Medicine and Health Sciences Commons^™

Combined Genome-Wide Linkage And Targeted Association Analysis Of Head Circumference In Autism Spectrum Disorder Families, M. Woodbury-Smith, D. A. Bilder, J. Morgan, L. Jerominski, T. Darlington, Thomas D. Dyer, A. D. Paterson, H. Coon

School of Medicine Publications

Background: It has long been recognized that there is an association between enlarged head circumference (HC) and autism spectrum disorder (ASD), but the genetics of HC in ASD is not well understood. In order to investigate the genetic underpinning of HC in ASD, we undertook a genome-wide linkage study of HC followed by linkage signal targeted association among a sample of 67 extended pedigrees with ASD.

Methods: HC measurements on members of 67 multiplex ASD extended pedigrees were used as a quantitative trait in a genome-wide linkage analysis. The Illumina 6K SNP linkage panel was used, and analyses were carried …

Molecular Profiling Of Human Induced Pluripotent Stem Cell-Derived Hypothalamic Neurones Provides Developmental Insights Into Genetic Loci For Body Weight Regulation, L. Yao, Y. Liu, Satish Kumar, Joanne E. Curran, John Blangero, Y. Chen, Donna M. Lehman

School of Medicine Publications

Recent data suggest that common genetic risks for metabolic disorders such as obesity may be human-specific and exert effects via the central nervous system. To overcome the limitation of human tissue access for study, we have generated induced human pluripotent stem cell (hiPSC)-derived neuronal cultures that recapture many features of hypothalamic neurones within the arcuate nucleus. In the present study, we have comprehensively characterised this model across development, benchmarked these neurones to in vivo events, and demonstrate a link between obesity risk variants and hypothalamic development. The dynamic transcriptome across neuronal maturation was examined using microarray and RNA sequencing methods …

Reproducibility Of Tract-Based White Matter Microstructural Measures Using The Enigma-Dti Protocol, Ashley Acheson, S Andrea Wijtenburg, Laura M. Rowland, Anderson M. Winkler, Charles W. Mathias, L Elliot Hong, Neda Jahanshad, Binish Patel, Nancy L. Thompson, Stephen A. Mcguire

School of Medicine Publications

Background: In preparation for longitudinal analyses of white matter development in youths with family histories of substance use disorders (FH+) or without such histories (FH-), we examined the reproducibility and reliability of global and regional measures of fractional anisotropy (FA) values, measured using the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA)-diffusion tensor imaging (DTI) protocol. Highly reliable measures are necessary to detect any subtle differences in brain development.

Methods: First, we analyzed reproducibility data in a sample of 12 healthy young adults (ages 20-28) imaged three times within a week. Next, we calculated the same metrics in data collected …

Mirna Nanotherapeutics For Cancer, Aditya Ganju, Sheema Khan, Bilal B. Hafeez, Stephen Behrman, Murali M. Yallapu, Subhash C. Chauhan, Meena Jaggi

School of Medicine Publications

miRNAs are noncoding RNA molecules that regulate gene expression through diverse mechanisms. Increasing evidence suggests that miRNA-based therapies, either restoring or repressing miRNA expression and activity, hold great promise. However, the efficient delivery of miRNAs to target tissues is a major challenge in the transition of miRNA therapy to the clinic. Cationic polymers or viral vectors are efficient delivery agents but their systemic toxicity and immunogenicity limit their clinical usage. Efficient targeting and sustained release of miRNAs/ anti-miRNAs using nanoparticles (NPs) conjugated with antibodies and/or peptides could reduce the required therapeutic dosage while minimizing systemic and cellular toxicity. Given their …

Novel Genetic Loci Associated With Hippocampal Volume, Derrek P. Hibar, Hieab H. H. Adams, Neda Jahanshad, Ganesh Chauhan, Jason L. Stein, Edith Hofer, Miguel E. Renteria, Joshua C. Bis, Laura Almasy, John Blangero, Joanne E. Curran, Ravi Duggirala, Harald H. H. Goring

