Genetic Manipulations of PPARs: Effects on Obesity and Metabolic Disease

The interest in genetic manipulations of PPARs is as old as their discovery as receptors of ligands with beneficial clinical activities. Considering the effects of PPAR ligands on critical aspects of systemic physiology, including obesity, lipid metabolism, insulin resistance, and diabetes, gene knockout (KO) in mice is the ideal platform for both hypothesis testing and discovery of new PPAR functions in vivo. With the fervent pursuit of the magic bullet to eradicate the obesity epidemic, special emphasis has been placed on the impacts of PPARs on obesity and its associated diseases. As detailed in this review, understanding how PPARs regulate gene expression and basic metabolic pathways is a necessary intermediate en route to deciphering their effects on obesity. Over a decade and dozens of genetic modifications of PPARs into this effort, valuable lessons have been learned, but we are left with more questions to be answered. These lessons and future prospects are the subject of this review

Advancing human health in the decade ahead: pregnancy as a key window for discovery: A Burroughs Wellcome Fund Pregnancy Think Tank.

Recent revolutionary advances at the intersection of medicine, omics, data sciences, computing, epidemiology, and related technologies inspire us to ponder their impact on health. Their potential impact is particularly germane to the biology of pregnancy and perinatal medicine, where limited improvement in health outcomes for women and children has remained a global challenge. We assembled a group of experts to establish a Pregnancy Think Tank to discuss a broad spectrum of major gestational disorders and adverse pregnancy outcomes that affect maternal-infant lifelong health and should serve as targets for leveraging the many recent advances. This report reflects avenues for future effects that hold great potential in 3 major areas: developmental genomics, including the application of methodologies designed to bridge genotypes, physiology, and diseases, addressing vexing questions in early human development; gestational physiology, from immune tolerance to growth and the timing of parturition; and personalized and population medicine, focusing on amalgamating health record data and deep phenotypes to create broad knowledge that can be integrated into healthcare systems and drive discovery to address pregnancy-related disease and promote general health. We propose a series of questions reflecting development, systems biology, diseases, clinical approaches and tools, and population health, and a call for scientific action. Clearly, transdisciplinary science must advance and accelerate to address adverse pregnancy outcomes. Disciplines not traditionally involved in the reproductive sciences, such as computer science, engineering, mathematics, and pharmacology, should be engaged at the study design phase to optimize the information gathered and to identify and further evaluate potentially actionable therapeutic targets. Information sources should include noninvasive personalized sensors and monitors, alongside instructive "liquid biopsies" for noninvasive pregnancy assessment. Future research should also address the diversity of human cohorts in terms of geography, racial and ethnic distributions, and social and health disparities. Modern technologies, for both data-gathering and data-analyzing, make this possible at a scale that was previously unachievable. Finally, the psychosocial and economic environment in which pregnancy takes place must be considered to promote the health and wellness of communities worldwide

Methacholine bronchial provocation measured by spirometry versus wheeze detection in preschool children

BACKGROUND: Determination of PC(20)-FEV(1) during Methacholine bronchial provocation test (MCT) is considered to be impossible in preschool children, as it requires repetitive spirometry sets. The aim of this study was to assess the feasibility of determining PC(20)-FEV(1) in preschool age children and compares the results to the wheeze detection (PCW) method. METHODS: 55 preschool children (ages 2.8–6.4 years) with recurrent respiratory symptoms were recruited. Baseline spirometry and MCT were performed according to ATS/ERS guidelines and the following parameters were determined at baseline and after each inhalation: spirometry-indices, lung auscultation at tidal breathing, oxygen saturation, respiratory and heart rate. Comparison between PCW and PC(20)-FEV(1) and clinical parameters at these end-points was done by paired Student's t-tests. RESULTS AND DISCUSSION: Thirty-six of 55 children (65.4%) successfully performed spirometry-sets up to the point of PCW. PC(20)-FEV(1) occurred at a mean concentration of 1.70+/-2.01 while PCW occurred at a mean concentration of 4.37+/-3.40 mg/ml (p < 0.05). At PCW, all spirometry-parameters were markedly reduced: FVC by 41.3+/-16.4% (mean +/-SD); FEV(1) by 44.7+/-14.5%; PEFR by 40.5+/-14.5 and FEF(25–75) by 54.7+/-14.4% (P < 0.01 for all parameters). This reduction was accompanied by de-saturation, hyperpnoea, tachycardia and a response to bronchodilators. CONCLUSION: Determination of PC(20)-FEV(1) by spirometry is feasible in many preschool children. PC(20)-FEV(1) often appears at lower provocation dose than PCW. The lower dose may shorten the test and encourage participation. Significant decrease in spirometry indices at PCW suggests that PC(20)-FEV(1) determination may be safer

