Medicine and Health Sciences Commons^™

Viridiflorol Induces Anti-Neoplastic Effects On Breast, Lung, And Brain Cancer Cells Through Apoptosis, Maaged A. Akiel, Ohoud Y. Alshehri, Shokran A. Aljihani, Amani Almuaysib, Ammar Bader, Ahmed I. Al‐Asmari, Hassan S. Alamri, Bahauddeen M. Alrfaei, Majed A. Halwani

Human and Molecular Genetics Publications

All active natural molecules are not fully exploited as therapeutic agents, causing delays in the advancement of anticancer drug discovery. Viridiflorol is a natural volatile element that may work as anti-cancer compound. We tested the anticancer properties of viridiflorol at different concentrations ranging from 0.03 to 300 μM in vitro on three cancer cells including breast (MCF-7), lung (A549) and brain (Daoy). The cancer cells responses were documented after treatment using MTT and Annexin V assays. Viridiflorol showed cytotoxic effects against all tested cell lines, reducing cell viability in a concentration-dependent manner with variable IC50 values. Daoy and A549 cell …

Prospective Longitudinal Study Of The Pregnancy Dna Methylome: The Us Pregnancy, Race, Environment, Genes (Preg) Study, Dana M. Lapato, Sara Moyer, Emily Olivares, Ananda B. Amstadter, Patricia A. Kinser, Shawn J. Latendresse, Colleen Jackson-Cook, Roxann Roberson-Nay, Jerome F. Strauss, Timothy P. York

Human and Molecular Genetics Publications

Purpose The goal of the Pregnancy, Race, Environment, Genes study was to understand how social and environmental determinants of health (SEDH), pregnancy-specific environments (PSE) and biological processes influence the timing of birth and account for the racial disparity in preterm birth. The study followed a racially diverse longitudinal cohort throughout pregnancy and included repeated measures of PSE and DNA methylation (DNAm) over the course of gestation and up to 1 year into the postpartum period.

Participants All women were between 18 and 40 years of age with singleton pregnancies and no diagnosis of diabetes or indication of assisted reproductive technology. …

Rare Mutations And Potentially Damaging Missense Variants In Genes Encoding Fibrillar Collagens And Proteins Involved In Their Production Are Candidates For Risk For Preterm Premature Rupture Of Membranes, Bhavi P. Modi, Maria E. Teves, Laurel N. Pearson, Hardik I. Parikh, Piya Chaemsaithong, Nihar U. Sheth, Timothy P. York, Roberto Romero, Jerome F. Strauss

Human and Molecular Genetics Publications

Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth with ~ 40% of preterm births being associated with PPROM and occurs in 1% - 2% of all pregnancies. We hypothesized that multiple rare variants in fetal genes involved in extracellular matrix synthesis would associate with PPROM, based on the assumption that impaired elaboration of matrix proteins would reduce fetal membrane tensile strength, predisposing to unscheduled rupture. We performed whole exome sequencing (WES) on neonatal DNA derived from pregnancies complicated by PPROM (49 cases) and healthy term deliveries (20 controls) to identify candidate mutations/variants. Genotyping for …

Sestrin2 Is Induced By Glucose Starvation Via The Unfolded Protein Response And Protects Cells From Non-Canonical Necroptotic Cell Death, Boxiao Ding, Anita Parmigiani, Ajit S. Divakaruni, Kellie Archer, Anne N. Murphy, Andrei V. Budanov

Human and Molecular Genetics Publications

Sestrin2 is a member of a family of stress responsive proteins, which controls cell viability via antioxidant activity and regulation of the mammalian target of rapamycin protein kinase (mTOR). Sestrin2 is induced by different stress insults, which diminish ATP production and induce energetic stress in the cells. Glucose is a critical substrate for ATP production utilized via glycolysis and mitochondrial respiration as well as for glycosylation of newly synthesized proteins in the endoplasmic reticulum (ER) and Golgi. Thus, glucose starvation causes both energy deficiency and activation of ER stress followed by the unfolding protein response (UPR). Here, we show that …

Rnaseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation As A Major Abnormality In Als Spinal Cord, David G. Brohawn, Laura C. O'Brien, James P. Bennett

Human and Molecular Genetics Publications

ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned >50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2 …

Krüppel-Like Transcription Factor Klf1 Is Required For Optimal Γ- And Β-Globin Expression In Human Fetal Erythroblasts, Divya Vinjamur, Yousef N. Alhashem, Safa Mohamad, Parth Amin, David C. Williams Jr., Joyce A. Lloyd

Human and Molecular Genetics Publications

In human adult erythroid cells, lower than normal levels of Krüppel-like transcription factor 1 (KLF1) are generally associated with decreased adult β- and increased fetal γ-globin gene expression. KLF1 also regulates BCL11A, a known repressor of adult γ-globin expression. In seeming contrast to the findings in adult cells, lower amounts of KLF1 correlate with both reduced embryonic and reduced fetal β-like globin mRNA in mouse embryonic erythroid cells. The role of KLF1 in primary human fetal erythroid cells, which express both γ- and β-globin mRNA, is less well understood. Therefore, we studied the role of KLF1 in ex vivo differentiated …

Perceived Stress Levels, Chemotherapy, Radiation Treatment And Tumor Characteristics Are Associated With A Persistent Increased Frequency Of Somatic Chromosomal Instability In Women Diagnosed With Breast Cancer: A One Year Longitudinal Study, Noran Aboalela, Debra E. Lyon, R. K. Elswick Jr., Debra Lynch Kelly, Jenni Brumelle, Harry D. Bear, Colleen Jackson-Cook

Human and Molecular Genetics Publications

While advances in therapeutic approaches have resulted in improved survival rates for women diagnosed with breast cancer, subsets of these survivors develop persistent psychoneurological symptoms (fatigue, depression/anxiety, cognitive dysfunction) that compromise their quality of life. The biological basis for these persistent symptoms is unclear, but could reflect the acquisition of soma-wide chromosomal instability following the multiple biological/psychological exposures associated with the diagnosis/treatment of breast cancer. An essential first step toward testing this hypothesis is to determine if these cancer-related exposures are indeed associated with somatic chromosomal instability frequencies. Towards this end, we longitudinally studied 71 women (ages 23-71) with early-stage …

Differential Expression Analysis Of Rna Sequencing Data By Incorporating Non-Exonic Mapped Reads, Hung-I Harry Chen, Yuanhang Liu, Yi Zou, Zhao Lai, Devanand Sarkar, Yufei Huang, Yidong Chen

Human and Molecular Genetics Publications

Background

RNA sequencing (RNA-seq) is a powerful tool for genome-wide expression profiling of biological samples with the advantage of high-throughput and high resolution. There are many existing algorithms nowadays for quantifying expression levels and detecting differential gene expression, but none of them takes the misaligned reads that are mapped to non-exonic regions into account. We developed a novel algorithm, XBSeq, where a statistical model was established based on the assumption that observed signals are the convolution of true expression signals and sequencing noises. The mapped reads in non-exonic regions are considered as sequencing noises, which follows a Poisson distribution. Given …

Depletion Of The Chromatin Remodeler Chd4 Sensitizes Aml Blasts To Genotoxic Agents And Reduces Tumor Formation, Justin Sperlazza, Mohamed Rahmani, Jason Beckta, Mandy Aust, Elisa Hawkins, Shou Zhen Wang, Sheng Zu Zhu, Shreya Podder, Catherine Dumur, Kellie Archer, Steven Grant, Gordon D. Ginder

Human and Molecular Genetics Publications

Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATPase that alters the phasing of nucleosomes on DNA and has recently been implicated in DNA double-stranded break (DSB) repair. Here, we show that depletion of CHD4 in acute myeloid leukemia (AML) blasts induces a global relaxation of chromatin that renders cells more susceptible to DSB formation, while concurrently impeding their repair. Furthermore, CHD4 depletion renders AML blasts more sensitive both in vitro and in vivo to genotoxic agents used in clinical therapy: daunorubicin (DNR) and cytarabine (ara-C). Sensitization to DNR and ara-C is mediated in part by activation of the ataxia-telangiectasia …