School of Medicine Publications

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence …

Genetic Variation Underlying Renal Uric Acid Excretion In Hispanic Children: The Viva La Familia Study, Geetha Chittoor, Karin Haack, Nitesh R. Mehta, Sandra Laston, Shelley A. Cole, Anthony G. Comuzzie, Nancy F. Butte, V. Saroja Voruganti

School of Medicine Publications

Background

Reduced renal excretion of uric acid plays a significant role in the development of hyperuricemia and gout in adults. Hyperuricemia has been associated with chronic kidney disease and cardiovascular disease in children and adults. There are limited genome-wide association studies associating genetic polymorphisms with renal urate excretion measures. Therefore, we investigated the genetic factors that influence the excretion of uric acid and related indices in 768 Hispanic children of the Viva La Familia Study.

Methods

We performed a genome-wide association analysis for 24-h urinary excretion measures such as urinary uric acid/urinary creatinine ratio, uric acid clearance, fractional excretion of …

In Silico Cd4+, Cd8+ T-Cell And B-Cell Immunity Associated Immunogenic Epitope Prediction And Hla Distribution Analysis Of Zika Virus, Essam Mohammed Janahi, Anupam Dhasmana, Vandana Srivastava, Aditya Narayan Sarangi, Sana Raza, Jamal M. Arif, Madan Lal Brahma Bhatt, Mohtashim Lohani, Mohammaed Y. Areeshi, Anand Murari Saxena, Shafiul Haque

School of Medicine Publications

Zika virus (ZIKV) is a mosquito-borne flavivirus distributed all over Africa, South America and Asia. The infection with the virus may cause acute febrile sickness that clinically resembles dengue fever, yet there is no vaccine, no satisfactory treatment, and no means of evaluating the risk of the disease or prognosis in the infected people. In the present study, the efficacy of the host's immune response in reducing the risk of infectious diseases was taken into account to carry out immuno-informatics driven epitope screening strategy of vaccine candidates against ZIKV. In this study, HLA distribution analysis was done to ensure the …

Parkinsonian Motor Impairment Predicts Personality Domains Related To Genetic Risk And Treatment Outcomes In Schizophrenia, Juan L. Molina, María Calvó, Eduardo Padilla, Mara Balda, Gabriela González Alemán, Néstor V. Florenzano, Gonzalo Guerrero, Danielle Kamis, Beatriz Molina Rangeon

School of Medicine Publications

Identifying endophenotypes of schizophrenia is of critical importance and has profound implications on clinical practice. Here we propose an innovative approach to clarify the mechanims through which temperament and character deviance relates to risk for schizophrenia and predict long-term treatment outcomes. We recruited 61 antipsychotic naïve subjects with chronic schizophrenia, 99 unaffected relatives, and 68 healthy controls from rural communities in the Central Andes. Diagnosis was ascertained with the Schedules of Clinical Assessment in Neuropsychiatry; parkinsonian motor impairment was measured with the Unified Parkinson's Disease Rating Scale; mesencephalic parenchyma was evaluated with transcranial ultrasound; and personality traits were assessed using …

Chemical Modification Of Ginsenoside On Cell Viability And Cytokine Secretion, Brandi Betts-Obregon, Magaly Salinas, Dale Oladunni, George R. Negrete, Andrew Tsin

School of Medicine Publications

Background: Rb1 is a ginsenoside steroid glycoside found exclusively in the plant Panax ginseng. In an earlier report, we showed that Rb1 increased cell proliferation and reduced VEGF (vascular endothelial growth factor) secretion by human retinal pigment epithelial (ARPE19) cells.

Objective: In the present study, we hypothesized that chemical modification of Rb1 changes the level of VEGF secretion by ARPE19 cells.

