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Braff D.L.,University of California at San Diego | Tamminga C.A.,UT Southwestern Medical School
Schizophrenia Bulletin | Year: 2017

First, we describe the hallmark contributions of Irv Gottesman's pioneering scholarship for schizophrenia research including concepts of polygenicity, gene × environment interactions, epigenetics and the endophenotype concept. Gottesman and colleagues' twin studies showed that genes, not social factors, mediate schizophrenia risk. He then showed that schizophrenia is highly polygenic. Next, he introduced the concept of epigenetics into schizophrenia research. Gottesman then introduced the quantitative endophenotype concept. Endophenotypes are laboratory-based measures that show deficits in schizophrenia patients and lesser deficits in their first degree "unaffected" relatives and are viewed as being more proximal to genes and having a simpler genetic architecture than are "fuzzy" qualitative diagnostic disorders. Endophenotypes offer an exciting path to gene discovery, neural circuits, genetic architecture and new treatment pathways of schizophrenia and related psychotic disorders. Second, we were asked to discuss 2 of many endophenotype Consortia and related studies, in order to illustrate the impact of Gottesman's work. We describe the Consortium on the Genetics of Schizophrenia (COGS) exploring neurocognitive and neurophysiological endophenotypes in family and case-control studies. Association, linkage, sequencing and epigenetic studies are described. The Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP) uses an array of endophenotypes including brain imaging in studies across the psychosis dimension, allowing for dimensional analyses. BSNIP results have led to the concept of biotypes, advancing the field. Irv Gottesman was imaginatively prescient in generating novel insights and predicting many major issues which challenge schizophrenia researchers who still use his concepts to guide current research approaches. © The Author 2016.


Stoilova-McPhie S.,UT Southwestern Medical School
Nanotechnology Reviews | Year: 2017

Biological membranes surround all living cells, confining internal organelles and participating in a variety of essential cellular functions, such as signaling, electrolyte balance, and energy conversion. Cell membranes are structurally and chemically heterogeneous environment composed of numerous types of lipids arranged as a continuous bilayer. The assembly of protein complexes at the membrane surface is responsible for fundamental biological processes such as synaptic transmission, blood coagulation, and apoptosis. Resolving the macromolecular organization of these complexes at the membrane surface will help to understand the structural basis of their function and significance for the associated biological processes. In this review, we present our work on direct structure determination of membrane-bound clotting factors, specifically factor VIII (FVIII), by cryogenic electron microscopy (CryoEM). To resolve the FVIII membrane-bound organization, we have optimized lipid nanostructures resembling the activated platelet membrane. Combining structural CryoEM, capable of near-atomic resolution, with customized lipid nanotechnologies is a powerful approach to investigate how the cellular membrane can modulate protein function at close to physiological conditions. The outcome will open novel avenues for developing lipid nanotechnologies of diverse shapes and composition that can be optimized for various protein systems, germane for both drug delivery and macromolecular structure determination. © 2017 Walter de Gruyter GmbH, Berlin/Boston.


Nguyen H.,Histology and Immunohistochemistry | John G.B.,UT Southwestern Medical School | Scherer P.E.,Touchstone Diabetes Center
Aesthetic Surgery Journal | Year: 2014

Background: Light and electron microscopy have not identified a distinct anatomical structure associated with either skin wrinkles or creases, and a histological difference between wrinkled and adjacent skin has not been identified. Objectives: The authors investigate whether facial wrinkles are related to underlying lymphatic vessels and perilymphatic fat. Methods: Lymphatic vessels with a specialized tube of perilymphatic fat were identified beneath palmar creases. Sections of skin, adipose tissue, and muscle were harvested from each of 13 cadavers. Three sites were investigated: the transverse forehead crease, lateral orbicularis oculi wrinkle (crows feet), and the nasojugal crease. The tissue was paraffin embedded and processed. Two-step indirect immunohistochemistry was performed, and images were examined using laser confocal microscopy. Measurements were taken with software. Results: Every wrinkle examined was found above and within 1 mm of a major lymphatic vessel and its surrounding tube of adipose tissue. The results satisfied our null hypothesis and were statistically significant. Lymphatic vessels were identified by positive immunofluorescence as well as histological criteria. These findings have been further validated by fluorochrome tracer studies. Conclusions: An anatomical basis for wrinkles was identified among the specimens studied. Lymphatic vessels, along with the surrounding distinct perilymphatic fat, traveled directly beneath wrinkles and creases. Lymphatic dysregulation leads to inflammation, scarring, and fibrosis, but inadvertent injection of these vessels can be avoided with anatomical knowledge. © 2013 The American Society for Aesthetic Plastic Surgery, Inc.