Knockdown Of Cdk2ap1 In Primary Human Fibroblasts Induces P53 Dependent Senescence, Khaled N. Alsayegh, Venkat S. Gadepalli, Shilpa Iyer, Raj R. Rao

Human and Molecular Genetics Publications

Cyclin Dependent Kinase-2 Associated Protein-1 (CDK2AP1) is known to be a tumor suppressor that plays a role in cell cycle regulation by sequestering monomeric CDK2, and targeting it for proteolysis. A reduction of CDK2AP1 expression is considered to be a negative prognostic indicator in patients with oral squamous cell carcinoma and also associated with increased invasion in human gastric cancer tissue. CDK2AP1 overexpression was shown to inhibit growth, reduce invasion and increase apoptosis in prostate cancer cell lines. In this study, we investigated the effect of CDK2AP1 downregulation in primary human dermal fibroblasts. Using a short-hairpin RNA to reduce its …

Evaluation Of Methyl-Binding Domain Based Enrichment Approaches Revisited, Karolina A. Aberg, Linying Xie, Robin F. Chan, Min Zhao, Ashutosh K. Pandey, Gaurav Kumar, Shaunna L. Clark, Edwin J. C. G. Van Den Oord

Human and Molecular Genetics Publications

Methyl-binding domain (MBD) enrichment followed by deep sequencing (MBD-seq), is a robust and cost efficient approach for methylome-wide association studies (MWAS). MBD-seq has been demonstrated to be capable of identifying differentially methylated regions, detecting previously reported robust associations and producing findings that replicate with other technologies such as targeted pyrosequencing of bisulfite converted DNA. There are several kits commercially available that can be used for MBD enrichment. Our previous work has involved MethylMiner (Life Technologies, Foster City, CA, USA) that we chose after careful investigation of its properties. However, in a recent evaluation of five commercially available MBD-enrichment kits the …

Tumor-Specific Expression And Detection Of A Cest Reporter Gene, Il Minn, Amnon Bar-Shir, Keerthi Yarlagadda, Jeff W. M. Bulte, Paul B. Fisher, Hao Wang, Assaf A. Gilad, Martin G. Pomper

Human and Molecular Genetics Publications

Purpose

To develop an imaging tool that enables the detection of malignant tissue with enhanced specificity using the exquisite spatial resolution of MRI.

Methods

Two mammalian gene expression vectors were created for the expression of the lysine-rich protein (LRP) under the control of the cytomegalovirus (CMV) promoter and the progression elevated gene-3 promoter (PEG-3 promoter) for constitutive and tumor-specific expression of LRP, respectively. Using those vectors, stable cell lines of rat 9L glioma, 9LCMV-LRP and 9LPEG-LRP, were established and tested for CEST contrast in vitro and in vivo.

Results

9LPEG-LRP cells showed increased CEST contrast compared with 9L cells …

Genetic Risks To Nicotine Dependence Predict Negative Mood And Affect In Current Non-Smokers, Xiangning Chen, Steven H. Aggen, Jingchun Chen, Lingxi Li, Kenneth S. Kendler, Melissa Blank, Thomas Eissenberg

Human and Molecular Genetics Publications

Nicotine is the psychoactive agent involved in nicotine dependence. However, nicotine as a drug, and its effects on human psychology are largely under-investigated in genetic studies. In this study, we recruited 208 current non-smokers to evaluate the effect of nicotine and its relationship to genetic risks to nicotine dependence. Exploratory and confirmatory factor analyses, as well as measurement invariance testing, were conducted to evaluate the latent factor structures of the POMS, PANAS and DEN questionnaires across 3 nicotine doses. Structural models were used to examine the effects of nicotine and their relationship to genetic risks of nicotine dependence. We found …

Tumor-Specific Expression And Detection Of A Cest Reporter Gene, Il Minn, Amnon Bar-Shir, Keerthi Yarlagadda, Jeff W. M. Bulte, Paul B. Fisher, Hao Wang, Assaf A. Gilad, Martin G. Pomper

Human and Molecular Genetics Publications

Purpose

To develop an imaging tool that enables the detection of malignant tissue with enhanced specificity using the exquisite spatial resolution of MRI.

