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Article ; Online: Repurposing an endogenous degradation domain for antibody-mediated disposal of cell-surface proteins.

Schmitt, Janika / Poole, Emma / Groves, Ian / Owen, David J / Graham, Stephen C / Sinclair, John / Kelly, Bernard T

2024 Volume 25, Issue 3, Page(s) 951–970

Abstract: The exquisite specificity of antibodies can be harnessed to effect targeted degradation of membrane proteins. Here, we demonstrate targeted protein removal utilising a protein degradation domain derived from the endogenous human protein Proprotein ... ...

Abstract	The exquisite specificity of antibodies can be harnessed to effect targeted degradation of membrane proteins. Here, we demonstrate targeted protein removal utilising a protein degradation domain derived from the endogenous human protein Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9). Recombinant antibodies genetically fused to this domain drive the degradation of membrane proteins that undergo constitutive internalisation and recycling, including the transferrin receptor and the human cytomegalovirus latency-associated protein US28. We term this approach PACTAC (PCSK9-Antibody Clearance-Targeting Chimeras).
MeSH term(s)	Humans ; Proprotein Convertase 9/metabolism ; Serine Endopeptidases ; Proprotein Convertases/metabolism ; Membrane Proteins ; Receptors, LDL/metabolism
Chemical Substances	PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-) ; Proprotein Convertases (EC 3.4.21.-) ; Membrane Proteins ; Receptors, LDL
Language	English
Publishing date	2024-01-29
Publishing country	England
Document type	Journal Article
ZDB-ID	2020896-0
ISSN	1469-3178 ; 1469-221X
ISSN (online)	1469-3178
ISSN	1469-221X
DOI	10.1038/s44319-024-00063-3
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Zs.A 5433: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 41: Show issues

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Article ; Online: Randomized trial comparing standard versus thermocontrolled haemodialysis using intradialytic cardiac, brain and renal magnetic resonance imaging.

Gullapudi, Venkata R Latha / Cox, Eleanor F / Buchanan, Charlotte E / Canaud, Bernard / White, Kelly / Taal, Maarten W / Selby, Nicholas M / Francis, Susan T

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

2023 Volume 39, Issue 2, Page(s) 233–241

Abstract: Background: Ischaemic end-organ damage during haemodialysis (HD) is a significant problem that may be ameliorated by intradialytic cooling. A randomised trial was performed to compare standard HD (SHD; dialysate temperature 37°C) and programmed cooling ... ...

Abstract	Background: Ischaemic end-organ damage during haemodialysis (HD) is a significant problem that may be ameliorated by intradialytic cooling. A randomised trial was performed to compare standard HD (SHD; dialysate temperature 37°C) and programmed cooling of the dialysate [thermocontrolled HD (TCHD)] using multiparametric magnetic resonance imaging (MRI) to assess structural, functional and blood flow changes in the heart, brain and kidneys. Methods: Prevalent HD patients were randomly allocated to receive either SHD or TCHD for 2 weeks before undergoing serial MRI at four time points: pre-, during (30 min and 180 min) and post-dialysis. MRI measures include cardiac index, myocardial strain, longitudinal relaxation time (T1), myocardial perfusion, internal carotid and basilar artery flow, grey matter perfusion and total kidney volume. Participants then crossed to the other modality to repeat the study protocol. Results: Eleven participants completed the study. Separation in blood temperature between TCHD (-0.1 ± 0.3°C) and SHD (+0.3 ± 0.2°C; P = .022) was observed, although there was no difference in tympanic temperature changes between arms. There were significant intradialytic reductions in cardiac index, cardiac contractility (left ventricular strain), left carotid and basilar artery blood flow velocities, total kidney volume, longitudinal relaxation time (T1) of the renal cortex and transverse relaxation rate (T2) of the renal cortex and medulla, but no differences between arms. Pre-dialysis T1 of the myocardium and left ventricular wall mass index were lower after 2 weeks of TCHD compared with SHD [1266 ms (interquartile range 1250-1291) versus 1311 ± 58 ms, P = .02; 66 ± 22 g/m2 versus 72 ± 23 g/m2, P = .004]. Conclusions:* HD adversely affects cardiac function, reduces carotid and basilar artery blood flow and total kidney volume, but mild dialysate cooling using a biofeedback module did not result in differences in intradialytic MRI measures compared with SHD.
MeSH term(s)	Humans ; Renal Dialysis/adverse effects ; Renal Dialysis/methods ; Kidney ; Kidney Failure, Chronic ; Dialysis Solutions ; Magnetic Resonance Imaging ; Brain/diagnostic imaging
Chemical Substances	Dialysis Solutions
Language	English
Publishing date	2023-06-28
Publishing country	England
Document type	Randomized Controlled Trial ; Journal Article
ZDB-ID	90594-x
ISSN	1460-2385 ; 0931-0509
ISSN (online)	1460-2385
ISSN	0931-0509
DOI	10.1093/ndt/gfad150
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Zs.A 2198: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 329: Show issues

