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Robert Gorman

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https://www.readbyqxmd.com/read/29290614/topoisomerase-3%C3%AE-is-required-for-decatenation-and-segregation-of-human-mtdna
#1
Thomas J Nicholls, Cristina A Nadalutti, Elisa Motori, Ewen W Sommerville, Gráinne S Gorman, Swaraj Basu, Emily Hoberg, Doug M Turnbull, Patrick F Chinnery, Nils-Göran Larsson, Erik Larsson, Maria Falkenberg, Robert W Taylor, Jack D Griffith, Claes M Gustafsson
How mtDNA replication is terminated and the newly formed genomes are separated remain unknown. We here demonstrate that the mitochondrial isoform of topoisomerase 3α (Top3α) fulfills this function, acting independently of its nuclear role as a component of the Holliday junction-resolving BLM-Top3α-RMI1-RMI2 (BTR) complex. Our data indicate that mtDNA replication termination occurs via a hemicatenane formed at the origin of H-strand replication and that Top3α is essential for resolving this structure. Decatenation is a prerequisite for separation of the segregating unit of mtDNA, the nucleoid, within the mitochondrial network...
December 14, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29285527/spatiotemporal-segmentation-and-modeling-of-the-mitral-valve-in-real-time-3d-echocardiographic-images
#2
Alison M Pouch, Ahmed H Aly, Eric K Lai, Natalie Yushkevich, Rutger H Stoffers, Joseph H Gorman, Albert T Cheung, Joseph H Gorman, Robert C Gorman, Paul A Yushkevich
Transesophageal echocardiography is the primary imaging modality for preoperative assessment of mitral valves with ischemic mitral regurgitation (IMR). While there are well known echocardiographic insights into the 3D morphology of mitral valves with IMR, such as annular dilation and leaflet tethering, less is understood about how quantification of valve dynamics can inform surgical treatment of IMR or predict short-term recurrence of the disease. As a step towards filling this knowledge gap, we present a novel framework for 4D segmentation and geometric modeling of the mitral valve in real-time 3D echocardiography (rt-3DE)...
September 2017: Medical Image Computing and Computer-assisted Intervention: MICCAI ..
https://www.readbyqxmd.com/read/29283441/pathological-mechanisms-underlying-single-large-scale-mitochondrial-dna-deletions
#3
Mariana C Rocha, Hannah S Rosa, John P Grady, Emma L Blakely, Langping He, Nadine Romain, Ronald G Haller, Jane Newman, Robert McFarland, Yi Shiau Ng, Grainne S Gorman, Andrew M Schaefer, Helen A Tuppen, Robert W Taylor, Doug M Turnbull
OBJECTIVE: Single, large-scale deletions in mitochondrial DNA (mtDNA) are a common cause of mitochondrial disease. This study aimed to investigate the relationship between the genetic defect and molecular phenotype to improve understanding of pathogenic mechanisms associated with single, large-scale mtDNA deletions in skeletal muscle. METHODS: We investigated 23 muscle biopsies taken from adult patients (6 males/17 females with a mean age of 43y) with characterised single, large-scale mtDNA deletions...
December 28, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/29214652/pharmacology-in-translation-the-preclinical-and-early-clinical-profile-of-the-novel-%C3%AE-2-3-functionally-selective-gabaa-receptor-positive-allosteric-modulator-pf-06372865
#4
Sarah A Nickolls, Rachel Gurrell, Guido van Amerongen, Juha Kammonen, Lishuang Cao, Adam R Brown, Clara Stead, Andy Mead, Christine Watson, Cathleen Hsu, Robert M Owen, Andy Pike, Rebecca L Fish, Laigao Chen, Ruolun Qiu, Evan D Morris, Gang Feng, Mark Whitlock, Donal Gorman, Joop van Gerven, David S Reynolds, Pinky Dua, Richard P Butt
BACKGROUND AND PURPOSE: Benzodiazepines (BZDs), non-selective positive allosteric modulators (PAMs) of GABAA receptors, have significant side-effects that limit their clinical utility. As many of these side-effects are mediated by the α1 subunit there has been a concerted effort to develop α2/3 subtype-selective PAMs. EXPERIMENTAL APPROACH: In vitro screening assays were used to identify molecules with functional selectivity for receptors containing α2/3 subunits over those containing α1 subunits...
