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Article ; Online: Detection of Post-translationally Modified p53 by Western Blotting.

Barber, Anna Estevan / Meek, David W

Methods in molecular biology (Clifton, N.J.)

2021 Volume 2267, Page(s) 7–18

Abstract: The p53 tumor suppressor has a central role in many key cellular processes including the DNA damage response, aging, stem cell differentiation, and fertility. p53 undergoes extensive regulatory post-translational modification through events such as ... ...

Abstract	The p53 tumor suppressor has a central role in many key cellular processes including the DNA damage response, aging, stem cell differentiation, and fertility. p53 undergoes extensive regulatory post-translational modification through events such as phosphorylation, acetylation, methylation, and ubiquitylation. Here, we describe western blotting-based methodology for the detection and relative quantification of individual phosphorylation events in p53. While we focus on well-established N-terminal modifications for the purpose of illustration, this approach can be used to investigate other post-translational modifications of the protein, drawing upon a broad range of commercially available modification-specific antibodies.
MeSH term(s)	Animals ; Blotting, Western/methods ; Cell Line ; Humans ; Phosphorylation ; Protein Processing, Post-Translational ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Tumor Suppressor Protein p53
Language	English
Publishing date	2021-03-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-1217-0_2
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Article ; Online: Regulation of the p53 response and its relationship to cancer.

Meek, David W

The Biochemical journal

2015 Volume 469, Issue 3, Page(s) 325–346

Abstract: p53 has been studied intensively as a major tumour suppressor that detects oncogenic events in cancer cells and eliminates them through senescence (a permanent non-proliferative state) or apoptosis. Consistent with this role, p53 activity is compromised ... ...

Abstract	p53 has been studied intensively as a major tumour suppressor that detects oncogenic events in cancer cells and eliminates them through senescence (a permanent non-proliferative state) or apoptosis. Consistent with this role, p53 activity is compromised in a high proportion of all cancer types, either through mutation of the TP53 gene (encoding p53) or changes in the status of p53 modulators. p53 has additional roles, which may overlap with its tumour-suppressive capacity, in processes including the DNA damage response, metabolism, aging, stem cell differentiation and fertility. Moreover, many mutant p53 proteins, termed 'gain-of-function' (GOF), acquire new activities that help drive cancer aggression. p53 is regulated mainly through protein turnover and operates within a negative-feedback loop with its transcriptional target, MDM2 (murine double minute 2), an E3 ubiquitin ligase which mediates the ubiquitylation and proteasomal degradation of p53. Induction of p53 is achieved largely through uncoupling the p53-MDM2 interaction, leading to elevated p53 levels. Various stress stimuli acting on p53 (such as hyperproliferation and DNA damage) use different, but overlapping, mechanisms to achieve this. Additionally, p53 activity is regulated through critical context-specific or fine-tuning events, mediated primarily through post-translational mechanisms, particularly multi-site phosphorylation and acetylation. In the present review, I broadly examine these events, highlighting their regulatory contributions, their ability to integrate signals from cellular events towards providing most appropriate response to stress conditions and their importance for tumour suppression. These are fascinating aspects of molecular oncology that hold the key to understanding the molecular pathology of cancer and the routes by which it may be tackled therapeutically.
MeSH term(s)	Animals ; Humans ; Neoplasms/genetics ; Neoplasms/metabolism ; Proto-Oncogene Proteins c-mdm2/genetics ; Proto-Oncogene Proteins c-mdm2/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Tumor Suppressor Protein p53 ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2015-08-01
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BJ20150517
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Article ; Online: Proceedings of the United Kingdom Periprosthetic Joint Infection Meeting 2022: Combined and Arthroplasty Sessions.

Razii, Nima / Kennedy, John W / Shields, David W / Hrycaiczuk, Alex / Morgan-Jones, Rhidian / Meek, R M Dominic / Jamal, Bilal

The Journal of arthroplasty

2023 Volume 39, Issue 1, Page(s) 218–223

Abstract: Considerable variation in practice exists in the prevention, diagnosis, and treatment of periprosthetic joint infection (PJI), which is a devastating complication for patients and surgeons. The consensus principle has been increasingly embraced by the ... ...