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Article ; Online: Mobility and Sporting Activity After Renal Trauma: A Survey Regarding Best Clinical Practice During the Recovery Stage.

't Hoen, Lisette A / O'Kelly, Fardod / Lammers, Rianne J M / Dönmez, Muhammet İrfan / Baydilli, Numan / Sforza, Simone / Bindi, Eduardo / Atwa, Ahmed / Haid, Bernard / Quiroz, Yesica / Marco, Beatriz Bañuelos

Urology

2023 Volume 183, Page(s) 199–203

Abstract: Objective: To evaluate strategies that are followed after pediatric renal trauma during the recovery stage, with an emphasis on mobility and involvement in subsequent sporting activities. Renal trauma is the most common urogenital trauma in children. ... ...

Abstract	Objective: To evaluate strategies that are followed after pediatric renal trauma during the recovery stage, with an emphasis on mobility and involvement in subsequent sporting activities. Renal trauma is the most common urogenital trauma in children. The American Association for the Surgery of Trauma (AAST) scale is most commonly used to stratify the severity of injury. There is no consensus in the existing literature with respect to the recovery stage following renal trauma. Methods: A survey was constructed by the European Association of Urology (EAU) - Young Academic Urologists (YAU) Pediatric Urology Working Group and then made digitally available on SurveyMonkey. The survey consists of 15 questions exploring relevant factors and timing to start again with mobility and activity. Results: In total 153 people responded, of whom 107 completed the entire survey. The presence of pain and severity of trauma were acknowledged as most important factors to commence mobilization, whereas presence of hematuria was identified as an additional factor for sporting activity. Regardless of severity of trauma a minimum of 90% of respondents recommend return to noncontact sports within 12weeks. For contact sports, a minimum of 33% of respondents advised >12weeks minimum before starting again. A small number of respondents would never allow sporting activities again. Conclusion: The time to allow sporting activity shows high variation among the respondents, some even restricting sporting activities completely. This survey highlights the need for a standardized protocol based on multicenter follow-up data.
MeSH term(s)	Humans ; Child ; Sports ; Surveys and Questionnaires ; Urology ; Pain ; Kidney
Language	English
Publishing date	2023-10-06
Publishing country	United States
Document type	Multicenter Study ; Journal Article
ZDB-ID	192062-5
ISSN	1527-9995 ; 0090-4295
ISSN (online)	1527-9995
ISSN	0090-4295
DOI	10.1016/j.urology.2023.09.030
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Zs.A 1142: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 275: Show issues

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Article ; Online: Architecture of the AP2/clathrin coat on the membranes of clathrin-coated vesicles.

Kovtun, Oleksiy / Dickson, Veronica Kane / Kelly, Bernard T / Owen, David J / Briggs, John A G

Science advances

2020 Volume 6, Issue 30, Page(s) eaba8381

Abstract: Clathrin-mediated endocytosis (CME) is crucial for modulating the protein composition of a cell's plasma membrane. Clathrin forms a cage-like, polyhedral outer scaffold around a vesicle, to which cargo-selecting clathrin adaptors are attached. Adaptor ... ...

