422 results on '"P. E. Garrett"'
Search Results
2. The observation of vibrating pear-shapes in radon nuclei
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P. A. Butler, L. P. Gaffney, P. Spagnoletti, J. Konki, M. Scheck, J. F. Smith, K. Abrahams, M. Bowry, J. Cederkäll, T. Chupp, G. de Angelis, H. De Witte, P. E. Garrett, A. Goldkuhle, C. Henrich, A. Illana, K. Johnston, D. T. Joss, J. M. Keatings, N. A. Kelly, M. Komorowska, T. Kröll, M. Lozano, B. S. Nara Singh, D. O’Donnell, J. Ojala, R. D. Page, L. G. Pedersen, C. Raison, P. Reiter, J. A. Rodriguez, D. Rosiak, S. Rothe, T. M. Shneidman, B. Siebeck, M. Seidlitz, J. Sinclair, M. Stryjczyk, P. Van Duppen, S. Vinals, V. Virtanen, N. Warr, K. Wrzosek-Lipska, and M. Zielinska
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Science - Abstract
Octupole deformation in nuclei is important to understand nuclear structure and electric dipole moments of heavy atoms. Here the authors measure energies of excited quantum states in radon isotopes and find that these isotopes do not provide favourable conditions in the search for CP-violation.
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- 2019
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3. Publisher Correction: The observation of vibrating pear-shapes in radon nuclei
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P. A. Butler, L. P. Gaffney, P. Spagnoletti, J. Konki, M. Scheck, J. F. Smith, K. Abrahams, M. Bowry, J. Cederkäll, T. Chupp, G. de Angelis, H. De Witte, P. E. Garrett, A. Goldkuhle, C. Henrich, A. Illana, K. Johnston, D. T. Joss, J. M. Keatings, N. A. Kelly, M. Komorowska, T. Kröll, M. Lozano, B. S. Nara Singh, D. O’Donnell, J. Ojala, R. D. Page, L. G. Pedersen, C. Raison, P. Reiter, J. A. Rodriguez, D. Rosiak, S. Rothe, T. M. Shneidman, B. Siebeck, M. Seidlitz, J. Sinclair, M. Stryjczyk, P. Van Duppen, S. Vinals, V. Virtanen, N. Warr, K. Wrzosek-Lipska, and M. Zielinska
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Science - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2020
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4. Single-nucleus multi-omics of Parkinson’s disease reveals a glutamatergic neuronal subtype susceptible to gene dysregulation via alteration of transcriptional networks
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E. Keats Shwab, Daniel C. Gingerich, Zhaohui Man, Julia Gamache, Melanie E. Garrett, Gregory E. Crawford, Allison E. Ashley-Koch, Geidy E. Serrano, Thomas G. Beach, Michael W. Lutz, and Ornit Chiba-Falek
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Parkinson’s disease ,Single-nucleus (sn)RNA-seq ,snATAC-seq ,Candidate cis regulatory element (cCRE) ,Regulatory networks ,Glutamatergic neurons ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract The genetic architecture of Parkinson’s disease (PD) is complex and multiple brain cell subtypes are involved in the neuropathological progression of the disease. Here we aimed to advance our understanding of PD genetic complexity at a cell subtype precision level. Using parallel single-nucleus (sn)RNA-seq and snATAC-seq analyses we simultaneously profiled the transcriptomic and chromatin accessibility landscapes in temporal cortex tissues from 12 PD compared to 12 control subjects at a granular single cell resolution. An integrative bioinformatic pipeline was developed and applied for the analyses of these snMulti-omics datasets. The results identified a subpopulation of cortical glutamatergic excitatory neurons with remarkably altered gene expression in PD, including differentially-expressed genes within PD risk loci identified in genome-wide association studies (GWAS). This was the only neuronal subtype showing significant and robust overexpression of SNCA. Further characterization of this neuronal-subpopulation showed upregulation of specific pathways related to axon guidance, neurite outgrowth and post-synaptic structure, and downregulated pathways involved in presynaptic organization and calcium response. Additionally, we characterized the roles of three molecular mechanisms in governing PD-associated cell subtype-specific dysregulation of gene expression: (1) changes in cis-regulatory element accessibility to transcriptional machinery; (2) changes in the abundance of master transcriptional regulators, including YY1, SP3, and KLF16; (3) candidate regulatory variants in high linkage disequilibrium with PD-GWAS genomic variants impacting transcription factor binding affinities. To our knowledge, this study is the first and the most comprehensive interrogation of the multi-omics landscape of PD at a cell-subtype resolution. Our findings provide new insights into a precise glutamatergic neuronal cell subtype, causal genes, and non-coding regulatory variants underlying the neuropathological progression of PD, paving the way for the development of cell- and gene-targeted therapeutics to halt disease progression as well as genetic biomarkers for early preclinical diagnosis.
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- 2024
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5. Posttraumatic stress disorder, trauma, and accelerated biological aging among post-9/11 veterans
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Kyle J. Bourassa, Melanie E. Garrett, Avshalom Caspi, Michelle Dennis, Katherine S. Hall, Terrie E. Moffitt, Gregory A. Taylor, VA Mid Atlantic MIRECC Workgroup, Allison E. Ashley-Koch, Jean C. Beckham, and Nathan A. Kimbrel
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract People who experience trauma and develop posttraumatic stress disorder (PTSD) are at increased risk for poor health. One mechanism that could explain this risk is accelerated biological aging, which is associated with the accumulation of chronic diseases, disability, and premature mortality. Using data from 2309 post-9/11 United States military veterans who participated in the VISN 6 MIRECC’s Post-Deployment Mental Health Study, we tested whether PTSD and trauma exposure were associated with accelerated rate of biological aging, assessed using a validated DNA methylation (DNAm) measure of epigenetic aging—DunedinPACE. Veterans with current PTSD were aging faster than those who did not have current PTSD, β = 0.18, 95% CI [0.11, 0.27], p
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- 2024
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6. An Investigation in Relationship Manifestations through Writing Pedagogical Practices
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Megan E. Garrett Quebedeaux
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This dissertation investigated the relationship between students and teachers in the context of writing pedagogical practices and writing curriculum. This study sought to extend the understanding of classroom relationships, specifically centered around writing instruction. Three dyads of teachers and students were observed as they interacted and moved through the mandated curriculum and normal routines of the classroom. Through a basic, interpretive qualitative methodology using principles of ethnography, this investigation sought to identify, describe, and interpret the themes of relationships between teacher and student in the writing classroom. Over the course of several weeks, data was collected from the dyads through participant observations and audio/video recordings of these observations. Additional data, serving as a secondary dataset were collected from semi-structured interviews with the teachers and students, and writing samples were collected from the students. The relational themes were interpreted and described in detail as well as triangulated via secondary data sources. Results of this investigation demonstrated how the relationship between student and teacher influenced and interacted with pedagogical practices and curriculum. Five relational themes were identified and described in detail. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]
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- 2023
7. Multi-ancestry epigenome-wide analyses identify methylated sites associated with aortic augmentation index in TOPMed MESA
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Xiaowei Hu, Jeongok G. Logan, Younghoon Kwon, Joao A. C. Lima, David R. Jacobs, Daniel Duprez, Lyndia Brumback, Kent D. Taylor, Peter Durda, W. Craig Johnson, Elaine Cornell, Xiuqing Guo, Yongmei Liu, Russell P. Tracy, Thomas W. Blackwell, George Papanicolaou, Gary F. Mitchell, Stephen S. Rich, Jerome I. Rotter, David J. Van Den Berg, Julio A. Chirinos, Timothy M. Hughes, Francine E. Garrett-Bakelman, and Ani Manichaikul
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Medicine ,Science - Abstract
Abstract Despite the prognostic value of arterial stiffness (AS) and pulsatile hemodynamics (PH) for cardiovascular morbidity and mortality, epigenetic modifications that contribute to AS/PH remain unknown. To gain a better understanding of the link between epigenetics (DNA methylation) and AS/PH, we examined the relationship of eight measures of AS/PH with CpG sites and co-methylated regions using multi-ancestry participants from Trans-Omics for Precision Medicine (TOPMed) Multi-Ethnic Study of Atherosclerosis (MESA) with sample sizes ranging from 438 to 874. Epigenome-wide association analysis identified one genome-wide significant CpG (cg20711926-CYP1B1) associated with aortic augmentation index (AIx). Follow-up analyses, including gene set enrichment analysis, expression quantitative trait methylation analysis, and functional enrichment analysis on differentially methylated positions and regions, further prioritized three CpGs and their annotated genes (cg23800023-ETS1, cg08426368-TGFB3, and cg17350632-HLA-DPB1) for AIx. Among these, ETS1 and TGFB3 have been previously prioritized as candidate genes. Furthermore, both ETS1 and HLA-DPB1 have significant tissue correlations between Whole Blood and Aorta in GTEx, which suggests ETS1 and HLA-DPB1 could be potential biomarkers in understanding pathophysiology of AS/PH. Overall, our findings support the possible role of epigenetic regulation via DNA methylation of specific genes associated with AIx as well as identifying potential targets for regulation of AS/PH.