December 7, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29161071/risk-of-concussion-during-sports-versus-physical-education-among-new-mexico-middle-and-high-school-students
#5
Richard A Campbell, Stephanie A Gorman, Robert J Thoma, Robert D Annett, Christopher A McGrew, Ronald A Yeo, Andrew R Mayer, John H King, Andrew S Rowland
OBJECTIVES: To measure the risk of concussion among New Mexico middle and high school students during both sports and physical education. METHODS: Athletic directors or athletic trainers in 147 schools were asked to report the number of concussions occurring during sports and physical education in the 2013 to 2014 school year. We calculated 1-year cumulative incidence rates. RESULTS: Of the 147 schools, 99 responded (67%). During the school year, 598 students were removed from athletics because of a concussion, a 1-year cumulative incidence of 3...
November 21, 2017: American Journal of Public Health
https://www.readbyqxmd.com/read/29046338/regulation-of-valve-interstitial-cell-homeostasis-by-mechanical-deformation-implications-for-heart-valve-disease-and-surgical-repair
#6
Salma Ayoub, Chung-Hao Lee, Kathryn H Driesbaugh, Wanda Anselmo, Connor T Hughes, Giovanni Ferrari, Robert C Gorman, Joseph H Gorman, Michael S Sacks
Mechanical stress is one of the major aetiological factors underlying soft-tissue remodelling, especially for the mitral valve (MV). It has been hypothesized that altered MV tissue stress states lead to deviations from cellular homeostasis, resulting in subsequent cellular activation and extracellular matrix (ECM) remodelling. However, a quantitative link between alterations in the organ-level in vivo state and in vitro-based mechanobiology studies has yet to be made. We thus developed an integrated experimental-computational approach to elucidate MV tissue and interstitial cell responses to varying tissue strain levels...
October 2017: Journal of the Royal Society, Interface
https://www.readbyqxmd.com/read/28983742/multi-resolution-geometric-modeling-of-the-mitral-heart-valve-leaflets
#7
Amir H Khalighi, Andrew Drach, Robert C Gorman, Joseph H Gorman, Michael S Sacks
An essential element of cardiac function, the mitral valve (MV) ensures proper directional blood flow between the left heart chambers. Over the past two decades, computational simulations have made marked advancements toward providing powerful predictive tools to better understand valvular function and improve treatments for MV disease. However, challenges remain in the development of robust means for the quantification and representation of MV leaflet geometry. In this study, we present a novel modeling pipeline to quantitatively characterize and represent MV leaflet surface geometry...
October 5, 2017: Biomechanics and Modeling in Mechanobiology
https://www.readbyqxmd.com/read/28942898/the-need-for-pediatric-drug-development
#8
Robert M Ward, Daniel K Benjamin, Jonathan M Davis, Richard L Gorman, Ralph Kauffman, Gregory L Kearns, Mary Dianne Murphy, Catherine M T Sherwin
No abstract text is available yet for this article.
September 21, 2017: Journal of Pediatrics
https://www.readbyqxmd.com/read/28913697/developing-a-post-treatment-survivorship-care-plan-to-help-breast-cancer-survivors-understand-their-fertility
#9
Jessica R Gorman, Anne K Julian, Samantha A Roberts, Sally A D Romero, Jennifer L Ehren, Michael L Krychman, Sarah G Boles, Jun Mao, H Irene Su
PURPOSE: Reproductive-aged breast cancer survivors (BCS) who have completed initial cancer treatment frequently want to know about their future fertility potential. The purpose of this qualitative study was to assess if the fertility-related content presented in the survivorship care plan prototype met the informational needs of post-treatment BCS and to provide an opportunity for the target audience to review and react to the proposed content and design. METHODS: We conducted and analyzed transcripts from seven focus groups with BCS to evaluate their reactions to the survivorship care plan prototype...