Abstract	Clathrin-mediated endocytosis (CME) is crucial for modulating the protein composition of a cell's plasma membrane. Clathrin forms a cage-like, polyhedral outer scaffold around a vesicle, to which cargo-selecting clathrin adaptors are attached. Adaptor protein complex (AP2) is the key adaptor in CME. Crystallography has shown AP2 to adopt a range of conformations. Here, we used cryo-electron microscopy, tomography, and subtomogram averaging to determine structures, interactions, and arrangements of clathrin and AP2 at the key steps of coat assembly, from AP2 in solution to membrane-assembled clathrin-coated vesicles (CCVs). AP2 binds cargo and PtdIns(4,5)
Language	English
Publishing date	2020-07-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.aba8381
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Article ; Online: Using selenomethionyl derivatives to assign sequence in low-resolution structures of the AP2 clathrin adaptor.

Kelly, Bernard T / Graham, Stephen C / Owen, David J

Acta crystallographica. Section D, Structural biology

2016 Volume 72, Issue Pt 3, Page(s) 336–345

Abstract: Selenomethionine incorporation is a powerful technique for assigning sequence to regions of electron density at low resolution. Genetic introduction of methionine point mutations and the subsequent preparation and crystallization of selenomethionyl ... ...

Abstract	Selenomethionine incorporation is a powerful technique for assigning sequence to regions of electron density at low resolution. Genetic introduction of methionine point mutations and the subsequent preparation and crystallization of selenomethionyl derivatives permits unambiguous sequence assignment by enabling the placement of the anomalous scatterers (Se atoms) thus introduced. Here, the use of this approach in the assignment of sequence in a part of the AP2 clathrin adaptor complex that is responsible for clathrin binding is described. AP2 plays a pivotal role in clathrin-mediated endocytosis, a tightly regulated process in which cell-surface transmembrane proteins are internalized from the plasma membrane by incorporation into lipid-enclosed transport vesicles. AP2 binds cargo destined for internalization and recruits clathrin, a large trimeric protein that helps to deform the membrane to produce the transport vesicle. By selenomethionine labelling of point mutants, it was shown that the clathrin-binding site is buried within a deep cleft of the AP2 complex. A membrane-stimulated conformational change in AP2 releases the clathrin-binding site from autoinhibition, thereby linking clathrin recruitment to membrane localization.
MeSH term(s)	Adaptor Protein Complex 2/chemistry ; Adaptor Protein Complex 2/metabolism ; Animals ; Binding Sites ; Clathrin/metabolism ; Crystallization ; Crystallography, X-Ray ; Endocytosis ; Humans ; Mice ; Models, Molecular ; Protein Binding ; Protein Conformation ; Rats ; Selenomethionine/chemistry
Chemical Substances	Adaptor Protein Complex 2 ; Clathrin ; Selenomethionine (964MRK2PEL)
Language	English
Publishing date	2016-03-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2020492-9
ISSN	2059-7983 ; 1399-0047 ; 0907-4449
ISSN (online)	2059-7983 ; 1399-0047
ISSN	0907-4449
DOI	10.1107/S2059798315021580
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Book: Firm volatility in granual networks

Herskovic, Bernard / Kelly, Bryan T / Lustig, Hanno / Nieuwerburgh, Stijn van

(Discussion paper series / Centre for Economic Policy Research : Financial economics ; DP 12284)

2017

Author's details	Bernard Herskovic, Bryan Kelly, Hanno Lustig and Stijn van Nieuwerburgh
Series title	Discussion paper series / Centre for Economic Policy Research : Financial economics ; DP 12284
Language	English
Size	47 Seiten, Illustrationen
Publisher	Centre for Economic Policy Research
Publishing place	London
Document type	Book
Note	Erscheint auch als Online-Ausgabe
Database	ECONomics Information System

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Article ; Online: Prevalence of Fibromyalgia Syndrome in Active-Duty Military Personnel.