Ambartsoumian G.,University of Texas at Arlington | Gouia-Zarrad R.,University of Texas at Arlington | Lewis M.A.,UT Southwestern Medical School
Inverse Problems | Year: 2010

The representation of a function by its circular Radon transform (CRT) and various related problems arise in many areas of mathematics, physics and imaging science. There has been a substantial spike of interest toward these problems in the last decade mainly due to the connection between the CRT and mathematical models of several emerging medical imaging modalities. This paper contains some new results about the existence and uniqueness of the representation of a function by its CRT with partial data. A new inversion formula is presented in the case of the circular acquisition geometry for both interior and exterior problems when the Radon transform is known for only a part of all possible radii. The results are not only interesting as original mathematical discoveries, but can also be useful for applications, e.g., in medical imaging. © 2010 IOP Publishing Ltd.


Tamminga C.A.,Southwestern Medical Center | Pearlson G.,Hartford Hospital Yale | Keshavan M.,Harvard University | Sweeney J.,UT Southwestern Medical School | And 2 more authors.
Schizophrenia Bulletin | Year: 2014

Bipolar and schizophrenia network for intermediate phenotypes is a network of investigator-driven laboratories focused on developing phenotypes, genotypes, and biomarkers for psychosis. Over the last 5 years, the consortium has accomplished a dense phenotyping protocol using probands with a lifetime history of psychosis, their relatives, and healthy controls. This has established a library of biomarker information on individuals with schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis. The founding goal of establishing disease biomarkers for current psychotic diagnoses has been poorly met, because the cognitive, electrophysiologic, eye movement, and brain imaging biomarkers did not regularly discriminate individuals with different DSM psychosis diagnoses. In future, we will use this biomarker information to establish a pathway to biomarker-based classification in psychoses. © 2014 © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.


Luby-Phelps K.,UT Southwestern Medical School
Molecular Biology of the Cell | Year: 2013

From the point of view of intermolecular interactions, the cytoplasmic space is more like a crowded party in a house full of furniture than a game of tag in an empty field. Understanding the physical chemical properties of cytoplasm is thus of key importance for understanding cellular function. This article attempts to provide an entrée into the current literature on this subject and offers some general guidelines for thinking about intracellular biochemistry. © 2013 Luby-Phelps.


Li X.-D.,UT Southwestern Medical School | Chen Z.J.,UT Southwestern Medical School | Chen Z.J.,Howard Hughes Medical Institute
eLife | Year: 2012

Toll-like receptors (TLRs) detect microbial infections and trigger innate immune responses. Among vertebrate TLRs, the role of TLR13 and its ligand are unknown. Here we show that TLR13 detects the 23S ribosomal RNA of both gram-positive and gram-negative bacteria. A sequence containing 13 nucleotides near the active site of 23S rRNA ribozyme, which catalyzes peptide bond synthesis, was both necessary and sufficient to trigger TLR13-dependent interleukin-1β production. Single point mutations within this sequence destroyed the ability of the 23S rRNA to stimulate the TLR13 pathway. Knockout of TLR13 in mice abolished the induction of interleukin-1β and other cytokines by the 23S rRNA sequence. Thus, TLR13 detects bacterial RNA with exquisite sequence specificity. © Li et al.


Das T.,UT Southwestern Medical School | Ivleva E.I.,UT Southwestern Medical School | Wagner A.D.,Stanford University | Stark C.E.L.,University of California at Irvine | Tamminga C.A.,UT Southwestern Medical School
Schizophrenia Research | Year: 2014