Methods

Two mammalian gene expression vectors were created for the expression of the lysine-rich protein (LRP) under the control of the cytomegalovirus (CMV) promoter and the progression elevated gene-3 promoter (PEG-3 promoter) for constitutive and tumor-specific expression of LRP, respectively. Using those vectors, stable cell lines of rat 9L glioma, 9LCMV-LRP and 9LPEG-LRP, were established and tested for CEST contrast in vitro and in vivo.

Results

9LPEG-LRP cells showed increased CEST contrast compared with 9L cells …

Perceived Stress Levels, Chemotherapy, Radiation Treatment And Tumor Characteristics Are Associated With A Persistent Increased Frequency Of Somatic Chromosomal Instability In Women Diagnosed With Breast Cancer: A One Year Longitudinal Study, Noran Aboalela, Debra E. Lyon, R. K. Elswick Jr., Debra Lynch Kelly, Jenni Brumelle, Harry D. Bear, Colleen Jackson-Cook

Human and Molecular Genetics Publications

While advances in therapeutic approaches have resulted in improved survival rates for women diagnosed with breast cancer, subsets of these survivors develop persistent psychoneurological symptoms (fatigue, depression/anxiety, cognitive dysfunction) that compromise their quality of life. The biological basis for these persistent symptoms is unclear, but could reflect the acquisition of soma-wide chromosomal instability following the multiple biological/psychological exposures associated with the diagnosis/treatment of breast cancer. An essential first step toward testing this hypothesis is to determine if these cancer-related exposures are indeed associated with somatic chromosomal instability frequencies. Towards this end, we longitudinally studied 71 women (ages 23-71) with early-stage …

Knockdown Of Cdk2ap1 In Primary Human Fibroblasts Induces P53 Dependent Senescence, Khaled N. Alsayegh, Venkat S. Gadepalli, Shilpa Iyer, Raj R. Rao

Human and Molecular Genetics Publications

Cyclin Dependent Kinase-2 Associated Protein-1 (CDK2AP1) is known to be a tumor suppressor that plays a role in cell cycle regulation by sequestering monomeric CDK2, and targeting it for proteolysis. A reduction of CDK2AP1 expression is considered to be a negative prognostic indicator in patients with oral squamous cell carcinoma and also associated with increased invasion in human gastric cancer tissue. CDK2AP1 overexpression was shown to inhibit growth, reduce invasion and increase apoptosis in prostate cancer cell lines. In this study, we investigated the effect of CDK2AP1 downregulation in primary human dermal fibroblasts. Using a short-hairpin RNA to reduce its …

Comparison Of Effects Of P53 Null And Gain-Of-Function Mutations On Salivary Tumors In Mmtv-Hras Transgenic Mice, Dadi Jiang, Catherine I. Dumur, H. Davis Massey, Viswanathan Ramakrishnan, Mark A. Subler, Jolene J. Windle

Human and Molecular Genetics Publications

p53 is an important tumor suppressor gene which is mutated in ~50% of all human cancers. Some of these mutants appear to have acquired novel functions beyond merely losing wild-type functions. To investigate these gain-of-function effects in vivo, we generated mice of three different genotypes: MMTV-Hras/p53+/+, MMTV-Hras/p53-/-, and MMTV-Hras/p53R172H/R172H. Salivary tumors from these mice were characterized with regard to age of tumor onset, tumor growth rates, cell cycle distribution, apoptotic levels, tumor histopathology, as well as response to doxorubicin treatment. Microarray analysis was also performed to profile gene expression. The MMTV-Hras/p53-/- and …

