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Article ; Online: Oncogenic cell tagging and single-cell transcriptomics reveal cell type-specific and time-resolved responses to Vhl inactivation in the kidney.

Kurlekar, Samvid / Lima, Joanna D C C / Li, Ran / Lombardi, Olivia / Masson, Norma / Barros, Ayslan B / Pontecorvi, Virginia / Mole, David R / Pugh, Christopher W / Adam, Julie / Ratcliffe, Peter J

Cancer research

2024

Abstract: Defining the initial events in oncogenesis and the cellular responses they entrain, even in advance of morphological abnormality, is a fundamental challenge in understanding cancer initiation. As a paradigm to address this, we longitudinally studied the ... ...

Abstract	Defining the initial events in oncogenesis and the cellular responses they entrain, even in advance of morphological abnormality, is a fundamental challenge in understanding cancer initiation. As a paradigm to address this, we longitudinally studied the changes induced by loss of the tumor suppressor gene von Hippel Lindau (VHL), which ultimately drives clear cell renal cell carcinoma. Vhl inactivation was directly coupled to expression of a tdTomato reporter within a single allele, allowing accurate visualization of affected cells in their native context and retrieval from the kidney for single-cell RNA-sequencing. This strategy uncovered cell-type specific responses to Vhl inactivation, defined a proximal tubular cell class with oncogenic potential, and revealed longer term adaptive changes in the renal epithelium and the interstitium. Oncogenic cell tagging also revealed markedly heterogeneous cellular effects including time-limited proliferation and elimination of specific cell types. Overall, this study reports an experimental strategy for understanding oncogenic processes in which cells bearing genetic alterations can be generated in their native context, marked, and analyzed over time. The observed effects of loss of Vhl in kidney cells provide insights into VHL tumor suppressor action and development of renal cell carcinoma.
Language	English
Publishing date	2024-03-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-23-3248
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Article: Hypoxia signaling pathways in cancer metabolism: the importance of co-selecting interconnected physiological pathways.

Masson, Norma / Ratcliffe, Peter J

Cancer & metabolism

2014 Volume 2, Issue 1, Page(s) 3

Abstract: Both tumor hypoxia and dysregulated metabolism are classical features of cancer. Recent analyses have revealed complex interconnections between oncogenic activation, hypoxia signaling systems and metabolic pathways that are dysregulated in cancer. These ... ...

Abstract	Both tumor hypoxia and dysregulated metabolism are classical features of cancer. Recent analyses have revealed complex interconnections between oncogenic activation, hypoxia signaling systems and metabolic pathways that are dysregulated in cancer. These studies have demonstrated that rather than responding simply to error signals arising from energy depletion or tumor hypoxia, metabolic and hypoxia signaling pathways are also directly connected to oncogenic signaling mechanisms at many points. This review will summarize current understanding of the role of hypoxia inducible factor (HIF) in these networks. It will also discuss the role of these interconnected pathways in generating the cancer phenotype; in particular, the implications of switching massive pathways that are physiologically 'hard-wired' to oncogenic mechanisms driving cancer.
Language	English
Publishing date	2014-02-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2700141-6
ISSN	2049-3002
ISSN	2049-3002
DOI	10.1186/2049-3002-2-3
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Article ; Online: Widespread hydroxylation of unstructured lysine-rich protein domains by JMJD6.

Cockman, Matthew E / Sugimoto, Yoichiro / Pegg, Hamish B / Masson, Norma / Salah, Eidarus / Tumber, Anthony / Flynn, Helen R / Kirkpatrick, Joanna M / Schofield, Christopher J / Ratcliffe, Peter J

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

2022 Volume 119, Issue 32, Page(s) e2201483119

Abstract: The Jumonji domain-containing protein JMJD6 is a 2-oxoglutarate-dependent dioxygenase associated with a broad range of biological functions. Cellular studies have implicated the enzyme in chromatin biology, transcription, DNA repair, mRNA splicing, and ... ...

