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Article ; Online: Early Treatment with Vigabatrin Does Not Decrease Focal Seizures or Improve Cognition in Tuberous Sclerosis Complex: The PREVeNT Trial.

2023

Abstract: Objective: This study was undertaken to test the hypothesis that early vigabatrin treatment in tuberous sclerosis complex (TSC) infants improves neurocognitive outcome at 24 months of age.: Methods: A phase IIb multicenter randomized double-blind ... ...

Abstract	Objective: This study was undertaken to test the hypothesis that early vigabatrin treatment in tuberous sclerosis complex (TSC) infants improves neurocognitive outcome at 24 months of age. Methods: A phase IIb multicenter randomized double-blind placebo-controlled trial was conducted of vigabatrin at first epileptiform electroencephalogram (EEG) versus vigabatrin at seizure onset in infants with TSC. Primary outcome was Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) cognitive assessment score at 24 months. Secondary outcomes were prevalence of drug-resistant epilepsy, additional developmental outcomes, and safety of vigabatrin. Results: Of 84 infants enrolled, 12 were screen failures, 4 went straight to open label vigabatrin, and 12 were not randomized (normal EEG throughout). Fifty-six were randomized to early vigabatrin (n = 29) or placebo (n = 27). Nineteen of 27 in the placebo arm transitioned to open label vigabatrin, with a median delay of 44 days after randomization. Bayley-III cognitive composite scores at 24 months were similar for participants randomized to vigabatrin or placebo. Additionally, no significant differences were found between groups in overall epilepsy incidence and drug-resistant epilepsy at 24 months, time to first seizure after randomization, and secondary developmental outcomes. Incidence of infantile spasms was lower and time to spasms after randomization was later in the vigabatrin group. Adverse events were similar across groups. Interpretation: Preventative treatment with vigabatrin based on EEG epileptiform activity prior to seizure onset does not improve neurocognitive outcome at 24 months in TSC children, nor does it delay onset or lower the incidence of focal seizures and drug-resistant epilepsy at 24 months. Preventative vigabatrin was associated with later time to onset and lower incidence of infantile spasms. ANN NEUROL 2023.
Language	English
Publishing date	2023-08-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	80362-5
ISSN	1531-8249 ; 0364-5134
ISSN (online)	1531-8249
ISSN	0364-5134
DOI	10.1002/ana.26778
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Article ; Online: The chemical biology of protein phosphorylation.

Tarrant, Mary Katherine / Cole, Philip A

Annual review of biochemistry

2009 Volume 78, Page(s) 797–825

Abstract: The explosion of scientific interest in protein kinase-mediated signaling networks has led to the infusion of new chemical methods and their applications related to the analysis of phosphorylation pathways. We highlight some of these chemical biology ... ...

Abstract	The explosion of scientific interest in protein kinase-mediated signaling networks has led to the infusion of new chemical methods and their applications related to the analysis of phosphorylation pathways. We highlight some of these chemical biology approaches across three areas. First, we discuss the development of chemical tools to modulate the activity of protein kinases to explore kinase mechanisms and their contributions to phosphorylation events and cellular processes. Second, we describe chemical techniques developed in the past few years to dissect the structural and functional effects of phosphate modifications at specific sites in proteins. Third, we cover newly developed molecular imaging approaches to elucidate the spatiotemporal aspects of phosphorylation cascades in live cells. Exciting advances in our understanding of protein phosphorylation have been obtained with these chemical biology approaches, but continuing opportunities for technological innovation remain.
MeSH term(s)	Animals ; Humans ; Phosphorylation ; Protein Kinases/chemistry ; Protein Kinases/metabolism ; Proteins/chemistry ; Proteins/metabolism ; Signal Transduction
Chemical Substances	Proteins ; Protein Kinases (EC 2.7.-)
Language	English
Publishing date	2009-06-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	207924-0
ISSN	1545-4509 ; 0066-4154
ISSN (online)	1545-4509
ISSN	0066-4154
DOI	10.1146/annurev.biochem.78.070907.103047
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Article ; Online: Design and implementation of a digital site-less clinical study of serial rapid antigen testing to identify asymptomatic SARS-CoV-2 infection.