Contrasting Influences Of Drosophila White/Mini-White On Ethanol Sensitivity In Two Different Behavioral Assays, Robin F. Chan, Carol Atkinson Lewellyn, Jacqueline M. Deloyht, Kristyn Sennett, Scarlett Coffman, Matthew Hewitt, Jill C. Bettinger, John M. Warrick, Mike Grotewiel

Human and Molecular Genetics Publications

Background

The fruit fly Drosophila melanogaster has been used extensively to investigate genetic mechanisms of ethanol-related behaviors. Many past studies in flies, including studies from our laboratory, have manipulated gene expression using transposons carrying the genetic-phenotypic marker mini-white, a derivative of the endogenous gene white. Whether the mini-white transgenic marker or the endogenous white gene influence behavioral responses to acute ethanol exposure in flies has not been systematically investigated.

Methods

We manipulated mini-white and white expression via (i) transposons marked with mini-white, (ii) RNAi against mini-white and white and (iii) a null allele of white. We assessed ethanol sensitivity and …

Correction: The Role Of Tumor-Associated Macrophages In Tumor Vascularization, Chunqing Guo, Annicole Buranych, Devanand Sarkar, Paul B. Fisher, Xiang-Yang Wang

Human and Molecular Genetics Publications

This is a correction to a previously published article.

Dietary Regimens Modify Early Onset Of Obesity In Mice Haploinsufficient For Rai1, Joseph T. Alaimo, Natalie H. Hahn, Sureni V. Mullegama, Sarah H. Elsea

Human and Molecular Genetics Publications

Smith-Magenis syndrome is a complex genomic disorder in which a majority of individuals are obese by adolescence. While an interstitial deletion of chromosome 17p11.2 is the leading cause, mutation or deletion of the RAI1 gene alone results in most features of the disorder. Previous studies have shown that heterozygous knockout of Rai1 results in an obese phenotype in mice and that Smith-Magenis syndrome mouse models have a significantly reduced fecundity and an altered transmission pattern of the mutant Rai1 allele, complicating large, extended studies in these models. In this study, we show that breeding C57Bl/6J Rai1+/−mice with FVB/NJ to …

A Placebo-Controlled, Double-Blind, Randomized, Multicenter Study To Assess The Effects Of Dronedarone 400 Mg Twice Daily For 12 Weeks On Atrial Fibrillation Burden In Subjects With Permanent Pacemakers, Michael D. Ezekowitz, Kenneth Ellenbogen , M.D., John P. Dimarco, Karoly Kaszala, Alexander Boddy, Gregory Geba P., Andrew Koren

Human and Molecular Genetics Publications

Purpose

Dronedarone is a benzofuran derivative with a pharmacological profile similar to amiodarone but has a more rapid onset of action and a much shorter half-life (13–19 h). Our goal was to evaluate the efficacy of dronedarone in atrial fibrillation (AF) patients using dual-chamber pacemakers capable of quantifying atrial fibrillation burden.

Methods

Pacemakers were adjusted to optimize AF detection. Patients with AF burden >1 % were randomized to dronedarone 400 mg twice daily (BID) or placebo. Pacemakers were interrogated after 4 and 12 weeks of treatment. The primary endpoint was the change in AF burden from baseline over the 12-week …

Lipopolysaccharide-Induced Neuronal Activation In The Paraventricular And Dorsomedial Hypothalamus Depends On Ambient Temperature, Samuel P. Wanner, Kyoko Yoshida, Vladimir A. Kulchitsky, Andrei I. Ivanov, Kazuyuki Kanosue, Andrej A. Romanovsky

Human and Molecular Genetics Publications

Systemic inflammatory response syndrome is associated with either fever or hypothermia, but the mechanisms responsible for switching from one to the other are unknown. In experimental animals, systemic inflammation is often induced by bacterial lipopolysaccharide (LPS). To identify the diencephalic and brainstem structures involved in the fever-hypothermia switch, we studied the expression of c-Fos protein, a marker of neuronal activation, in rats treated with the same high dose of LPS (0.5 mg/kg, intravenously) either in a thermoneutral (30°C) or cool (24°C) environment. At 30°C, LPS caused fever; at 24°C, the same dose caused profound hypothermia. Both fever and hypothermia were …

