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Gucy2c Opposes Systemic Genotoxic Tumorigenesis By Regulating Akt-Dependent Intestinal Barrier Integrity, Jieru Egeria Lin, Adam Eugene Snook, Peng Li, Brian Arthur Stoecker, Gilbert Won Kim, Michael Sullivan Magee, Alex Vladimir Mejia Garcia, Michael Anthony Valentino, Terry Hyslop, Stephanie Schulz, Scott Arthur Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The barrier separating mucosal and systemic compartments comprises epithelial cells, annealed by tight junctions, limiting permeability. GUCY2C recently emerged as an intestinal tumor suppressor coordinating AKT1-dependent crypt-villus homeostasis. Here, the contribution of GUCY2C to barrier integrity opposing colitis and systemic tumorigenesis is defined. Mice deficient in GUCY2C (Gucy2c^−/−) exhibited barrier hyperpermeability associated with reduced junctional proteins. Conversely, activation of GUCY2C in mice reduced barrier permeability associated with increased junctional proteins. Further, silencing GUCY2C exacerbated, while activation reduced, chemical barrier disruption and colitis. Moreover, eliminating GUCY2C amplified, while activation reduced, systemic oxidative DNA damage. This genotoxicity was associated …

Ovarian Cancer Progression Is Controlled By Phenotypic Changes In Dendritic Cells, Uciane K. Scarlett, Melanie R. Rutkowski, Adam M. Rauwerdink, Jennifer Fields, Ximena Escovar-Fadul, Jason Baird, Juan R. Cubillos-Ruiz, Ana C. Jacobs, Jorge L. Gonzalez, John Weaver, Steven Fiering, Jose R. Conejo-Garcia

Dartmouth Scholarship

We characterized the initiation and evolution of the immune response against a new inducible p53-dependent model of aggressive ovarian carcinoma that recapitulates the leukocyte infiltrates and cytokine milieu of advanced human tumors. Unlike other models that initiate tumors before the development of a mature immune system, we detect measurable antitumor immunity from very early stages, which is driven by infiltrating dendritic cells (DCs) and prevents steady tumor growth for prolonged periods. Coinciding with a phenotypic switch in expanding DC infiltrates, tumors aggressively progress to terminal disease in a comparatively short time. Notably, tumor cells remain immunogenic at advanced stages, but …

Identification Of Functionally Distinct Traf Proinflammatory And Pi3k/Mek Transforming Activities Emanating From The Ret/Ptc Fusion Oncoprotein, Josephine H.F. Wixted, Jay L. Rothstein, Laurence C. Eisenlohr

Kimmel Cancer Center Faculty Papers

Thyroid carcinomas that harbor RET/PTC oncogenes are well differentiated, relatively benign neoplasms compared with those expressing oncogenic RAS or BRAF mutations despite signaling through shared transforming pathways. A distinction, however, is that RET/PTCs induce immunostimulatory programs, suggesting that, in the case of this tumor type, the additional pro-inflammatory pathway reduces aggressiveness. Here, we demonstrate that pro-inflammatory programs are selectively activated by TRAF2 and TRAF6 association with RET/PTC oncoproteins. Eliminating this mechanism reduces pro-inflammatory cytokine production without decreasing transformation efficiency. Conversely, ablating MEK/ERK or PI3K/AKT signaling eliminates transformation but not pro-inflammatory cytokine secretion. Functional uncoupling of the two pathways demonstrates that …

John Blair Deaver, M.D., And His Marvelous Retractor., Timothy E. Newhook, Md, Charles J. Yeo, Md, Pinckney J. Maxwell, Iv, Md