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- 2023
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8. Integrative single-nucleus multi-omics analysis prioritizes candidate cis and trans regulatory networks and their target genes in Alzheimer’s disease brains
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Julia Gamache, Daniel Gingerich, E. Keats Shwab, Julio Barrera, Melanie E. Garrett, Cordelia Hume, Gregory E. Crawford, Allison E. Ashley-Koch, and Ornit Chiba-Falek
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Late onset Alzheimer’s disease ,Single-nucleus (sn)RNA-seq ,snATAC-seq ,Regulatory networks ,Chromatin accessibility ,Transcriptomics ,Biotechnology ,TP248.13-248.65 ,Biology (General) ,QH301-705.5 ,Biochemistry ,QD415-436 - Abstract
Abstract Background The genetic underpinnings of late-onset Alzheimer’s disease (LOAD) are yet to be fully elucidated. Although numerous LOAD-associated loci have been discovered, the causal variants and their target genes remain largely unknown. Since the brain is composed of heterogenous cell subtypes, it is imperative to study the brain on a cell subtype specific level to explore the biological processes underlying LOAD. Methods Here, we present the largest parallel single-nucleus (sn) multi-omics study to simultaneously profile gene expression (snRNA-seq) and chromatin accessibility (snATAC-seq) to date, using nuclei from 12 normal and 12 LOAD brains. We identified cell subtype clusters based on gene expression and chromatin accessibility profiles and characterized cell subtype-specific LOAD-associated differentially expressed genes (DEGs), differentially accessible peaks (DAPs) and cis co-accessibility networks (CCANs). Results Integrative analysis defined disease-relevant CCANs in multiple cell subtypes and discovered LOAD-associated cell subtype-specific candidate cis regulatory elements (cCREs), their candidate target genes, and trans-interacting transcription factors (TFs), some of which, including ELK1, JUN, and SMAD4 in excitatory neurons, were also LOAD-DEGs. Finally, we focused on a subset of cell subtype-specific CCANs that overlap known LOAD-GWAS regions and catalogued putative functional SNPs changing the affinities of TF motifs within LOAD-cCREs linked to LOAD-DEGs, including APOE and MYO1E in a specific subtype of microglia and BIN1 in a subpopulation of oligodendrocytes. Conclusions To our knowledge, this study represents the most comprehensive systematic interrogation to date of regulatory networks and the impact of genetic variants on gene dysregulation in LOAD at a cell subtype resolution. Our findings reveal crosstalk between epigenetic, genomic, and transcriptomic determinants of LOAD pathogenesis and define catalogues of candidate genes, cCREs, and variants involved in LOAD genetic etiology and the cell subtypes in which they act to exert their pathogenic effects. Overall, these results suggest that cell subtype-specific cis–trans interactions between regulatory elements and TFs, and the genes dysregulated by these networks contribute to the development of LOAD.
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- 2023
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9. A study protocol for risk stratification in children with concussion (RSiCC): Theoretical framework, design, and methods.
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Karin Reuter-Rice, Amanda N Fitterer, Peter Duquette, Qing Yang, Anushka K Palipana, Daniel Laskowitz, Melanie E Garrett, Margaret Fletcher, Julia Smith, Lynn Makor, Gerald Grant, Kristen Ramsey, O Josh Bloom, and Allison E Ashley-Koch
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Medicine ,Science - Abstract
Research shows that one in five children will experience a concussion by age 16. Compared to adults, children experience longer and more severe postconcussive symptoms (PCS), with severity and duration varying considerably among children and complicating management of these patients. Persistent PCS can result in increased school absenteeism, social isolation, and psychological distress. Although early PCS diagnosis and access to evidence-based interventions are strongly linked to positive health and academic outcomes, symptom severity and duration are not fully explained by acute post-injury symptoms. Prior research has focused on the role of neuroinflammation in mediating PCS and associated fatigue; however relationship between inflammatory biomarkers and PCS severity, has not examined longitudinally. To identify which children are at high risk for persistent PCS and poor health, academic, and social outcomes, research tracking PCS trajectories and describing school-based impacts across the entire first year postinjury is critically needed. This study will 1) define novel PCS trajectory typologies in a racially/ethnically diverse population of 500 children with concussion (11-17 years, near equal distribution by sex), 2) identify associations between these typologies and patterns of inflammatory biomarkers and genetic variants, 3) develop a risk stratification model to identify children at risk for persistent PCS; and 4) gain unique insights and describe PCS impact, including fatigue, on longer-term academic and social outcomes. We will be the first to use NIH's symptom science model and patient-reported outcomes to explore the patterns of fatigue and other physical, cognitive, psychological, emotional and academic responses to concussion in children over a full year. Our model will enable clinicians and educators to identify children most at risk for poor long-term health, social, and academic outcomes after concussion. This work is critical to meeting our long-term goal of developing personalized concussion symptom-management strategies to improve outcomes and reduce disparities in the health and quality of life of children.
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- 2024
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10. Gene-metabolite annotation with shortest reactional distance enhances metabolite genome-wide association studies results
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Cantin Baron, Sarah Cherkaoui, Sandra Therrien-Laperriere, Yann Ilboudo, Raphaël Poujol, Pamela Mehanna, Melanie E. Garrett, Marilyn J. Telen, Allison E. Ashley-Koch, Pablo Bartolucci, John D. Rioux, Guillaume Lettre, Christine Des Rosiers, Matthieu Ruiz, and Julie G. Hussin
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Association analysis ,Computational bioinformatics ,Quantitative genetics ,Science - Abstract
Summary: Metabolite genome-wide association studies (mGWAS) have advanced our understanding of the genetic control of metabolite levels. However, interpreting these associations remains challenging due to a lack of tools to annotate gene-metabolite pairs beyond the use of conservative statistical significance threshold. Here, we introduce the shortest reactional distance (SRD) metric, drawing from the comprehensive KEGG database, to enhance the biological interpretation of mGWAS results. We applied this approach to three independent mGWAS, including a case study on sickle cell disease patients. Our analysis reveals an enrichment of small SRD values in reported mGWAS pairs, with SRD values significantly correlating with mGWAS p values, even beyond the standard conservative thresholds. We demonstrate the utility of SRD annotation in identifying potential false negatives and inaccuracies within current metabolic pathway databases. Our findings highlight the SRD metric as an objective, quantitative and easy-to-compute annotation for gene-metabolite pairs, suitable to integrate statistical evidence to biological networks.
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- 2023
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11. Correction: Integrative analysis identifies an older female-linked AML patient group with better risk in ECOG-ACRIN Cancer Research Group’s clinical trial E3999
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Franck Rapaport, Kenneth Seier, Yaseswini Neelamraju, Duane Hassane, Timour Baslan, Daniel T. Gildea, Samuel Haddox, Tak Lee, H. Moses Murdock, Caroline Sheridan, Alexis Thurmond, Ling Wang, Martin Carroll, Larry D. Cripe, Hugo Fernandez, Christopher E. Mason, Elisabeth Paietta, Gail J. Roboz, Zhuoxin Sun, Martin S. Tallman, Yanming Zhang, Mithat Gönen, Ross Levine, Ari M. Melnick, Maria Kleppe, and Francine E. Garrett-Bakelman
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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12. Large epigenome-wide association study identifies multiple novel differentially methylated CpG sites associated with suicidal thoughts and behaviors in veterans
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Nathan A. Kimbrel, Melanie E. Garrett, Mariah K. Evans, Clara Mellows, Michelle F. Dennis, Lauren P. Hair, Michael A. Hauser, the VA Mid-Atlantic MIRECC Workgroup, Allison E. Ashley-Koch, Jean C. Beckham, Patrick S. Calhoun, Eric Dedert, Eric B. Elbogen, John A. Fairbank, Robin A. Hurley, Jason D. Kilts, Angela Kirby, Sarah L. Martindale, Christine E. Marx, Scott D. McDonald, Scott D. Moore, Rajendra A. Morey, Jennifer C. Naylor, Jared Rowland, Robert D. Shura, Cindy Swinkels, Larry A. Tupler, Elizabeth E. Van Voorhees, and Ruth Yoash-Gantz
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suicide ,epigenetics ,methylation ,psychiatry ,suicidal ideation ,Psychiatry ,RC435-571 - Abstract
IntroductionThe U.S. suicide mortality rate has steadily increased during the past two decades, particularly among military veterans; however, the epigenetic basis of suicidal thoughts and behaviors (STB) remains largely unknown.MethodsTo address this issue, we conducted an epigenome-wide association study of DNA methylation (DNAm) of peripheral blood samples obtained from 2,712 U.S. military veterans.ResultsThree DNAm probes were significantly associated with suicide attempts, surpassing the multiple testing threshold (FDR q-value
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- 2023
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13. Long COVID: Is there a kidney link?