Genetic, Maternal And Placental Factors In The Association Between Birth Weight And Physical Fitness: A Longitudinal Twin Study, Robert N. H. Touwaslagar, Marji Gielen, Grans E. S. Tan, Antonius L. M. Mulder, Williem J. M. Gerver, Luc J. Zimmermann, Alfons J. H. M. Houben, Maurice P. Zeegers, Catherine Derom, Robert Vlietinck, Hermine Maes, Coen D. A. Stehouwer, Martine Thomis

Human and Molecular Genetics Publications

Background

Adult cardiorespiratory fitness and muscle strength are related to all-cause and cardiovascular mortality. Both are possibly related to birth weight, but it is unclear what the importance is of genetic, maternal and placental factors in these associations.

Design

Peak oxygen uptake and measures of strength, flexibility and balance were obtained yearly during adolescence (10–18 years) in 114 twin pairs in the Leuven Longitudinal Twin Study. Their birth weights had been collected prospectively within the East Flanders Prospective Twin Survey.

Results

We identified linear associations between birth weight and adolescent vertical jump (b = 1.96 cm per kg birth weight, …

Increased Frequency Of Micronuclei In Adults With A History Of Childhood Sexual Abuse: A Discordant Monozygotic Twin Study, Timothy P. York, Jenni Brumelle, Jane Juusola, Kenneth S. Kendler, Lindon J. Eaves, Ananda B. Amstadler, Steven H. Aggen, Kimberly H. Jones, Andrea Ferreira-Gonzalez, Colleen Jackson-Cook

Human and Molecular Genetics Publications

Background

Childhood sexual abuse (CSA) is a traumatic life event associated with an increased lifetime risk for psychopathology/morbidity. The long-term biological consequences of CSA-elicited stress on chromosomal stability in adults are unknown. The primary aim of this study was to determine if the rate of acquired chromosomal changes, measured using the cytokinesis-block micronucleus assay on stimulated peripheral blood lymphocytes, differs in adult female monozygotic twins discordant for CSA.

Methods

Monozygotic twin pairs discordant for CSA were identified from a larger population-based sample of female adult twins for whom the experience of CSA was assessed by self-report (51 individuals including a …

The Role Of Tumor-Associated Macrophages In Tumor Vascularization, Chunqing Guo, Annicole Buranych, Devanand Sarkar, Paul B. Fisher, Xiang-Yang Wang

Human and Molecular Genetics Publications

Tumor vascularization is a highly complex process that involves the interaction between tumors and their surrounding stroma, as well as many distinct angiogenesis-regulating factors. Tumor associated macrophages (TAMs) represent one of the most abundant cell components in the tumor environment and key contributors to cancer-related inflammation. A large body of evidence supports the notion that TAMs play a critical role in promoting the formation of an abnormal tumor vascular network and subsequent tumor progression and invasion. Clinical and experimental evidence has shown that high levels of infiltrating TAMs are associated with poor patient prognosis and tumor resistance to therapies. In …

Rapid And Inexpensive Screening Of Genomic Copy Number Variations Using A Novel Quantitative Fluorescent Pcr Method, Martin Stofanko, Joan C. Han, Sarah H. Elsea, Heloísa B. Pena, Higgor Gonçalves-Dornelas, Sérgio Danilo Junho Pena

Human and Molecular Genetics Publications

Detection of human microdeletion and microduplication syndromes poses significant burden on public healthcare systems in developing countries. With genome-wide diagnostic assays frequently inaccessible, targeted low-cost PCR-based approaches are preferred. However, their reproducibility depends on equally efficient amplification using a number of target and control primers. To address this, the recently described technique called Microdeletion/Microduplication Quantitative Fluorescent PCR (MQF-PCR) was shown to reliably detect four human syndromes by quantifying DNA amplification in an internally controlled PCR reaction. Here, we confirm its utility in the detection of eight human microdeletion syndromes, including the more common WAGR, Smith-Magenis, and Potocki-Lupski syndromes with 100% …

