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Sahin G, Palanduz A, Aydogan G, Cassar O, Ertem AU, Telhan L, Canpolat N, Jouanguy E, Picard C, Gessain A, Abel L, Casanova JL, Plancoulaine S
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Classic Kaposi Sarcoma in 3 Unrelated Turkish Children Born to Consanguineous Kindreds
PEDIATRICS 2010 MAR; 125(3):E704-E708
Infection by human herpesvirus 8 (HHV-8) in childhood is common in the Mediterranean basin; however, classic Kaposi sarcoma (KS) is exceedingly rare in children not infected with HIV and not receiving immunosuppression, with only 30 cases having been reported since 1960. We recently reported 2 children with autosomal and X-linked recessive primary immunodeficiencies underlying KS in a context of multiple clinical manifestations. These reports suggested that classic KS in otherwise healthy children might also result from inborn errors of immunity more specific to HHV-8. In this article, we describe 3 unrelated Turkish children with classic KS born to first-cousin parents. The first patient, a girl, developed KS at 2 years of age with disseminated cutaneous and mucosal lesions. The clinical course progressed rapidly, and the patient died within 3 months despite treatment with vincristine. The other 2 children developed a milder form of KS at the age of 9 years, with multiple cutaneous lesions. A boy treated with interferon alpha therapy for 12 months is now in full remission at the age of 14, 2 years after treatment. The second girl is currently stabilized with etoposide, which was begun 4 months ago. None of the 3 children had any relevant familial history or other clinical features. The occurrence of classic KS in 3 unrelated Turkish children, each born to consanguineous parents, strongly suggests that autosomal recessive predisposition may drive the rare occurrence of HHV-8-associated classic KS in children. Pediatrics 2010; 125: e704-e708
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Identification and filtering of uncharacteristic noise in the CMS hadron calorimeter
JOURNAL OF INSTRUMENTATION 2010 MAR; 5(?):? Article T03014
Commissioning studies of the CMS hadron calorimeter have identified sporadic uncharacteristic noise and a small number of malfunctioning calorimeter channels. Algorithms have been developed to identify and address these problems in the data. The methods have been tested on cosmic ray muon data, calorimeter noise data, and single beam data collected with CMS in 2008. The noise rejection algorithms can be applied to LHC collision data at the trigger level or in the offline analysis. The application of the algorithms at the trigger level is shown to remove 90% of noise events with fake missing transverse energy above 100 GeV, which is sufficient for the CMS physics trigger operation.
Zhou MM, Rebholz H, Brocia C, Warner-Schmidt JL, Fienberg AA, Nairn AC, Greengard P, Flajolet M
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Forebrain overexpression of CK1 delta leads to down-regulation of dopamine receptors and altered locomotor activity reminiscent of ADHD
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2010 MAR 2; 107(9):4401-4406
Dopamine neurotransmission controls motor and perseverative behavior, is mediated by protein phosphorylation, and may be perturbed in disorders of attention and hyperactivity. To assess the role of casein kinase I (CK1) in the regulation of dopamine signaling, we generated a genetically modified mouse line that overexpresses CK1 delta (CK1 delta OE) specifically in the forebrain. Overexpression was confirmed both at the mRNA and at the protein levels. Under basal conditions, CK1 delta OE mice exhibited horizontal and vertical hyperactivity, reduced anxiety, and nesting behavior deficiencies. The CK1 delta OE mice also presented paradoxical responses to dopamine receptor stimulation, showing hypoactivity following injection of d-amphetamine or methylphenidate, indicating that CK1 activity has a profound effect on dopamine signaling in vivo. Interestingly, CK1 delta overexpression led to significantly reduced D1R and D2R dopamine receptor levels. All together, under basal conditions and in response to drug stimulation, the behavioral phenotype of CK1 delta OE mice is reminiscent of the symptoms and drug responses observed in attention-deficit/hyperactivity disorder and therefore the CK1 delta OE mice appear to be a model for this disorder.