Abstract	Considerable variation in practice exists in the prevention, diagnosis, and treatment of periprosthetic joint infection (PJI), which is a devastating complication for patients and surgeons. The consensus principle has been increasingly embraced by the orthopaedic community to help guide practice, especially where high-level evidence remains unavailable. The third United Kingdom Periprosthetic Joint Infection (UK PJI) Meeting was held in Glasgow on April 1, 2022, with more than 180 delegates in attendance, representing orthopaedics, microbiology, infectious diseases, plastic surgery, anesthetics, and allied health professions, including pharmacy and arthroplasty nurses. The meeting comprised a combined session for all delegates, and separate breakout sessions for arthroplasty and fracture-related infection. Consensus questions for each session were prepared in advance by the UK PJI working group, based upon topics that were proposed at previous UK PJI Meetings, and delegates participated in an anonymized electronic voting process. We present the findings of the combined and arthroplasty sessions of the meeting in this article, and each consensus topic is discussed in relation to the contemporary literature.
MeSH term(s)	Humans ; Arthroplasty, Replacement, Knee/adverse effects ; Arthroplasty, Replacement, Hip/adverse effects ; Prosthesis-Related Infections/etiology ; Prosthesis-Related Infections/surgery ; Orthopedic Procedures/adverse effects ; Arthritis, Infectious/etiology ; Arthritis, Infectious/surgery ; Retrospective Studies
Language	English
Publishing date	2023-06-30
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	632770-9
ISSN	1532-8406 ; 0883-5403
ISSN (online)	1532-8406
ISSN	0883-5403
DOI	10.1016/j.arth.2023.06.039
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Article ; Online: Phage display uncovers a sequence motif that drives polypeptide binding to a conserved regulatory exosite of O-GlcNAc transferase.

Alteen, Matthew G / Meek, Richard W / Kolappan, Subramania / Busmann, Jil A / Cao, Jessica / O'Gara, Zoe / Chou, Ying / Derda, Ratmir / Davies, Gideon J / Vocadlo, David J

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

2023 Volume 120, Issue 42, Page(s) e2303690120

Abstract: The modification of nucleocytoplasmic proteins ... ...

Abstract	The modification of nucleocytoplasmic proteins by
MeSH term(s)	Humans ; Amino Acid Sequence ; Peptides ; N-Acetylglucosaminyltransferases/metabolism ; Mutation ; Bacteriophages/metabolism
Chemical Substances	O-GlcNAc transferase (EC 2.4.1.-) ; Peptides ; N-Acetylglucosaminyltransferases (EC 2.4.1.-)
Language	English
Publishing date	2023-10-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2303690120
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Article ; Online: Potent De Novo Macrocyclic Peptides That Inhibit O-GlcNAc Transferase through an Allosteric Mechanism.

Alteen, Matthew G / Peacock, Hayden / Meek, Richard W / Busmann, Jil A / Zhu, Sha / Davies, Gideon J / Suga, Hiroaki / Vocadlo, David J

Angewandte Chemie (International ed. in English)

2022 Volume 62, Issue 5, Page(s) e202215671

Abstract: Glycosyltransferases are a superfamily of enzymes that are notoriously difficult to inhibit. Here we apply an mRNA display technology integrated with genetic code reprogramming, referred to as the RaPID (random non-standard peptides integrated discovery) ...

Abstract	Glycosyltransferases are a superfamily of enzymes that are notoriously difficult to inhibit. Here we apply an mRNA display technology integrated with genetic code reprogramming, referred to as the RaPID (random non-standard peptides integrated discovery) system, to identify macrocyclic peptides with high binding affinities for O-GlcNAc transferase (OGT). These macrocycles inhibit OGT activity through an allosteric mechanism that is driven by their binding to the tetratricopeptide repeats of OGT. Saturation mutagenesis in a maturation screen using 39 amino acids, including 22 non-canonical residues, led to an improved unnatural macrocycle that is ≈40 times more potent than the parent compound (K
MeSH term(s)	Peptides/genetics ; N-Acetylglucosaminyltransferases/genetics ; N-Acetylglucosaminyltransferases/metabolism ; Mutagenesis
Chemical Substances	O-GlcNAc transferase (EC 2.4.1.-) ; Peptides ; N-Acetylglucosaminyltransferases (EC 2.4.1.-)
Language	English
Publishing date	2022-12-27
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.202215671
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Article ; Online: The primary familial brain calcification-associated protein MYORG is an α-galactosidase with restricted substrate specificity.

Meek, Richard W / Brockerman, Jacob / Fordwour, Osei B / Zandberg, Wesley F / Davies, Gideon J / Vocadlo, David J

PLoS biology

2022 Volume 20, Issue 9, Page(s) e3001764

Abstract: Primary familial brain calcification (PFBC) is characterised by abnormal deposits of calcium phosphate within various regions of the brain that are associated with severe cognitive impairments, psychiatric conditions, and movement disorders. Recent ... ...

