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Article ; Online: A 10-year impact assessment of the Efficacy and Mechanism Evaluation (EME) programme

Maike C Rentel / Kelly Simpson / Anoushka Davé / Scott Carter / Margaret Blake / Jan Franke / Chris Hale / Peter Varnai

Efficacy and Mechanism Evaluation, Vol 8, Iss

an independent mixed-method evaluation study

2021 Volume 20

Abstract: Background: The Efficacy and Mechanism Evaluation (EME) programme – a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership – funds trials that evaluate the efficacy of interventions with the potential to promote ... ...

Abstract	Background: The Efficacy and Mechanism Evaluation (EME) programme – a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership – funds trials that evaluate the efficacy of interventions with the potential to promote health and studies that improve our understanding of the mechanisms of underlying diseases and their treatments. Objective: To conduct an independent review of the EME programme’s impact and identify opportunities for future improvement. Design: A mixed-methods approach, including desk research, an analysis of secondary data, stakeholder consultation and the development of impact case studies. Participants: Chief investigators of EME awards, unfunded applicants to the EME programme and key opinion leaders relevant to the programme and research ecosystem. Interventions: No interventions were tested, as this was a retrospective programme evaluation. Main outcome measures: The evaluation was guided by a set of 15 evaluation questions. Results: The EME programme bridges the gap between proof-of-concept and effectiveness studies that are located among other MRC and NIHR schemes and grants from charities in the funding landscape. Mechanistic studies alongside EME trials add value by lending confidence to trial findings and providing insights into the underlying biology. Between 2009 and September 2018, £175.7M in funding was approved for 145 EME projects. EME programme-funded research has started to deliver value to the NHS and patients by improving treatments and providing more efficient use of resources. Of the 43 completed trials, 14% (n = 6) showed that the intervention had a positive effect, whereas 74% (n = 32) of trials did not. The remaining five (12%) trials were unable to recruit participants or did not proceed to the full-trial stage. Seven projects (i.e. 16% of completed trials) have informed clinical guidelines or regulatory approval decisions and another eight projects have the potential to do so in the future, given the nature of their findings. Projects ...
Keywords	eme programme ; health needs ; research funding ; evaluation ; impact ; outcome ; barriers ; enablers ; Medicine ; R
Subject code	306
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	NIHR Journals Library
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Oxidative stress-induced calcium signaling in Arabidopsis.

Rentel, Maike C / Knight, Marc R

Plant physiology

2004 Volume 135, Issue 3, Page(s) 1471–1479

Abstract: Many environmental stresses result in increased generation of active oxygen species in plant cells. This leads to the induction of protective mechanisms, including changes in gene expression, which lead to antioxidant activity, the recovery of redox ... ...

Abstract	Many environmental stresses result in increased generation of active oxygen species in plant cells. This leads to the induction of protective mechanisms, including changes in gene expression, which lead to antioxidant activity, the recovery of redox balance, and recovery from damage/toxicity. Relatively little is known about the signaling events that link perception of increased active oxygen species levels to gene expression in plants. We have investigated the role of calcium signaling in H2O2-induced expression of the GLUTATHIONE-S-TRANSFERASE1 (GST1) gene. Challenge with H2O2 triggered a biphasic Ca2+ elevation in Arabidopsis seedlings. The early Ca2+ peak localized to the cotyledons, whereas the late Ca2+ rise was restricted to the root. The two phases of the Ca2+ response were independent of each other, as shown by severing shoot from root tissues before H2O2 challenge. Modulation of the height of Ca2+ rises had a corresponding effect upon H2O2-induced GST1 expression. Application of the calcium channel blocker lanthanum reduced the height of the first Ca2+ peak and concomitantly inhibited GST1 expression. Conversely, enhancing the height of the H2O2-triggered Ca2+ signature by treatment with L-buthionine-[S,R]-sulfoximine (an inhibitor of glutathione synthesis) lead to enhancement of GST1 induction. This finding also indicates that changes in the cellular redox balance constitute an early event in H2O2 signal transduction as reduction of the cellular redox buffer and thus the cell's ability to maintain a high GSH/GSSG ratio potentiated the plant's antioxidant response.
MeSH term(s)	Arabidopsis/drug effects ; Arabidopsis/genetics ; Arabidopsis/physiology ; Arabidopsis Proteins/genetics ; Calcium Signaling/physiology ; Glutathione Transferase/genetics ; Hydrogen Peroxide/pharmacology ; Oxidative Stress/physiology ; Plant Shoots/drug effects ; Plant Shoots/physiology
Chemical Substances	Arabidopsis Proteins ; Hydrogen Peroxide (BBX060AN9V) ; Glutathione Transferase (EC 2.5.1.18)
Language	English
Publishing date	2004-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208914-2
ISSN	1532-2548 ; 0032-0889
ISSN (online)	1532-2548
ISSN	0032-0889
DOI	10.1104/pp.104.042663
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Article: Recognition of the Hyaloperonospora parasitica effector ATR13 triggers resistance against oomycete, bacterial, and viral pathogens