September 14, 2017: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
https://www.readbyqxmd.com/read/28888476/computational-sensitivity-investigation-of-hydrogel-injection-characteristics-for-myocardial-support
#10
Hua Wang, Christopher B Rodell, Madonna E Lee, Neville N Dusaj, Joseph H Gorman, Jason A Burdick, Robert C Gorman, Jonathan F Wenk
Biomaterial injection is a potential new therapy for augmenting ventricular mechanics after myocardial infarction (MI). Recent in vivo studies have demonstrated that hydrogel injections can mitigate the adverse remodeling due to MI. More importantly, the material properties of these injections influence the efficacy of the therapy. The goal of the current study is to explore the interrelated effects of injection stiffness and injection volume on diastolic ventricular wall stress and thickness. To achieve this, finite element models were constructed with different hydrogel injection volumes (150µL and 300 µL), where the modulus was assessed over a range of 0...
November 7, 2017: Journal of Biomechanics
https://www.readbyqxmd.com/read/28861630/an-integrated-inverse-model-experimental-approach-to-determine-soft-tissue-three-dimensional-constitutive-parameters-application-to-post-infarcted-myocardium
#11
Reza Avazmohammadi, David S Li, Thomas Leahy, Elizabeth Shih, João S Soares, Joseph H Gorman, Robert C Gorman, Michael S Sacks
Knowledge of the complete three-dimensional (3D) mechanical behavior of soft tissues is essential in understanding their pathophysiology and in developing novel therapies. Despite significant progress made in experimentation and modeling, a complete approach for the full characterization of soft tissue 3D behavior remains elusive. A major challenge is the complex architecture of soft tissues, such as myocardium, which endows them with strongly anisotropic and heterogeneous mechanical properties. Available experimental approaches for quantifying the 3D mechanical behavior of myocardium are limited to preselected planar biaxial and 3D cuboidal shear tests...
August 31, 2017: Biomechanics and Modeling in Mechanobiology
https://www.readbyqxmd.com/read/28833674/c-h-cyanation-of-6-ring-n-containing-heteroaromatics
#12
Bryony L Elbert, Alistair J M Farley, Timothy W Gorman, Tarn C Johnson, Christophe Genicot, Bénédicte Lallemand, Patrick Pasau, Jakub Flasz, José L Castro, Malcolm MacCoss, Robert S Paton, Christopher J Schofield, Martin D Smith, Michael C Willis, Darren J Dixon
Heteroaromatic nitriles are important compounds in drug discovery, both for their prevalence in the clinic and due to the diverse range of transformations they can undergo. As such, efficient and reliable methods to access them have the potential for far-reaching impact across synthetic chemistry and the biomedical sciences. Herein, we report an approach to heteroaromatic C-H cyanation through triflic anhydride activation, nucleophilic addition of cyanide, followed by elimination of trifluoromethanesulfinate to regenerate the cyanated heteroaromatic ring...
August 23, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28821329/cardiac-progenitor-cell-recruitment-drives-fetal-cardiac-regeneration-by-enhanced-angiogenesis
#13
Carlos Zgheib, Maggie M Hodges, Myron W Allukian, Junwang Xu, Kara L Spiller, Joseph H Gorman, Robert C Gorman, Kenneth W Liechty
BACKGROUND: In contrast to adults, the fetal response to myocardial infarction (MI) is regenerative, requiring the recruitment of cardiac progenitor cells to replace infarcted myocardium. Macrophage contribution to tissue repair depends on their phenotype: M1 are proinflammatory and initiate angiogenesis; M2a are profibrotic and contribute to blood vessels maturation; and M2c are proremodeling and proangiogenesis. The goal of the present study was to expand on this work by examining cardiac progenitor cells recruitment, and the role of macrophages in promoting angiogenesis and cardiac regeneration in the fetal heart after MI...