Method: Three derivatives of Rb1 were chemically synthesized by hydrogenation (Rb1-H2), acetylation (Rb1-Acyl), and epoxidation (Rb1-Epoxy). Structural modifications were confirmed by 1H Nuclear Magnetic Resonance (NMR) spectra and Mass Spectrometry (MS). To test the biological activity, chemically modified compounds …

The Antihypertensive Mthfr Gene Polymorphism Rs17367504-G Is A Possible Novel Protective Locus For Preeclampsia, Liv Cecilie V. Thomsen, Nina S. Mccarthy, Phillip E. Melton, Gemma Cadby, Rigmor Austgulen

School of Medicine Publications

Objective:

Preeclampsia is a complex heterogeneous disease commonly defined by new-onset hypertension and proteinuria in pregnancy. Women experiencing preeclampsia have increased risk for cardiovascular diseases (CVD) later in life. Preeclampsia and CVD share risk factors and pathophysiologic mechanisms, including dysregulated inflammation and raised blood pressure. Despite commonalities, little is known about the contribution of shared genes (pleiotropy) to these diseases. This study aimed to investigate whether genetic risk factors for hypertension or inflammation are pleiotropic by also being associated with preeclampsia.

Methods:

We genotyped 122 single nucleotide polymorphisms (SNPs) in women with preeclampsia (n = 1006) and nonpreeclamptic controls …

The Little Big Genome: The Organization Of Mitochondrial Dna, Iraselia Garcia, Edith Jones, Manuel Ramos, Wendy Innis-Whitehouse, Robert Gilkerson

School of Medicine Publications

The small (16,569 base pair) human mitochondrial genome plays a significant role in cell metabolism and homeostasis. Mitochondrial DNA (mtDNA) contributes to the generation of complexes which are essential to oxidative phosphorylation (OXPHOS). As such, mtDNA is directly integrated into mitochondrial biogenesis and signaling and regulates mitochondrial metabolism in concert with nuclear-encoded mitochondrial factors. Mitochondria are a highly dynamic, pleiomorphic network that undergoes fission and fusion events. Within this network, mtDNAs are packaged into structures called nucleoids which are actively distributed in discrete foci within the network. This sensitive organelle is frequently disrupted by insults such as oxidants and inflammatory …

In Silico Study Of Rxlr Effectors Of Phytophthora Infestans Hp-10-31, A2 Mating Type Potato Late Blight Pathogen, Youvika Singh, Virupaksh U. Patil, Anupam Dhasmana, Swarup K. Chakraborty, Pradeep K. Shukla, Shashi Rawat

School of Medicine Publications

Phytophthora infestans is one of the most compelling plant pathogen among the scientific community throughout the world. It is the causative agent of potato late blight and responsible for tremendous economic loss worldwide. Pathogenic effector proteins are instrumental in modulating host immunity and disease resistance has been a major concern. In P. infestans, a class of cytoplasmic effectors recognized as RxLR is characterized by highly conserved region and abet in parasitic colonization by modifying the host defense system. We have sequenced an Indian strain of P. infestans HP-10-31 genome and identified several RxLR motif-containing genes.In this study we selected two …

Autocrine And Paracrine Secretion Of Vascular Endothelial Growth Factor In The Pre-Hypoxic Diabetic Retina, Jeffery G. Grigsby, Donald M. Allen, Ana S. Ferrigno, Sandeep Vellanki, Cindy E. Pouw, Whitney A. Hejny, Andrew Tsin

School of Medicine Publications

Vascular endothelial growth factor (VEGF) is well established as the main agent responsible for vascular leakage and angiogenesis in the diabetic retina. While VEGF can have positive effects on hyperglycemia stressed retinal tissues, it also plays a role in events progressing to the oxygen- stressed, i.e. hypoxic, diabetic retina. Some VEGF makes its way to the retina from systemic sources and some is produced locally within the eye. Hyperglycemia, oxidants, inflammation, and advanced glycation end-products are all stimulants to VEGF production, both in the hypoxic and the pre-hypoxic retina. Endothelial cells, pericytes, Müller cells, microglia, astrocytes, retinal pigment epithelium and …