Soni, Apurv / Herbert, Carly / Pretz, Caitlin / Stamegna, Pamela / Filippaios, Andreas / Shi, Qiming / Suvarna, Thejas / Harman, Emma / Schrader, Summer / Nowak, Chris / Schramm, Eric / Kheterpal, Vik / Behar, Stephanie / Tarrant, Seanan / Ferranto, Julia / Hafer, Nathaniel / Robinson, Matthew / Achenbach, Chad / Murphy, Robert L /

Journal of clinical and translational science

2023 Volume 7, Issue 1, Page(s) e120

Abstract: Background: Rapid antigen detection tests (Ag-RDT) for SARS-CoV-2 with emergency use authorization generally include a condition of authorization to evaluate the test's performance in asymptomatic individuals when used serially. We aim to describe a ... ...

Abstract	Background: Rapid antigen detection tests (Ag-RDT) for SARS-CoV-2 with emergency use authorization generally include a condition of authorization to evaluate the test's performance in asymptomatic individuals when used serially. We aim to describe a novel study design that was used to generate regulatory-quality data to evaluate the serial use of Ag-RDT in detecting SARS-CoV-2 virus among asymptomatic individuals. Methods: This prospective cohort study used a siteless, digital approach to assess longitudinal performance of Ag-RDT. Individuals over 2 years old from across the USA with no reported COVID-19 symptoms in the 14 days prior to study enrollment were eligible to enroll in this study. Participants throughout the mainland USA were enrolled through a digital platform between October 18, 2021 and February 15, 2022. Participants were asked to test using Ag-RDT and molecular comparators every 48 hours for 15 days. Enrollment demographics, geographic distribution, and SARS-CoV-2 infection rates are reported. Key results: A total of 7361 participants enrolled in the study, and 492 participants tested positive for SARS-CoV-2, including 154 who were asymptomatic and tested negative to start the study. This exceeded the initial enrollment goals of 60 positive participants. We enrolled participants from 44 US states, and geographic distribution of participants shifted in accordance with the changing COVID-19 prevalence nationwide. Conclusions: The digital site-less approach employed in the "Test Us At Home" study enabled rapid, efficient, and rigorous evaluation of rapid diagnostics for COVID-19 and can be adapted across research disciplines to optimize study enrollment and accessibility.
Language	English
Publishing date	2023-05-10
Publishing country	England
Document type	Journal Article
ISSN	2059-8661
ISSN (online)	2059-8661
DOI	10.1017/cts.2023.540
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Article ; Online: Protein phosphorylation by semisynthesis: from paper to practice.

Szewczuk, Lawrence M / Tarrant, Mary Katherine / Cole, Philip A

Methods in enzymology

2009 Volume 462, Page(s) 1–24

Abstract: Deconvolution of specific phosphorylation events can be complicated by the reversibility of modification. Protein semisynthesis with phosphonate analogues offers an attractive approach to functional analysis of signaling pathways. In this technique, N- ... ...

Abstract	Deconvolution of specific phosphorylation events can be complicated by the reversibility of modification. Protein semisynthesis with phosphonate analogues offers an attractive approach to functional analysis of signaling pathways. In this technique, N- and C-terminal synthetic peptides containing nonhydrolyzable phosphonates at target residues can be ligated to recombinant proteins of interest. The resultant semisynthetic proteins contain site specific, stoichiometric phosphonate modifications and are completely resistant to phosphatases. Control of stoichiometry, specificity, and reversibility allows for complex signaling systems to be broken down into individual events and discretely examined. This chapter outlines the general methods and considerations for designing and carrying out phosphoprotein semisynthetic projects.
MeSH term(s)	Alanine/analogs & derivatives ; Alanine/chemistry ; Animals ; Humans ; Inteins ; Organophosphonates/chemical synthesis ; Organophosphonates/chemistry ; Phenylalanine/analogs & derivatives ; Phenylalanine/chemistry ; Phosphoamino Acids/chemistry ; Phosphopeptides/chemical synthesis ; Phosphoproteins/chemistry ; Phosphoproteins/metabolism ; Phosphorylation ; Phosphoserine/analogs & derivatives ; Phosphoserine/chemistry ; Phosphothreonine/analogs & derivatives ; Phosphothreonine/chemistry ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/metabolism
Chemical Substances	Organophosphonates ; Phosphoamino Acids ; Phosphopeptides ; Phosphoproteins ; Recombinant Fusion Proteins ; phosphonodifluoromethylene alanine ; phosphonodifluoromethylphenylalanine ; Phosphothreonine (1114-81-4) ; Phosphoserine (17885-08-4) ; Phenylalanine (47E5O17Y3R) ; Alanine (OF5P57N2ZX)
Language	English
Publishing date	2009-07-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1557-7988
ISSN (online)	1557-7988
DOI	10.1016/S0076-6879(09)62001-2
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Article: Finding a Needle in a Haystack: Design and Implementation of a Digital Site-less Clinical Study of Serial Rapid Antigen Testing to Identify Asymptomatic SARS-CoV-2 Infection.

medRxiv : the preprint server for health sciences

2023

Abstract: Background: Rapid antigen tests (Ag-RDT) for SARS-CoV-2 with Emergency Use Authorization generally include a condition of authorization to evaluate the test's performance in asymptomatic individuals when used serially.: Objective: To describe a novel ...

