Publication misconduct and plagiarism retractions: a systematic, retrospective study.

Objectives: To investigate whether plagiarism is more prevalent in publications retracted from the medical literature when first authors are affiliated with lower-income countries versus higher-income countries. Secondary objectives included investigating other factors associated with plagiarism (e.g.

Lack of involvement of medical writers and the pharmaceutical industry in publications retracted for misconduct: a systematic, controlled, retrospective study.

Objectives: The primary objective of this study was to quantify how many publications retracted because of misconduct involved declared medical writers (i.e., not ghostwriters) or declared pharmaceutical industry support.

A global role for KLF1 in erythropoiesis revealed by ChIP-seq in primary erythroid cells.

KLF1 regulates a diverse suite of genes to direct erythroid cell differentiation from bipotent progenitors. To determine the local cis-regulatory contexts and transcription factor networks in which KLF1 operates, we performed KLF1 ChIP-seq in the mouse. We found at least 945 sites in the genome of E14.

EKLF/KLF1 controls cell cycle entry via direct regulation of E2f2.

Differentiation of erythroid cells requires precise control over the cell cycle to regulate the balance between cell proliferation and differentiation. The zinc finger transcription factor, erythroid Krüppel-like factor (EKLF/KLF1), is essential for proper erythroid cell differentiation and regulates many erythroid genes. Here we show that loss of EKLF leads to aberrant entry into S-phase of the cell cycle during both primitive and definitive erythropoiesis.

Indian hedgehog supports definitive erythropoiesis.

Indian hedgehog (Ihh) has been reported to stimulate haematopoiesis ex vivo. In this study we studied the consequences of loss of function of Ihh for murine haematopoietic development. Ihh has no essential role in primitive erythropoiesis, but it is required in a non cell autonomous fashion for definitive erythropoieisis.

A mechanism for Ikaros regulation of human globin gene switching.

The human beta globin locus consists of an upstream LCR and functional genes arranged sequentially in the order of their expression during development: 5'-HBE1, HBG2, HBG1, HBD, HBB-3'. Haemoglobin switching entails the successive recruitment of these genes into an active chromatin hub (ACH). Here we show that the transcription factor Ikaros plays a major role in the formation of the beta-globin ACH, and in haemoglobin switching.

Distinct roles of E2F proteins in vascular smooth muscle cell proliferation and intimal hyperplasia.

Intimal hyperplasia (IH) and restenosis limit the long-term utility of bypass surgery and angioplasty due to pathological proliferation and migration of vascular smooth muscle cells (VSMCs) into the intima of treated vessels. Consequently, much attention has been focused on developing inhibitory agents that reduce this pathogenic process. The E2F transcription factors are key cell cycle regulators that play important roles in modulating cell proliferation and cell fate.

Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2.

beta-adrenergic receptors (beta-ARs), prototypic G-protein-coupled receptors (GPCRs), play a critical role in regulating numerous physiological processes. The GPCR kinases (GRKs) curtail G-protein signaling and target receptors for internalization. Nitric oxide (NO) and/or S-nitrosothiols (SNOs) can prevent the loss of beta-AR signaling in vivo, but the molecular details are unknown.

Erythroid Kruppel-like factor regulates the G1 cyclin dependent kinase inhibitor p18INK4c.

Erythroid Kruppel-like factor (EKLF, KLF1) is an essential erythroid cell specific C(2)H(2) zinc finger transcription factor that binds CACC box elements in promoters and distant regulatory elements to activate transcription. Forced expression of EKLF arrests cell division. The cyclin dependent kinase (Cdk) inhibitor p18(INK4c) was identified as a potential novel EKLF target gene from an expression profiling study.

Erythroid Krüppel-like factor directly activates the basic Krüppel-like factor gene in erythroid cells.

The Sp/Krüppel-like factor (Sp/Klf) family is comprised of around 25 zinc finger transcription factors that recognize CACCC boxes and GC-rich elements. We have investigated basic Krüppel-like factor (Bklf/Klf3) and show that in erythroid tissues its expression is highly dependent on another family member, erythroid Krüppel-like factor (Eklf/Klf1). We observe that Bklf mRNA is significantly reduced in erythroid tissues from Eklf-null murine embryos.

Genomic organisation and regulation of murine alpha haemoglobin stabilising protein by erythroid Kruppel-like factor.

Alpha haemoglobin stabilising protein (AHSP) binds free alpha-globin chains and plays an important role in the protection of red cells, particularly during beta-thalassaemia. Murine ASHP was discovered as a GATA-1 target gene and human AHSP is directly regulated by GATA-1. More recently, AHSP was rediscovered as a highly erythroid Kruppel-like factor (EKLF) -dependent transcript.

Lymphocyte levels of GRK2 (betaARK1) mirror changes in the LVAD-supported failing human heart: lower GRK2 associated with improved beta-adrenergic signaling after mechanical unloading.

Background: In human heart failure, increased expression of G protein-coupled receptor kinases (GRKs) causes the loss of beta-adrenergic receptor (betaAR) signaling and function. Mechanical unloading with a left ventricular assist device (LVAD) promotes reverse remodeling, which includes restoration of betaAR responsiveness. We tested the hypothesis that LVAD support of the failing human heart alters the expression and activity of GRKs and we sought to determine whether changes in myocardial GRKs could be tracked in lymphocytes.