Department of Surgery Gibbon Society Historical Profiles

John Blair Deaver was born near Buck, Pennsylvania, in Lancaster County on July 25, 1855, to Dr. Joshua Montgomery Deaver and Elizabeth Clair Moore. The elder Deaver was a reputable country physician, educated at the University of Maryland, who fathered three physicians and a college president. John Blair Deaver (Fig. 1) went to boarding school at West Nottingham Academy in Maryland. After boarding school he taught in Lancaster County country schools to raise funds to attend the nation’s first medical school, the University of Pennsylvania. On receiving his M.D. degree in 1878, Dr. Deaver completed 1-year internships at both Germantown …

Mir-25 Targets Tnf-Related Apoptosis Inducing Ligand (Trail) Death Receptor-4 And Promotes Apoptosis Resistance In Cholangiocarcinoma., Nataliya Razumilava, Steve F. Bronk, Rory L. Smoot, Christian D. Fingas, Nathan W. Werneburg, Lewis R. Roberts, Justin L. Mott

Journal Articles: Biochemistry & Molecular Biology

It has been established that microRNA expression and function contribute to phenotypic features of malignant cells, including resistance to apoptosis. Although targets and functional roles for a number of microRNAs have been described in cholangiocarcinoma, many additional microRNAs dysregulated in this tumor have not been assigned functional roles. In this study, we identify elevated miR-25 expression in malignant cholangiocarcinoma cell lines as well as patient samples. In cultured cells, treatment with the Smoothened inhibitor, cyclopamine, reduced miR-25 expression, suggesting Hedgehog signaling stimulates miR-25 production. Functionally, miR-25 was shown to protect cells against TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Correspondingly, antagonism of …

The Formal And Informal Surgical Ethics Curriculum: Views Of Resident And Staff Surgeons In Toronto., Frazer Howard, Martin F. Mckneally, Ross E.G. Upshur, Alex V. Levin

Wills Eye Hospital Papers

BACKGROUND: Understanding what staff surgeons think surgical trainees should learn and the ethical issues that trainees need to manage can strengthen surgical ethics education.

METHODS: Participants were recruited from the 15 surgical specialty and subspecialty programs at the University of Toronto. Semistructured interviews and focus groups were conducted with 13 ethics coordinators from the surgical staff and 64 resident trainees. Data were analyzed qualitatively using modified thematic analysis.

RESULTS: All coordinators and trainees felt that ethics education was an important component of surgical training. Real cases, varying teaching methods, and teachers with applicable clinical experience were valued. Trainees identified intraprofessional …

Inflammatory Signaling Compromises Cell Responses To Interferon Alpha., W-C Huangfu, J Qian, C Liu, J Liu, A E Lokshin, D P Baker, H Rui, S Y Fuchs

Department of Cancer Biology Faculty Papers

Interferon alpha (IFNα) is widely used for treatment of melanoma and certain other malignancies. This cytokine as well as the related IFNβ exerts potent anti-tumorigenic effects; however, their efficacy in patients is often suboptimal. Here, we report that inflammatory signaling impedes the effects of IFNα/β. Melanoma cells can secrete pro-inflammatory cytokines that inhibit cellular responses to IFNα/β via activating the ligand-independent pathway for the phosphorylation and subsequent ubiquitination and accelerated degradation of the IFNAR1 chain of type I IFN receptor. Catalytic activity of the p38 protein kinase was required for IFNAR1 downregulation and inhibition of IFNα/β signaling induced by proinflammatory …

Usp8 Promotes Smoothened Signaling By Preventing Its Ubiquitination And Changing Its Subcellular Localization, Ruohan Xia, Hongge Jia, Junkai Fan, Yajuan Liu, Jianhang Jia

Molecular and Cellular Biochemistry Faculty Publications

The seven transmembrane protein Smoothened (Smo) is a critical component of the Hedgehog (Hh) signaling pathway and is regulated by phosphorylation, dimerization, and cell-surface accumulation upon Hh stimulation. However, it is not clear how Hh regulates Smo accumulation on the cell surface or how Hh regulates the intracellular trafficking of Smo. In addition, little is known about whether ubiquitination is involved in Smo regulation. In this study, we demonstrate that Smo is multi-monoubiquitinated and that Smo ubiquitination is inhibited by Hh and by phosphorylation. Using an in vivo RNAi screen, we identified ubiquitin-specific protease 8 (USP8) as a deubiquitinase that …