Cordycepin Induces Human Lung Cancer Cell Apoptosis By Inhibiting Nitric Oxide Mediated Erk/Slug Signaling Pathway, Jung-Hoo Hwang, Soo Kyung Park, Won Gyo Ko, Seong-Mun Kang, Da Bin Lee, Junho Bang, Byunghun Lee, Byung-Joo Park, Chung-Beum Wee, Dae Joon Kim

School of Medicine Publications

Nitric oxide (NO) is an important signaling molecule and a component of the inflammatory cascade. Besides, it is also involved in tumorigenesis. Aberrant upregulation and activation of the ERK cascade by NO often leads to tumor cell development. However, the role of ERK inactivation induced by the negative regulation of NO during apoptosis is not completely understood. In this study, treatment of A549 and PC9 human lung adenocarcinoma cell lines with cordycepin led to a reduction in their viability. Analysis of the effect of cordycepin treatment on ERK/Slug signaling activity in the A549 cell line revealed that LPS-induced inflammatory microenvironments …

Association Of Cardiometabolic Genes With Arsenic Metabolism Biomarkers In American Indian Communities: The Strong Heart Family Study (Shfs), Poojitha Balakrishnan, Dhananjay Vaidya, Nora Franceschini, V. Saroja Voruganti, Matthew O. Gribble, Karin Haack, Sandra Laston, Jason G. Umans, Kevin A. Francesconi, Walter Goessler

School of Medicine Publications

Background:

Metabolism of inorganic arsenic (iAs) is subject to inter-individual variability, which is explained partly by genetic determinants.

Objectives:

We investigated the association of genetic variants with arsenic species and principal components of arsenic species in the Strong Heart Family Study (SHFS).

Methods:

We examined variants previously associated with cardiometabolic traits (~ 200,000 from Illumina Cardio MetaboChip) or arsenic metabolism and toxicity (670) among 2,428 American Indian participants in the SHFS. Urine arsenic species were measured by high performance liquid chromatography–inductively coupled plasma mass spectrometry (HPLC-ICP-MS), and percent arsenic species [iAs, monomethylarsonate (MMA), and dimethylarsinate (DMA), divided by their sum …

Time Related Effects On Functional Brain Connectivity After Serotonergic And Cholinergic Neuromodulation, Bernadet L. Klaassens, Serge A. Rombouts, Anderson M. Winkler, Helene C. Van Gorsel, Jeroen Van Der Grond, Joop M A Van Gerven

School of Medicine Publications

Psychopharmacological research, if properly designed, may offer insight into both timing and area of effect, increasing our understanding of the brain's neurotransmitter systems. For that purpose, the acute influence of the selective serotonin reuptake inhibitor citalopram (30 mg) and the acetylcholinesterase inhibitor galantamine (8 mg) was repeatedly measured in 12 healthy young volunteers with resting state functional magnetic resonance imaging (RS-fMRI). Eighteen RS-fMRI scans were acquired per subject during this randomized, double blind, placebo-controlled, crossover study. Within-group comparisons of voxelwise functional connectivity with 10 functional networks were examined (P < 0.05, FWE-corrected) using a non-parametric multivariate approach with cerebrospinal fluid, white matter, heart rate, and baseline measurements as covariates. Although both compounds did not change cognitive performance on several tests, significant effects were found on connectivity with multiple resting state networks. Serotonergic stimulation primarily reduced connectivity with the sensorimotor network and structures that are related to self-referential mechanisms, whereas galantamine affected networks and regions that are more involved in learning, memory, and visual perception and processing. These results are consistent with the serotonergic and cholinergic trajectories and their functional relevance. In addition, this study demonstrates the power of using repeated measures after drug administration, which offers the chance to explore both combined and time specific effects. Hum Brain Mapp 38:308-325, 2017. © 2016 Wiley Periodicals, Inc.

The Application Of Half-Life In Clinical Decision Making: Comparison Of The Pharmacokinetics Of Extended-Release Topiramate (Usl255) And Immediate-Release Topiramate, Barry E. Gidal, Annie M. Clark, Bob Anders, Frank G. Gilliam

School of Medicine Publications

Highlights

• t1/2z may not adequately describe drug accumulation and distribution for some drugs.