Ross LF, Loup A, Nelson RM, Botkin JR, Kost R, Smith GR, Gehlert S
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HUMAN SUBJECTS PROTECTIONS IN COMMUNITY-ENGAGED RESEARCH: A RESEARCH ETHICS FRAMEWORK
JOURNAL OF EMPIRICAL RESEARCH ON HUMAN RESEARCH ETHICS 2010 MAR; 5(1):5-17
IN THE 30 YEARS SINCE THE BELMONT Report, the role of the community in research has evolved and has taken on greater moral significance. Today, more and more translational research is being performed with the active engagement of individuals and communities rather than merely upon them. This engagement requires a critical examination of the range of risks that may arise when communities become partners in research. In attempting to provide such an examination, one must distinguish between established communities (groups that have their own organizational structure and leadership and exist regardless of the research) and unstructured groups (groups that may exist because of a shared trait but do not have defined leadership or internal cohesiveness). In order to participate in research as a community, unstructured groups must develop structure either by external means (by partnering with a Community-Based Organization) or by internal means (by empowering the group to organize and establish structure and leadership). When groups participate in research, one must consider risks to well-being due to process and outcomes. These risks may occur to the individual qua individual, but there are also risks that occur to the individual qua member of a group and also risks that occur to the group qua group. There are also risks to agency, both to the individual and the group. A 3-by-3 grid including 3 categories of risks (risks to well-being secondary to process, risks to well-being secondary to outcome and risks to agency) must be evaluated against the 3 distinct agents: individuals as individual participants, individuals as members of a group (both as participants and as non-participants) and to communities as a whole. This new framework for exploring the risks in community-engaged research can help academic researchers and community partners ensure the mutual respect that community-engaged research requires.
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Commissioning and performance of the CMS silicon strip tracker with cosmic ray muons
JOURNAL OF INSTRUMENTATION 2010 MAR; 5(?):? Article T03008
During autumn 2008, the Silicon Strip Tracker was operated with the full CMS experiment in a comprehensive test, in the presence of the 3.8 T magnetic field produced by the CMS superconducting solenoid. Cosmic ray muons were detected in the muon chambers and used to trigger the readout of all CMS sub-detectors. About 15 million events with a muon in the tracker were collected. The efficiency of hit and track reconstruction were measured to be higher than 99% and consistent with expectations from Monte Carlo simulation. This article details the commissioning and performance of the Silicon Strip Tracker with cosmic ray muons.
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Koybasi O, Laasanen AT, Leonardo N, Liu C, Maroussov V, Merkel P, Miller DH, Neumeister N, Sedov A, Shipsey I, Yoo HD, Zheng Y, Jindal P, Parashar N, Cuplov V, Ecklund KM, Geurts FJM, Liu JH, Maronde D, Matveev M, Padley BP, Redjimi R, Roberts J, Sabbatini L, Tumanov A, Betchart B, Bodek A, Budd H, Chung YS, de Barbaro P, Demina R, Flacher H, Gotra Y, Harel A, Korjenevski S, Miner DC, Orbaker D, Petrillo G, Vishnevskiy D, Zielinski M, Bhatti A, Demortier L, Goulianos K, Hatakeyama K, Lungu G, Mesropian C, Yan M, Atramentov O, Bartz E, Gershtein Y, Halkiadakis E, Hits D, Lath A, Rose K, Schnetzer S, Somalwar S, Stone R, Thomas S, Watts TL, Cerizza G, Hollingsworth M, Spanier S, Yang ZC, York A, Asaadi J, Aurisano A, Eusebi R, Golyash A, Gurrola A, Kamon T, Nguyen CN, Pivarski J, Safonov A, Sengupta S, Toback D, Weinberger M, Akchurin N, Berntzon L, Gumus K, Jeong C, Kim H, Lee SW, Popescu S, Roh Y, Sill A, Volobouev I, Washington E, Wigmans R, Yazgan E, Engh D, Florez C, Johns W, Pathak S, Sheldon P, Andelin D, Arenton MW, Balazs M, Boutle S, Buehler M, Conetti S, Cox B, Hirosky R, Ledovskoy A, Neu C, Phillips D, Ronquest M, Yohay R, Gollapinni S, Gunthoti K, Harr R, Karchin PE, Mattson M, Sakharov A, Anderson M, Bachtis M, Bellinger JN, Carlsmith D, Crotty I, Dasu S, Dutta S, Efron J, Feyzi F, Flood K, Gray L, Grogg KS, Grothe M, Hall-Wilton R, Jaworski M, Klabbers P, Klukas J, Lanaro A, Lazaridis C, Leonard J, Loveless R, de Abril MM, Mohapatra A, Ott G, Polese G, Reeder D, Savin A, Smith WH, Sourkov A, Swanson J, Weinberg M, Wenman D, Wensveen M, White A
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CMS data processing workflows during an extended cosmic ray run
JOURNAL OF INSTRUMENTATION 2010 MAR; 5(?):? Article T03006
The CMS Collaboration conducted a month-long data taking exercise, the Cosmic Run At Four Tesla, during October-November 2008, with the goal of commissioning the experiment for extended operation. With all installed detector systems participating, CMS recorded 270 million cosmic ray events with the solenoid at a magnetic field strength of 3.8 T. This paper describes the data flow from the detector through the various online and offline computing systems, as well as the workflows used for recording the data, for aligning and calibrating the detector, and for analysis of the data.
