Posts Tagged: humans

Standards and Methodological Rigor in Pulmonary Arterial Hypertension Preclinical and Translational Research

Standards and Methodological Rigor in Pulmonary Arterial Hypertension Preclinical and Translational Research

Steeve Provencher, Stephen L. Archer, F. Daniel Ramirez, Benjamin Hibbert, Roxane Paulin, Olivier Boucherat, Yves Lacasse, Sébastien Bonnet

Adaptation of statistical and methodological rigor according to the nature of the study. There is no single type of laboratory study. For confirmatory studies, the most rigorous application of randomized controlled trial-like approaches should be applied, including prespecified study design and statistical analysis plan, describing eligibility criteria, sample size calculation, relevant study read-outs, interim analysis (if any), and corrections for multiple analyses, as well as randomization and concealment procedures, validation of the results, and potentially study preregistration. However, this type of approach may be expensive and cumbersome, and applying randomized controlled trial-like standards to studies focusing on discovery and elucidating fundamental biological processes may not add the same level of value. Thus, expectations and methodological rigor must be appropriately calibrated to the goals of the study. In all cases, however, the choice of an appropriate animal model that is representative of the human disease, the development of standardized operating procedures, blinded outcome assessment, and transparent reporting is critical. [Powerpoint File]

Sleep Apnea and Cardiovascular Disease: An Enigmatic Risk Factor

Sleep Apnea and Cardiovascular Disease: An Enigmatic Risk Factor

John S. Floras

Group mean gray matter differences in key cortical autonomic regions between individuals with and without obstructive sleep apnea (OSA). Cortical thickness (A) and voxel-based morphometric (B) analysis of 19 sex- and age-matched control (C) participants with no or mild OSA and 22 with moderate-to-severe OSA demonstrates, in the latter, significant thinning of the left dorsal posterior insular cortex (L dpIC) and thickening of the left midcingulate cortex (L MCC). L dpIC thinning correlated inversely with participants’ oxygen desaturation index; L MCC thickness correlated directly with muscle sympathetic burst incidence recorded with participants awake and resting supine (r=0.46; P=0.002). Reprinted from Taylor et al60 with permission. Copyright ©2017, Oxford University Press. [Powerpoint File]

Epigenomics: Technologies and Applications

Epigenomics: Technologies and Applications

Kevin C. Wang, Howard Y. Chang

New molecular tools available to interrogate chromatin accessibility and chromosomal organization. A, Measurement of long-range contact of DNA elements highlighted by single-cell ATAC-seq (scATACT-seq). Structured cis-variability across single epigenomes highlighted by scATACT-seq. Pearson correlation coefficient representing chromosome compartment signal of interaction frequency from a population chromatin conformation capture assay (left) or scATAC-seq (middle) from chromosome 1. Data in white represent masked regions because of highly repetitive regions. Right, upper box, Permuted cis-correlation map for chromosome 1. Right, lower box, Representative region depicting long-range covariability. Reprinted from Buenrostro et al40 with permission. Copyright ©2017, Macmillan Publishers Limited, part of Springer Nature. B, Schematic of chromatin loop reorganization using clustered regularly interspaced short palindromic repeats–deactivated Cas9 (CLOuD9) as a reversible method for manipulating chromosomal loops. Addition of abscisic acid (ABA, green) brings 2 complementary CLOuD9 constructs (CLOuD9 Streptococcus pyogenes [CSP], CLOuD9 Streptococcus aureus [CSA], red and blue, respectively) into proximity, remodeling chromatin structure. Removal of ABA restores the endogenous chromatin conformation. Reprinted from Morgan et al38 with permission. Copyright ©2015, Macmillan Publishers Limited, part of Springer Nature. [Powerpoint File]

Translational Implications of Platelets as Vascular First Responders

Translational Implications of Platelets as Vascular First Responders

Richard C. Becker, Travis Sexton, Susan S. Smyth

Platelet participation in neutrophil extracellular trap formation (NETosis). Activated platelets interact with neutrophils via platelet P-selectin and neutrophil PSGL-1 (P-selectin glycoprotein ligand-1), with interactions stabilized by a series of secondary adhesion interactions, including the ones mediated by platelet GP (glycoprotein) Ib and leukocyte Mac-1 (αMβ2). This interaction can contribute to trigger the release of NETs, consisting of chromatin containing citrullinated histones complexed with antimicrobial proteases, such as elastase and myeloperoxidase, in a process called NETosis. NETs serve to enhance the clearance of pathogens. They also contribute to clot formation by forming a mesh with platelets and fibrin and accumulating coagulation factors, such as tissue factor (TF). [Powerpoint File]

Translational Implications of Platelets as Vascular First Responders

Translational Implications of Platelets as Vascular First Responders

Richard C. Becker, Travis Sexton, Susan S. Smyth

Role for platelets in inflammation and response to pathogens. At sites of damaged or inflamed endothelium, platelet adhesion occurs through various interactions, such as with exposed subendothelium, P-selectin expression on activated endothelium, and release of ultralarge vWF (von Willebrand factor). Adherent platelets, in turn, recruit white blood cells (WBCs), which can subsequently transmigrate across the endothelium. Heterotypic cell interactions between platelets and WBCs or red blood cells (RBCs) can occur and are associated with increases in systemic inflammation. Activated platelets can trigger the release of neutrophil extracellular traps (NETs), which contribute to microbial clearance and clot formation. Platelets also interact with viral and bacterial pathogens to contribute to their clearance and respond to gut microbiota that can modulate platelet function. [Powerpoint File]