• t1/2eff may be more appropriate; it describes drug-loss rate over dosing interval.

• For IR and XR topiramate, t1/2z was similar but t1/2eff was 1.5× longer for XR.

• Steady-state simulations predicted reduced fluctuation for XR topiramate vs IR.

Abstract

Objective

For extended-release drugs with multi-compartment kinetics, such as topiramate, effective half-life (t1/2eff) may be a more clinically relevant parameter than elimination half-life (t1/2z). Using topiramate as a real-life example, the objective was to compare these half-life values for immediate- and extended-release topiramate (TPM-IR and USL255, respectively) …

Thrombectomy 6 To 24 Hours After Stroke With A Mismatch Between Deficit And Infarct, Raul G. Nogueira, Ashutosh P. Jadhav, Diogo C. Haussen, Alain Bonafe, Ronald J. Budzik, Parita Bhuva, Dileep R. Yavagal, Christophe Cognard, Ameer E. Hassan, Wondwossen G. Tekle

School of Medicine Publications

Background The effect of endovascular thrombectomy that is performed more than 6 hours after the onset of ischemic stroke is uncertain. Patients with a clinical deficit that is disproportionately severe relative to the infarct volume may benefit from late thrombectomy.

Methods We enrolled patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, with mismatch criteria defined according to age (<80 years or ≥80 years). Patients were randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to standard care alone (the control group). The coprimary end points were the mean score for disability on the utility-weighted modified Rankin scale (which ranges from 0 [death] to 10 [no symptoms or disability]) and the rate of functional independence (a score of 0, 1, or 2 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating more severe disability) at 90 days.

Results A total of 206 patients …

Genome-Wide Meta-Analysis Of 241,258 Adults Accounting For Smoking Behaviour Identifies Novel Loci For Obesity Traits, Anne E. Justice, Thomas W. Winkler, Mary F. Feitosa, Misa Graff, Virginia A. Fisher, Kristin Leonard, Kristin Young, Llilda Barata, Xuan Deng, John Blangero, Joanne E. Curran

School of Medicine Publications

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an …

Effects Of Conjugated Linoleic Acid And Metformin On Insulin Sensitivity In Obese Children: Randomized Clinical Trial, Nayely Garibay-Nieto, Gloria Queipo-García, Flor Alvarez, Mayra Bustos, Erendira Villanueva, Fernando Ramírez, Mireya León, Estibalitz Laresgoiti-Servitje, Juan Carlos Lopez Alvarenga, Ravi Duggirala

School of Medicine Publications

Context: Insulin resistance precedes metabolic syndrome abnormalities and may promote cardiovascular disease and type 2 diabetes in children with obesity. Results of lifestyle modification programs have been discouraging, and the use of adjuvant strategies has been necessary.

Objective: This study aimed to evaluate the effects of metformin and conjugated linoleic acid (CLA) on insulin sensitivity, measured via euglycemic-hyperinsulinemic clamp technique and insulin pathway expression molecules in muscle biopsies of children with obesity.

Design: A randomized, double-blinded, placebo-controlled clinical trial was conducted.

Setting: Children with obesity were randomly assigned to receive metformin, CLA, or placebo.

Results: Intervention had a …

The Intracranial Aneurysm Gene Thsd1 Connects Endosome Dynamics To Nascent Focal Adhesion Assembly, Yan-Ning Rui, Zhen Yu, Xiaoqian Fang, Miriam R. Menezes, Julien Balzeau, Airu Niu, John P. Hagan, Dong H. Kim

School of Medicine Publications

Background/aims: We recently discovered that harmful variants in THSD1 (Thrombospondin type-1 domain-containing protein 1) likely cause intracranial aneurysm and subarachnoid hemorrhage in a subset of both familial and sporadic patients with supporting evidence from two vertebrate models. The current study seeks to elucidate how THSD1 and patient-identified variants function molecularly in focal adhesions.