Abstract	Primary familial brain calcification (PFBC) is characterised by abnormal deposits of calcium phosphate within various regions of the brain that are associated with severe cognitive impairments, psychiatric conditions, and movement disorders. Recent studies in diverse populations have shown a link between mutations in myogenesis-regulating glycosidase (MYORG) and the development of this disease. MYORG is a member of glycoside hydrolase (GH) family 31 (GH31) and, like the other mammalian GH31 enzyme α-glucosidase II, this enzyme is found in the lumen of the endoplasmic reticulum (ER). Though presumed to act as an α-glucosidase due to its localization and sequence relatedness to α-glucosidase II, MYORG has never been shown to exhibit catalytic activity. Here, we show that MYORG is an α-galactosidase and present the high-resolution crystal structure of MYORG in complex with substrate and inhibitor. Using these structures, we map detrimental mutations that are associated with MYORG-associated brain calcification and define how these mutations may drive disease progression through loss of enzymatic activity. Finally, we also detail the thermal stabilisation of MYORG afforded by a clinically approved small molecule ligand, opening the possibility of using pharmacological chaperones to enhance the activity of mutant forms of MYORG.
MeSH term(s)	Animals ; Brain/metabolism ; Brain Diseases/genetics ; Brain Diseases/metabolism ; Glycoside Hydrolases/genetics ; Humans ; Ligands ; Mammals/metabolism ; Muscle Development ; Pedigree ; Substrate Specificity ; alpha-Galactosidase/genetics ; alpha-Galactosidase/metabolism ; alpha-Glucosidases/metabolism
Chemical Substances	Ligands ; Glycoside Hydrolases (EC 3.2.1.-) ; alpha-Glucosidases (EC 3.2.1.20) ; alpha-Galactosidase (EC 3.2.1.22)
Language	English
Publishing date	2022-09-21
Publishing country	United States
Document type	Journal Article ; 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.3001764
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Article ; Online: Tumour suppression by p53: a role for the DNA damage response?

Meek, David W

Nature reviews. Cancer

2009 Volume 9, Issue 10, Page(s) 714–723

Abstract: Loss of p53 function occurs during the development of most, if not all, tumour types. This paves the way for genomic instability, tumour-associated changes in metabolism, insensitivity to apoptotic signals, invasiveness and motility. However, the nature ... ...

Abstract	Loss of p53 function occurs during the development of most, if not all, tumour types. This paves the way for genomic instability, tumour-associated changes in metabolism, insensitivity to apoptotic signals, invasiveness and motility. However, the nature of the causal link between early tumorigenic events and the induction of the p53-mediated checkpoints that constitute a barrier to tumour progression remains uncertain. This Review considers the role of the DNA damage response, which is activated during the early stages of tumour development, in mobilizing the tumour suppression function of p53. The relationship between these events and oncogene-induced p53 activation through the ARF pathway is also discussed.
MeSH term(s)	DNA Damage/physiology ; Humans ; Neoplasms/metabolism ; Signal Transduction ; Tumor Suppressor Protein p14ARF/metabolism ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Tumor Suppressor Protein p14ARF ; Tumor Suppressor Protein p53
Language	English
Publishing date	2009-09-04
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2062767-1
ISSN	1474-1768 ; 1474-175X
ISSN (online)	1474-1768
ISSN	1474-175X
DOI	10.1038/nrc2716
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Article: Obesity is associated with higher complication rates in revision total hip arthroplasty.

Kennedy, John W / Young, David / Meek, Dominic R M / Patil, Sanjeev R

Journal of orthopaedics

2018 Volume 15, Issue 1, Page(s) 70–72

Abstract: We examined differences in complication rates between obese and non-obese patients undergoing revision total hip arthroplasty. Sixty-five patients with a BMI ≥30 kg/ ... ...

Abstract	We examined differences in complication rates between obese and non-obese patients undergoing revision total hip arthroplasty. Sixty-five patients with a BMI ≥30 kg/m
Language	English
Publishing date	2018-01-30
Publishing country	India
Document type	Journal Article
ZDB-ID	2240839-3
ISSN	0972-978X
ISSN	0972-978X
DOI	10.1016/j.jor.2018.01.018
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Article ; Online: Cryo-EM structure provides insights into the dimer arrangement of the O-linked β-N-acetylglucosamine transferase OGT.