Abstract	Background: Rapid antigen tests (Ag-RDT) for SARS-CoV-2 with Emergency Use Authorization generally include a condition of authorization to evaluate the test's performance in asymptomatic individuals when used serially. Objective: To describe a novel study design to generate regulatory-quality data to evaluate serial use of Ag-RDT in detecting SARS-CoV-2 virus among asymptomatic individuals. Design: Prospective cohort study using a decentralized approach. Participants were asked to test using Ag-RDT and molecular comparators every 48 hours for 15 days. Setting: Participants throughout the mainland United States were enrolled through a digital platform between October 18, 2021 and February 15, 2022. Ag-RDTs were completed at home, and molecular comparators were shipped to a central laboratory. Participants: Individuals over 2 years old from across the U.S. with no reported COVID-19 symptoms in the 14 days prior to study enrollment were eligible to enroll in this study. Measurements: Enrollment demographics, geographic distribution, and SARS-CoV-2 infection rates are reported. Key results: A total of 7,361 participants enrolled in the study, and 492 participants tested positive for SARS-CoV-2, including 154 who were asymptomatic and tested negative to start the study. This exceeded the initial enrollment goals of 60 positive participants. We enrolled participants from 44 U.S. states, and geographic distribution of participants shifted in accordance with the changing COVID-19 prevalence nationwide. Limitations: New, complex workflows required significant operational and data team support. Conclusions: The digital site-less approach employed in the 'Test Us At Home' study enabled rapid, efficient, and rigorous evaluation of rapid diagnostics for COVID-19, and can be adapted across research disciplines to optimize study enrollment and accessibility.
Language	English
Publishing date	2023-01-23
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.08.04.22278274
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Article ; Online: Design and implementation of a digital site-less clinical study of serial rapid antigen testing to identify asymptomatic SARS-CoV-2 infection

Apurv Soni / Carly Herbert / Caitlin Pretz / Pamela Stamegna / Andreas Filippaios / Qiming Shi / Thejas Suvarna / Emma Harman / Summer Schrader / Chris Nowak / Eric Schramm / Vik Kheterpal / Stephanie Behar / Seanan Tarrant / Julia Ferranto / Nathaniel Hafer / Matthew Robinson / Chad Achenbach / Robert L. Murphy /

Journal of Clinical and Translational Science, Vol

2023 Volume 7

Abstract: Abstract Background: Rapid antigen detection tests (Ag-RDT) for SARS-CoV-2 with emergency use authorization generally include a condition of authorization to evaluate the test’s performance in asymptomatic individuals when used serially. We aim to ... ...

Abstract	Abstract Background: Rapid antigen detection tests (Ag-RDT) for SARS-CoV-2 with emergency use authorization generally include a condition of authorization to evaluate the test’s performance in asymptomatic individuals when used serially. We aim to describe a novel study design that was used to generate regulatory-quality data to evaluate the serial use of Ag-RDT in detecting SARS-CoV-2 virus among asymptomatic individuals. Methods:This prospective cohort study used a siteless, digital approach to assess longitudinal performance of Ag-RDT. Individuals over 2 years old from across the USA with no reported COVID-19 symptoms in the 14 days prior to study enrollment were eligible to enroll in this study. Participants throughout the mainland USA were enrolled through a digital platform between October 18, 2021 and February 15, 2022. Participants were asked to test using Ag-RDT and molecular comparators every 48 hours for 15 days. Enrollment demographics, geographic distribution, and SARS-CoV-2 infection rates are reported. Key Results:A total of 7361 participants enrolled in the study, and 492 participants tested positive for SARS-CoV-2, including 154 who were asymptomatic and tested negative to start the study. This exceeded the initial enrollment goals of 60 positive participants. We enrolled participants from 44 US states, and geographic distribution of participants shifted in accordance with the changing COVID-19 prevalence nationwide. Conclusions:The digital site-less approach employed in the “Test Us At Home” study enabled rapid, efficient, and rigorous evaluation of rapid diagnostics for COVID-19 and can be adapted across research disciplines to optimize study enrollment and accessibility.
Keywords	Covid-19 ; study recruitment ; digital trial ; rapid antigen tests ; point-of-care diagnostics ; Medicine ; R
Subject code	150
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Cambridge University Press
Document type	Article ; Online
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Article ; Online: Mechanistic insights into the activation of oncogenic forms of EGF receptor.

