Publications by authors named "Michael Sheldon"

27 Publications

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Integrated Collection of Stem Cell Bank Data, a Data Portal for Standardized Stem Cell Information.

Stem Cell Reports 2021 Apr 18;16(4):997-1005. Epub 2021 Mar 18.

Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Sho-goin, Sakyo-ku, Kyoto 606-8507, Japan. Electronic address:

The past decade has witnessed an extremely rapid increase in the number of newly established stem cell lines. However, due to the lack of a standardized format, data exchange among stem cell line resources has been challenging, and no system can search all stem cell lines across resources worldwide. To solve this problem, we have developed the Integrated Collection of Stem Cell Bank data (ICSCB) (http://icscb.stemcellinformatics.org/), the largest database search portal for stem cell line information, based on the standardized data items and terms of the MIACARM framework. Currently, ICSCB can retrieve >16,000 cell lines from four major data resources in Europe, Japan, and the United States. ICSCB is automatically updated to provide the latest cell line information, and its integrative search helps users collect cell line information for over 1,000 diseases, including many rare diseases worldwide, which has been a formidable task, thereby distinguishing itself from other database search portals.
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http://dx.doi.org/10.1016/j.stemcr.2021.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072026PMC
April 2021

Detection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Is Comparable in Clinical Samples Preserved in Saline or Viral Transport Medium.

J Mol Diagn 2020 07 13;22(7):871-875. Epub 2020 May 13.

Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey; Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey. Electronic address:

As the coronavirus disease 2019 (COVID-19) pandemic sweeps across the world, the availability of viral transport medium (VTM) has become severely limited, contributing to delays in diagnosis and rationing of diagnostic testing. Given that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA has demonstrated stability, we posited that phosphate-buffered saline (PBS) may be a viable transport medium, as an alternative to VTM, for clinical real-time quantitative PCR (qPCR) testing. The intra-individual reliability and interindividual reliability of SARS-CoV-2 qPCR were assessed in clinical endotracheal secretion samples transported in VTM or PBS to evaluate the stability of the qPCR signal for three viral targets (N gene, ORF1ab, and S gene) when samples were stored in these media at room temperature for up to 18 hours. We report that the use of PBS as a transport medium allows high intra-individual and interindividual reliability, maintains viral stability, and compares with VTM in the detection of the three SARS-CoV-2 genes through 18 hours of storage. This study establishes PBS as a clinically useful medium that can be readily deployed for transporting and short-term preservation of specimens containing SARS-CoV-2. Use of PBS as a transport medium has the potential to increase testing capacity for SARS-CoV-2, aiding more widespread screening and early diagnosis of COVID-19.
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http://dx.doi.org/10.1016/j.jmoldx.2020.04.209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219422PMC
July 2020

A Report from a Workshop of the International Stem Cell Banking Initiative, Held in Collaboration of Global Alliance for iPSC Therapies and the Harvard Stem Cell Institute, Boston, 2017.

Stem Cells 2019 09 6;37(9):1130-1135. Epub 2019 Aug 6.

International Stem Cell Banking Initiative, Royston, United Kingdom.

This report summarizes the recent activity of the International Stem Cell Banking Initiative held at Harvard Stem Cell Institute, Boston, MA, USA, on June 18, 2017. In this meeting, we aimed to find consensus on ongoing issues of quality control (QC), safety, and efficacy of human pluripotent stem cell banks and their derivative cell therapy products for the global harmonization. In particular, assays for the QC testing such as pluripotency assays test and general QC testing criteria were intensively discussed. Moreover, the recent activities of global stem cell banking centers and the regulatory bodies were briefly summarized to provide an overview on global developments and issues. Stem Cells 2019;37:1130-1135.
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http://dx.doi.org/10.1002/stem.3003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187460PMC
September 2019

Validation of Current Good Manufacturing Practice Compliant Human Pluripotent Stem Cell-Derived Hepatocytes for Cell-Based Therapy.

Stem Cells Transl Med 2019 02 19;8(2):124-137. Epub 2018 Nov 19.

Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom.

Recent advancements in the production of hepatocytes from human pluripotent stem cells (hPSC-Heps) afford tremendous possibilities for treatment of patients with liver disease. Validated current good manufacturing practice (cGMP) lines are an essential prerequisite for such applications but have only recently been established. Whether such cGMP lines are capable of hepatic differentiation is not known. To address this knowledge gap, we examined the proficiency of three recently derived cGMP lines (two hiPSC and one hESC) to differentiate into hepatocytes and their suitability for therapy. hPSC-Heps generated using a chemically defined four-step hepatic differentiation protocol uniformly demonstrated highly reproducible phenotypes and functionality. Seeding into a 3D poly(ethylene glycol)-diacrylate fabricated inverted colloid crystal scaffold converted these immature progenitors into more advanced hepatic tissue structures. Hepatic constructs could also be successfully encapsulated into the immune-privileged material alginate and remained viable as well as functional upon transplantation into immune competent mice. This is the first report we are aware of demonstrating cGMP-compliant hPSCs can generate cells with advanced hepatic function potentially suitable for future therapeutic applications. Stem Cells Translational Medicine 2019;8:124&14.
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http://dx.doi.org/10.1002/sctm.18-0084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344902PMC
February 2019

Quality control guidelines for clinical-grade human induced pluripotent stem cell lines.

Regen Med 2018 10 12;13(7):859-866. Epub 2018 Sep 12.

Global Alliance for iPSC Therapies (GAiT), The Jack Copland Centre, Edinburgh, UK.

Use of clinical-grade human induced pluripotent stem cell (iPSC) lines as a starting material for the generation of cellular therapeutics requires demonstration of comparability of lines derived from different individuals and in different facilities. This requires agreement on the critical quality attributes of such lines and the assays that should be used. Working from established recommendations and guidance from the International Stem Cell Banking Initiative for human embryonic stem cell banking, and concentrating on those issues more relevant to iPSCs, a series of consensus workshops has made initial recommendations on the minimum dataset required to consider an iPSC line of clinical grade, which are outlined in this report. Continued evolution of this field will likely lead to revision of these guidelines on a regular basis.
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http://dx.doi.org/10.2217/rme-2018-0095DOI Listing
October 2018

A Standard Nomenclature for Referencing and Authentication of Pluripotent Stem Cells.

Stem Cell Reports 2018 01;10(1):1-6

European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.

Unambiguous cell line authentication is essential to avoid loss of association between data and cells. The risk for loss of references increases with the rapidity that new human pluripotent stem cell (hPSC) lines are generated, exchanged, and implemented. Ideally, a single name should be used as a generally applied reference for each cell line to access and unify cell-related information across publications, cell banks, cell registries, and databases and to ensure scientific reproducibility. We discuss the needs and requirements for such a unique identifier and implement a standard nomenclature for hPSCs, which can be automatically generated and registered by the human pluripotent stem cell registry (hPSCreg). To avoid ambiguities in PSC-line referencing, we strongly urge publishers to demand registration and use of the standard name when publishing research based on hPSC lines.
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http://dx.doi.org/10.1016/j.stemcr.2017.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768986PMC
January 2018

Report of the International Stem Cell Banking Initiative Workshop Activity: Current Hurdles and Progress in Seed-Stock Banking of Human Pluripotent Stem Cells.

Stem Cells Transl Med 2017 11 24;6(11):1956-1962. Epub 2017 Oct 24.

UK Stem Cell Bank, Division of Advanced Therapies, NIBSC, South Mimms, UK.