Hiv-1 Tat Triggers Nuclear Localization Of Zo-1 Via Rho Signaling And Camp Response Element-Binding Protein Activation, Yu Zhong, Bei Zhang, Sung Yong Eum, Michal Toborek

Neurosurgery Faculty Publications

The human immunodeficiency virus (HIV)-specific protein trans-activator of transcription (Tat) can contribute to the dysfunction of brain endothelial cells and HIV trafficking into the brain by disrupting tight junction (TJ) integrity at the blood–brain barrier (BBB) level. Specific TJ proteins, such as zonula occludens (ZO) proteins, localize not only at the cell–cell borders but are also present in the nuclei. The objective of the present study was to evaluate the mechanisms and significance of Tat-induced nuclear localization of ZO-1. Treatment of a brain endothelial cell line (hCMEC/D3 cells) with Tat resulted in a decrease in total levels of ZO-1 but …

Persistent Systemic Inflammation Is Associated With Poor Clinical Outcomes In Copd: A Novel Phenotype, Alvar Agustí, Lisa D. Edwards, Stephen I. Rennard, William Macnee, Ruth Tal-Singer, Bruce E. Miller, Jørgen Vestbo, David A. Lomas, Peter M.A. Calverley, Emiel Wouters, Courtney Crim, Julie C. Yates, Edwin K. Silverman, Harvey O. Coxson, Per Bakke, Ruth J. Mayer, Bartolome Celli, Evaluation Of Copd Longitudinally To Identify Predictive Surrogate Endpoints (Eclipse) Investigators

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies. To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552).

METHODS AND FINDINGS: Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-α levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years. We found that, at baseline, 30% of …

Identification Of The Functional Binding Pocket For Compounds Targeting Small-Conductance Ca²⁺-Activated Potassium Channels., Miao Zhang, John M Pascal, Marcel Schumann, Roger S Armen, Ji-Fang Zhang

Department of Molecular Physiology and Biophysics Faculty Papers

Small- and intermediate-conductance Ca(2+)-activated potassium channels, activated by Ca(2+)-bound calmodulin, have an important role in regulating membrane excitability. These channels are also linked to clinical abnormalities. A tremendous amount of effort has been devoted to developing small molecule compounds targeting these channels. However, these compounds often suffer from low potency and lack of selectivity, hindering their potential for clinical use. A key contributing factor is the lack of knowledge of the binding site(s) for these compounds. Here we demonstrate by X-ray crystallography that the binding pocket for the compounds of the 1-ethyl-2-benzimidazolinone (1-EBIO) class is located at the calmodulin-channel interface. …

Measurement And Correlates Of Empathy Among Female Japanese Physicians., Hitomi U Kataoka, Norio Koide, Mohammadreza Hojat, Joseph S Gonnella

CRMEHC Faculty Papers

BACKGROUND: The measurement of empathy is important in the assessment of physician competence and patient outcomes. The prevailing view is that female physicians have higher empathy scores compared with male physicians. In Japan, the number of female physicians has increased rapidly in the past ten years. In this study, we focused on female Japanese physicians and addressed factors that were associated with their empathic engagement in patient care.