Rentel, Maike C / Leonelli, Lauriebeth / Dahlbeck, Douglas / Zhao, Bingyu / Staskawicz, Brian J

Proceedings of the National Academy of Sciences of the United States of America. 2008 Jan. 22, v. 105, no. 3

2008

Abstract: Phytopathogenic oomycetes cause some of the most devastating diseases affecting agricultural crops. Hyaloperonospora parasitica is a native oomycete pathogen of Arabidopsis and is related to other oomycete phytopathogens that include several species of ... ...

Abstract	Phytopathogenic oomycetes cause some of the most devastating diseases affecting agricultural crops. Hyaloperonospora parasitica is a native oomycete pathogen of Arabidopsis and is related to other oomycete phytopathogens that include several species of Phytophthora, including the causal agent of potato late blight. Recently, four oomycete effector genes have been isolated, and several oomycete genomes have been sequenced. We have developed an efficient and genetically amenable system to test putative effector genes using the bacterial pathogen Pseudomonas syringae pv. tomato DC3000. The H. parasitica effector protein ATR13 was delivered via P. syringae by fusing the ATR13 gene with the avrRpm1 type three secretion signal peptide, a bacterial sequence that allows transfer of proteins into the host cell through the bacterial type III secretion system. We also inserted ATR13 into the genome of the turnip mosaic virus, a single-stranded RNA virus. Our results show that delivery of ATR13 via the bacterial or viral pathogen triggers defense responses in plants containing the cognate resistance protein RPP13Nd, which restricts proliferation of both pathogens. Hence, recognition of ATR13 by RPP13 initiates defense responses that are effective against oomycete, bacterial and viral pathogens, pointing to a common defense mechanism. We have characterized regions of the RPP13Nd resistance protein that are essential for effector recognition and/or downstream signaling, using transient coexpression in Nicotiana benthamiana.
Keywords	Arabidopsis thaliana ; Nicotiana benthamiana ; fungal diseases of plants ; Peronospora parasitica ; Pseudomonas syringae pv. tomato ; Turnip mosaic virus ; disease resistance ; genetically engineered microorganisms ; host-pathogen relationships ; fungal proteins ; genes ; gene transfer ; resistance mechanisms
Language	English
Dates of publication	2008-0122
Size	p. 1091-1096.
Publishing place	National Academy of Sciences
Document type	Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Recognition of the Hyaloperonospora parasitica effector ATR13 triggers resistance against oomycete, bacterial, and viral pathogens.

Rentel, Maike C / Leonelli, Lauriebeth / Dahlbeck, Douglas / Zhao, Bingyu / Staskawicz, Brian J

Proceedings of the National Academy of Sciences of the United States of America

2008 Volume 105, Issue 3, Page(s) 1091–1096

Abstract	Phytopathogenic oomycetes cause some of the most devastating diseases affecting agricultural crops. Hyaloperonospora parasitica is a native oomycete pathogen of Arabidopsis and is related to other oomycete phytopathogens that include several species of Phytophthora, including the causal agent of potato late blight. Recently, four oomycete effector genes have been isolated, and several oomycete genomes have been sequenced. We have developed an efficient and genetically amenable system to test putative effector genes using the bacterial pathogen Pseudomonas syringae pv. tomato DC3000. The H. parasitica effector protein ATR13 was delivered via P. syringae by fusing the ATR13 gene with the avrRpm1 type three secretion signal peptide, a bacterial sequence that allows transfer of proteins into the host cell through the bacterial type III secretion system. We also inserted ATR13 into the genome of the turnip mosaic virus, a single-stranded RNA virus. Our results show that delivery of ATR13 via the bacterial or viral pathogen triggers defense responses in plants containing the cognate resistance protein RPP13(Nd), which restricts proliferation of both pathogens. Hence, recognition of ATR13 by RPP13 initiates defense responses that are effective against oomycete, bacterial and viral pathogens, pointing to a common defense mechanism. We have characterized regions of the RPP13(Nd) resistance protein that are essential for effector recognition and/or downstream signaling, using transient coexpression in Nicotiana benthamiana.
MeSH term(s)	Algal Proteins/genetics ; Algal Proteins/metabolism ; Alleles ; Apoptosis ; Arabidopsis/genetics ; Arabidopsis/growth & development ; Arabidopsis/metabolism ; Arabidopsis Proteins/genetics ; Arabidopsis Proteins/metabolism ; Gene Expression ; Mosaic Viruses/genetics ; Mosaic Viruses/pathogenicity ; Mosaic Viruses/physiology ; Oomycetes/genetics ; Oomycetes/pathogenicity ; Oomycetes/physiology ; Plant Diseases/genetics ; Plant Diseases/immunology ; Plant Diseases/microbiology ; Plant Diseases/virology ; Pseudomonas syringae/genetics ; Pseudomonas syringae/physiology ; Nicotiana/cytology ; Nicotiana/genetics ; Nicotiana/growth & development ; Nicotiana/metabolism
Chemical Substances	Algal Proteins ; Arabidopsis Proteins ; RPP13 protein, Arabidopsis
Language	English
Publishing date	2008-01-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0711215105
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Article ; Online: Hem-1 complexes are essential for Rac activation, actin polymerization, and myosin regulation during neutrophil chemotaxis.