This article summarizes the recent activity of the International Stem Cell Banking Initiative (ISCBI) held at the California Institute for Regenerative Medicine (CIRM) in California (June 26, 2016) and the Korean National Institutes for Health in Korea (October 19-20, 2016). Through the workshops, ISCBI is endeavoring to support a new paradigm for human medicine using pluripotent stem cells (hPSC) for cell therapies. Priority considerations for ISCBI include ensuring the safety and efficacy of a final cell therapy product and quality assured source materials, such as stem cells and primary donor cells. To these ends, ISCBI aims to promote global harmonization on quality and safety control of stem cells for research and the development of starting materials for cell therapies, with regular workshops involving hPSC banking centers, biologists, and regulatory bodies. Here, we provide a brief overview of two such recent activities, with summaries of key issues raised. Stem Cells Translational Medicine 2017;6:1956-1962.
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http://dx.doi.org/10.1002/sctm.17-0144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430055PMC
November 2017

First Proposal of Minimum Information About a Cellular Assay for Regenerative Medicine.

Stem Cells Transl Med 2016 10 12;5(10):1345-1361. Epub 2016 Jul 12.

Center for iPS Cell Research and Application, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan

: Advances in stem cell research have triggered scores of studies in regenerative medicine in a large number of institutions and companies around the world. However, reproducibility and data exchange among laboratories or cell banks are constrained by the lack of a standardized format for experiments. To enhance information flow in stem cell and derivative cell research, here we propose a minimum information standard to describe cellular assay data to facilitate practical regenerative medicine. Based on the existing Minimum Information About a Cellular Assay, we developed Minimum Information About a Cellular Assay for Regenerative Medicine (MIACARM), which allows for the description of advanced cellular experiments with defined taxonomy of human cell types. By using controlled terms, such as ontologies, MIACARM will provide a platform for cellular assay data exchange among cell banks or registries that have been established at more than 20 sites in the world.

Significance: Currently, there are more than 20 human cell information storage sites around the world. However, reproducibility and data exchange among different laboratories or cell information providers are usually inadequate or nonexistent because of the lack of a standardized format for experiments. This study, which is the fruit of collaborative work by scientists at stem cell banks and cellular information registries worldwide, including those in the U.S., the U.K., Europe, and Japan, proposes new minimum information guidelines, Minimum Information About a Cellular Assay for Regenerative Medicine (MIACARM), for cellular assay data deposition. MIACARM is intended to promote data exchange and facilitation of practical regenerative medicine.
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http://dx.doi.org/10.5966/sctm.2015-0393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031183PMC
October 2016

Policy-Making Theory as an Analytical Framework in Policy Analysis: Implications for Research Design and Professional Advocacy.

Phys Ther 2016 Jan 8;96(1):101-10. Epub 2015 Oct 8.

M.R. Sheldon, PT, PhD, Department of Physical Therapy, University of New England, 716 Stevens Ave, Portland, ME 04103 (USA).

Policy studies are a recent addition to the American Physical Therapy Association's Research Agenda and are critical to our understanding of various federal, state, local, and organizational policies on the provision of physical therapist services across the continuum of care. Policy analyses that help to advance the profession's various policy agendas will require relevant theoretical frameworks to be credible. The purpose of this perspective article is to: (1) demonstrate the use of a policy-making theory as an analytical framework in a policy analysis and (2) discuss how sound policy analysis can assist physical therapists in becoming more effective change agents, policy advocates, and partners with other relevant stakeholder groups. An exploratory study of state agency policy responses to address work-related musculoskeletal disorders is provided as a contemporary example to illustrate key points and to demonstrate the importance of selecting a relevant analytical framework based on the context of the policy issue under investigation.
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http://dx.doi.org/10.2522/ptj.20150032DOI Listing
January 2016

International coordination of large-scale human induced pluripotent stem cell initiatives: Wellcome Trust and ISSCR workshops white paper.

Stem Cell Reports 2014 Dec;3(6):931-9

Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine and Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. Electronic address:

There is growing recognition of the potential value of human induced pluripotent stem cells (hiPSC) for understanding disease and identifying drugs targets. This has been reflected in the establishment of multiple large-scale hiPSC initiatives worldwide. Representatives of these met recently at a workshop supported by the Welcome Trust in the UK and in a focus session at the 2014 ISSCR annual meeting in Vancouver. The purpose was to discuss strategies for making thousands of hiPSC lines widely available with as few restrictions as possible while retaining financial viability and donor privacy. The outcome of these discussions is described here.
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http://dx.doi.org/10.1016/j.stemcr.2014.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4263998PMC
December 2014

De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder.