December 2017: Annals of Thoracic Surgery
https://www.readbyqxmd.com/read/28812649/decreased-male-reproductive-success-in-association-with-mitochondrial-dysfunction
#14
Mika H Martikainen, John P Grady, Yi Shiau Ng, Charlotte L Alston, Grainne S Gorman, Robert W Taylor, Robert McFarland, Doug M Turnbull
The reproductive success of men with mitochondrial disease is to date unreported. We compared the age- and era-adjusted reproductive success of 94 British male patients with mitochondrial disease to that of the UK general male population. The reproductive success of men with mitochondrial disease was 65% of that in the general population (95% confidence interval: 53%; 79%), and the effect magnitude was related to the disease severity. This contrasts with the two previous studies finding that the reproductive success of women with mitochondrial DNA disease is not impaired...
October 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28731789/age-and-cancer-treatment-are-related-to-receiving-treatment-summaries-and-survivorship-care-plans-in-female-young-adult-cancer-survivors
#15
Ksenya Shliakhtsitsava, Sally A D Romero, Brian W Whitcomb, Jessica R Gorman, Samantha Roberts, H Irene Su
The study determined factors associated with patient-reported receipt of survivorship care plans and/or treatment summaries (SCP/TS). Two hundred forty female young adult cancer survivors ages 18-44 completed a web-based survey that included self-report on receiving SCP/TS. Mean age was 32.8 (standard deviation 5.8) years; 20% were diagnosed with cancer at age <21. Only 47% reported receipt of SCP/TS. Age <21 at diagnosis (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.0-3.9), chemotherapy (OR 2...
July 21, 2017: Journal of Adolescent and Young Adult Oncology
https://www.readbyqxmd.com/read/28728784/mitral-annuloplasty-ring-suture-forces-impact-of-surgeon-ring-and-use-conditions
#16
Eric L Pierce, Charles H Bloodworth, Andrew W Siefert, Thomas F Easley, Tetsushi Takayama, Tomonori Kawamura, Robert C Gorman, Joseph H Gorman, Ajit P Yoganathan
OBJECTIVE: The study objective was to quantify the effect of ring type, ring-annulus sizing, suture position, and surgeon on the forces required to tie down and constrain a mitral annuloplasty ring to a beating heart. METHODS: Physio (Edwards Lifesciences, Irvine, Calif) or Profile 3D (Medtronic, Dublin, Ireland) annuloplasty rings were instrumented with suture force transducers and implanted in ovine subjects (N = 23). Tie-down forces and cyclic contractile forces were recorded and analyzed at 10 suture positions and at 3 levels of increasing peak left ventricular pressure...
June 21, 2017: Journal of Thoracic and Cardiovascular Surgery
https://www.readbyqxmd.com/read/28666979/predicting-the-response-to-ctla-4-blockade-by-longitudinal-noninvasive-monitoring-of-cd8-t-cells
#17
Mohammad Rashidian, Jessica R Ingram, Michael Dougan, Anushka Dongre, Katherine A Whang, Camille LeGall, Juan J Cragnolini, Brian Bierie, Monica Gostissa, James Gorman, Gijsbert M Grotenbreg, Atul Bhan, Robert A Weinberg, Hidde L Ploegh
Immunotherapy using checkpoint-blocking antibodies against targets such as CTLA-4 and PD-1 can cure melanoma and non-small cell lung cancer in a subset of patients. The presence of CD8 T cells in the tumor correlates with improved survival. We show that immuno-positron emission tomography (immuno-PET) can visualize tumors by detecting infiltrating lymphocytes and, through longitudinal observation of individual animals, distinguish responding tumors from those that do not respond to therapy. We used 89Zr-labeled PEGylated single-domain antibody fragments (VHHs) specific for CD8 to track the presence of intratumoral CD8+ T cells in the immunotherapy-susceptible B16 melanoma model in response to checkpoint blockade...