Weiner, Orion D / Rentel, Maike C / Ott, Alex / Brown, Glenn E / Jedrychowski, Mark / Yaffe, Michael B / Gygi, Steven P / Cantley, Lewis C / Bourne, Henry R / Kirschner, Marc W

PLoS biology

2006 Volume 4, Issue 2, Page(s) e38

Abstract: ... actin-mediated feedback circuit that organizes the leading edge; and (c) prevents exclusion of activated ...

Abstract	Migrating cells need to make different actin assemblies at the cell's leading and trailing edges and to maintain physical separation of signals for these assemblies. This asymmetric control of activities represents one important form of cell polarity. There are significant gaps in our understanding of the components involved in generating and maintaining polarity during chemotaxis. Here we characterize a family of complexes (which we term leading edge complexes), scaffolded by hematopoietic protein 1 (Hem-1), that organize the neutrophil's leading edge. The Wiskott-Aldrich syndrome protein family Verprolin-homologous protein (WAVE)2 complex, which mediates activation of actin polymerization by Rac, is only one member of this family. A subset of these leading edge complexes are biochemically separable from the WAVE2 complex and contain a diverse set of potential polarity-regulating proteins. RNA interference-mediated knockdown of Hem-1-containing complexes in neutrophil-like cells: (a) dramatically impairs attractant-induced actin polymerization, polarity, and chemotaxis; (b) substantially weakens Rac activation and phosphatidylinositol-(3,4,5)-tris-phosphate production, disrupting the (phosphatidylinositol-(3,4,5)-tris-phosphate)/Rac/F-actin-mediated feedback circuit that organizes the leading edge; and (c) prevents exclusion of activated myosin from the leading edge, perhaps by misregulating leading edge complexes that contain inhibitors of the Rho-actomyosin pathway. Taken together, these observations show that versatile Hem-1-containing complexes coordinate diverse regulatory signals at the leading edge of polarized neutrophils, including but not confined to those involving WAVE2-dependent actin polymerization.
MeSH term(s)	Actins/metabolism ; Animals ; Cell Line ; Cell Polarity ; Chemotaxis ; Enzyme Activation ; Humans ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Molecular Sequence Data ; Myosins/metabolism ; Neutrophils/cytology ; Neutrophils/metabolism ; Phosphatidylinositol Phosphates/biosynthesis ; Phosphorylation ; Protein Binding ; Protein Subunits/metabolism ; Reactive Oxygen Species/metabolism ; Terminology as Topic ; Wiskott-Aldrich Syndrome Protein Family/metabolism ; rac GTP-Binding Proteins/metabolism
Chemical Substances	Actins ; Membrane Proteins ; Phosphatidylinositol Phosphates ; Protein Subunits ; Reactive Oxygen Species ; WASF2 protein, human ; Wiskott-Aldrich Syndrome Protein Family ; phosphatidylinositol 3,4,5-triphosphate ; NCKAP1L protein, human (144351-15-5) ; Myosins (EC 3.6.4.1) ; rac GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2006-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.0040038
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Article ; Online: Hem-1 complexes are essential for Rac activation, actin polymerization, and myosin regulation during neutrophil chemotaxis.

Orion D Weiner / Maike C Rentel / Alex Ott / Glenn E Brown / Mark Jedrychowski / Michael B Yaffe / Steven P Gygi / Lewis C Cantley / Henry R Bourne / Marc W Kirschner

PLoS Biology, Vol 4, Iss 2, p e

2006 Volume 38

Abstract: ... actin-mediated feedback circuit that organizes the leading edge; and (c) prevents exclusion of activated ...