Wang, Zhihong / Longo, Patti A / Tarrant, Mary Katherine / Kim, Kwangsoo / Head, Sarah / Leahy, Daniel J / Cole, Philip A

Nature structural & molecular biology

2011 Volume 18, Issue 12, Page(s) 1388–1393

Abstract: Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly activated by mutation in non-small cell lung cancer. The mechanism of this oncogenic activation is not completely understood, but in contrast to that of the wild-type ... ...

Abstract	Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly activated by mutation in non-small cell lung cancer. The mechanism of this oncogenic activation is not completely understood, but in contrast to that of the wild-type EGFR, it is proposed to be independent of kinase domain dimerization. Mechanistic studies on EGFR have mainly relied on cell-based assays or isolated kinase domain measurements. Here we show, using purified, near full-length human EGFR proteins (tEGFRs), that two oncogenic mutants are fully active independently of EGF and highly resistant to the therapeutic and endogenous inhibitors cetuximab, lapatinib and MIG6. Based on the pattern of inhibition and the effects of additional asymmetric kinase dimer interface mutations, we propose that these oncogenic EGFR mutants drive and strongly depend on the formation of the asymmetric kinase dimer for activation, which has implications for drug design and cancer treatment strategies.
MeSH term(s)	Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal, Humanized ; Cetuximab ; Epidermal Growth Factor/metabolism ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/chemistry ; ErbB Receptors/genetics ; HEK293 Cells ; Humans ; Kinetics ; Lapatinib ; Lung Neoplasms/genetics ; Models, Molecular ; Mutation ; Quinazolines/pharmacology ; Tumor Suppressor Proteins/chemistry
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Quinazolines ; Tumor Suppressor Proteins ; Lapatinib (0VUA21238F) ; Epidermal Growth Factor (62229-50-9) ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; Cetuximab (PQX0D8J21J)
Language	English
Publishing date	2011-11-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/nsmb.2168
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Article ; Online: Site-specific introduction of an acetyl-lysine mimic into peptides and proteins by cysteine alkylation.

Huang, Rong / Holbert, Marc A / Tarrant, Mary Katherine / Curtet, Sandrine / Colquhoun, David R / Dancy, Beverley M / Dancy, Blair C / Hwang, Yousang / Tang, Yong / Meeth, Katrina / Marmorstein, Ronen / Cole, Robert N / Khochbin, Saadi / Cole, Philip A

Journal of the American Chemical Society

2010 Volume 132, Issue 29, Page(s) 9986–9987

Abstract: Protein acetylation on Lys residues is recognized as a significant post-translational modification in cells, but it is often difficult to discern the direct structural and functional effects of individual acetylation events. Here we describe a new tool, ... ...

Abstract	Protein acetylation on Lys residues is recognized as a significant post-translational modification in cells, but it is often difficult to discern the direct structural and functional effects of individual acetylation events. Here we describe a new tool, methylthiocarbonyl-aziridine, to install acetyl-Lys mimics site-specifically into peptides and proteins by alkylation of Cys residues. We demonstrate that the resultant thiocarbamate modification can be recognized by the Brdt bromodomain and site-specific antiacetyl-Lys antibodies, is resistant to histone deacetylase cleavage, and can confer activation of the histone acetyltransferase Rtt109 by simulating autoacetylation. We also use this approach to obtain functional evidence that acetylation of CK2 protein kinase on Lys102 can stimulate its catalytic activity.
MeSH term(s)	Acetylation ; Alkylation ; Animals ; Aziridines/chemistry ; Aziridines/metabolism ; Binding Sites ; Biomimetic Materials/chemistry ; Biomimetic Materials/metabolism ; Cysteine/metabolism ; Histones/chemistry ; Histones/metabolism ; Lysine/metabolism ; Peptides/chemistry ; Peptides/metabolism ; Proteins/chemistry ; Proteins/metabolism ; Substrate Specificity
Chemical Substances	Aziridines ; Histones ; Peptides ; Proteins ; aziridine (54P5FEX9FH) ; Lysine (K3Z4F929H6) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2010-07-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/ja103954u
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Article ; Online: Seven features of safety in maternity units: a framework based on multisite ethnography and stakeholder consultation.