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Raymond E. Garrett, Carlos H. Palacio, and David Bar-Or
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SARS-CoV-2 (COVID 19) ,kynurenine (KYN) ,creatine phosphate (CP) ,glomerular reclamation ,proximal tubule cell ,long COVID ,Medicine (General) ,R5-920 - Abstract
Metabolic causes such as altered bioenergetics and amino acid metabolism may play a major role in Long COVID. Renal-metabolic regulation is an integral part of these pathways but has not been systematically or routinely investigated in Long COVID. Here we discuss the biochemistry of renal tubular injury as it may contribute to Long COVID symptoms. We propose three potential mechanisms that could be involved in Long COVID namely creatine phosphate metabolism, un-reclaimed glomerular filtrate and COVID specific proximal tubule cells (PTC) injury-a tryptophan paradigm. This approach is intended to allow for improved diagnostics and therapy for the long-haul sufferers.
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- 2023
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14. Genome-wide association study identifies four pan-ancestry loci for suicidal ideation in the Million Veteran Program.
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Allison E Ashley-Koch, Nathan A Kimbrel, Xue J Qin, Jennifer H Lindquist, Melanie E Garrett, Michelle F Dennis, Lauren P Hair, Jennifer E Huffman, Daniel A Jacobson, Ravi K Madduri, Hilary Coon, Anna R Docherty, Jooeun Kang, Niamh Mullins, Douglas M Ruderfer, VA Million Veteran Program (MVP), MVP Suicide Exemplar Workgroup, International Suicide Genetics Consortium, Philip D Harvey, Benjamin H McMahon, David W Oslin, Elizabeth R Hauser, Michael A Hauser, and Jean C Beckham
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Genetics ,QH426-470 - Abstract
Suicidal ideation (SI) often precedes and predicts suicide attempt and death, is the most common suicidal phenotype and is over-represented in veterans. The genetic architecture of SI in the absence of suicide attempt (SA) is unknown, yet believed to have distinct and overlapping risk with other suicidal behaviors. We performed the first GWAS of SI without SA in the Million Veteran Program (MVP), identifying 99,814 SI cases from electronic health records without a history of SA or suicide death (SD) and 512,567 controls without SI, SA or SD. GWAS was performed separately in the four largest ancestry groups, controlling for sex, age and genetic substructure. Ancestry-specific results were combined via meta-analysis to identify pan-ancestry loci. Four genome-wide significant (GWS) loci were identified in the pan-ancestry meta-analysis with loci on chromosomes 6 and 9 associated with suicide attempt in an independent sample. Pan-ancestry gene-based analysis identified GWS associations with DRD2, DCC, FBXL19, BCL7C, CTF1, ANNK1, and EXD3. Gene-set analysis implicated synaptic and startle response pathways (q's
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- 2023
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15. Validation of CRISPR targeting for proliferation and cytarabine resistance control genes in the acute myeloid leukemia cell line MOLM-13
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Subhash C Prajapati, Nicholas Dunham, Hao Fan, and Francine E Garrett-Bakelman
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acute myeloid leukemia ,CDA ,CRISPR-Cas9 ,cytarabine ,DCK ,MOLM-13 ,Biology (General) ,QH301-705.5 - Abstract
Acute myeloid leukemia patients with FMS-like tyrosine kinase 3–internal tandem duplications and mixed lineage leukemia–protein AF9 fusion proteins suffer from poor clinical outcomes. The MOLM-13 acute myeloid leukemia cell line harbors both of these abnormalities and is used in CRISPR experiments to identify disease drivers. However, experimental observations may be biased or inconclusive in the absence of experimentally validated positive control genes. We validated sgRNAs for knockdown of TP53 for cell proliferation and for DCK knockdown and CDA upregulation for cytarabine resistance control genes in MOLM-13 cells. We have provided a detailed CRISPR protocol applicable to both gene knockdown or activation experiments and downstream leukemic phenotype analyses. Inclusion of these controls in CRISPR experiments will enhance the capacity to identify novel myeloid leukemia drivers in MOLM-13 cells.
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- 2022
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16. Sex differences in progression of kidney disease in sickle cell disease
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Kenneth I. Ataga, Qingning Zhou, Santosh L. Saraf, Jane S. Hankins, Emily J. Ciccone, Laura R. Loehr, Melanie E. Garrett, Allison E. Ashley-Koch, Jianwen Cai, Marilyn J. Telen, and Vimal K. Derebail
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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17. Variation and impact of polygenic hematologic traits in monogenic sickle cell disease
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Thomas Pincez, Ken Sin Lo, Anne-Laure Pham Hung d’Alexandry d’Orengiani, Melanie E. Garrett, Carlo Brugnara, Allison E. Ashley-Koch, Marilyn J. Telen, Frederic Galacteros, Philippe Joly, Pablo Bartolucci, and Guillaume Lettre
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Several of the complications observed in sickle cell disease (SCD) are influenced by variation in hematologic traits (HT), such as fetal hemoglobin (HbF) level and neutrophil count. Previous large-scale genome-wide association studies carried out in largely healthy individuals have identified thousands of variants associated with HT, which have then been used to develop multi-ancestry polygenic trait scores (PTS). Here, we tested whether these PTS associate with HT in SCD patients and if they can improve statistical models associated with SCD-related complications. In 2,056 SCD patients, we found that the PTS predicted less HT variance than in non-SCD individuals of African ancestry. This was particularly striking at the Duffy/DARC locus, where we observed an epistatic interaction between the SCD genotype and the Duffy null variant (rs2814778) that led to a two-fold weaker effect on neutrophil count. PTS for these HT which are measured as part of routine practice were not associated with complications in SCD. In contrast, we found that a simple PTS for HbF that includes only six variants explained a large fraction of the phenotypic variation (20.5-27.1%), associated with acute chest syndrome and stroke risk, and improved the statistical modeling of the vaso-occlusive crisis rate. Using Mendelian randomization, we found that increasing HbF by 4.8% reduces stroke risk by 39% (P=0.0006). Taken together, our results highlight the importance of validating PTS in large diseased populations before proposing their implementation in the context of precision medicine initiatives.
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- 2022
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18. Detailed analysis of antibody responses to SARS-CoV-2 vaccination and infection in macaques.
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Alexandra C Willcox, Kevin Sung, Meghan E Garrett, Jared G Galloway, Jesse H Erasmus, Jennifer K Logue, David W Hawman, Helen Y Chu, Kim J Hasenkrug, Deborah H Fuller, Frederick A Matsen Iv, and Julie Overbaugh
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Macaques are a commonly used model for studying immunity to human viruses, including for studies of SARS-CoV-2 infection and vaccination. However, it is unknown whether macaque antibody responses resemble the response in humans. To answer this question, we employed a phage-based deep mutational scanning approach (Phage-DMS) to compare which linear epitopes are targeted on the SARS-CoV-2 Spike protein in convalescent humans, convalescent (re-infected) rhesus macaques, mRNA-vaccinated humans, and repRNA-vaccinated pigtail macaques. We also used Phage-DMS to determine antibody escape pathways within each epitope, enabling a granular comparison of antibody binding specificities at the locus level. Overall, we identified some common epitope targets in both macaques and humans, including in the fusion peptide (FP) and stem helix-heptad repeat 2 (SH-H) regions. Differences between groups included a response to epitopes in the N-terminal domain (NTD) and C-terminal domain (CTD) in vaccinated humans but not vaccinated macaques, as well as recognition of a CTD epitope and epitopes flanking the FP in convalescent macaques but not convalescent humans. There was also considerable variability in the escape pathways among individuals within each group. Sera from convalescent macaques showed the least variability in escape overall and converged on a common response with vaccinated humans in the SH-H epitope region, suggesting highly similar antibodies were elicited. Collectively, these findings suggest that the antibody response to SARS-CoV-2 in macaques shares many features with humans, but with substantial differences in the recognition of certain epitopes and considerable individual variability in antibody escape profiles, suggesting a diverse repertoire of antibodies that can respond to major epitopes in both humans and macaques. Differences in macaque species and exposure type may also contribute to these findings.