Abstract	Migrating cells need to make different actin assemblies at the cell's leading and trailing edges and to maintain physical separation of signals for these assemblies. This asymmetric control of activities represents one important form of cell polarity. There are significant gaps in our understanding of the components involved in generating and maintaining polarity during chemotaxis. Here we characterize a family of complexes (which we term leading edge complexes), scaffolded by hematopoietic protein 1 (Hem-1), that organize the neutrophil's leading edge. The Wiskott-Aldrich syndrome protein family Verprolin-homologous protein (WAVE)2 complex, which mediates activation of actin polymerization by Rac, is only one member of this family. A subset of these leading edge complexes are biochemically separable from the WAVE2 complex and contain a diverse set of potential polarity-regulating proteins. RNA interference-mediated knockdown of Hem-1-containing complexes in neutrophil-like cells: (a) dramatically impairs attractant-induced actin polymerization, polarity, and chemotaxis; (b) substantially weakens Rac activation and phosphatidylinositol-(3,4,5)-tris-phosphate production, disrupting the (phosphatidylinositol-(3,4,5)-tris-phosphate)/Rac/F-actin-mediated feedback circuit that organizes the leading edge; and (c) prevents exclusion of activated myosin from the leading edge, perhaps by misregulating leading edge complexes that contain inhibitors of the Rho-actomyosin pathway. Taken together, these observations show that versatile Hem-1-containing complexes coordinate diverse regulatory signals at the leading edge of polarized neutrophils, including but not confined to those involving WAVE2-dependent actin polymerization.
Keywords	Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2006-02-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: OXI1 kinase is necessary for oxidative burst-mediated signalling in Arabidopsis.

Rentel, Maike C / Lecourieux, David / Ouaked, Fatma / Usher, Sarah L / Petersen, Lindsay / Okamoto, Haruko / Knight, Heather / Peck, Scott C / Grierson, Claire S / Hirt, Heribert / Knight, Marc R

Nature

2004 Volume 427, Issue 6977, Page(s) 858–861

Abstract: Active oxygen species (AOS) generated in response to stimuli and during development can function as signalling molecules in eukaryotes, leading to specific downstream responses. In plants these include such diverse processes as coping with stress (for ... ...

Abstract	Active oxygen species (AOS) generated in response to stimuli and during development can function as signalling molecules in eukaryotes, leading to specific downstream responses. In plants these include such diverse processes as coping with stress (for example pathogen attack, wounding and oxygen deprivation), abscisic-acid-induced guard-cell closure, and cellular development (for example root hair growth). Despite the importance of signalling via AOS in eukaryotes, little is known about the protein components operating downstream of AOS that mediate any of these processes. Here we show that expression of an Arabidopsis thaliana gene (OXI1) encoding a serine/threonine kinase is induced in response to a wide range of H2O2-generating stimuli. OXI1 kinase activity is itself also induced by H2O2 in vivo. OXI1 is required for full activation of the mitogen-activated protein kinases (MAPKs) MPK3 and MPK6 after treatment with AOS or elicitor and is necessary for at least two very different AOS-mediated processes: basal resistance to Peronospora parasitica infection, and root hair growth. Thus, OXI1 is an essential part of the signal transduction pathway linking oxidative burst signals to diverse downstream responses.
MeSH term(s)	Arabidopsis/enzymology ; Arabidopsis/genetics ; Arabidopsis/metabolism ; Arabidopsis/parasitology ; Arabidopsis Proteins/genetics ; Arabidopsis Proteins/metabolism ; Cellulase/metabolism ; Enzyme Activation/drug effects ; Enzyme Induction/drug effects ; Genes, Reporter ; Genetic Complementation Test ; Hydrogen Peroxide/metabolism ; Hydrogen Peroxide/pharmacology ; MAP Kinase Signaling System/drug effects ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Phytophthora/physiology ; Plant Diseases/genetics ; Plant Diseases/parasitology ; Plant Roots/enzymology ; Plant Roots/growth & development ; Plant Roots/metabolism ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; Respiratory Burst
Chemical Substances	Arabidopsis Proteins ; RNA, Messenger ; Reactive Oxygen Species ; Hydrogen Peroxide (BBX060AN9V) ; OXI1 protein, Arabidopsis (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; ATMPK1 protein, Arabidopsis (EC 2.7.11.24) ; AtMPK3 protein, Arabidopsis (EC 2.7.11.24) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2) ; Cellulase (EC 3.2.1.4)
Language	English
Publishing date	2004-02-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature02353
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