Meek, Richard W / Blaza, James N / Busmann, Jil A / Alteen, Matthew G / Vocadlo, David J / Davies, Gideon J

Nature communications

2021 Volume 12, Issue 1, Page(s) 6508

Abstract: The O-linked β-N-acetylglucosamine modification is a core signalling mechanism, with erroneous patterns leading to cancer and neurodegeneration. Although thousands of proteins are subject to this modification, only a single essential glycosyltransferase ... ...

Abstract	The O-linked β-N-acetylglucosamine modification is a core signalling mechanism, with erroneous patterns leading to cancer and neurodegeneration. Although thousands of proteins are subject to this modification, only a single essential glycosyltransferase catalyses its installation, the O-GlcNAc transferase, OGT. Previous studies have provided truncated structures of OGT through X-ray crystallography, but the full-length protein has never been observed. Here, we report a 5.3 Å cryo-EM model of OGT. We show OGT is a dimer, providing a structural basis for how some X-linked intellectual disability mutations at the interface may contribute to disease. We observe that the catalytic section of OGT abuts a 13.5 tetratricopeptide repeat unit region and find the relative positioning of these sections deviate from the previously proposed, X-ray crystallography-based model. We also note that OGT exhibits considerable heterogeneity in tetratricopeptide repeat units N-terminal to the dimer interface with repercussions for how OGT binds protein ligands and partners.
MeSH term(s)	Amino Acids/chemistry ; Amino Acids/metabolism ; Chromium/chemistry ; Chromium/metabolism ; Cryoelectron Microscopy/methods ; Crystallography, X-Ray ; Glycomics ; Mutation/genetics ; Nicotinic Acids/chemistry ; Nicotinic Acids/metabolism ; Protein Structure, Secondary
Chemical Substances	Amino Acids ; Nicotinic Acids ; glucose tolerance factor ; Chromium (0R0008Q3JB)
Language	English
Publishing date	2021-11-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-26796-6
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Article ; Online: Cement-in-cement femoral component revision : a comparison of two different taper-slip designs with medium-term follow up.

Kennedy, John W / Ng, Nigel Y B / Young, David / Kane, Nicholas / Marsh, Andrew G / Meek, R M Dominic

The bone & joint journal

2021 Volume 103-B, Issue 7, Page(s) 1215–1221

Abstract: Aims: Cement-in-cement revision of the femoral component represents a widely practised technique for a variety of indications in revision total hip arthroplasty. In this study, we compare the clinical and radiological outcomes of two polished tapered ... ...

Abstract	Aims: Cement-in-cement revision of the femoral component represents a widely practised technique for a variety of indications in revision total hip arthroplasty. In this study, we compare the clinical and radiological outcomes of two polished tapered femoral components. Methods: From our prospectively collated database, we identified all patients undergoing cement-in-cement revision from January 2005 to January 2013 who had a minimum of two years' follow-up. All cases were performed by the senior author using either an Exeter short revision stem or the C-Stem AMT high offset No. 1 prosthesis. Patients were followed-up annually with clinical and radiological assessment. Results: A total of 97 patients matched the inclusion criteria (50 Exeter and 47 C-Stem AMT components). There were no significant differences between the patient demographic data in either group. Mean follow-up was 9.7 years. A significant improvement in Oxford Hip Score (OHS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and 12-item Short-Form Survey (SF-12) scores was observed in both cohorts. Leg lengths were significantly shorter in the Exeter group, with a mean of -4 mm in this cohort compared with 0 mm in the C-Stem AMT group. One patient in the Exeter group had early evidence of radiological loosening. In total, 16 patients (15%) underwent further revision of the femoral component (seven in the C-Stem AMT group and nine in the Exeter group). No femoral components were revised for aseptic loosening. There were two cases of femoral component fracture in the Exeter group. Conclusion: Our series shows promising mid-term outcomes for the cement-in-cement revision technique using either the Exeter or C-Stem AMT components. These results demonstrate that cement-in-cement revision using a double or triple taper-slip design is a safe and reliable technique when used for the correct indications. Cite this article:
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Arthroplasty, Replacement, Hip/instrumentation ; Arthroplasty, Replacement, Hip/methods ; Cementation ; Female ; Follow-Up Studies ; Hip Prosthesis ; Humans ; Male ; Middle Aged ; Prospective Studies ; Prosthesis Design ; Reoperation/statistics & numerical data
Language	English
Publishing date	2021-06-30
Publishing country	England
Document type	Comparative Study ; Journal Article
ZDB-ID	2697156-2
ISSN	2049-4408 ; 2049-4394
ISSN (online)	2049-4408
ISSN	2049-4394
DOI	10.1302/0301-620X.103B7.BJJ-2020-1953.R2
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