Lawrence-Wolff, Katrina M / Higgs, Jay B / Young-McCaughan, Stacey / Mintz, Jim / Foa, Edna B / Resick, Patricia A / Kelly, Kevin M / Maurer, Douglas M / Borah, Adam M / Yarvis, Jeffrey S / Litz, Brett T / Hildebrand, Bernard A / Williamson, Douglas E / Peterson, Alan L

Arthritis care & research

2022 Volume 75, Issue 3, Page(s) 667–673

Abstract: Objective: Previous research with civilian populations has found strong associations between fibromyalgia (FM) and posttraumatic stress disorder (PTSD). We undertook this study to investigate the prevalence of FM in military service members with and ... ...

Abstract	Objective: Previous research with civilian populations has found strong associations between fibromyalgia (FM) and posttraumatic stress disorder (PTSD). We undertook this study to investigate the prevalence of FM in military service members with and without PTSD. Methods: Participants were active duty military personnel recruited into either an epidemiologic cohort study of service members before a military deployment or 1 of 3 PTSD treatment trials. Instruments used to document FM and PTSD included the PTSD Checklist-Stressor-Specific Version, the PTSD Symptom Scale-Interview, and the 2012 American College of Rheumatology FM questionnaire. Results: Across the 4 studies, 4,376 subjects completed surveys. The prevalence of FM was 2.9% in the predeployment cohort, and the prevalence was significantly higher in individuals with PTSD (10.8%) compared with those without PTSD (0.8%). In the treatment trials, all of the participants met criteria for PTSD before starting treatment, and the prevalence of FM was 39.7%. Conclusion: The prevalence of FM in active duty service members preparing to deploy is similar to that reported for the general population of the US but is higher than expected for a predominantly male cohort. Furthermore, the prevalence of FM was significantly higher in service members with comorbid PTSD and was highest among those seeking treatment for PTSD. Further investigation is needed to determine the factors linking PTSD and FM.
MeSH term(s)	Humans ; Male ; Female ; Military Personnel ; Fibromyalgia/diagnosis ; Fibromyalgia/epidemiology ; Cohort Studies ; Prevalence ; Stress Disorders, Post-Traumatic/diagnosis ; Stress Disorders, Post-Traumatic/epidemiology ; Stress Disorders, Post-Traumatic/therapy
Language	English
Publishing date	2022-10-31
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	645059-3
ISSN	2151-4658 ; 0893-7524 ; 2151-464X
ISSN (online)	2151-4658
ISSN	0893-7524 ; 2151-464X
DOI	10.1002/acr.24801
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Zs.A 2446: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.A 24: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Endocytic sorting of transmembrane protein cargo.

Kelly, Bernard T / Owen, David J

Current opinion in cell biology

2011 Volume 23, Issue 4, Page(s) 404–412

Abstract: The accurate distribution and recycling of transmembrane proteins amongst the membrane-bound organelles of the cell is vital to ensure its correct functioning. Transmembrane protein cargo destined for clathrin-mediated endocytosis and transport along the ...

Abstract	The accurate distribution and recycling of transmembrane proteins amongst the membrane-bound organelles of the cell is vital to ensure its correct functioning. Transmembrane protein cargo destined for clathrin-mediated endocytosis and transport along the endocytic pathway is sorted into transport vesicles by interactions with adaptors, which simultaneously link clathrin to the membrane. Clathrin adaptors recognize a variety of signals present in the cytoplasmic portions of cargo proteins; recent structural, biophysical and cell biological studies have elucidated new types of cargo-adaptor interactions and probed the molecular mechanisms regulating cargo selection and vesicle maturation. Here, we review this recent progress in the context of our existing knowledge of endocytic sorting mechanisms.
MeSH term(s)	Animals ; Clathrin/metabolism ; Clathrin-Coated Vesicles/metabolism ; Endocytosis ; Humans ; Protein Transport ; Proteins/chemistry ; Proteins/metabolism ; Signal Transduction ; Transport Vesicles/metabolism
Chemical Substances	Clathrin ; Proteins
Language	English
Publishing date	2011-03-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1026381-0
ISSN	1879-0410 ; 0955-0674
ISSN (online)	1879-0410
ISSN	0955-0674
DOI	10.1016/j.ceb.2011.03.004
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Zs.A 2963: Show issues

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Article ; Online: Temporal Ordering in Endocytic Clathrin-Coated Vesicle Formation via AP2 Phosphorylation.