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- 2022
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19. Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed
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Margaret A. Taub, Matthew P. Conomos, Rebecca Keener, Kruthika R. Iyer, Joshua S. Weinstock, Lisa R. Yanek, John Lane, Tyne W. Miller-Fleming, Jennifer A. Brody, Laura M. Raffield, Caitlin P. McHugh, Deepti Jain, Stephanie M. Gogarten, Cecelia A. Laurie, Ali Keramati, Marios Arvanitis, Albert V. Smith, Benjamin Heavner, Lucas Barwick, Lewis C. Becker, Joshua C. Bis, John Blangero, Eugene R. Bleecker, Esteban G. Burchard, Juan C. Celedón, Yen Pei C. Chang, Brian Custer, Dawood Darbar, Lisa de las Fuentes, Dawn L. DeMeo, Barry I. Freedman, Melanie E. Garrett, Mark T. Gladwin, Susan R. Heckbert, Bertha A. Hidalgo, Marguerite R. Irvin, Talat Islam, W. Craig Johnson, Stefan Kaab, Lenore Launer, Jiwon Lee, Simin Liu, Arden Moscati, Kari E. North, Patricia A. Peyser, Nicholas Rafaels, Christine Seidman, Daniel E. Weeks, Fayun Wen, Marsha M. Wheeler, L. Keoki Williams, Ivana V. Yang, Wei Zhao, Stella Aslibekyan, Paul L. Auer, Donald W. Bowden, Brian E. Cade, Zhanghua Chen, Michael H. Cho, L. Adrienne Cupples, Joanne E. Curran, Michelle Daya, Ranjan Deka, Celeste Eng, Tasha E. Fingerlin, Xiuqing Guo, Lifang Hou, Shih-Jen Hwang, Jill M. Johnsen, Eimear E. Kenny, Albert M. Levin, Chunyu Liu, Ryan L. Minster, Take Naseri, Mehdi Nouraie, Muagututi‘a Sefuiva Reupena, Ester C. Sabino, Jennifer A. Smith, Nicholas L. Smith, Jessica Lasky-Su, James G. Taylor, VI, Marilyn J. Telen, Hemant K. Tiwari, Russell P. Tracy, Marquitta J. White, Yingze Zhang, Kerri L. Wiggins, Scott T. Weiss, Ramachandran S. Vasan, Kent D. Taylor, Moritz F. Sinner, Edwin K. Silverman, M. Benjamin Shoemaker, Wayne H.-H. Sheu, Frank Sciurba, David A. Schwartz, Jerome I. Rotter, Daniel Roden, Susan Redline, Benjamin A. Raby, Bruce M. Psaty, Juan M. Peralta, Nicholette D. Palmer, Sergei Nekhai, Courtney G. Montgomery, Braxton D. Mitchell, Deborah A. Meyers, Stephen T. McGarvey, Angel C.Y. Mak, Ruth J.F. Loos, Rajesh Kumar, Charles Kooperberg, Barbara A. Konkle, Shannon Kelly, Sharon L.R. Kardia, Robert Kaplan, Jiang He, Hongsheng Gui, Frank D. Gilliland, Bruce D. Gelb, Myriam Fornage, Patrick T. Ellinor, Mariza de Andrade, Adolfo Correa, Yii-Der Ida Chen, Eric Boerwinkle, Kathleen C. Barnes, Allison E. Ashley-Koch, Donna K. Arnett, Christine Albert, Cathy C. Laurie, Goncalo Abecasis, Deborah A. Nickerson, James G. Wilson, Stephen S. Rich, Daniel Levy, Ingo Ruczinski, Abraham Aviv, Thomas W. Blackwell, Timothy Thornton, Jeff O’Connell, Nancy J. Cox, James A. Perry, Mary Armanios, Alexis Battle, Nathan Pankratz, Alexander P. Reiner, and Rasika A. Mathias
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telomeres ,telomere length genetics ,trans-population genome-wide association study ,Genetics ,QH426-470 ,Internal medicine ,RC31-1245 - Abstract
Summary: Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes.
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- 2022
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20. Comprehensive characterization of the antibody responses to SARS-CoV-2 Spike protein finds additional vaccine-induced epitopes beyond those for mild infection
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Meghan E Garrett, Jared G Galloway, Caitlin Wolf, Jennifer K Logue, Nicholas Franko, Helen Y Chu, Frederick A Matsen IV, and Julie M Overbaugh
- Subjects
SARS-CoV-2 ,antibody epitope ,escape mutations ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Background: Control of the COVID-19 pandemic will rely on SARS-CoV-2 vaccine-elicited antibodies to protect against emerging and future variants; an understanding of the unique features of the humoral responses to infection and vaccination, including different vaccine platforms, is needed to achieve this goal. Methods: The epitopes and pathways of escape for Spike-specific antibodies in individuals with diverse infection and vaccination history were profiled using Phage-DMS. Principal component analysis was performed to identify regions of antibody binding along the Spike protein that differentiate the samples from one another. Within these epitope regions, we determined potential sites of escape by comparing antibody binding of peptides containing wild-type residues versus peptides containing a mutant residue. Results: Individuals with mild infection had antibodies that bound to epitopes in the S2 subunit within the fusion peptide and heptad-repeat regions, whereas vaccinated individuals had antibodies that additionally bound to epitopes in the N- and C-terminal domains of the S1 subunit, a pattern that was also observed in individuals with severe disease due to infection. Epitope binding appeared to change over time after vaccination, but other covariates such as mRNA vaccine dose, mRNA vaccine type, and age did not affect antibody binding to these epitopes. Vaccination induced a relatively uniform escape profile across individuals for some epitopes, whereas there was much more variation in escape pathways in mildly infected individuals. In the case of antibodies targeting the fusion peptide region, which was a common response to both infection and vaccination, the escape profile after infection was not altered by subsequent vaccination. Conclusions: The finding that SARS-CoV-2 mRNA vaccination resulted in binding to additional epitopes beyond what was seen after infection suggests that protection could vary depending on the route of exposure to Spike antigen. The relatively conserved escape pathways to vaccine-induced antibodies relative to infection-induced antibodies suggests that if escape variants emerge they may be readily selected for across vaccinated individuals. Given that the majority of people will be first exposed to Spike via vaccination and not infection, this work has implications for predicting the selection of immune escape variants at a population level. Funding: This work was supported by NIH grants AI138709 (PI JMO) and AI146028 (PI FAM). JMO received support as the Endowed Chair for Graduate Education (FHCRC). The research of FAM was supported in part by a Faculty Scholar grant from the Howard Hughes Medical Institute and the Simons Foundation. Scientific Computing Infrastructure at Fred Hutch was funded by ORIP grant S10OD028685.
- Published
- 2022
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21. COCOA: coordinate covariation analysis of epigenetic heterogeneity
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John T. Lawson, Jason P. Smith, Stefan Bekiranov, Francine E. Garrett-Bakelman, and Nathan C. Sheffield
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Epigenetics ,DNA methylation ,Chromatin accessibility ,Principal component analysis ,Dimensionality reduction ,Data integration ,Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract A key challenge in epigenetics is to determine the biological significance of epigenetic variation among individuals. We present Coordinate Covariation Analysis (COCOA), a computational framework that uses covariation of epigenetic signals across individuals and a database of region sets to annotate epigenetic heterogeneity. COCOA is the first such tool for DNA methylation data and can also analyze any epigenetic signal with genomic coordinates. We demonstrate COCOA’s utility by analyzing DNA methylation, ATAC-seq, and multi-omic data in supervised and unsupervised analyses, showing that COCOA provides new understanding of inter-sample epigenetic variation. COCOA is available on Bioconductor ( http://bioconductor.org/packages/COCOA ).