Abstract	The Jumonji domain-containing protein JMJD6 is a 2-oxoglutarate-dependent dioxygenase associated with a broad range of biological functions. Cellular studies have implicated the enzyme in chromatin biology, transcription, DNA repair, mRNA splicing, and cotranscriptional processing. Although not all studies agree, JMJD6 has been reported to catalyze both hydroxylation of lysine residues and demethylation of arginine residues. However, despite extensive study and indirect evidence for JMJD6 catalysis in many cellular processes, direct assignment of JMJD6 catalytic substrates has been limited. Examination of a reported site of proline hydroxylation within a lysine-rich region of the tandem bromodomain protein BRD4 led us to conclude that hydroxylation was in fact on lysine and catalyzed by JMJD6. This prompted a wider search for JMJD6-catalyzed protein modifications deploying mass spectrometric methods designed to improve the analysis of such lysine-rich regions. Using lysine derivatization with propionic anhydride to improve the analysis of tryptic peptides and nontryptic proteolysis, we report 150 sites of JMJD6-catalyzed lysine hydroxylation on 48 protein substrates, including 19 sites of hydroxylation on BRD4. Most hydroxylations were within lysine-rich regions that are predicted to be unstructured; in some, multiple modifications were observed on adjacent lysine residues. Almost all of the JMJD6 substrates defined in these studies have been associated with membraneless organelle formation. Given the reported roles of lysine-rich regions in subcellular partitioning by liquid-liquid phase separation, our findings raise the possibility that JMJD6 may play a role in regulating such processes in response to stresses, including hypoxia.
MeSH term(s)	Cell Cycle Proteins/metabolism ; Humans ; Hydroxylation ; Intrinsically Disordered Proteins/metabolism ; Jumonji Domain-Containing Histone Demethylases/chemistry ; Jumonji Domain-Containing Histone Demethylases/metabolism ; Lysine/metabolism ; Protein Domains ; Transcription Factors/metabolism
Chemical Substances	BRD4 protein, human ; Cell Cycle Proteins ; Intrinsically Disordered Proteins ; Transcription Factors ; JMJD6 protein, human (EC 1.14.11.-) ; Jumonji Domain-Containing Histone Demethylases (EC 1.14.11.-) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2022-08-05
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.2201483119
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Article ; Online: Two antioxidants are better than one.

Lappin, Terence / Masson, Norma

Blood

2011 Volume 117, Issue 20, Page(s) 5276–5277

Abstract: New evidence suggests that the cellular oxygen-sensing hypoxia-inducible factor(HIF) pathway may be protected by a double buffer of cellular antioxidant defense. Key players in the oxygen-dependent regulation of this pathway are the prolyl hydroxylase ... ...

Abstract	New evidence suggests that the cellular oxygen-sensing hypoxia-inducible factor(HIF) pathway may be protected by a double buffer of cellular antioxidant defense. Key players in the oxygen-dependent regulation of this pathway are the prolyl hydroxylase domain-containing enzymes (PHDs) that catalyze the prolyl-4-hydroxylation of HIFα, dependent on the presence of oxygen, 2-oxoglutarate, and iron in the ferrous (Fe(2+)) form. Vitamin C is also required as a cofactor, possibly to maintain the catalytic iron center in its functional Fe(2+)) state, although both the mechanism and the in vivo requirement are not absolutely clear.
Language	English
Publishing date	2011-05-19
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2011-03-340414
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Article ; Online: Fundamentals of HDX-MS.

Vinciauskaite, Vanesa / Masson, Glenn R

Essays in biochemistry

2022 Volume 67, Issue 2, Page(s) 301–314

Abstract: Hydrogen deuterium exchange mass spectrometry (HDX-MS) is becoming part of the standard repertoire ... of a standard HDX-MS experiment, as well as highlighting emerging novel experimental advances, which point ...

Abstract	Hydrogen deuterium exchange mass spectrometry (HDX-MS) is becoming part of the standard repertoire of techniques used by molecular biologists to investigate protein structure and dynamics. This is partly due to the increased use of automation in all stages of the technique and its versatility of application-many proteins that present challenges with techniques such as X-ray crystallography and cryoelectron microscopy are amenable to investigation with HDX-MS. The present review is aimed at scientists who are curious about the technique, and how it may aid their research. It describes the fundamental basis of solvent exchange, the basics of a standard HDX-MS experiment, as well as highlighting emerging novel experimental advances, which point to where the field is heading.
MeSH term(s)	Hydrogen Deuterium Exchange-Mass Spectrometry ; Mass Spectrometry/methods ; Cryoelectron Microscopy ; Deuterium Exchange Measurement/methods ; Proteins/chemistry
Chemical Substances	Proteins
Language	English
Publishing date	2022-10-17
Publishing country	England
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1744-1358 ; 0071-1365
ISSN (online)	1744-1358
ISSN	0071-1365
DOI	10.1042/EBC20220111
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Article ; Online: Conformational Stability and Denaturation Processes of Proteins Investigated by Electrophoresis under Extreme Conditions.