METHODS: The Jefferson Scale of Empathy (JSE) was translated into Japanese by using the back-translation procedure, and was administered to 285 female Japanese physicians. We designed this study to examine the psychometrics …

Erk2 Phosphorylation Of Serine 77 Regulates Bmf Pro-Apoptotic Activity., Y Shao, A E Aplin

Department of Cancer Biology Faculty Papers

B-cell lymphoma 2 (Bcl-2) homology 3 (BH3)-only proteins represent a class of pro-apoptotic factors that neutralize pro-survival Bcl-2 proteins, and, in some cases, directly activate Bax. The mechanisms of control and the role of BH3-only proteins, such as Bcl-2 like protein 11 extra large and Bad are well studied. By contrast, relatively little is known about the regulation and role of Bcl-2 modifying factor (Bmf). The B-RAF oncogene is mutated in ∼8% of human tumors. We have previously shown that Bmf is upregulated at the transcript level and is required for apoptosis induced by targeting B-RAF signaling in tumor cells …

Lesion-Specific Dna-Binding And Repair Activities Of Human O⁶-Alkylguanine Dna Alkyltransferase, Manana Melikishvili, Michael G. Fried

Center for Structural Biology Faculty Publications

Binding experiments with alkyl-transfer-active and -inactive mutants of human O⁶-alkylguanine DNA alkyltransferase (AGT) show that it forms an O⁶-methylguanine (6mG)-specific complex on duplex DNA that is distinct from non-specific assemblies previously studied. Specific complexes with duplex DNA have a 2:1 stoichiometry that is formed without accumulation of a 1:1 intermediate. This establishes a role for cooperative interactions in lesion binding. Similar specific complexes could not be detected with single-stranded DNA. The small difference between specific and non-specific binding affinities strongly limits the roles that specific binding can play in the lesion search process. Alkyl-transfer kinetics with …

Curcumin-Loaded Magnetic Nanoparticles For Breast Cancer Therapeutics And Imaging Applications., Murali M. Yallapu, Shadi F. Othman, Evan Curtis, Nichole A. Bauer, Neeraj Chauhan, Deepak Kumar, Meena Jaggi, Subhash C. Chauhan

All Faculty Articles - School of Engineering and Computer Science

BACKGROUND: The next generation magnetic nanoparticles (MNPs) with theranostic applications have attracted significant attention and will greatly improve nanomedicine in cancer therapeutics. Such novel MNP formulations must have ultra-low particle size, high inherent magnetic properties, effective imaging, drug targeting, and drug delivery properties. To achieve these characteristic properties, a curcumin-loaded MNP (MNP-CUR) formulation was developed.

METHODS: MNPs were prepared by chemical precipitation method and loaded with curcumin (CUR) using diffusion method. The physicochemical properties of MNP-CUR were characterized using dynamic light scattering, transmission electron microscopy, and spectroscopy. The internalization of MNP-CUR was achieved after 6 hours incubation with MDA-MB-231 breast …

Gene Expression Signatures Modulated By Epidermal Growth Factor Receptor Activation And Their Relationship To Cetuximab Resistance In Head And Neck Squamous Cell Carcinoma., Elana J Fertig, Qing Ren, Haixia Cheng, Hiromitsu Hatakeyama, Adam Dicker Md, Phd, Ulrich Rodeck, Michael Considine, Michael F Ochs, Christine H Chung

Department of Radiation Oncology Faculty Papers

BACKGROUND: Aberrant activation of signaling pathways downstream of epidermal growth factor receptor (EGFR) has been hypothesized to be one of the mechanisms of cetuximab (a monoclonal antibody against EGFR) resistance in head and neck squamous cell carcinoma (HNSCC). To infer relevant and specific pathway activation downstream of EGFR from gene expression in HNSCC, we generated gene expression signatures using immortalized keratinocytes (HaCaT) subjected to ligand stimulation and transfected with EGFR, RELA/p65, or HRASVal12D.