Cell Rep 2014 Oct 2;9(1):16-23. Epub 2014 Oct 2.

Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, People's Republic of China; National Institute of Biological Sciences, Beijing 102206, People's Republic of China. Electronic address:

Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 × 10(-9)), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.
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http://dx.doi.org/10.1016/j.celrep.2014.08.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4194132PMC
October 2014

Persistent infection by HSV-1 is associated with changes in functional architecture of iPSC-derived neurons and brain activation patterns underlying working memory performance.

Schizophr Bull 2015 Jan 12;41(1):123-32. Epub 2014 Mar 12.

Department of Psychiatry, WPIC, University of Pittsburgh, School of Medicine, Pittsburgh PA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA

Background: Herpes simplex virus, type 1 (HSV-1) commonly produces lytic mucosal lesions. It invariably initiates latent infection in sensory ganglia enabling persistent, lifelong infection. Acute HSV-1 encephalitis is rare and definitive evidence of latent infection in the brain is lacking. However, exposure untraceable to encephalitis has been repeatedly associated with impaired working memory and executive functions, particularly among schizophrenia patients.

Methods: Patterns of HSV-1 infection and gene expression changes were examined in human induced pluripotent stem cell (iPSC)-derived neurons. Separately, differences in blood oxygenation level-dependent (BOLD) responses to working memory challenges using letter n-back tests were investigated using functional magnetic resonance imaging (fMRI) among schizophrenia cases/controls.

Results: HSV-1 induced lytic changes in iPSC-derived glutamatergic neurons and neuroprogenitor cells. In neurons, HSV-1 also entered a quiescent state following coincubation with antiviral drugs, with distinctive changes in gene expression related to functions such as glutamatergic signaling. In the fMRI studies, main effects of schizophrenia (P = .001) and HSV-1 exposure (1-back, P = 1.76 × 10(-4); 2-back, P = 1.39 × 10(-5)) on BOLD responses were observed. We also noted increased BOLD responses in the frontoparietal, thalamus, and midbrain regions among HSV-1 exposed schizophrenia cases and controls, compared with unexposed persons.

Conclusions: The lytic/quiescent cycles in iPSC-derived neurons indicate that persistent neuronal infection can occur, altering cellular function. The fMRI studies affirm the associations between nonencephalitic HSV-1 infection and functional brain changes linked with working memory impairment. The fMRI and iPSC studies together provide putative mechanisms for the cognitive impairments linked to HSV-1 exposure.
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http://dx.doi.org/10.1093/schbul/sbu032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266288PMC
January 2015

Identification and characterisation of the early differentiating cells in neural differentiation of human embryonic stem cells.

PLoS One 2012 15;7(5):e37129. Epub 2012 May 15.

Department of Surgery and Cancer, Faculty of Medicine, Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.

One of the challenges in studying early differentiation of human embryonic stem cells (hESCs) is being able to discriminate the initial differentiated cells from the original pluripotent stem cells and their committed progenies. It remains unclear how a pluripotent stem cell becomes a lineage-specific cell type during early development, and how, or if, pluripotent genes, such as Oct4 and Sox2, play a role in this transition. Here, by studying the dynamic changes in the expression of embryonic surface antigens, we identified the sequential loss of Tra-1-81 and SSEA4 during hESC neural differentiation and isolated a transient Tra-1-81(-)/SSEA4(+) (TR-/S4+) cell population in the early stage of neural differentiation. These cells are distinct from both undifferentiated hESCs and their committed neural progenitor cells (NPCs) in their gene expression profiles and response to extracellular signalling; they co-express both the pluripotent gene Oct4 and the neural marker Pax6. Furthermore, these TR-/S4+ cells are able to produce cells of both neural and non-neural lineages, depending on their environmental cues. Our results demonstrate that expression of the pluripotent factor Oct4 is progressively downregulated and is accompanied by the gradual upregulation of neural genes, whereas the pluripotent factor Sox2 is consistently expressed at high levels, indicating that these pluripotent factors may play different roles in the regulation of neural differentiation. The identification of TR-S4+ cells provides a cell model for further elucidation of the molecular mechanisms underlying hESC neural differentiation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0037129PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352872PMC
January 2013

Preparing rehabilitation healthcare providers in the 21st century: implementation of interprofessional education through an academic-clinical site partnership.