Identification of Widespread Ultra-Edited Human RNAs

Adenosine-to-inosine modification of RNA molecules (A-to-I RNA editing) is an important mechanism that increases transciptome diversity. It occurs when a genomically encoded adenosine (A) is converted to an inosine (I) by ADAR proteins. Sequencing reactions read inosine as guanosine (G); therefore, current methods to detect A-to-I editing sites align RNA sequences to their corresponding DNA regions and identify A-to-G mismatches. However, such methods perform poorly on RNAs that underwent extensive editing (“ultra”-editing), as the large number of mismatches obscures the genomic origin of these RNAs. Therefore, only a few anecdotal ultra-edited RNAs have been discovered so far. Here we introduce and apply a novel computational method to identify ultra-edited RNAs. We detected 760 ESTs containing 15,646 editing sites (more than 20 sites per EST, on average), of which 13,668 are novel. Ultra-edited RNAs exhibit the known sequence motif of ADARs and tend to localize in sense strand Alu elements. Compared to sites of mild editing, ultra-editing occurs primarily in Alu-rich regions, where potential base pairing with neighboring, inverted Alus creates particularly long double-stranded RNA structures. Ultra-editing sites are underrepresented in old Alu subfamilies, tend to be non-conserved, and avoid exons, suggesting that ultra-editing is usually deleterious. A possible biological function of ultra-editing could be mediated by non-canonical splicing and cleavage of the RNA near the editing sites

PPAR Signaling in Placental Development and Function

With the major attention to the pivotal roles of PPARs in diverse aspects of energy metabolism, the essential functions of PPARγ and PPARβ/δ in placental development came as a surprise and were often considered a nuisance en route to their genetic analysis. However, these findings provided an opportune entrée into placental biology. Genetic and pharmacological studies, primarily of knockout animal models and cell culture, uncovered networks of PPARγ and PPARδ, their heterodimeric RXR partners, associated transcriptional coactivators, and target genes, that regulate various aspects of placental development and function. These studies furnish both specific information about trophoblasts and the placenta and potential hints about the functions of PPARs in other tissues and cell types. They reveal that the remarkable versatility of PPARs extends beyond the orchestration of metabolism to the regulation of cellular differentiation, tissue development, and trophoblast-specific functions. This information and its implications are the subject of this review

doi:10.1155/2008/142082 Review Article PPAR Signaling in Placental Development and Function

With the major attention to the pivotal roles of PPARs in diverse aspects of energy metabolism, the essential functions of PPARγ and PPARβ/δ in placental development came as a surprise and were often considered a nuisance en route to their genetic analysis. However, these findings provided an opportune entrée into placental biology. Genetic and pharmacological studies, primarily of knockout animal models and cell culture, uncovered networks of PPARγ and PPARδ, their heterodimeric RXR partners, associated transcriptional coactivators, and target genes, that regulate various aspects of placental development and function. These studies furnish both specific information about trophoblasts and the placenta and potential hints about the functions of PPARs in other tissues and cell types. They reveal that the remarkable versatility of PPARs extends beyond the orchestration of metabolism to the regulation of cellular differentiation, tissue development, and trophoblast-specific functions. This information and its implications are the subject of this review. Copyright © 2008 Yaacov Barak et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 1