- Published
- 2020
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22. The mechanism of hamstring injuries – a systematic review
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Adam Danielsson, Alexandra Horvath, Carl Senorski, Eduard Alentorn-Geli, William E. Garrett, Ramón Cugat, Kristian Samuelsson, and Eric Hamrin Senorski
- Subjects
Running ,Sprinting ,Biomechanics ,Strength ,Muscle injury ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract Background Injuries to the hamstring muscles are among the most common in sports and account for significant time loss. Despite being so common, the injury mechanism of hamstring injuries remains to be determined. Purpose To investigate the hamstring injury mechanism by conducting a systematic review. Study design A systematic review following the PRISMA statement. Methods A systematic search was conducted using PubMed, EMBASE and the Cochrane Library. Studies 1) written in English and 2) deciding on the mechanism of hamstring injury were eligible for inclusion. Literature reviews, systematic reviews, meta-analyses, conference abstracts, book chapters and editorials were excluded, as well as studies where the full text could not be obtained. Results Twenty-six of 2372 screened original studies were included and stratified to the mechanism or methods used to determine hamstring injury: stretch-related injuries, kinematic analysis, electromyography-based kinematic analysis and strength-related injuries. All studies that reported the stretch-type injury mechanism concluded that injury occurs due to extensive hip flexion with a hyperextended knee. The vast majority of studies on injuries during running proposed that these injuries occur during the late swing phase of the running gait cycle. Conclusion A stretch-type injury to the hamstrings is caused by extensive hip flexion with an extended knee. Hamstring injuries during sprinting are most likely to occur due to excessive muscle strain caused by eccentric contraction during the late swing phase of the running gait cycle. Level of evidence Level IV
- Published
- 2020
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23. The effect of performance demands on lower extremity biomechanics during landing and cutting tasks
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Boyi Dai, William E. Garrett, Michael T. Gross, Darin A. Padua, Robin M. Queen, and Bing Yu
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Sports ,GV557-1198.995 ,Sports medicine ,RC1200-1245 - Abstract
Background: Anterior cruciate ligament (ACL) injuries commonly occur during the early phase of landing and cutting tasks that involve sudden decelerations. The purpose of this study was to investigate the effects of jump height and jump speed on lower extremity biomechanics during a stop-jump task and the effect of cutting speed on lower extremity biomechanics during a side-cutting task. Methods: Thirty-six recreational athletes performed a stop-jump task under 3 conditions: jumping fast, jumping for maximum height, and jumping for 60% of maximum height. Participants also performed a side-cutting task under 2 conditions: cutting at maximum speed and cutting at 60% of maximum speed. Three-dimensional kinematic and kinetic data were collected. Results: The jumping fast condition resulted in increased peak posterior ground reaction force (PPGRF), knee extension moment at PPGRF, and knee joint stiffness and decreased knee flexion angle compared with the jumping for maximum height condition. The jumping for 60% of maximum height condition resulted in decreased knee flexion angle compared with the jumping for maximum height condition. Participants demonstrated greater PPGRF, knee extension moment at PPGRF, knee valgus angle and varus moment at PPGRF, knee joint stiffness, and knee flexion angle during the cutting at maximum speed condition compared with the cutting at 60% maximum speed condition. Conclusion: Performing jump landing at an increased jump speed resulted in lower extremity movement patterns that have been previously associated with an increase in ACL loading. Cutting speed also affected lower extremity biomechanics. Jump speed and cutting speed need to be considered when designing ACL injury risk screening and injury prevention programs. Keywords: ACL injury, Injury prevention, Kinematics, Kinetics, Loading mechanism, Risk factor
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- 2019
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24. Development of antibody-dependent cell cytotoxicity function in HIV-1 antibodies
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Laura E Doepker, Sonja Danon, Elias Harkins, Duncan K Ralph, Zak Yaffe, Meghan E Garrett, Amrit Dhar, Cassia Wagner, Megan M Stumpf, Dana Arenz, James A Williams, Walter Jaoko, Kishor Mandaliya, Kelly K Lee, Frederick A Matsen IV, and Julie M Overbaugh
- Subjects
HIV ,antibody development ,ADCC ,SHM ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
A prerequisite for the design of an HIV vaccine that elicits protective antibodies is understanding the developmental pathways that result in desirable antibody features. The development of antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) is particularly relevant because such antibodies have been associated with HIV protection in humans. We reconstructed the developmental pathways of six human HIV-specific ADCC antibodies using longitudinal antibody sequencing data. Most of the inferred naive antibodies did not mediate detectable ADCC. Gain of antigen binding and ADCC function typically required mutations in complementarity determining regions of one or both chains. Enhancement of ADCC potency often required additional mutations in framework regions. Antigen binding affinity and ADCC activity were correlated, but affinity alone was not sufficient to predict ADCC potency. Thus, elicitation of broadly active ADCC antibodies may require mutations that enable high-affinity antigen recognition along with mutations that optimize factors contributing to functional ADCC activity.
- Published
- 2021
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25. Rapid decline in estimated glomerular filtration rate in sickle cell anemia: results of a multicenter pooled analysis
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Kenneth I. Ataga, Qingning Zhou, Vimal K. Derebail, Santosh L. Saraf, Jane S. Hankins, Laura R. Loehr, Melanie E. Garrett, Allison E. Ashley-Koch, Jianwen Cai, and Marilyn J. Telen
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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26. Characterization of Learning, Motivation, and Visual Perception in Five Transgenic Mouse Lines Expressing GCaMP in Distinct Cell Populations
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Peter A. Groblewski, Douglas R. Ollerenshaw, Justin T. Kiggins, Marina E. Garrett, Chris Mochizuki, Linzy Casal, Sissy Cross, Kyla Mace, Jackie Swapp, Sahar Manavi, Derric Williams, Stefan Mihalas, and Shawn R. Olsen
- Subjects
mouse behavior ,GCaMP transgenic mice ,visual perception ,motivation ,learning ,change detection ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
To study the mechanisms of perception and cognition, neural measurements must be made during behavior. A goal of the Allen Brain Observatory is to map the activity of distinct cortical cell classes underlying visual and behavioral processing. Here we describe standardized methodology for training head-fixed mice on a visual change detection task, and we use our paradigm to characterize learning and behavior of five GCaMP6-expressing transgenic lines. We used automated training procedures to facilitate comparisons across mice. Training times varied, but most transgenic mice learned the behavioral task. Motivation levels also varied across mice. To compare mice in similar motivational states we subdivided sessions into over-, under-, and optimally motivated periods. When motivated, the pattern of perceptual decisions were highly correlated across transgenic lines, although overall performance (d-prime) was lower in one line labeling somatostatin inhibitory cells. These results provide important context for using these mice to map neural activity underlying perception and behavior.
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- 2020
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27. Relationships among hamstring muscle optimal length and hamstring flexibility and strength
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Xianglin Wan, Feng Qu, William E. Garrett, Hui Liu, and Bing Yu
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Injury risk factor ,Muscle biomechanics ,Muscle length–tension relationship ,Muscle optimal length ,Muscle strain ,Muscle strain injury ,Sports ,GV557-1198.995 ,Sports medicine ,RC1200-1245 - Abstract
Background: Hamstring muscle strain injury (hamstring injury) due to excessive muscle strain is one of the most common injuries in sports. The relationships among hamstring muscle optimal lengths and hamstring flexibility and strength were unknown, which limited our understanding of risk factors for hamstring injury. This study was aimed at examining the relationships among hamstring muscle optimal length and flexibility and strength. Methods: Hamstring flexibility and isokinetic strength data and three-dimensional kinematic data for hamstring isokinetic tests were collected for 11 male and 10 female recreational athletes. The maximal hamstring muscle forces, optimal lengths, and muscle lengths in standing were determined for each participant. Results: Hamstring muscle optimal lengths were significantly correlated to hamstring flexibility score and gender, but not to hamstring strength. The greater the flexibility score, the longer the hamstring muscle optimal length. With the same flexibility score, females tend to have shorter hamstring optimal muscle lengths compared to males. Hamstring flexibility score and hamstring strength were not correlated. Hamstring muscle optimal lengths were longer than but not significantly correlated to corresponding hamstring muscle lengths in standing. Conclusion: Hamstring flexibility may affect hamstring muscle maximum strain in movements. With similar hamstring flexibility, hamstring muscle maximal strain in a given movement may be different between genders. Hamstring muscle lengths in standing should not be used as an approximation of their optimal lengths in calculation of hamstring muscle strain in musculoskeletal system modeling.
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- 2017
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28. First Evidence of Axial Shape Asymmetry and Configuration Coexistence in Zn74 : Suggestion for a Northern Extension of the N=40 Island of Inversion
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M. Rocchini, P. E. Garrett, M. Zielińska, S. M. Lenzi, D. D. Dao, F. Nowacki, V. Bildstein, A. D. MacLean, B. Olaizola, Z. T. Ahmed, C. Andreoiu, A. Babu, G. C. Ball, S. S. Bhattacharjee, H. Bidaman, C. Cheng, R. Coleman, I. Dillmann, A. B. Garnsworthy, S. Gillespie, C. J. Griffin, G. F. Grinyer, G. Hackman, M. Hanley, A. Illana, S. Jones, A. T. Laffoley, K. G. Leach, R. S. Lubna, J. McAfee, C. Natzke, S. Pannu, C. Paxman, C. Porzio, A. J. Radich, M. M. Rajabali, F. Sarazin, K. Schwarz, S. Shadrick, S. Sharma, J. Suh, C. E. Svensson, D. Yates, and T. Zidar
- Subjects
General Physics and Astronomy - Published
- 2023
29. Biomechanical characteristics of an anterior cruciate ligament injury in javelin throwing
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Boyi Dai, Min Mao, William E. Garrett, and Bing Yu
- Subjects
ACL injury ,Biomechanics ,Injury mechanism ,Injury prevention ,Risk factors ,Sports ,GV557-1198.995 ,Sports medicine ,RC1200-1245 - Abstract
Purpose: The purpose of this study was to understand the mechanism of an anterior cruciate ligament (ACL) injury in javelin throwing and javelin throwing techniques relevant to this ACL injury. Methods: The patient in this study was an elite female javelin thrower who completed the first three trials and sustained a non-contact ACL injury on her left knee in the fourth trial of javelin throwing during a recent track and field meet. Three-dimensional kinematic data were collected in the injury and non-injury trials. The kinematic data of 52 male and 54 female elite javelin throwers were obtained from a javelin throwing biomechanical database. Results: The patient had greater forward center of mass velocity and less vertical center of mass velocity after the first 25% of the delivery phase in the injury trial compared to non-injury trials. The patient had less left knee flexion angle and angular velocity but similar left knee valgus and internal rotation angles during the first 21% of the delivery phase in the injury trial compared to non-injury trials. The video images showed an obvious tibia anterior translation at the 30% of the delivery phase in the injury trial. The left knee flexion angle and angular velocity at the time of the left foot landing and the maximal left knee flexion angle during the delivery phase were not significantly correlated to the official distance for 52 male and 54 female elite javelin throwers. Conclusion: The ACL injury in this study occurred during the first 30% of the delivery phase, most likely during the first 25% of the delivery phase. A stiff landing of the left leg with a small knee flexion angle was the primary contributor to this injury. Javelin throwers may have a soft left leg landing with a flexed knee, which may help them prevent ACL injuries without compromising performance.