Work 2012 ;41(3):269-75

Department of Occupational Therapy, University of New England, Portland, ME 04103, USA.

Objective: Health profession education programs often struggle with barriers to implementing interprofesssional educational (IPE) initiatives, limiting early and consistent exposure of students to core IPE competencies. Few published reports are available to guide the implementation of IPE programs into practice. This article describes a successful and evolving partnership between an independent university and a tertiary care hospital. The IPE goals of this partnership were to expose students to roles of other disciplines in the complex hospital environment and integrate acute care exposure throughout the Doctor of Physical Therapy and Master of Science in Occupational Therapy curricula.

Results: Faculty and students, patients and families, and occupational and physical therapy clinicians participated in a series of learning activities in an acute care setting involving interprofessional teams of students. Activities included observations of OT and PT clinicians providing standard patient care, practice conducting team patient interviews, and interactive treatment planning sessions conducted live via videoconferencing technology between a patient's hospital room and an academic classroom on the university campus. The activities generally were designed to improve student preparedness for working as part of an interprofessional team in an acute care setting.

Conclusions: Student and clinician feedback support the early development of student IPE competencies, including the appreciation and understanding of professional roles in the team approach to patient care and the development of effective communication skills. The partnership between the academic institution and tertiary care hospital is an effective vehicle to deliver and sustain IPE educational initiatives in the acute care setting. Current and planned IPE curriculum integration are discussed along with a preliminary analysis of IPE outcomes.
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http://dx.doi.org/10.3233/WOR-2012-1299DOI Listing
July 2012

Interleukin-7 induces recruitment of monocytes/macrophages to endothelium.

Eur Heart J 2012 Dec 30;33(24):3114-23. Epub 2011 Jul 30.

Department of Medicine, Baylor College of Medicine, Houston, TX, USA.

Aims: Interleukin-7 (IL-7) is a master regulator of T-cell development and homoeostasis. Increased IL-7 levels are associated with inflammatory diseases. The aims of this study were to determine whether IL-7 is a biomarker for inflammatory conditions or an active participant in atherogenesis.

Methods And Results: Advanced atherosclerotic lesions in Apoe(-/-) mice were regressed by long-term cholesterol lowering through treatment with a helper-dependent adenovirus expressing apolipoprotein E (n= 6-10). Using this model, gene expression patterns in the aorta were analysed at an early phase of regression by microarray. After stringent statistical analysis, we found that IL-7 expression is significantly reduced in response to lowering of cholesterol (n= 6). To understand the importance of IL-7 down-regulation for atherosclerotic regression, we studied the effects and mechanisms of action of IL-7 on endothelial cells (ECs) in vitro as well as in vivo. Our major findings are: (i) IL-7 up-regulates cell adhesion molecules and monocyte chemoattractant protein-1 in ECs and promotes monocyte adhesion to ECs; (ii) this regulation is mediated by phosphatidylinositol 3-kinase (PI3K)/AKT-dependent and -independent activation of NF-κB; (iii) elevation of plasma IL-7 induces recruitment of monocytes/macrophages to endothelium without affecting plasma cholesterol (n= 5, 6); and (4) lack of IL-7 in bone marrow-derived cells reduces migration of monocytes/macrophages to the lesions (n= 5, 6).

Conclusion: These results suggest that IL-7 inflames endothelium via PI3K/AKT-dependent and -independent activation of NF-κB and recruits monocytes/macrophages to the endothelium, thus playing an active role in atherogenesis.
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http://dx.doi.org/10.1093/eurheartj/ehr245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598429PMC
December 2012

Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism.