Wrobel, Antoni G / Kadlecova, Zuzana / Kamenicky, Jan / Yang, Ji-Chun / Herrmann, Torsten / Kelly, Bernard T / McCoy, Airlie J / Evans, Philip R / Martin, Stephen / Müller, Stefan / Salomon, Susanne / Sroubek, Filip / Neuhaus, David / Höning, Stefan / Owen, David J

Developmental cell

2020 Volume 52, Issue 5, Page(s) 673

Language	English
Publishing date	2020-03-10
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2054967-2
ISSN	1878-1551 ; 1534-5807
ISSN (online)	1878-1551
ISSN	1534-5807
DOI	10.1016/j.devcel.2020.02.010
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Zs.A 5742: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 76: Show issues

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Article ; Online: Cellular and viral peptides bind multiple sites on the N-terminal domain of clathrin.

Muenzner, Julia / Traub, Linton M / Kelly, Bernard T / Graham, Stephen C

Traffic (Copenhagen, Denmark)

2016 Volume 18, Issue 1, Page(s) 44–57

Abstract: Short peptide motifs in unstructured regions of clathrin-adaptor proteins recruit clathrin to membranes to facilitate post-Golgi membrane transport. Three consensus clathrin-binding peptide sequences have been identified and structural studies show that ... ...

Abstract	Short peptide motifs in unstructured regions of clathrin-adaptor proteins recruit clathrin to membranes to facilitate post-Golgi membrane transport. Three consensus clathrin-binding peptide sequences have been identified and structural studies show that each binds distinct sites on the clathrin heavy chain N-terminal domain (NTD). A fourth binding site for adaptors on NTD has been functionally identified but not structurally characterised. We have solved high resolution structures of NTD bound to peptide motifs from the cellular clathrin adaptors β2 adaptin and amphiphysin plus a putative viral clathrin adaptor, hepatitis D virus large antigen (HDAg-L). Surprisingly, with each peptide we observe simultaneous peptide binding at multiple sites on NTD and viral peptides binding to the same sites as cellular peptides. Peptides containing clathrin-box motifs (CBMs) with the consensus sequence LΦxΦ[DE] bind at the 'arrestin box' on NTD, between β-propeller blades 4 and 5, which had previously been thought to bind a distinct consensus sequence. Further, we structurally define the fourth peptide binding site on NTD, which we term the Royle box. In vitro binding assays show that clathrin is more readily captured by cellular CBMs than by HDAg-L, and site-directed mutagenesis confirms that multiple binding sites on NTD contribute to efficient capture by CBM peptides.
MeSH term(s)	Adaptor Proteins, Vesicular Transport/metabolism ; Amino Acid Sequence ; Binding Sites/physiology ; Clathrin Heavy Chains/metabolism ; Hepatitis delta Antigens/metabolism ; Humans ; Nerve Tissue Proteins/metabolism ; Peptides/metabolism ; Protein Binding/physiology
Chemical Substances	Adaptor Proteins, Vesicular Transport ; Hepatitis delta Antigens ; Nerve Tissue Proteins ; Peptides ; hepatitis delta virus large antigen ; Clathrin Heavy Chains (114899-12-6) ; amphiphysin (147954-52-7)
Language	English
Publishing date	2016-12-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1483852-7
ISSN	1600-0854 ; 1398-9219
ISSN (online)	1600-0854
ISSN	1398-9219
DOI	10.1111/tra.12457
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