- Published
- 2015
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30. Mechanism of hamstring muscle strain injury in sprinting
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Bing Yu, Hui Liu, and William E. Garrett
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Sports ,GV557-1198.995 ,Sports medicine ,RC1200-1245 - Published
- 2017
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31. Coulomb excitation of Ru102 with C12 and O16
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P. E. Garrett, M. Zielińska, A. Bergmaier, T. R. Rodríguez, D. Kalaydjieva, M. Siciliano, H. Bidaman, V. Bildstein, C. Burbadge, A. Diaz Varela, D. T. Doherty, T. Faestermann, K. Hadyńska-Klȩk, R. Hertenberger, N. Keeley, A. Laffoley, A. D. MacLean, M. Mahgoub, A. J. Radich, M. Rocchini, P. Spagnoletti, S. Triambak, M. Vandebrouck, and K. Wrzosek-Lipska
- Published
- 2022
32. Anterior cruciate ligament injuries in soccer: Loading mechanisms, risk factors, and prevention programs
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Boyi Dai, Dewei Mao, William E. Garrett, and Bing Yu
- Subjects
ACL injuries ,Biomechanics ,Injury prevention ,Soccer ,Sports ,GV557-1198.995 ,Sports medicine ,RC1200-1245 - Abstract
Anterior cruciate ligament (ACL) injuries are common in soccer. Understanding ACL loading mechanisms and risk factors for ACL injury is critical for designing effective prevention programs. The purpose of this review is to summarize the relevant literature on ACL loading mechanisms, ACL injury risk factors, and current ACL injury prevention programs for soccer players. Literature has shown that tibial anterior translation due to shear force at the proximal end of tibia is the primary ACL loading mechanism. No evidence has been found showing that knee valgus moment is the primary ACL loading mechanism. ACL loading mechanisms are largely ignored in previous studies on risk factors for ACL injury. Identified risk factors have little connections to ACL loading mechanisms. The results of studies on ACL injury prevention programs for soccer players are inconsistent. Current ACL injury prevention programs for soccer players are clinically ineffective due to low compliance. Future studies are urgently needed to identify risk factors for ACL injury in soccer that are connected to ACL loading mechanisms and have cause-and-effect relationships with injury rate, and to develop new prevention programs to improve compliance.
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- 2014
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33. Proton capture on P30 in novae: On the existence of states at 6.40 MeV and 6.65 MeV in S31
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M. Kamil, S. Triambak, G. C. Ball, V. Bildstein, A. Diaz Varela, T. Faestermann, P. E. Garrett, F. Ghazi Moradi, R. Hertenberger, N. Y. Kheswa, N. J. Mukwevho, B. M. Rebeiro, and H.-F. Wirth
- Published
- 2022
34. Phase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease.
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Jennifer F Doss, Jude C Jonassaint, Melanie E Garrett, Allison E Ashley-Koch, Marilyn J Telen, and Jen-Tsan Chi
- Subjects
Medicine ,Science - Abstract
Sickle cell disease (SCD) is the most common inherited hemoglobinopathy worldwide. Our previous results indicate that the reduced oxidative stress capacity of sickle erythrocytes may be caused by decreased expression of NRF2 (Nuclear factor (erythroid-derived 2)-like 2), an oxidative stress regulator. We found that activation of NRF2 with sulforaphane (SFN) in erythroid progenitors significantly increased the expression of NRF2 targets HMOX1, NQO1, and HBG1 (subunit of fetal hemoglobin) in a dose-dependent manner. Therefore, we hypothesized that NRF2 activation with SFN may offer therapeutic benefits for SCD patients by restoring oxidative capacity and increasing fetal hemoglobin concentration. To test this hypothesis, we performed a Phase 1, open-label, dose-escalation study of SFN, contained in a broccoli sprout homogenate (BSH) that naturally contains SFN, in adults with SCD. The primary and secondary study endpoints were safety and physiological response to NRF2 activation, respectively. We found that BSH was well tolerated, and the few adverse events that occurred during the trial were not likely related to BSH consumption. We observed an increase in the mean relative whole blood mRNA levels for the NRF2 target HMOX1 (p = 0.02) on the last day of BSH treatment, compared to pre-treatment. We also observed a trend toward increased mean relative mRNA levels of the NRF2 target HBG1 (p = 0.10) from baseline to end of treatment, but without significant changes in HbF protein. We conclude that BSH, in the provided doses, is safe in stable SCD patients and may induce changes in gene expression levels. We therefore propose investigation of more potent NRF2 inducers, which may elicit more robust physiological changes and offer clinical benefits to SCD patients. Trial registration: ClinicalTrials.gov NCT01715480.
- Published
- 2016
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35. Isospin mixing and the cubic isobaric multiplet mass equation in the lowest T=2 , A=32 quintet
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M. Kamil, S. Triambak, A. Magilligan, A. García, B. A. Brown, P. Adsley, V. Bildstein, C. Burbadge, A. Diaz Varela, T. Faestermann, P. E. Garrett, R. Hertenberger, N. Y. Kheswa, K. G. Leach, R. Lindsay, D. J. Marín-Lámbarri, F. Ghazi Moradi, N. J. Mukwevho, R. Neveling, J. C. Nzobadila Ondze, P. Papka, L. Pellegri, V. Pesudo, B. M. Rebeiro, M. Scheck, F. D. Smit, and H.-F. Wirth
- Published
- 2021
36. Comment on 'The late swing and early stance of sprinting are most hazardous for hamstring injuries' by Liu et al.
- Author
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Bing Yu, Hui Liu, and William E. Garrett
- Subjects
Sports ,GV557-1198.995 ,Sports medicine ,RC1200-1245 - Published
- 2017
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37. First direct measurement of Cu59(p,α)Ni56 : A step towards constraining the Ni-Cu cycle in the cosmos
- Author
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K. Kapoor, J. S. Randhawa, C. Waterfield, C. E. Svensson, S. Upadhyayula, J. Williams, Corina Andreoiu, R. Kanungo, G. Hackman, P. E. Garrett, A. J. Radich, Mansi Saxena, R. Krücken, G. F. Grinyer, B. Nikhil, A. T. Laffoley, Z. Meisel, S. S. Bhattacharjee, A. Psaltis, Tan Ahn, J. F. Liang, R. Jain, J. Refsgaard, G. Christian, M. Singh, A. Lennarz, A. Talebitaher, M. Rocchini, P. Subramaniam, Michael Williams, R. Coleman, J. Hollett, N. Saei, A. Chen, Barry Davids, E. Gyabeng Fuakye, P. Mohr, and M. Alcorta
- Subjects
Physics ,0103 physical sciences ,Astrophysics ,010306 general physics ,010303 astronomy & astrophysics ,01 natural sciences - Published
- 2021
38. Comment on ' g Factor of the Zr99(7/2+) Isomer: Monopole Evolution in the Shape-Coexisting Region'
- Author
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P. E. Garrett
- Subjects
Materials science ,Condensed matter physics ,010308 nuclear & particles physics ,g factor ,0103 physical sciences ,Magnetic monopole ,General Physics and Astronomy ,010306 general physics ,01 natural sciences - Published
- 2021
39. Spectroscopy of states in Ba136 using the Ba138(p,t) reaction
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B. M. Rebeiro, S. Triambak, P. E. Garrett, B. A. Brown, G. C. Ball, R. Lindsay, P. Adsley, V. Bildstein, C. Burbadge, A. Diaz-Varela, T. Faestermann, R. Hertenberger, B. Jigmeddorj, M. Kamil, K. G. Leach, P. Z. Mabika, J. C. Nzobadila Ondze, J. N. Orce, A. Radich, and H.-F. Wirth
- Subjects
Physics ,Foundation (engineering) ,Library science - Abstract
We thank Marcus Scheck for fruitful discussions. Funding support from the National Research Foundation (NRF), South Africa, under Grant No. 85100, the U.S. Department of Energy Office of Science under Grants No. DE-SC0017649 and No. DE-FG02-93ER40789 and the National Science Foundation under Grant No. PHY-1811855 are gratefully acknowledged. P.A. thanks the Claude Leon Foundation for his postdoctoral fellowship. P.Z.M. and J.C.N.O. are grateful to the NRF funded MaNuS/MatSci program at UWC for financial support during their M.Sc.