Neuron 2011 Jun;70(5):863-85

Program on Neurogenetics, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA.

We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 × 10(-7)). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.
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http://dx.doi.org/10.1016/j.neuron.2011.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3939065PMC
June 2011

Cell cycle regulator gene CDC5L, a potential target for 6p12-p21 amplicon in osteosarcoma.

Mol Cancer Res 2008 Jun;6(6):937-46

Texas Children's Cancer Center, Baylor College of Medicine, 6621 Fannin Street, MC 3-3320, Houston, TX 77030, USA.

Osteosarcoma is a primary malignant tumor of bone arising from primitive bone-forming mesenchymal cells and accounts for approximately 60% of malignant bone tumors. Our comparative genomic hybridization (CGH) studies have identified frequent amplification at 6p12-p21, 12q13-q15, and 17p11.2 in osteosarcoma. Of these amplified regions, 6p12-p21 is particularly interesting because of its association with progression and poor prognosis in patients with osteosarcoma. In an attempt to identify aberrantly expressed gene(s) mapping to the 6p12-p21 amplicon, a region-specific array was generated using 108 overlapping BAC and P1 clones covering a 28.8-Mb region at 0.26-Mb intervals. Based on array CGH analysis, the 6p amplicon was refined to 7.9 Mb between the clones RP11-91E11 and RP1-244F2 and 10 amplified clones, with possible target genes, were identified. To study the expression pattern of the target genes from the hotspot amplicon and known candidate genes from 6p12-21, we did quantitative reverse transcription-PCR analysis of MAPK14, MAPK13, CDKN1A, PIM1, MDGA1, BTB9, DNAH8, CCND3, PTK7, CDC5L, and RUNX2 on osteosarcoma patient samples and seven cell lines. The combined array CGH and quantitative reverse transcription-PCR analysis identified amplification and overexpression of CDC5L, CCND3, and RUNX2. We screened these three genes for protein expression by Western blotting and immunohistochemistry and detected overexpression of CDC5L. Furthermore, we used an in vivo assay to show that CDC5L possesses potential oncogenic activity. These results indicate that CDC5L, a cell cycle regulator important for the G2-M transition, is the most likely candidate oncogene for the 6p12-p21 amplicon found in osteosarcoma.
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http://dx.doi.org/10.1158/1541-7786.MCR-07-2115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693718PMC
June 2008

Evidence-based practice in occupational health: description and application of an implementation effectiveness model.

Work 2007 ;29(2):137-43

Department of Physical Therapy, University of New England, Portland, ME 04103, USA.

Work-related muscuoloskeletal disorders (WMSDs) continue to represent the most costly category of occupational diseases. There is a growing body of literature regarding the causal nature of these injuries and effective intervention strategies. In this context, the consistent utilization of evidence-based practice (EBP) to address these problems can be viewed as one indicator of occupational health effectiveness. However, the routine integration of EBP remains elusive in occupational and physical therapy practice, including the occupational health arena. This article describes an implementation effectiveness model from the field of organizational management and applies it to the implementation of EBP within the occupational health practice arena. As a predictive or evaluative tool regarding implementation success, the model can assist clinic managers and clinicians in developing targeted approaches to EBP initiatives within any health care facility.
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November 2007

Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia.

Ann Neurol 2006 Oct;60(4):420-9

Cain Foundation Laboratories, Texas Children's Hospital, Houston, TX, USA.

Objective: The cortex of patients with cortical dysplasia contains several abnormal cell types. Among the dysplastic cells, cytomegalic neurons are known to be electrically hyperactive and may contribute to epileptic activity. In this study, we sought to identify molecular markers of cytomegalic neurons in focal or hemispheric cortical dysplasia and to determine whether the activity of the mammalian target of rapamycin (mTOR) kinase is abnormally high in these cells.

Methods: Microarray analysis of gene expression in large dysplastic cells microdissected from cortical dysplasia surgical specimens was used to identify markers of cytomegalic neurons. Immunohistochemistry and immunofluorescence analysis of cortical sections was used to validate the microarray results and to probe the activity of mTOR in cytomegalic neurons using phospho-specific antibodies directed against known mTOR targets.