RESULTS: The gene expression patterns that distinguished the HaCaT variants and conditions were inferred using the Markov chain Monte Carlo (MCMC) matrix factorization algorithm Coordinated Gene Activity …

Comparative Genomics Of Brachyspira Pilosicoli Strains: Genome Rearrangements, Reductions And Correlation Of Genetic Compliment With Phenotypic Diversity, Luke Mappley, Michael Black, Manal Abuoun, Alistair C. Darby, Martin J. Woodward, Julian Parkhill, A. Keith Turner, Matthew I. Bellgard, Tom La, Nyree D. Phillips, Roberto M. La Ragione, David J. Hampson

Research outputs 2012

Background: The anaerobic spirochaete Brachyspira pilosicoli causes enteric disease in avian, porcine and human hosts, amongst others. To date, the only available genome sequence of B. pilosicoli is that of strain 95/1000, a porcine isolate. In the first intra-species genome comparison within the Brachyspira genus, we report the whole genome sequence of B. pilosicoli B2904, an avian isolate, the incomplete genome sequence of B. pilosicoli WesB, a human isolate, and the comparisons with B. pilosicoli 95/1000. We also draw on incomplete genome sequences from three other Brachyspira species. Finally we report the first application of the high-throughput Biolog phenotype screening …

Age And Premorbid Intelligence Suppress Complaint-Performance Congruency In Raw Score Measures Of Memory, Matthew Merema, Craig Speelman, Elizabeth Kaczmarek, Jonathan Foster

Research outputs 2012

Background: We aimed to examine the role of age and premorbid intelligence (IQ) in suppressing the relationship between subjective memory complaints (SMCs) and raw score memory performance. Methods: We used a community sample of older adults aged 66"90 years (N = 121) to test whether the inclusion of age and a premorbid IQ measure in multiple regression analyses increased semipartial correlations of raw score memory performance in predicting SMCs. Rank contrast correlations were also carried out to observe how age and premorbid IQ are related to complaint"performance congruency. Measures utilized in the study included the Memory Functioning Questionnaire (for SMCs), …

Lifestyle And Late Life Cognitive Health: Sufficient Evidence To Act Now?, Bruce Barber, D Ames, Kathryn Ellis, Ralph Martins, C Masters, C Szoeke

Research outputs 2012

No abstract provided.

Eae/Ase Recommendations For Image Acquisition And Display Using Three-Dimensional Echocardiography., Roberto M. Lang, Luigi P. Badano, Wendy Tsang, David H. Adams, Eustachio Agricola, Thomas Buck, Francesco F. Faletra, Andreas Franke, Judy Hung, Leopoldo Pérez De Isla, Otto Kamp, Jaroslaw D. Kasprzak, Patrizio Lancellotti, Thomas H. Marwick, Marti L. Mcculloch, Mark J. Monaghan, Petros Nihoyannopoulos, Natesa G. Pandian, Patricia A. Pellikka, Mauro Pepi, David A. Roberson, Stanton K. Shernan, Girish S. Shirali, Lissa Sugeng, Folkert J. Ten Cate, Mani A. Vannan, Jose Luis Zamorano, William A. Zoghbi, American Society Of Echocardiography, European Association Of Echocardiography

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.

Accuracy Of Automated Attenuation-Based 3-Dimensional Segmentation: In The Analysis Of Left Ventricular Function Compared With Magnetic Resonance Imaging, Harald Brodoefel, Ilias Tsiflikas, Ulrich Kramer, Nina Lang, Anja Reimann, Christoph Burgstahler, Claus D Claussen, Martin Heuschmid

The Texas Heart Institute Journal

We evaluated attenuation-based 3-dimensional segmentation for the analysis of left ventricular function, using as our standard of reference magnetic resonance imaging and dual-source computed tomography with traditional short-axis planimetry.

Twenty patients with known or suspected coronary artery disease were examined prospectively. In all magnetic resonance and computed tomographic datasets, global functional values were determined by 2-dimensional planimetry. Computed tomographic scans were further evaluated by automated 3-dimensional segmentation, and the results were compared by Pearson correlation and Bland-Altman analysis.

