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Search Results: 1 - 10 of 151545 matches for " Kevin F. Sullivan "
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Premitotic Assembly of Human CENPs -T and -W Switches Centromeric Chromatin to a Mitotic State
Lisa Prendergast,Chelly van Vuuren,Agnieszka Kaczmarczyk,Volker Doering,Daniela Hellwig,Nadine Quinn,Christian Hoischen,Stephan Diekmann,Kevin F. Sullivan
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1001082
Abstract: Centromeres are differentiated chromatin domains, present once per chromosome, that direct segregation of the genome in mitosis and meiosis by specifying assembly of the kinetochore. They are distinct genetic loci in that their identity in most organisms is determined not by the DNA sequences they are associated with, but through specific chromatin composition and context. The core nucleosomal protein CENP-A/cenH3 plays a primary role in centromere determination in all species and directs assembly of a large complex of associated proteins in vertebrates. While CENP-A itself is stably transmitted from one generation to the next, the nature of the template for centromere replication and its relationship to kinetochore function are as yet poorly understood. Here, we investigate the assembly and inheritance of a histone fold complex of the centromere, the CENP-T/W complex, which is integrated with centromeric chromatin in association with canonical histone H3 nucleosomes. We have investigated the cell cycle regulation, timing of assembly, generational persistence, and requirement for function of CENPs -T and -W in the cell cycle in human cells. The CENP-T/W complex assembles through a dynamic exchange mechanism in late S-phase and G2, is required for mitosis in each cell cycle and does not persist across cell generations, properties reciprocal to those measured for CENP-A. We propose that the CENP-A and H3-CENP-T/W nucleosome components of the centromere are specialized for centromeric and kinetochore activities, respectively. Segregation of the assembly mechanisms for the two allows the cell to switch between chromatin configurations that reciprocally support the replication of the centromere and its conversion to a mitotic state on postreplicative chromatin.
Premitotic Assembly of Human CENPs -T and -W Switches Centromeric Chromatin to a Mitotic State
Lisa Prendergast,Chelly van Vuuren,Agnieszka Kaczmarczyk,Volker Doering,Daniela Hellwig,Nadine Quinn,Christian Hoischen,Stephan Diekmann,Kevin F. Sullivan
PLOS Biology , 2011, DOI: 10.1371/journal.pbio.1001082
Abstract: Centromeres are differentiated chromatin domains, present once per chromosome, that direct segregation of the genome in mitosis and meiosis by specifying assembly of the kinetochore. They are distinct genetic loci in that their identity in most organisms is determined not by the DNA sequences they are associated with, but through specific chromatin composition and context. The core nucleosomal protein CENP-A/cenH3 plays a primary role in centromere determination in all species and directs assembly of a large complex of associated proteins in vertebrates. While CENP-A itself is stably transmitted from one generation to the next, the nature of the template for centromere replication and its relationship to kinetochore function are as yet poorly understood. Here, we investigate the assembly and inheritance of a histone fold complex of the centromere, the CENP-T/W complex, which is integrated with centromeric chromatin in association with canonical histone H3 nucleosomes. We have investigated the cell cycle regulation, timing of assembly, generational persistence, and requirement for function of CENPs -T and -W in the cell cycle in human cells. The CENP-T/W complex assembles through a dynamic exchange mechanism in late S-phase and G2, is required for mitosis in each cell cycle and does not persist across cell generations, properties reciprocal to those measured for CENP-A. We propose that the CENP-A and H3-CENP-T/W nucleosome components of the centromere are specialized for centromeric and kinetochore activities, respectively. Segregation of the assembly mechanisms for the two allows the cell to switch between chromatin configurations that reciprocally support the replication of the centromere and its conversion to a mitotic state on postreplicative chromatin.
