tissue models for in vitro biomedical research

3D bioprinting has the potential to provide a unified framework for the manufacturing of tissue models for biomedical research, including drug discovery, disease modeling, and regenerative medicine. However, it remains challenging to 3D print replicas of human tissues that have accurate cell types, cellular densities, extracellular matrix compositions, and that can be assayed in a minimally invasive manner for chronic studies. Here, we review how recent breakthroughs in stem cell biology, tissue engineering, and materials science have led to novel 3D printing strategies that have the potential to solve these challenges