Methods: Co-immunostaining and co-immunoprecipitation were performed to define THSD1 subcellular localization and interacting partners. Transient expression of patient-identified THSD1 protein variants and siRNA-mediated loss-of-function THSD1 were used to interrogate gene function in focal adhesion and cell attachment to collagen I in comparison to controls.

Results: THSD1 is …

Multiethnic Genome-Wide Meta-Analysis Of Ectopic Fat Depots Identifies Loci Associated With Adipocyte Development And Differentiation, Audrey Y. Chu, Xuan Deng, Virginia A. Fisher, Alexander Drong, Yang Zhang, Mary F. Feitosa, Ching-Ti Liu, Olivia Weeks, Audrey C. Choh, Qing Duan, Thomas D. Dyer

School of Medicine Publications

Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men for six ectopic fat traits in European, African, Hispanic, and Chinese ancestry populations, with and without sex stratification. In total, 7 new loci were identified in association with ectopic fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; PATXN1 and UBE2E2 …

The Genetic Basis Of The Comorbidity Between Cannabis Use And Major Depression, Karen Hodgson, Laura Almasy, Emma E. M. Knowles, Jack W. Kent Jr., Joanne E. Curran, Thomas D. Dyer, Harald H. H. Goring, Rene L. Olvera, Mary D. Woolsey, Ravindranath Duggirala, Peter T. Fox, John Blangero, David C. Glahn

School of Medicine Publications

Background and aims—While the prevalence of major depression is elevated amongst cannabis users, the role of genetics in this pattern of comorbidity is not clear. This study aimed to estimate the heritability of cannabis use and major depression, quantify the genetic overlap between these two traits, and localize regions of the genome that segregate in families with cannabis use and major depression.

Design—Family-based univariate and bivariate genetic analysis.

Setting—San Antonio, Texas, USA

Participants—Genetics of Brain Structure and Function study (GOBS) participants: 1,284 Mexican-Americans from 75 large multi-generation families and an additional 57 genetically unrelated spouses.

Measurements …

Vitamin D Receptor Gene Bsm1 Polymorphism And Risk Of Breast Cancer, Sana Raza, Roshan Jahan, Anupam Dhasmana, Madan Lal Brahma Bhatt, Mohtashim Lohani, Jamal M. Arif

School of Medicine Publications

Breast cancer is a leading cause of death among women, around the world. It is a multifactorial disease involving genetic and environmental factors. Vitamin D is known to modulate biological processes like immune response, bone metabolism, cell growth regulation. The protective actions of vitamin D in cancer development are only sparsely understood, however, evidence shows that vitamin D participates in cell growth regulation, apoptosis and cell differentiation. It has also been implicated in the suppression of cancer cell invasion, angiogenesis and metastasis. The cellular effects of Vitamin D are mediated via Vitamin D receptor (VDR), which is a member of …

Interhospital Transfer Before Thrombectomy Is Associated With Delayed Treatment And Worse Outcome In The Stratis Registry (Systematic Evaluation Of Patients Treated With Neurothrombectomy Devices For Acute Ischemic Stroke), Michael T. Froehler, Jeffrey L. Saver, Osama O. Zaidat, Reza Jahan, Ameer E. Hassan

School of Medicine Publications

BACKGROUND: Endovascular treatment with mechanical thrombectomy (MT) is beneficial for patients with acute stroke suffering a large-vessel occlusion, although treatment efficacy is highly time-dependent. We hypothesized that interhospital transfer to endovascular-capable centers would result in treatment delays and worse clinical outcomes compared with direct presentation.