Hyperacute Therapies for Childhood Stroke: A Case Report and Review of the Literature
Jose Irazuzta,Kevin J. Sullivan
Neurology Research International , 2010, DOI: 10.1155/2010/497326
Abstract: Objective. The optimal management of pediatric patients with arterial ischemic stroke (AIS) is not known. Despite this, goal-oriented, time-sensitive therapies geared to rapid reestablishment of arterial blood flow are occasionally applied with beneficial effects. The inconsistent approach to AIS is in part due to a lack of knowledge and preparedness. Methods. Case report of a 12-year-old male with right middle cerebral artery (MCA) occlusion resulting in dense left hemiplegia and mutism and review of the literature. Intervention(s). Mechanical thrombectomy, intra-arterial administration of rt-PA, vasodilators, and platelet inhibitors, and systemic anticoagulation and subsequent critical care support. Results. Restoration of right MCA blood flow and complete resolution of neurologic deficits. Conclusion. We report the gratifying outcome of treatment of a case of AIS in a pediatric patient treated with hyperacute therapies geared to arterial recanalization and subsequent neurologic critical care and review the pertinent literature. Guidelines for the emergency room management of pediatric AIS from prospective, randomized trials are needed. 1. Introduction Arterial ischemic stroke (AIS) occurs more commonly in adults than children. In children the clinical presentation is often interpreted as other neurologic conditions or intoxications resulting in a delay in diagnosis due to the lack of awareness of pediatrician or that the symptoms do not systematically evoke a stroke. Adult AIS occurs in the setting of the principal risk factors of hypertension and atherosclerosis, while pediatric risk factors are heterogeneous and include focal intracranial arteriopathies, congenital cardiovascular diseases, and hemoglobinopathies [1, 2]. Recent advances in the management of AIS have emphasized the importance of timely diagnosis and restoration of arterial flow in the affected vascular territories. Adult victims have access to time-sensitive or hyperacute therapies due to an awareness of the severity of the disease, organization of delivery of medical care from the emergency room that includes designation of stroke centers, and protocol-driven preparedness for such emergencies [3–6]. Unfortunately, this is not the case for pediatric victims, because it is not known whether thrombolytic therapies are appropriate. We describe the case of a 12-year-old male with AIS who presented to medical attention with a potentially devastating neurological injury. A resolute strategy utilizing hyperacute therapies aimed at restoring blood flow followed by neurointensive care support
Current Opinions in Pediatric Septic Shock
José Irazuzta,Kevin J. Sullivan
Journal of Pediatric Sciences , 2009,
Abstract: Objectives: Our aim is to describe the current clinical practice related to the management of septic shock (SS). Methods: Review of medical literature using the MEDLINE database. Articles were selected according to their relevancy to the objective and according to the author’s opinion. Summary of the findings: The outcome from SS is dependent on an early recognition and a sequential implementation of time-sensitive goal-directed therapies. The goals of the resuscitation are rapid restoration of micro circulation and improved organ tissue perfusion. Clinical and laboratory markers are needed to assess the adequacy of the treatments. Initial resuscitation involves the use of isotonic solutions (>60ml/kg) either crystalloid (normal saline) or colloid infusion often followed by vasoactive medications. Altered pharmacokinetics and pharmacodynamics responses dictate that vasoactive agents should be adjusted to achieve predetermined goals. An assessment of central venous pressure complements clinical and serological findings to tailor therapies. Elective airway instrumentation and mechanical ventilation as well as adjunctive therapy with stress dose of corticosteroid are indicated in selected populations. In neonates, a special attention to the presence of electrolyte imbalance and increase pulmonary vascular resistance needs to be considered early. Conclusions: Septic shock hemodynamic is a changing process that requires frequent assessment and therapeutic adjustments.
An assessment of medical students’ awareness of radiation exposures associated with diagnostic imaging investigations
Jennifer O’Sullivan,Owen J. O’Connor,Kevin O’Regan,Bronagh Clarke,Louise N. Burgoyne,Max F. Ryan,Michael M. Maher
Insights into Imaging , 2010, DOI: 10.1007/s13244-010-0009-8
Abstract: Assessment of students’ awareness of radiation exposures in diagnostic imaging demonstrates improved performance with increasing years in medical school and/or increasing exposure to CICR. Findings support the Euroatom 97 directive position, advocating implementation of radiation protection instruction into the undergraduate medical curriculum.
Impact of KRAS Mutations on Management of Colorectal Carcinoma
Kevin M. Sullivan,Peter S. Kozuch
Pathology Research International , 2011, DOI: 10.4061/2011/219309
Abstract: The epidermal growth factor receptor (EGFR) pathway is a therapeutic target in the management of colorectal cancer (CRC). EGFR antagonists are active in this disease; however, only a subset of patients respond to such therapy. A Kirsten ras sarcoma viral oncogene (KRAS) wild-type (WT) status of the tumor is necessary, but possibly not sufficient, for a response to anti-EGFR monoclonal antibody therapy. Mechanisms of primary resistance to such therapy in patients harboring KRAS WT tumors are discussed. Strategies to overcome resistance to anti-EGFR monoclonal antibody therapy, including novel agents and combinations of novel therapies, are explored. Also, the use of anti-EGFR monoclonal antibodies in the adjuvant and neoadjuvant setting is reviewed. 1. Introduction Tumor growth and progression depends in part on the activity of cell surface membrane receptors which control signal transduction pathways. These growth factor receptors can have aberrations in their expression and regulation and activation of growth factor pathways is common in many malignancies [1]. The EGFR, a transmembrane glycoprotein also called ERBB-1 or HER1, is a member of a family of receptor tyrosine kinases (TKs). The EGFR is involved in signaling pathways controlling cell growth, differentiation, and proliferation and is expressed in many different types of normal tissues as well as several tumor types, including CRC [2, 3]. Figure 1 illustrates the main EGFR signaling pathways described [4]. When a ligand binds to the EGFR, the receptor forms a dimer resulting in a signaling cascade within the cell via tyrosine kinase activity [5]. This signaling cascade occurs by the activation of receptor autophosphorylation which triggers a number of intracellular pathways regulating cell proliferation, prevention of apoptosis, and promotion of invasion, metastasis, and neovascularization [6]. The proto-oncogene c-erb-B encodes the EGFR, and activation of the proto-oncogene results in EGFR expression in many tumors [7, 8]. There was therefore interest in investigating this pathway as a potential anticancer therapy target. Figure 1: EGFR signaling pathway [ 4]. (Reprinted with permission from American Society of Clinical Oncology 2008. All rights reserved.) Pharmacologically, there are two classes of EGFR antagonists currently in clinical use: antiEGFR monoclonal antibodies directed against the extracellular domain of the receptor and oral small-molecule EGFR TK inhibitors which block the receptor TK activity competitively [10]. The antiEGFR monoclonal antibodies, cetuximab and panitumumab, act
The Genetics of Schizophrenia
Patrick F Sullivan
PLOS Medicine , 2005, DOI: 10.1371/journal.pmed.0020212
Abstract:
The genetics of schizophrenia.