Liberati, Elisa Giulia / Tarrant, Carolyn / Willars, Janet / Draycott, Tim / Winter, Cathy / Kuberska, Karolina / Paton, Alexis / Marjanovic, Sonja / Leach, Brandi / Lichten, Catherine / Hocking, Lucy / Ball, Sarah / Dixon-Woods, Mary

BMJ quality & safety

2020 Volume 30, Issue 6, Page(s) 444–456

Abstract: Background: Reducing avoidable harm in maternity services is a priority globally. As well as learning from mistakes, it is important to produce rigorous descriptions of 'what good looks like'.: Objective: We aimed to characterise features of safety ... ...

Abstract	Background: Reducing avoidable harm in maternity services is a priority globally. As well as learning from mistakes, it is important to produce rigorous descriptions of 'what good looks like'. Objective: We aimed to characterise features of safety in maternity units and to generate a plain language framework that could be used to guide learning and improvement. Methods: We conducted a multisite ethnography involving 401 hours of non-participant observations 33 semistructured interviews with staff across six maternity units, and a stakeholder consultation involving 65 semistructured telephone interviews and one focus group. Results: We identified seven features of safety in maternity units and summarised them into a framework, named Conclusions: This large qualitative study has enabled the generation of a new plain language framework-For Us-that identifies the behaviours and practices that appear to be features of safe care in hospital-based maternity units.
MeSH term(s)	Anthropology, Cultural ; Female ; Focus Groups ; Humans ; Pregnancy ; Qualitative Research ; Referral and Consultation
Language	English
Publishing date	2020-09-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2592909-4
ISSN	2044-5423 ; 2044-5415
ISSN (online)	2044-5423
ISSN	2044-5415
DOI	10.1136/bmjqs-2020-010988
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Article ; Online: Regulation of CK2 by phosphorylation and O-GlcNAcylation revealed by semisynthesis.

Tarrant, Mary Katherine / Rho, Hee-Sool / Xie, Zhi / Jiang, Yu Lin / Gross, Christopher / Culhane, Jeffrey C / Yan, Gai / Qian, Jiang / Ichikawa, Yoshitaka / Matsuoka, Tatsuji / Zachara, Natasha / Etzkorn, Felicia A / Hart, Gerald W / Jeong, Jun Seop / Blackshaw, Seth / Zhu, Heng / Cole, Philip A

Nature chemical biology

2012 Volume 8, Issue 3, Page(s) 262–269

Abstract: Protein serine-threonine kinase casein kinase II (CK2) is involved in a myriad of cellular processes including cell growth and proliferation through its phosphorylation of hundreds of substrates, yet how CK2 function is regulated is poorly understood. ... ...

Abstract	Protein serine-threonine kinase casein kinase II (CK2) is involved in a myriad of cellular processes including cell growth and proliferation through its phosphorylation of hundreds of substrates, yet how CK2 function is regulated is poorly understood. Here we report that the CK2 catalytic subunit CK2α is modified by O-linked β-N-acetyl-glucosamine (O-GlcNAc) on Ser347, proximal to a cyclin-dependent kinase phosphorylation site (Thr344). We use protein semisynthesis to show that phosphorylation of Thr344 increases the cellular stability of CK2α by strengthening its interaction with Pin1, whereas glycosylation of Ser347 seems to be antagonistic to Thr344 phosphorylation and permissive to proteasomal degradation. By performing kinase assays with site-specifically phospho- and glyco-modified CK2α in combination with CK2β and Pin1 binding partners on human protein microarrays, we show that the kinase substrate selectivity of CK2 is modulated by these specific post-translational modifications. This study suggests how a promiscuous protein kinase can be regulated at multiple levels to achieve particular biological outputs.
MeSH term(s)	Acetylglucosamine/metabolism ; Animals ; Casein Kinase II/biosynthesis ; Casein Kinase II/chemistry ; Casein Kinase II/metabolism ; Cell Line ; Humans ; NIMA-Interacting Peptidylprolyl Isomerase ; Peptidylprolyl Isomerase/chemistry ; Peptidylprolyl Isomerase/metabolism ; Phosphorylation ; Rats ; Serine/metabolism
Chemical Substances	NIMA-Interacting Peptidylprolyl Isomerase ; Serine (452VLY9402) ; Casein Kinase II (EC 2.7.11.1) ; PIN1 protein, human (EC 5.2.1.8) ; Peptidylprolyl Isomerase (EC 5.2.1.8) ; Acetylglucosamine (V956696549)
Language	English
Publishing date	2012-01-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2202962-X
ISSN	1552-4469 ; 1552-4450
ISSN (online)	1552-4469
ISSN	1552-4450
DOI	10.1038/nchembio.771
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