Agreement between magnetic resonance imaging and dual-source computed tomographic 2-dimensional planimetry was good for all values (end-diastolic volume, bias= −4.2, r=0.99; end-systolic …

Constrictive Pericarditis Treated By Surgery, Alireza A Ghavidel, Maziar Gholampour, Majid Kyavar, Yalda Mirmesdagh, Mohammad-Bagher Tabatabaie

The Texas Heart Institute Journal

We reviewed the records of 45 patients (mean age, 46.6 ± 14.9 yr; range, 21–84 yr) with a diagnosis of constrictive pericarditis who had undergone pericardiectomy from 1994 through 2006. Preoperatively, 2 of the patients (4.4%) were in New York Heart Association (NYHA) functional class I, 20 (44.4%) in class II, 22 (48.9%) in class III, and 1 (2.2%) in class IV. Pericardial calcification was detected in 20% of plain chest radiographs. Constrictive pericarditis was caused by tuberculosis in 22.2%, chronic renal failure in 8.9%, a history of sternotomy in 4.4%, and malignancy in 4.4%. The cause was idiopathic in …

Nitinol Thermoreactive Clips For Secondary Sternal Closure In Cases Of Noninfective Sternal Dehiscence, Arif Gucu, Faruk Toktas, Cuneyt Eris, Yusuf Ata, Tamer Turk

The Texas Heart Institute Journal

Postoperative sternal dehiscence is a potentially catastrophic sequela to median sternotomy that can cause not only chest-wall discomfort and pulmonary dysfunction but infection, both superficial and mediastinal. Nitinol thermoreactive clips use a novel material in the treatment of sternal dehiscence. We sought to determine whether the use of these clips is an effective remedy for noninfective sternal dehiscence.

From January 2008 through December 2011, we retrospectively studied the data on 10 patients whose sternums had been closed with nitinol thermoreactive clips after the development of noninfective sternal dehiscence. Diagnosis was made on the bases of clinical criteria, chest radiography, and …

Control Of Interneuron Dendritic Growth Through Nrg1/Erbb4-Mediated Kalirin-7 Disinhibition., M. E. Cahill, K. A. Jones, I. Rafalovich, Z. Xie, C. S. Barros, U. Müller, P. Penzes

Peninsula Medical School

Neuregulin 1 (NRG1) is a secreted trophic factor that activates the postsynaptic erbB4 receptor tyrosine kinase. Both NRG1 and erbB4 have been repeatedly associated with schizophrenia, but their downstream targets are not well characterized. ErbB4 is highly abundant in interneurons, and NRG1-mediated erbB4 activation has been shown to modulate interneuron function, but the role for NRG1-erbB4 signaling in regulating interneuron dendritic growth is not well understood. Here we show that NRG1/erbB4 promote the growth of dendrites in mature interneurons through kalirin, a major dendritic Rac1-GEF. Recent studies have shown associations of the KALRN gene with schizophrenia. Our data point to …

C6 Pyridinium Ceramide Influences Alternative Pre-Mrna Splicing By Inhibiting Protein Phosphatase-1, Chiranthani Sumanasekera, Olga Kelemen, Monique Beullens, Brandon E. Aubol, Joseph A. Adams, Manjula Sunkara, Andrew J. Morris, Mathieu Bollen, Athena Andreadis, Stefan Stamm

Molecular and Cellular Biochemistry Faculty Publications

Alternative pre-mRNA processing is a central element of eukaryotic gene regulation. The cell frequently alters the use of alternative exons in response to physiological stimuli. Ceramides are lipid-signaling molecules composed of sphingosine and a fatty acid. Previously, water-insoluble ceramides were shown to change alternative splicing and decrease SR-protein phosphorylation by activating protein phosphatase-1 (PP1). To gain further mechanistical insight into ceramide-mediated alternative splicing, we analyzed the effect of C6 pyridinium ceramide (PyrCer) on alternative splice site selection. PyrCer is a water-soluble ceramide analog that is under investigation as a cancer drug. We found that PyrCer binds to the PP1 catalytic …