Motivated by evidence that the dentate gyrus differentially mediates the pattern separation (PS) component of declarative memory function and that dentate gyrus harbors molecular and cellular pathologies in schizophrenia, we examined whether PS performance is altered in volunteers with schizophrenia (SZV) relative to healthy volunteers (HV). In groups of well-characterized SZV (n = 14) and HV (n = 15), we contrasted performance on the Behavioral Pattern Separation (BPS) Task, acquiring two outcome measures, a PS parameter and a Recognition Memory (RM) parameter, as well as specific recognition data by stimulus type. The SZVs showed a significant decrement in PS performance relative to HV (mean ± SEM, SZV: 3.1 ± 2.7%; HV: 17.1 ± 5.8%; p = 0.039, d′ = 0.86); whereas SZV and HV did not significantly differ in RM performance (SZV: 50.1 ± 8.1%; HV: 59.3 ± 5.5%; p = 0.350, d′ = 0.36). Moreover, the SZVs showed a selective defect in correctly identifying similar lure items (SZV: 24.0 ± 3.7%; HV: 41.2 ± 4.6%; p < 0.05), but demonstrated no impairment in identifying targets and novel foils. These data suggest that the dentate gyrus is dysfunctional in schizophrenia, a feature that could contribute to declarative memory impairment in the disorder and possibly to psychosis, a conclusion consistent with the considerable molecular pathology in the dentate gyrus in schizophrenia. © 2014 Elsevier B.V. All rights reserved.


Keshavan M.S.,Harvard University | Clementz B.A.,University of Georgia | Pearlson G.D.,Yale University | Sweeney J.A.,UT Southwestern Medical School | Tamminga C.A.,UT Southwestern Medical School
Schizophrenia Research | Year: 2013

Objectives: Current approaches to defining and classifying psychotic disorders are compromised by substantive heterogeneity within, blurred boundaries between, as well as overlaps across the various disorders in outcome, treatment response, emerging evidence regarding pathophysiology and presumed etiology. Methods: We herein review the evolution, current status and the constraints posed by classic symptom-based diagnostic approaches. We compare the continuing constructs that underlie the current classification of psychoses, and contrast those to evolving new thinking in other areas of medicine. Results: An important limitation in current psychiatric nosology may stem from the fact that symptom-based diagnoses do not "carve nature at its joints"; while symptom-based classifications have improved our reliability, they may lack validity. Next steps in developing a more valid scientific nosology for psychoses include a) agnostic deconstruction of disease dimensions, identifying disease markers and endophenotypes; b) mapping such markers across translational domains from behaviors to molecules, c) reclustering cross-cutting bio-behavioral data using modern phenotypic and biometric approaches, and finally d) validating such entities using etio-pathology, outcome and treatment-response measures. Conclusions: The proposed steps of deconstruction and "bottom-up" disease definition, as elsewhere in medicine, may well provide a better foundation for developing a nosology for psychotic disorders that may have better utility in predicting outcome, treatment response and etiology, and identifying novel treatment approaches. © 2013 Elsevier B.V.


News Article | November 10, 2016
Site: www.prweb.com

Residents and guests heralded the recent openings of new Physical Therapy Centers with grand celebrations at The Tradition-Lovers Lane and The Tradition-Prestonwood Assisted Living and Memory Care communities. The events included a presentation by the Centers’ physical therapist, Lyn Hardage (with VISTA Physical Therapy). “We are very excited to add these much-anticipated Centers to our Tradition communities,” said Tradition CEO, Jonathan Perlman. “And getting Lyn on board is a real coup. Her academic pedigree and wide range of experience make her ideal. In addition, she has a true heart for seniors." Among the offerings at each of the spacious Physical Therapy Centers is a HydroWorx therapy pool kept at 91 degrees with an underwater treadmill, parallel bars, and an electric lift. The therapy pool provides buoyancy, taking the weight off of painful joints, as well as heat, which allows for added mobility. The pool assists in increasing cardio, balance, and strength. The Centers also provide a treadmill with a set of parallel bars to help increase stability and support. “When I meet a new patient, I immediately ask them what their goals are,” commented Lyn Hardage. “It might be as simple as wanting to walk without the aid of a walker or to get back on the golf course! We also work very closely with each patient’s physician to include an initial consultation and regular follow-up, with progress reports every 10 days.” Lyn has been a physical therapist for several years, attaining a B.A. at the University of Texas at Austin and a physical therapy license at UT Southwestern Medical School, Dallas. After working in pediatrics and sports medicine, she found her true calling in providing physical therapy for seniors. The Physical Therapy Centers are open to the public and are, of course, available to all residents of The Tradition-Lovers Lane and The Tradition-Prestonwood Independent, Assisted Living, and Memory Care communities. For an appointment or more information, call 469-310-1700. Tradition Senior Living, LP Tradition Senior Living, LP is a Texas limited partnership engaged solely in the development, construction, marketing and management of a growing number of Tradition senior living communities. Management and construction are administered in-house by personnel who have corporate-level experience in the senior living industry. Jonathan Perlman is the Founder and CEO of Tradition Senior Living, LP.

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