Results: We demonstrate that the neurofilament heavy chain is a reliable marker of cytomegalic neurons and that targets of the mTOR kinase, such as the ribosomal protein S6, eIF4G, and Akt, are hyperphosphorylated in these dysplastic neurons.

Interpretation: We conclude that mTOR kinase hyperactivation is a molecular mechanism underlying the development of cytomegalic neurons. This finding may lead to the development of novel therapeutic approaches for childhood epilepsy associated with cortical dysplasia.
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http://dx.doi.org/10.1002/ana.20949DOI Listing
October 2006

Soliton-induced waveguides in an organic photorefractive glass.

Opt Lett 2005 Mar;30(5):519-21

Department of Physics and Astronomy, San Francisco State University, San Francisco, California 94132, USA.

We demonstrate optical waveguiding of a probe beam at 980 nm by a soliton beam at 780 nm in an organic photorefractive monolithic glass. Both planar and circular waveguides induced by one- and two-dimensional spatial solitons formed as a result of orientationally enhanced photorefractive nonlinearity are produced in the organic glass. Possibilities for increasing the speed of waveguide formation are discussed.
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http://dx.doi.org/10.1364/ol.30.000519DOI Listing
March 2005

Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2-Dab1 pathway.

Neuron 2004 Jan;41(1):71-84

The Cain Foundation Laboratories, Houston, TX 77030, USA.

Reelin is a secreted glycoprotein that regulates neuronal positioning in cortical brain structures through the VLDLR and ApoER2 receptors and the adaptor protein Dab1. In addition to cellular disorganization, dendrite abnormalities are present in the brain of reeler mice lacking Reelin. It is unclear whether these defects are due primarily to cellular ectopia or the absence of Reelin. Here we examined dendrite development in the hippocampus of normal and mutant mice and in dissociated cultures. We found that dendrite complexity is severely reduced in homozygous mice deficient in Reelin signaling both in vivo and in vitro, and it is also reduced in heterozygous mice in the absence of cellular ectopia. Addition of Reelin interfering antibodies, receptor antagonists, and Dab1 phosphorylation inhibitors prevented dendrite outgrowth from normal neurons, whereas addition of recombinant Reelin rescued the deficit in reeler cultures. Thus, the same signaling pathway controls both neuronal migration and dendrite maturation.
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http://dx.doi.org/10.1016/s0896-6273(03)00819-5DOI Listing
January 2004

Interaction of reelin signaling and Lis1 in brain development.

Nat Genet 2003 Nov 26;35(3):270-6. Epub 2003 Oct 26.

Cain Foundation Laboratories and Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.

Loss-of-function mutations in RELN (encoding reelin) or PAFAH1B1 (encoding LIS1) cause lissencephaly, a human neuronal migration disorder. In the mouse, homozygous mutations in Reln result in the reeler phenotype, characterized by ataxia and disrupted cortical layers. Pafah1b1(+/-) mice have hippocampal layering defects, whereas homozygous mutants are embryonic lethal. Reln encodes an extracellular protein that regulates layer formation by interacting with VLDLR and ApoER2 (Lrp8) receptors, thereby phosphorylating the Dab1 signaling molecule. Lis1 associates with microtubules and modulates neuronal migration. We investigated interactions between the reelin signaling pathway and Lis1 in brain development. Compound mutant mice with disruptions in the Reln pathway and heterozygous Pafah1b1 mutations had a higher incidence of hydrocephalus and enhanced cortical and hippocampal layering defects. Dab1 and Lis1 bound in a reelin-induced phosphorylation-dependent manner. These data indicate genetic and biochemical interaction between the reelin signaling pathway and Lis1.
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http://dx.doi.org/10.1038/ng1257DOI Listing
November 2003

Reelin promotes peripheral synapse elimination and maturation.

Science 2003 Aug;301(5633):649-53

The Cain Foundation Laboratories, Houston, TX 77030, USA.