- Published
- 2021
40. Ba145 and La145,146 structure from lifetime measurements
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G. Hackman, R. Umashankar, A. Estrade, B. Olaizola, A. Diaz-Varela, C. E. Svensson, A. D. MacLean, D. Southall, P. E. Garrett, J. Measures, R. Dunlop, A. B. Garnsworthy, R. Cabellero-Folch, B. Shaw, K. Whitmore, Iris Dillmann, M. Bowry, G. C. Ball, C. J. Pearson, T. Zidar, C. Burbadge, V. Bildstein, A. Babu, and J. Turko
- Subjects
Physics ,010308 nuclear & particles physics ,0103 physical sciences ,Structure (category theory) ,Order (ring theory) ,Atomic physics ,Nuclear Experiment ,010306 general physics ,Spin (physics) ,Parity (mathematics) ,01 natural sciences - Abstract
The occurrence of octupole shapes in even-mass neutron-rich Ba isotopes has been well established. However, the situation with the odd-mass Ba and odd or odd-odd La nuclei around them is not so clear. In order to shed light on these less-studied isotopes, a fast-timing experiment was performed using the GRIFFIN spectrometer at TRIUMF-ISAC. A wealth of excited-state lifetimes in the 100 ps to few ns range have been measured in $^{144,145,146}\mathrm{Ba}$ and $^{145,146}\mathrm{La}$ populated in the ${\ensuremath{\beta}}^{\ensuremath{-}}$ and ${\ensuremath{\beta}}^{\ensuremath{-}}\text{\ensuremath{-}}n$ decay of $^{145,146}\mathrm{Cs}$. The results do not allow one to draw firm conclusions about the possible octupole deformation of these nuclei but suggest different spin and parity assignments than previous works. This work highlights the need for more detailed study of the odd and odd-odd isotopes in this region to properly understand their structure.
- Published
- 2021
41. Corrigendum to 'Benchmarking 136Xe neutrinoless ββ decay matrix element calculations with the 138Ba(p,t) reaction' [Phys. Lett. B 809 (2020) 135702]
- Author
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B. Rebeiro, M. Kamil, B. A. Brown, Mihai Horoi, J. C. Nzobadila Ondze, P. Z. Mabika, P. E. Garrett, Dong-Liang Fang, S. Triambak, J. N. Orce, P. Adsley, C. Burbadge, Robert S. Lindsay, K. G. Leach, H.-F. Wirth, A. Diaz Varela, B. Jigmeddorj, T. Faestermann, Ralf Hertenberger, G. C. Ball, and V. Bildstein
- Subjects
Nuclear physics ,Physics ,Nuclear and High Energy Physics ,QC1-999 ,Matrix element ,Benchmarking - Published
- 2021
42. Correction: In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress.
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Blair R Anderson, David N Howell, Karen Soldano, Melanie E Garrett, Nicholas Katsanis, Marilyn J Telen, Erica E Davis, and Allison E Ashley-Koch
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Genetics ,QH426-470 - Published
- 2015
- Full Text
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43. In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress.
- Author
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Blair R Anderson, David N Howell, Karen Soldano, Melanie E Garrett, Nicholas Katsanis, Marilyn J Telen, Erica E Davis, and Allison E Ashley-Koch
- Subjects
Genetics ,QH426-470 - Abstract
African Americans have a disproportionate risk for developing nephropathy. This disparity has been attributed to coding variants (G1 and G2) in apolipoprotein L1 (APOL1); however, there is little functional evidence supporting the role of this protein in renal function. Here, we combined genetics and in vivo modeling to examine the role of apol1 in glomerular development and pronephric filtration and to test the pathogenic potential of APOL1 G1 and G2. Translational suppression or CRISPR/Cas9 genome editing of apol1 in zebrafish embryos results in podocyte loss and glomerular filtration defects. Complementation of apol1 morphants with wild-type human APOL1 mRNA rescues these defects. However, the APOL1 G1 risk allele does not ameliorate defects caused by apol1 suppression and the pathogenicity is conferred by the cis effect of both individual variants of the G1 risk haplotype (I384M/S342G). In vivo complementation studies of the G2 risk allele also indicate that the variant is deleterious to protein function. Moreover, APOL1 G2, but not G1, expression alone promotes developmental kidney defects, suggesting a possible dominant-negative effect of the altered protein. In sickle cell disease (SCD) patients, we reported previously a genetic interaction between APOL1 and MYH9. Testing this interaction in vivo by co-suppressing both transcripts yielded no additive effects. However, upon genetic or chemical induction of anemia, we observed a significantly exacerbated nephropathy phenotype. Furthermore, concordant with the genetic interaction observed in SCD patients, APOL1 G2 reduces myh9 expression in vivo, suggesting a possible interaction between the altered APOL1 and myh9. Our data indicate a critical role for APOL1 in renal function that is compromised by nephropathy-risk encoding variants. Moreover, our interaction studies indicate that the MYH9 locus is also relevant to the phenotype in a stressed microenvironment and suggest that consideration of the context-dependent functions of both proteins will be required to develop therapeutic paradigms.
- Published
- 2015
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44. An examination of the association between 5-HTTLPR, combat exposure, and PTSD diagnosis among U.S. veterans.
- Author
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Yutao Liu, Melanie E Garrett, Michelle F Dennis, Kimberly T Green, VA Mid-Atlantic MIRECC Registry Workgroup, Allison E Ashley-Koch, Michael A Hauser, Jean C Beckham, and Nathan A Kimbrel
- Subjects
Medicine ,Science - Abstract
To examine the association between the 5-HTTLPR polymorphism of the serotonin transporter (SLC6A4) gene, combat exposure, and posttraumatic stress disorder (PTSD) diagnosis and among two samples of combat-exposed veterans.The first sample included 550 non-Hispanic Black (NHB) combat-exposed veterans. The second sample included 555 non-Hispanic White (NHW) combat-exposed veterans. Participants were genotyped for the 5-HTTLPR/rs25531 variants of the SLC6A4 gene. A structured clinical interview was used to diagnose PTSD. Combat and civilian trauma exposure were assessed with validated self-report instruments. Logistic regression was used to test for main effects of 5-HTTLPR on PTSD diagnosis as well as gene x environment (GxE) interactions after adjusting for sex, ancestry proportion scores, civilian trauma exposure, and combat exposure.Within the NHB sample, a significant additive effect was observed for 5-HTTLPR (OR = 1.502, p = .0025), such that the odds of having a current diagnosis of PTSD increased by 1.502 for each additional S' allele. No evidence for an association between 5-HTTLPR and PTSD was observed in the NHW sample. In addition, no evidence for combat x 5-HTTLPR effects were observed in either sample.The present study suggests that there may be an association between 5-HTTLPR genotype and PTSD diagnosis among NHB veterans; however, no evidence for the hypothesized 5-HTTLPR x combat interaction was found.