Masson, Patrick / Lushchekina, Sofya

Molecules (Basel, Switzerland)

2022 Volume 27, Issue 20

Abstract: ... to extremes of physical conditions, electrophoresis under standard conditions provides information ...

Abstract	The functional structure of proteins results from marginally stable folded conformations. Reversible unfolding, irreversible denaturation, and deterioration can be caused by chemical and physical agents due to changes in the physicochemical conditions of pH, ionic strength, temperature, pressure, and electric field or due to the presence of a cosolvent that perturbs the delicate balance between stabilizing and destabilizing interactions and eventually induces chemical modifications. For most proteins, denaturation is a complex process involving transient intermediates in several reversible and eventually irreversible steps. Knowledge of protein stability and denaturation processes is mandatory for the development of enzymes as industrial catalysts, biopharmaceuticals, analytical and medical bioreagents, and safe industrial food. Electrophoresis techniques operating under extreme conditions are convenient tools for analyzing unfolding transitions, trapping transient intermediates, and gaining insight into the mechanisms of denaturation processes. Moreover, quantitative analysis of electrophoretic mobility transition curves allows the estimation of the conformational stability of proteins. These approaches include polyacrylamide gel electrophoresis and capillary zone electrophoresis under cold, heat, and hydrostatic pressure and in the presence of non-ionic denaturing agents or stabilizers such as polyols and heavy water. Lastly, after exposure to extremes of physical conditions, electrophoresis under standard conditions provides information on irreversible processes, slow conformational drifts, and slow renaturation processes. The impressive developments of enzyme technology with multiple applications in fine chemistry, biopharmaceutics, and nanomedicine prompted us to revisit the potentialities of these electrophoretic approaches. This feature review is illustrated with published and unpublished results obtained by the authors on cholinesterases and paraoxonase, two physiologically and toxicologically important enzymes.
MeSH term(s)	Protein Denaturation ; Protein Conformation ; Deuterium Oxide ; Aryldialkylphosphatase ; Electrophoresis, Polyacrylamide Gel ; Cholinesterases ; Biological Products ; Thermodynamics ; Protein Folding
Chemical Substances	Deuterium Oxide (J65BV539M3) ; Aryldialkylphosphatase (EC 3.1.8.1) ; Cholinesterases (EC 3.1.1.8) ; Biological Products
Language	English
Publishing date	2022-10-13
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules27206861
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Article ; Online: Investigating the relationship between the Bayes factor and the separation of credible intervals.

Wei, Zhengxiao / Nathoo, Farouk S / Masson, Michael E J

Psychonomic bulletin & review

2023 Volume 30, Issue 5, Page(s) 1759–1781

Abstract: ... for shrinkage and account for uncertainty in the estimation of random effects; and (5) the standard Bayesian ... we considered five intervals: (1) the within-subject confidence interval of Loftus and Masson (1994); (2 ...

Abstract	We examined the relationship between the Bayes factor and the separation of credible intervals in between- and within-subject designs under a range of effect and sample sizes. For the within-subject case, we considered five intervals: (1) the within-subject confidence interval of Loftus and Masson (1994); (2) the within-subject Bayesian interval developed by Nathoo et al. (2018), whose derivation conditions on estimated random effects; (3) and (4) two modifications of (2) based on a proposal by Heck (2019) to allow for shrinkage and account for uncertainty in the estimation of random effects; and (5) the standard Bayesian highest-density interval. We derived and observed through simulations a clear and consistent relationship between the Bayes factor and the separation of credible intervals. Remarkably, for a given sample size, this relationship is described well by a simple quadratic exponential curve and is most precise in case (4). In contrast, interval (5) is relatively wide due to between-subjects variability and is likely to obscure effects when used in within-subject designs, rendering its relationship with the Bayes factor unclear in that case. We discuss how the separation percentage of (4), combined with knowledge of the sample size, could provide evidence in support of either a null or an alternative hypothesis. We also present a case study with example data and provide an R package 'rmBayes' to enable computation of each of the within-subject credible intervals investigated here using a number of possible prior distributions.
MeSH term(s)	Humans ; Bayes Theorem ; Sample Size ; Uncertainty
Language	English
Publishing date	2023-05-11
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2031311-1
ISSN	1531-5320 ; 1069-9384
ISSN (online)	1531-5320
ISSN	1069-9384
DOI	10.3758/s13423-023-02295-1
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Article ; Online: The Activity of JmjC Histone Lysine Demethylase KDM4A is Highly Sensitive to Oxygen Concentrations.