Sullivan Patrick F
PLOS Medicine , 2005,
Abstract:
Brief Treatment of Symptoms of Post-Traumatic Stress Disorder (PTSD) by Use of Accelerated Resolution Therapy (ART?)
Kevin E. Kip,Carrie A. Elk,Kelly L. Sullivan,Rajendra Kadel,Cecile A. Lengacher,Christopher J. Long,Laney Rosenzweig,Amy Shuman,Diego F. Hernandez,Jennifer D. Street,Sue Ann Girling,David M. Diamond
Behavioral Sciences , 2012, DOI: 10.3390/bs2020115
Abstract: Post-Traumatic Stress Disorder (PTSD) is a prevalent, disabling anxiety disorder. This prospective cohort study reports on a new exposure-based therapy known as Accelerated Resolution Therapy (ART ?) that incorporates the use of eye movements administered in a brief treatment period (1–5 one-hour sessions within three weeks). Eighty adults aged 21–60 years with symptoms of PTSD were recruited from the Tampa Bay area. The ART-based psychotherapy was designed to minimize anxiety and body sensations associated with recall of traumatic memories and to replace distressing images with favorable ones. Participants’ mean age was 40 years, 77% were female, and 29% were Hispanic. Participants underwent a median of three ART sessions, 66 of 80 (82.5%) completed treatment, and 54 of 66 (81.8%) provided 2-month follow-up data. Mean scores pre- and post-ART and at 2-month follow-up were: PTSD Checklist: 54.5 ± 12.2 vs. 31.2 ± 11.4 vs. 30.0 ± 12.4; Brief Symptom Inventory: 30.8 ± 14.6 vs. 10.1 ± 10.8 vs. 10.1 ± 12.1; Center for Epidemiologic Studies Depression Scale: 29.5 ± 10.9 vs. 11.8 ± 11.1 vs. 13.5 ± 12.1; Trauma Related Growth Inventory-Distress scale: 18.9 ± 4.1 vs. 7.4 ± 5.9 vs. 8.2 ± 5.9 ( p < 0.0001 for all pre-ART vs. post-ART and 2-month comparisons). No serious adverse events were reported. ART appears to be a brief, safe, and effective treatment for symptoms of PTSD.
A Re-Evaluation of the Size of the White Shark (Carcharodon carcharias) Population off California, USA
George H. Burgess, Barry D. Bruce, Gregor M. Cailliet, Kenneth J. Goldman, R. Dean Grubbs, Christopher G. Lowe, M. Aaron MacNeil, Henry F. Mollet, Kevin C. Weng, John B. O'Sullivan
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098078
Abstract: White sharks are highly migratory and segregate by sex, age and size. Unlike marine mammals, they neither surface to breathe nor frequent haul-out sites, hindering generation of abundance data required to estimate population size. A recent tag-recapture study used photographic identifications of white sharks at two aggregation sites to estimate abundance in “central California” at 219 mature and sub-adult individuals. They concluded this represented approximately one-half of the total abundance of mature and sub-adult sharks in the entire eastern North Pacific Ocean (ENP). This low estimate generated great concern within the conservation community, prompting petitions for governmental endangered species designations. We critically examine that study and find violations of model assumptions that, when considered in total, lead to population underestimates. We also use a Bayesian mixture model to demonstrate that the inclusion of transient sharks, characteristic of white shark aggregation sites, would substantially increase abundance estimates for the adults and sub-adults in the surveyed sub-population. Using a dataset obtained from the same sampling locations and widely accepted demographic methodology, our analysis indicates a minimum all-life stages population size of >2000 individuals in the California subpopulation is required to account for the number and size range of individual sharks observed at the two sampled sites. Even accounting for methodological and conceptual biases, an extrapolation of these data to estimate the white shark population size throughout the ENP is inappropriate. The true ENP white shark population size is likely several-fold greater as both our study and the original published estimate exclude non-aggregating sharks and those that independently aggregate at other important ENP sites. Accurately estimating the central California and ENP white shark population size requires methodologies that account for biases introduced by sampling a limited number of sites and that account for all life history stages across the species' range of habitats.
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