Mir-128 Inhibits Tumor Growth And Angiogenesis By Targeting P70s6k1., Zhu-Mei Shi, Jing Wang, Zhiping Yan, Yong-Ping You, Chong-Yong Li, Xu Qian, Yu Yin, Peng Zhao, Ying-Ying Wang, Xie-Feng Wang, Ming-Na Li, Ling-Zhi Liu, Ning Liu, Bing-Hua Jiang

Kimmel Cancer Center Faculty Papers

MicroRNAs are a class of small noncoding RNAs that function as critical gene regulators through targeting mRNAs for translational repression or degradation. In this study, we showed that miR-128 expression levels were decreased in glioma, and identified p70S6K1 as a novel direct target of miR-128. Overexpression of miR-128 suppressed p70S6K1 and its downstream signaling molecules such as HIF-1 and VEGF expression, and attenuated cell proliferation, tumor growth and angiogenesis. Forced expression of p70S6K1 can partly rescue the inhibitory effect of miR-128 in the cells. Taken together, these findings will shed light to the role and mechanism of miR-128 in regulating …

The Formin Fmnl3 Is A Cytoskeletal Regulator Of Angiogenesis, Clare Hetheridge, Alice N. Scott, Rajeeb K. Swain, John W. Copeland, Henry N. Higgs

Dartmouth Scholarship

The process of angiogenesis requires endothelial cells (ECs) to undergo profound changes in shape and polarity. Although this must involve remodelling of the EC cytoskeleton, little is known about this process or the proteins that control it. We used a co-culture assay of angiogenesis to examine the cytoskeleton of ECs actively undergoing angiogenic morphogenesis. We found that elongation of ECs during angiogenesis is accompanied by stabilisation of microtubules and their alignment into parallel arrays directed at the growing tip. In other systems, similar microtubule alignments are mediated by the formin family of cytoskeletal regulators. We screened a library of human …

Cdk1 And Plk1 Mediate A Clasp2 Phospho-Switch That Stabilizes Kinetochore–Microtubule Attachments, Ana R. R. Maia, Zaira Garcia, Lilian Kabeche, Marin Barisic

Dartmouth Scholarship

Accurate chromosome segregation during mitosis relies on a dynamic kinetochore (KT)-microtubule (MT) interface that switches from a labile to a stable condition in response to correct MT attachments. This transition is essential to satisfy the spindle-assembly checkpoint (SAC) and couple MT-generated force with chromosome movements, but the underlying regulatory mechanism remains unclear. In this study, we show that during mitosis the MT- and KT-associated protein CLASP2 is progressively and distinctively phosphorylated by Cdk1 and Plk1 kinases, concomitant with the establishment of KT-MT attachments. CLASP2 S1234 was phosphorylated by Cdk1, which primed CLASP2 for association with Plk1. Plk1 recruitment to KTs …

Src Binds Cortactin Through An Sh2 Domain Cystine-Mediated Linkage, J. V. Evans, A. G. Ammer, J. E. Jett, C. A. Bolcato, J. C. Breaux, K. H. Martin, M. V. Culp, P. M. Gannett, S. A. Weed

Faculty & Staff Scholarship

No abstract provided.

A Pilot Online Survey Assessing Risk Factors For Hiv Acquisition In The Navy And Marine Corps, 2005-2010, Shilpa Hakre, Adam W. Armstrong, Robert J. O'Connell, Nelson L. Michael, Paul T. Scott, David Brett-Major

Journal Articles: Epidemiology

The Department of Defense policy Don't Ask, Don't Tell (DADT) ended in September, 2011. The Navy Bloodborne Infection Management Center conducted a post-DADT pilot survey of HIV seroconverters identified when the DADT policy was in effect. Sailors and Marines newly diagnosed as HIV positive from 2005 to 2010 were invited to participate in an online survey. A structured questionnaire elicited risk information about the 3-year period before HIV diagnosis. Respondents reported engaging commonly in same sex sexual activity, having concurrent partners, and poor condom use for anal sex. In this first post-DADT repeal report of self-reported behaviors, male-to-male sexual contact …