Reelin is an extracellular protein that is crucial for layer formation in the embryonic brain. Here, we demonstrate that Reelin functions postnatally to regulate the development of the neuromuscular junction. Reelin is required for motor end-plate maturation and proper nerve-muscle connectivity, and it directly promotes synapse elimination. Unlike layer formation, neuromuscular junction development requires a function of Reelin that is not mediated by Disabled1 or very-low-density lipoprotein receptors and apolipoprotein E receptor 2 receptors but by a distinct mechanism involving its protease activity.
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http://dx.doi.org/10.1126/science.1082690DOI Listing
August 2003

Reelin and disabled-1 expression in developing and mature human cortical neurons.

J Neuropathol Exp Neurol 2003 Jun;62(6):676-84

Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.

In developing mammalian (mouse) brain, Reelin (Reln) is secreted by the Cajal-Retzius (CR) neurons in the marginal zone, binds apolipoprotein E receptor 2 (ApoER2) and very low density lipoprotein receptor (Vldlr), and induces the phosphorylation of the downstream cytoplasmic molecule disabled-1 (Dab1) in cortical plate neurons. Although this is a well-characterized signaling pathway in mice, it has not been well defined in human brain. In this paper we examined the expression of RELN, APOER2, VLDLR, and DAB1 in the developing human brain by RT-PCR. We further determined the cellular expression of the proteins RELN and DAB1 in 50 human brains ranging in age from 10 gestational weeks (GW) to 62 years using immunochemistry. We found that the pattern of expression of RELN and DAB1 in the human brain isnot identical to that observed in the mouse brain. In particular, we report the novel finding that human DAB1and RELN are coexpressed in CR neurons during cortical development and in cortical pyramidal neurons after neuronal migration is complete. Thus, in the human brain, the whole RELN signaling pathway is present within selected populations of cortical neurons throughout life. We speculate that RELN and DAB1 coexpression in these neurons is necessary for both normal cortical development and mature function.
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http://dx.doi.org/10.1093/jnen/62.6.676DOI Listing
June 2003

Total knee arthroplasty in patients

J Arthroplasty 2002 Aug;17(5):538-43

Department of Orthopaedic Surgery, The Johns Hopkins Medical Institute, Baltimore, Maryland, USA.

Thirty patients (30 knees) who underwent total knee arthroplasty at age
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http://dx.doi.org/10.1054/arth.2002.32174DOI Listing
August 2002

Total knee arthroplasty for osteonecrosis.

J Bone Joint Surg Am 2002 Apr;84(4):599-603

Department of Orthopedic Surgery, The Johns Hopins Medical Institute, Baltimore, Maryland 21287, USA.

Background: A patient with collapse of a femoral condyle caused by osteonecrosis has few treatment options other than total knee arthroplasty. The purpose of this study was to report the clinical and radiographic outcome of total knee arthroplasty for osteonecrosis.

Methods: Between 1987 and 1996, thirty-two total knee arthroplasties were performed with cement in thirty patients with osteonecrosis of the femoral condyle and/or tibial plateau. The study group included twenty-forty women and five men with a mean age of fifty-four years (range, thirty-one to seventy-seven years) at the time of the arthroplasty. Twenty-two patients had atraumatic osteonecrosis associated with corticosteroid use, and eight had spontaneous osteonecrosis. All patients had a complete clinical and radiographic evaluation at a mean of 108 months (range, forty-eight to 144 months) postoperatively.

Results: Overall, thirty-one (97%) of the thirty-two knees had a successful clinical outcome. The mean Knee Society score improved from 54 points preoperatively to 95 points at the time of the latest follow-up. No evidence of progressive radiolucency was found around any prosthetic component.

Conclusions: Previous studies have demonstrated less-than-optimal results following total knee arthroplasty in patients with osteonecrosis. The excellent results found in the present study may have been secondary to the use of cemented implants in all cases and ancillary stems when appropriate.
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http://dx.doi.org/10.2106/00004623-200204000-00014DOI Listing
April 2002