METHODS: STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) was a prospective, multicenter, observational, single-arm study of real-world MT for acute stroke because of anterior-circulation large-vessel occlusion performed at 55 sites over 2 years, including 1000 patients with severe stroke and treated within 8 hours. Patients underwent MT with or …

Thsd1 (Thrombospondin Type 1 Domain Containing Protein 1) Mutation In The Pathogenesis Of Intracranial Aneurysm And Subarachnoid Hemorrhage, Teresa Santiago-Sim, Xiaoqian Fang, Morgan L. Hennessy, Stephen V. Nalbach, Steven R. Depalma, Ming Sum Lee, Steven C. Greenway, Barbara Mcdonough, Georgene W. Hergenroeder

School of Medicine Publications

Background and Purpose

A ruptured intracranial aneurysm (IA) is the leading cause of a subarachnoid hemorrhage (SAH). This study seeks to define a specific gene whose mutation leads to disease.

Methods

More than 500 IA probands and 100 affected families were enrolled and clinically characterized. Whole exome sequencing was performed on a large family, revealing a segregating THSD1 mutation. THSD1 was sequenced in other probands and controls. Thsd1 loss-of-function studies in zebrafish and mice were used for in vivo analyses, and functional studies performed using an in vitro endothelial cell model.

Results

A nonsense mutation in THSD1 (thrombospondin type-1 domain-containing …

A Principal Component Meta-Analysis On Multiple Anthropometric Traits Identifies Novel Loci For Body Shape, Janina S. Ried, Janina Jeff M., Audrey Y. Chu, Jennifer L. Bragg-Gresham, Jennifer E. Huffman, Tarunveer S. Ahluwalia, Gemma Cadby, Niina Eklund, John Blangero

School of Medicine Publications

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. …

Multidimensional Heritability Analysis Of Neuroanatomical Shape, Tian Ge, Martin Reuter, Anderson M. Winkler, Avram J. Holmes, Phil H. Lee, Lee S. Tirrell, Joshua L. Roffman, Randy L. Buckner, Jordan W. Smoller, Mert R. Sabuncu

School of Medicine Publications

In the dawning era of large-scale biomedical data, multidimensional phenotype vectors will play an increasing role in examining the genetic underpinnings of brain features, behaviour and disease. For example, shape measurements derived from brain MRI scans are multidimensional geometric descriptions of brain structure and provide an alternate class of phenotypes that remains largely unexplored in genetic studies. Here we extend the concept of heritability to multidimensional traits, and present the first comprehensive analysis of the heritability of neuroanatomical shape measurements across an ensemble of brain structures based on genome-wide SNP and MRI data from 1,320 unrelated, young and healthy individuals. …

Cucurbitacin D Exhibits Potent Anticancer Activity In Cervical Cancer, Mohammed Sikander, Bilal B. Hafeez, Shabnam Malik, Abdulrhman Alsayari, Fathi T. Halaweish, Murali M. Yallapu, Subhash C. Chauhan, Meena Jaggi

School of Medicine Publications

In this study, we for the first time, investigated the potential anti-cancer effects of a novel analogue of cucurbitacin (Cucurbitacin D) against cervical cancer in vitro and in vivo. Cucurbitacin D inhibited viability and growth of cervical cancer cells (CaSki and SiHa) in a dose-dependent manner. IC50 of Cucurbitacin D was recorded at 400 nM and 250 nM in CaSki and SiHa cells, respectively. Induction of apoptosis was observed in Cucurbitacin D treated cervical cancer cells as measured by enhanced Annexin V staining and cleavage in PARP protein. Cucurbitacin D treatment of cervical cancer cells arrested the cell cycle in …

Faster Permutation Inference In Brain Imaging, Anderson M. Winkler, Gerard R. Ridgway, Gwenaëlle Douaud, Thomas E. Nichols, Stephen M. Smith

School of Medicine Publications

Permutation tests are increasingly being used as a reliable method for inference in neuroimaging analysis. However, they are computationally intensive. For small, non-imaging datasets, recomputing a model thousands of times is seldom a problem, but for large, complex models this can be prohibitively slow, even with the availability of inexpensive computing power. Here we exploit properties of statistics used with the general linear model (GLM) and their distributions to obtain accelerations irrespective of generic software or hardware improvements. We compare the following approaches: (i) performing a small number of permutations; (ii) estimating the p-value as a parameter of a negative …