- Published
- 2015
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45. The GRIFFIN facility for Decay-Spectroscopy studies at TRIUMF-ISAC
- Author
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Y. Linn, Mustafa Rajabali, D. Morris, Corina Andreoiu, C. Bartlett, S. W. Yates, E. T. Rand, K. Whitmore, R. Braid, D. S. Cross, D. Miller, J.E. Ash, T. Bruhn, M. Bowry, Erin E. Peters, James Smallcombe, A. B. Garnsworthy, S. Georges, F. A. Ali, D. Kisliuk, D. Brennan, G. Hackman, Elizabeth Padilla-Rodal, A.I. Kilic, R. Dunlop, E. MacConnachie, E. F. Zganjar, N. Bernier, S. Cruz, A.R. Mathews, E. McGee, J. Measures, M. Kuwabara, M. Ticu, E. Peters, V. Bildstein, C. Burbadge, R. Gudapati, P. C. Bender, R. Caballero-Folch, L.N. Morrison, B. Davids, Baharak Hadinia, R. Kokke, Panu Ruotsalainen, U. Rizwan, H. P. Patel, E. Timakova, B. Jigmeddorj, S. S. Bhattacharjee, S. Ciccone, K. G. Leach, Jack Henderson, M. R. Dunlop, F. H. Garcia, R Umashankar, W. J. Mills, W. Moore, Joochun Park, J. K. Smith, D. Southall, A. T. Laffoley, A. Cheeseman, Z. Beadle, P. E. Garrett, Z. M. Wang, M. Moukaddam, L. J. Evitts, C.R. Natzke, C. Lim, B. Olaizola, T. Ballast, K. Ortner, F. Sarazin, P. Boubel, H. Bidaman, R. Churchman, J. R. Leslie, S. A. Gillespie, C. E. Svensson, K. Kuhn, S. Wong, T. Zidar, B. Shaw, W.H. Ashfield, R. Krücken, Iris Dillmann, J. Turko, O. Paetkau, S. V. Ilyushkin, R. Lafleur, S. Hallam, G. C. Ball, D. Bishop, C. Unsworth, K. Raymond, A. Diaz Varela, J. L. Pore, Y. Saito, C. J. Pearson, A. J. Radich, K. Starosta, A. D. MacLean, and Aaron Chester
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Radioactive ion beams ,Nuclear and High Energy Physics ,Physics - Instrumentation and Detectors ,Physics::Instrumentation and Detectors ,Astrophysics::High Energy Astrophysical Phenomena ,FOS: Physical sciences ,chemistry.chemical_element ,Germanium ,01 natural sciences ,7. Clean energy ,Nuclear physics ,0103 physical sciences ,Nuclear Experiment (nucl-ex) ,Nuclear Experiment ,010306 general physics ,Spectroscopy ,Instrumentation ,Digital data acquisition system ,Physics ,Spectrometer ,010308 nuclear & particles physics ,Detector ,Instrumentation and Detectors (physics.ins-det) ,Semiconductor detector ,chemistry ,Physics::Accelerator Physics - Abstract
Gamma-Ray Infrastructure For Fundamental Investigations of Nuclei, GRIFFIN, is a new high-efficiency γ -ray spectrometer designed for use in decay spectroscopy experiments with low-energy radioactive ion beams provided by TRIUMF’s Isotope Separator and Accelerator (ISAC-I) facility. GRIFFIN is composed of sixteen Compton-suppressed large-volume clover-type high-purity germanium (HPGe) γ -ray detectors combined with a suite of ancillary detection systems and coupled to a custom digital data acquisition system. The infrastructure and detectors of the spectrometer as well as the performance characteristics and the analysis techniques applied to the experimental data are described.
- Published
- 2019
46. Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma.
- Author
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Megan Ulmer Carnes, Yangfan P Liu, R Rand Allingham, Benjamin T Whigham, Shane Havens, Melanie E Garrett, Chunyan Qiao, NEIGHBORHOOD Consortium Investigators, Nicholas Katsanis, Janey L Wiggs, Louis R Pasquale, Allison Ashley-Koch, Edwin C Oh, and Michael A Hauser
- Subjects
Genetics ,QH426-470 - Abstract
Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10(-11)). SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345), which was associated significantly with POAG (OR = 1.27, p = 4.2×10(-10)) in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141). Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss.
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- 2014
- Full Text
- View/download PDF
47. Investigation of pair-correlated 0+ states in Ba134 via the Ba136(p,t) reaction
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T. Faestermann, S. Triambak, J. C. Nzobadila Ondze, Ralf Hertenberger, J. N. Orce, G. C. Ball, P. E. Garrett, M. Kamil, H.-F. Wirth, A. Diaz Varela, B. Rebeiro, A. J. Radich, V. Bildstein, L. Atar, Robert S. Lindsay, and C. Burbadge
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Nuclear reaction ,Physics ,Double beta decay ,Excited state ,Nuclear structure ,Matrix element ,Context (language use) ,Atomic physics - Abstract
We performed a high resolution study of ${0}^{+}$ states in $^{134}\mathrm{Ba}$ using the $^{136}\mathrm{Ba}(p,t)$ two-neutron transfer reaction. Our experiment shows a significant portion of the $L=0$ pair-transfer strength concentrated at excited ${0}^{+}$ levels in $^{134}\mathrm{Ba}$. Potential implications in the context of $^{136}\mathrm{Xe}\phantom{\rule{4pt}{0ex}}\ensuremath{\rightarrow}\phantom{\rule{4pt}{0ex}}^{136}\mathrm{Ba}$ neutrinoless double beta decay matrix element calculations are briefly discussed.
- Published
- 2021
48. Comment on 'g Factor of the ^{99}Zr(7/2^{+}) Isomer: Monopole Evolution in the Shape-Coexisting Region'
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P E, Garrett
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Brain - Published
- 2021
49. Spectroscopic studies of neutron-rich In129 and its β -decay daughter, Sn129 , using the GRIFFIN spectrometer
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C. E. Svensson, J. Measures, Corina Andreoiu, N. Bernier, M. Ticu, Jack Henderson, H. Bidaman, J. L. Pore, M. Bowry, A. B. Garnsworthy, P. E. Garrett, J. K. Smith, K. Ortner, M. R. Dunlop, J. Turko, D. S. Cross, G. C. Ball, D. Southall, T. Zidar, V. Bildstein, K. Whitmore, C. M. Petrache, R. Dunlop, B. Olaizola, K. Raymond, Joochun Park, and F. H. Garcia
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Physics ,Nuclear physics ,Spectrometer ,010308 nuclear & particles physics ,Branching fraction ,Excited state ,0103 physical sciences ,Neutron ,010306 general physics ,Spin (physics) ,Ground state ,01 natural sciences ,Beta decay - Abstract
The $\beta$-decay of neutron-rich $^{129}$In into $^{129}$Sn was studied using the GRIFFIN spectrometer at the ISAC facility at TRIUMF. The study observed the half-lives of the ground state and each of the $\beta$-decaying isomers. The level scheme of $^{129}$Sn has been expanded with thirty-one new $\gamma$-ray transitions and nine new excited levels, leading to a re-evaluation of the $\beta$-branching ratios and level spin assignments. The observation of the $\beta$-decay of the (29/2$^{+}$) 1911-keV isomeric state in $^{129}$In is reported for the first time, with a branching ratio of 2.0(5)$\%$.
- Published
- 2021
50. High-precision branching ratio measurement and spin assignment implications for Ga62 superallowed β decay
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D. Yates, M. Moukaddam, C. Cheng, B. Olaizola, L. J. Evitts, J. Williams, A. Diaz-Varela, Joochun Park, V. Bildstein, R. Sultana, C. Burbadge, A. J. Radich, G. F. Grinyer, H. Bidaman, Jack Henderson, J. Turko, M. R. Dunlop, A. Babu, K. G. Leach, S. S. Bhattacharjee, J. L. Pore, Y. Saito, P. Finlay, R. Dunlop, S. Sharma, C. J. Griffin, G. Hackman, J. McAfee, G. C. Ball, A. D. MacLean, A. B. Garnsworthy, Corina Andreoiu, J. R. Leslie, C. E. Svensson, E. Gopaul, T. Zidar, A. T. Laffoley, Iris Dillmann, J. K. Smith, P. E. Garrett, C.R. Natzke, S. Nittala, B. Jigmeddorj, C. Porzio, S. A. Gillespie, Panu Ruotsalainen, E. Kassanda, C. Paxman, M. Bowry, James Smallcombe, and D. S. Cross
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Physics ,Spins ,010308 nuclear & particles physics ,Branching fraction ,01 natural sciences ,Beta decay ,Nuclear physics ,Excited state ,Isospin ,0103 physical sciences ,Symmetry breaking ,Nuclear Experiment ,010306 general physics ,Spin (physics) ,Fermi Gamma-ray Space Telescope - Abstract
A high-precision branching ratio measurement for the superallowed Fermi $\beta^{+}$ emitter $^{62}$Ga was performed with the Gamma-Ray Infrastructure for Fundamental Investigations of Nuclei (GRIFFIN) spectrometer at the Isotope Separator and Accelerator (ISAC) radioactive ion beam facility at TRIUMF. The high efficiency of the GRIFFIN spectrometer allowed 63 $\gamma$-ray transitions, with intensities down to $\approx$1 part per million (ppm) per $^{62}$Ga $\beta^{+}$ decay, to be placed in the level scheme of the daughter nucleus $^{62}$Zn, establishing the superallowed $\beta$ branching ratio for $^{62}$Ga decay to be 99.8577$^{+0.0023}_{-0.0029}\%$, a factor of 4 more precise than the previous world average. For several cascades, $\gamma-\gamma$ angular correlation measurements were performed to assign spins and/or determine the mixing ratios of transitions. In particular, the spin of the 2.342 MeV excited state in the daughter nucleus $^{62}$Zn was definitively assigned as $J = 0$. This assignment resolves a discrepancy between previous measurements and has important implications for the isospin symmetry breaking correction, $\delta_{C1}$, in $^{62}$Ga superallowed Fermi $\beta$ decay.
- Published
- 2020
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