Haurie V, Durrieu-Gaillard S, Dumay-Odelot H, Da Silva D, Rey C, Prochazkova M, Roeder RG, Besser D, Teichmann M
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Two isoforms of human RNA polymerase III with specific functions in cell growth and transformation
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2010 MAR 2; 107(9):4176-4181
Transcription in eukaryotic nuclei is carried out by DNA-dependent RNA polymerases I, II, and III. Human RNA polymerase III (Pol III) transcribes small untranslated RNAs that include tRNAs, 5S RNA, U6 RNA, and some microRNAs. Increased Pol III transcription has been reported to accompany or cause cell transformation. Here we describe a Pol III subunit (RPC32 beta) that led to the demonstration of two human Pol III isoforms (Pol III alpha and Pol III beta). RPC32 beta-containing Pol III beta is ubiquitously expressed and essential for growth of human cells. RPC32 alpha-containing Pol III alpha is dispensable for cell survival, with expression being restricted to undifferentiated ES cells and to tumor cells. In this regard, and most importantly, suppression of RPC32 alpha expression impedes anchorage-independent growth of HeLa cells, whereas ectopic expression of RPC32 alpha in IMR90 fibroblasts enhances cell transformation and dramatically changes the expression of several tumor-related mRNAs and that of a subset of Pol III RNAs. These results identify a human Pol III isoform and isoform-specific functions in the regulation of cell growth and transformation.
Nakamichi N, Kiba T, Henriques R, Mizuno T, Chua NH, Sakakibara H
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PSEUDO-RESPONSE REGULATORS 9, 7, and 5 Are Transcriptional Repressors in the Arabidopsis Circadian Clock
PLANT CELL 2010 MAR; 22(3):594-605
An interlocking transcriptional-translational feedback loop of clock-associated genes is thought to be the central oscillator of the circadian clock in plants. TIMING OF CEXPRESSION1 (also called PSEUDO-RESPONSE REGULATOR1 [PRR1]) and two MYB transcription factors, CIRCADIAN CLOCK ASSOCIATED1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY), play pivotal roles in the loop. Genetic studies have suggested that PRR9, PRR7, and PRR5 also act within or close to the loop; however, their molecular functions remain unknown. Here, we demonstrate that PRR9, PRR7, and PRR5 act as transcriptional repressors of CCA1 and LHY. PRR9, PRR7, and PRR5 each suppress CCA1 and LHY promoter activities and confer transcriptional repressor activity to a heterologous DNA binding protein in a transient reporter assay. Using a glucocorticoid-induced PRR5-GR (glucorticoid receptor) construct, we found that PRR5 directly downregulates CCA1 and LHY expression. Furthermore, PRR9, PRR7, and PRR5 associate with the CCA1 and LHY promoters in vivo, coincident with the timing of decreased CCA1 and LHY expression. These results suggest that the repressor activities of PRR9, PRR7, and PRR5 on the CCA1 and LHY promoter regions constitute the molecular mechanism that accounts for the role of these proteins in the feedback loop of the circadian clock.
Nograles KE, Suarez-Farinas M, Shemer A, Fuentes-Duculan J, Chiricozzi A, Cardinale I, Zaba LC, Kikuchi T, Ramon M, Bergman R, Krueger JG, Guttman-Yassky E
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Atopic dermatitis keratinocytes exhibit normal T(H)17 cytokine responses
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 2010 MAR; 125(3):744-746
Goldberg AD, Banaszynski LA, Noh KM, Lewis PW, Elsaesser SJ, Stadler S, Dewell S, Law M, Guo XY, Li X, Wen DC, Chapgier A, DeKelver RC, Miller JC, Lee YL, Boydston EA, Holmes MC, Gregory PD, Greally JM, Rafii S, Yang CW, Scambler PJ, Garrick D, Gibbons RJ, Higgs DR, Cristea IM, Urnov FD, Zheng DY, Allis CD
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Distinct Factors Control Histone Variant H3.3 Localization at Specific Genomic Regions
CELL 2010 MAR 5; 140(5):678-691
The incorporation of histone H3 variants has been implicated in the epigenetic memory of cellular state. Using genome editing with zinc-finger nucleases to tag endogenous H3.3, we report genome-wide profiles of H3 variants in mammalian embryonic stem cells and neuronal precursor cells. Genome-wide patterns of H3.3 are dependent on amino acid sequence and change with cellular differentiation at developmentally regulated loci. The H3.3 chaperone Hira is required for H3.3 enrichment at active and repressed genes. Strikingly, Hira is not essential for localization of H3.3 at telomeres and many transcription factor binding sites. Immunoaffinity purification and mass spectrometry reveal that the proteins Atrx and Daxx associate with H3.3 in a Hira-independent manner. Atrx is required for Hira-independent localization of H3.3 at telomeres and for the repression of telomeric RNA. Our data demonstrate that multiple and distinct factors are responsible for H3.3 localization at specific genomic locations in mammalian cells.