Identification Of Genes Potentially Regulated By Human Polynucleotide Phosphorylase (Hpnpaseold-35) Using Melanoma As A Model, Upneet K. Sokhi, Manny D. Bacolod, Santanu Dasgupta, Luni Emdad, Swadesh K. Das

Human and Molecular Genetics Publications

Human Polynucleotide Phosphorylase (hPNPaseold-35 or PNPT1) is an evolutionarily conserved 3′→5′ exoribonuclease implicated in the regulation of numerous physiological processes including maintenance of mitochondrial homeostasis, mtRNA import and aging-associated inflammation. From an RNase perspective, little is known about the RNA or miRNA species it targets for degradation or whose expression it regulates; except for c-myc and miR-221. To further elucidate the functional implications of hPNPaseold-35 in cellular physiology, we knocked-down and overexpressed hPNPaseold-35 in human melanoma cells and performed gene expression analyses to identify differentially expressed transcripts. Ingenuity Pathway Analysis indicated that knockdown of hPNPaseold-35 resulted in significant …

The Krüppel-Like Factor 2 And Krüppel-Like Factor 4 Genes Interact To Maintain Endothelial Integrity In Mouse Embryonic Vasculogenesis, Aditi R. Chiplunkar, Benjamin C. Curtis, Gabriel L. Eades, Megan S. Kane, Sean J. Fox, Jack L. Haar, Joyce A. Lloyd

Human and Molecular Genetics Publications

Background Krüppel-like Factor 2 (KLF2) plays an important role in vessel maturation during embryonic development. In adult mice, KLF2 regulates expression of the tight junction protein occludin, which may allow KLF2 to maintain vascular integrity. Adult tamoxifen-inducible Krüppel-like Factor 4 (KLF4) knockout mice have thickened arterial intima following vascular injury. The role of KLF4, and the possible overlapping functions of KLF2 and KLF4, in the developing vasculature are not well-studied.

Results Endothelial breaks are observed in a major vessel, the primary head vein (PHV), in KLF2-/-KLF4-/- embryos at E9.5. KLF2-/-KLF4-/- embryos die by E10.5, which is earlier than either single …

Krüppel-Like Factor 2 Is Required For Normal Mouse Cardiac Development, Aditi R. Chiplunkar, Tina K. Lung, Yousef Alhashem, Benjamin A. Koppenhaver, Fadi N. Salloum, Rakesh C. Kukreja, Jack L. Haar, Joyce A. Lloyd

Human and Molecular Genetics Publications

Krüppel-like factor 2 (KLF2) is expressed in endothelial cells in the developing heart, particularly in areas of high shear stress, such as the atrioventricular (AV) canal. KLF2 ablation leads to myocardial thinning, high output cardiac failure and death by mouse embryonic day 14.5 (E14.5) in a mixed genetic background. This work identifies an earlier and more fundamental role for KLF2 in mouse cardiac development in FVB/N mice. FVB/N KLF2−/− embryos die earlier, by E11.5. E9.5 FVB/N KLF2−/− hearts have multiple, disorganized cell layers lining the AV cushions, the primordia of the AV valves, rather than the normal single layer. By …

A Twin Study Of Early-Childhood Asthma In Puerto Ricans, Supinda Bunyavanich, Judy L. Silberg, Jessica Lasky-Su, Nathan A. Gillespie, Nancy E. Lange, Glorisa Canino, Juan C. Celedon

Human and Molecular Genetics Publications

Background

The relative contributions of genetics and environment to asthma in Hispanics or to asthma in children younger than 3 years are not well understood.

Objective

To examine the relative contributions of genetics and environment to early-childhood asthma by performing a longitudinal twin study of asthma in Puerto Rican children ≤3 years old.

Methods

678 twin infants from the Puerto Rico Neo-Natal Twin Registry were assessed for asthma at age 1 year, with follow-up data obtained for 624 twins at age 3 years. Zygosity was determined by DNA microsatellite profiling. Structural equation modeling was performed for three phenotypes at ages …