Vascular smooth muscle migration and proliferation in response to lysophosphatidic acid (LPA) is mediated by LPA receptors coupling to Gq.

Many G protein-coupled receptors can couple to multiple G proteins to convey their intracellular signaling cascades. The receptors for lysophosphatidic acid (LPA) possess this ability. LPA receptors are important mediators of a wide variety of biological actions including cell migration, proliferation and survival which are processes that can all have a considerable impact on vascular smooth muscle (VSM) and blood vessels.

A global role for EKLF in definitive and primitive erythropoiesis.

Erythroid Kruppel-like factor (EKLF, KLF1) plays an important role in definitive erythropoiesis and beta-globin gene regulation but failure to rectify lethal fetal anemia upon correction of globin chain imbalance suggested additional critical EKLF target genes. We employed expression profiling of EKLF-null fetal liver and EKLF-null erythroid cell lines containing an inducible EKLF-estrogen receptor (EKLF-ER) fusion construct to search for such targets. An overlapping list of EKLF-regulated genes from the 2 systems included alpha-hemoglobin stabilizing protein (AHSP), cytoskeletal proteins, hemesynthesis enzymes, transcription factors, and blood group antigens.

Vascular smooth muscle overexpression of G protein-coupled receptor kinase 5 elevates blood pressure, which segregates with sex and is dependent on Gi-mediated signaling.

Background: Essential hypertension involves an increase in sympathetic nervous system activity and an associated decrease in beta-adrenergic receptor (AR)-mediated dilation. In addition, increased levels of G protein-coupled receptor (GPCR) kinases (GRKs), which regulate GPCR signaling, are associated with increased blood pressure (BP).

Methods And Results: We generated transgenic mice with approximately 2-fold vascular smooth muscle (VSM)-specific overexpression of GRK5 to recapitulate a selective aspect of hypertension and understand the impact on GPCR regulation of BP.

Acute ischemic cardiac dysfunction is attenuated via gene transfer of a peptide inhibitor of the beta-adrenergic receptor kinase (betaARK1).

Acute myocardial ischemia is a critical adverse effect potentially occurring during cardiac procedures. A peptide inhibitor of the beta-adrenergic receptor kinase (betaARK1), betaARKct, has been successful in rescuing chronic myocardial ischemia. The present study focused on the effects of adenoviral-mediated betaARKct (Adv-betaARKct) delivery on left ventricle (LV) dysfunction induced by acute coronary occlusion.

Cardiac hypertrophy and altered beta-adrenergic signaling in transgenic mice that express the amino terminus of beta-ARK1.

The G protein-coupled receptor (GPCR) kinase beta-adrenergic receptor (beta-AR) kinase-1 (beta-ARK1) is elevated during heart failure; however, its role is not fully understood. Beta-ARK1 contains several domains that are capable of protein-protein interactions that may play critical roles in the regulation of GPCR signaling. In this study, we developed a novel line of transgenic mice that express an amino-terminal peptide of beta-ARK1 that is comprised of amino acid residues 50-145 (beta-ARKnt) in the heart to determine whether this domain has any functional significance in vivo.

Heterotopic transplantation as a model to study functional recovery of unloaded failing hearts.

Objectives: Recent studies have demonstrated cardiac improvement in patients supported with a ventricular assist device, suggesting that reverse remodeling and myocardial recovery are possible. We developed an animal model of cardiac unloading by adapting a heterotopic transplantation technique and used it to examine the pattern of functional recovery in the left ventricle of the failing heart.

Methods: Heart failure was induced in adult New Zealand rabbits by coronary artery ligation with subsequent myocardial infarction.

Donor heart contractile dysfunction following prolonged ex vivo preservation can be prevented by gene-mediated beta-adrenergic signaling modulation.

Objectives: Reperfusion after myocardial ischemia goes together with alteration of the beta-adrenergic (betaAR) signaling. Especially the level and catalytic activity of beta AR kinase (betaARK1) are increased. We hypothesized that myocardial expression of a betaARK1 inhibitor (betaARKct) may protect from post-reperfusion dysfunction.

Gq-coupled receptor agonists mediate cardiac hypertrophy via the vasculature.

The Gq-coupled receptor-signaling pathway has been implicated in the cardiac hypertrophic response to stress, but little is actually known about the contributions of Gq signaling in either the heart or the vasculature. Therefore, we developed a line of transgenic mice that express a peptide inhibitor of Gq (GqI) in vascular smooth muscle to determine if vascular Gq signaling was important in the cardiac hypertrophic response. After chronic administration of the Gq agonists phenylephrine, serotonin, and angiotensin II, we observed an attenuation of mean arterial blood pressure and an inhibition of cardiac hypertrophy in the transgenic mice with vascular-specific GqI expression.

Myocardial gene transfer and overexpression of beta2-adrenergic receptors potentiates the functional recovery of unloaded failing hearts.

Background: Mechanical assistance of the failing left ventricle (LV) can lead to functional recovery after a period of unloading, including restoration of beta-adrenergic receptor (betaAR) inotropic reserve. We tested whether prolonged LV unloading of failing rabbit hearts by use of a heterotopic transplantation technique could lead to recovery and whether adenoviral gene transfer of a beta2AR transgene (Adv-beta2AR) could alter this process.

Methods And Results: Heart failure was induced by coronary artery ligation in adult New Zealand White rabbits.