August 7, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28514685/virus-like-particles-identify-an-hiv-v1v2-apex-binding-neutralizing-antibody-that-lacks-a-protruding-loop
#18
Evan M Cale, Jason Gorman, Nathan A Radakovich, Ema T Crooks, Keiko Osawa, Tommy Tong, Jiaqi Li, Raju Nagarajan, Gabriel Ozorowski, David R Ambrozak, Mangai Asokan, Robert T Bailer, Anthony K Bennici, Xuejun Chen, Nicole A Doria-Rose, Aliaksandr Druz, Yu Feng, M Gordon Joyce, Mark K Louder, Sijy O'Dell, Courtney Oliver, Marie Pancera, Mark Connors, Thomas J Hope, Thomas B Kepler, Richard T Wyatt, Andrew B Ward, Ivelin S Georgiev, Peter D Kwong, John R Mascola, James M Binley
Most HIV-1-specific neutralizing antibodies isolated to date exhibit unusual characteristics that complicate their elicitation. Neutralizing antibodies that target the V1V2 apex of the HIV-1 envelope (Env) trimer feature unusually long protruding loops, which enable them to penetrate the HIV-1 glycan shield. As antibodies with loops of requisite length are created through uncommon recombination events, an alternative mode of apex binding has been sought. Here, we isolated a lineage of Env apex-directed neutralizing antibodies, N90-VRC38...
May 16, 2017: Immunity
https://www.readbyqxmd.com/read/28429161/on-the-in-vivo-function-of-the-mitral-heart-valve-leaflet-insights-into-tissue-interstitial-cell-biomechanical-coupling
#19
Chung-Hao Lee, Will Zhang, Kristen Feaver, Robert C Gorman, Joseph H Gorman, Michael S Sacks
There continues to be a critical need for developing data-informed computational modeling techniques that enable systematic evaluations of mitral valve (MV) function. This is important for a better understanding of MV organ-level biomechanical performance, in vivo functional tissue stresses, and the biosynthetic responses of MV interstitial cells (MVICs) in the normal, pathophysiological, and surgically repaired states. In the present study, we utilized extant ovine MV population-averaged 3D fiducial marker data to quantify the MV anterior leaflet (MVAL) deformations in various kinematic states...
April 20, 2017: Biomechanics and Modeling in Mechanobiology
https://www.readbyqxmd.com/read/28395030/clinical-features-molecular-heterogeneity-and-prognostic-implications-in-yars2-related-mitochondrial-myopathy
#20
Ewen W Sommerville, Yi Shiau Ng, Charlotte L Alston, Cristina Dallabona, Micol Gilberti, Langping He, Charlotte Knowles, Sophie L Chin, Andrew M Schaefer, Gavin Falkous, David Murdoch, Cheryl Longman, Marianne de Visser, Laurence A Bindoff, John M Rawles, John C S Dean, Richard K Petty, Maria E Farrugia, Tobias B Haack, Holger Prokisch, Robert McFarland, Douglass M Turnbull, Claudia Donnini, Robert W Taylor, Gráinne S Gorman
Importance: YARS2 mutations have been associated with a clinical triad of myopathy, lactic acidosis, and sideroblastic anemia in predominantly Middle Eastern populations. However, the identification of new patients expands the clinical and molecular spectrum of mitochondrial disorders. Objectives: To review the clinical, molecular, and genetic features of YARS2-related mitochondrial disease and to demonstrate a new Scottish founder variant. Design, Setting, and Participants: An observational case series study was conducted at a national diagnostic center for mitochondrial disease in Newcastle upon Tyne, England, and review of cases published in the literature...
June 1, 2017: JAMA Neurology
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