Hancock, Rebecca L / Masson, Norma / Dunne, Kate / Flashman, Emily / Kawamura, Akane

ACS chemical biology

2017 Volume 12, Issue 4, Page(s) 1011–1019

Abstract: The JmjC histone lysine demethylases (KDMs) are epigenetic regulators involved in the removal of methyl groups from post-translationally modified lysyl residues within histone tails, modulating gene transcription. These enzymes require molecular oxygen ... ...

Abstract	The JmjC histone lysine demethylases (KDMs) are epigenetic regulators involved in the removal of methyl groups from post-translationally modified lysyl residues within histone tails, modulating gene transcription. These enzymes require molecular oxygen for catalytic activity and, as 2-oxoglutarate (2OG)-dependent oxygenases, are related to the cellular oxygen sensing HIF hydroxylases PHD2 and FIH. Recent studies have indicated that the activity of some KDMs, including the pseudogene-encoded KDM4E, may be sensitive to changing oxygen concentrations. Here, we report detailed analysis of the effect of oxygen availability on the activity of the KDM4 subfamily member KDM4A, importantly demonstrating a high level of O
MeSH term(s)	Cell Line, Tumor ; Chromatin/metabolism ; Fluorescent Antibody Technique ; Humans ; Jumonji Domain-Containing Histone Demethylases/genetics ; Jumonji Domain-Containing Histone Demethylases/metabolism ; Kinetics ; Oxygen/metabolism ; Pseudogenes
Chemical Substances	Chromatin ; Jumonji Domain-Containing Histone Demethylases (EC 1.14.11.-) ; KDM4A protein, human (EC 1.5.-) ; Oxygen (S88TT14065)
Language	English
Publishing date	2017-02-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.6b00958
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Article ; Online: Residual cardiovascular risk, use of standard care treatments, and achievement of treatment goals in patients with cardiovascular disease.

Siniawski, Daniel / Masson, Gerardo / Masson, Walter / Barbagelata, Leandro / Destaville, Josefina / Lynch, Santiago / Vitagliano, Laura / Parodi, Josefina Belén / Berton, Felipe / Indavere, Agustin / Epstein, Teo / Huerin, Melina

International journal of cardiology. Cardiovascular risk and prevention

2023 Volume 18, Page(s) 200198

Abstract: ... population, the residual risk was considerable. Underutilization of standard care treatments and failure ...

Abstract	Background: Residual risk management in patients with previous cardiovascular disease (CVD) is a relevant issue. Objectives: 1) to assess the residual risk of patients with CVD using the new scores developed to predict recurrent CVD events (SMART score/SMART-REACH model); 2) to determine the use of therapies with cardiovascular benefit and the achievement of therapeutic goals in patients with very high residual risk. Methods: A multicenter, descriptive, cross-sectional study was performed. Individuals over 18 years of age with CVD were included consecutively. The 10-year risk of recurrent events was estimated using the SMART score and the SMART-REACH model. A value ≥ 30% was considered "very high risk". Results: In total, 296 patients (mean age 68.2 ± 9.4 years, 75.7% men) were included. Globally, 32.43% and 64.53% of the population was classified as very high risk by the SMART score and the SMART-REACH model, respectively. Among patients classified as very high risk by the SMART score, 45.7% and 33.3% were treated with high-intensity statins and reached the goal of LDL-C <55 mg/dL, respectively. The results were similar when evaluating very high patients according to the SMART-REACH model (high-intensity statins: 59.7%; LDL-C <55 mg/dL: 43.9%). Few very high-risk patients with diabetes were receiving glucose-lowering drugs with demonstrated cardiovascular benefit. Conclusion: In this secondary prevention population, the residual risk was considerable. Underutilization of standard care treatments and failure to achieve therapeutic goals were evident even in subjects with very high residual risk.
Language	English
Publishing date	2023-07-21
Publishing country	Netherlands
Document type	Journal Article
ISSN	2772-4875
ISSN (online)	2772-4875
DOI	10.1016/j.ijcrp.2023.200198
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Article ; Online: Collective climate action: When do people turn into collective environmental agents?

Fritsche, Immo / Masson, Torsten

Current opinion in psychology

2021 Volume 42, Page(s) 114–119

Abstract: ... research on how collective climate action is driven by ingroup identification, social norms, group-based ...

Abstract	Effectively protecting the climate requires the action of groups. In the present review article, we aim to understand when individuals turn into collective climate actors. We first discuss pertinent models of group-based action and their relevance for explaining climate action. Then, we review recent research on how collective climate action is driven by ingroup identification, social norms, group-based emotions, and collective efficacy. Finally, we focus on when and why people feel a sense of collective agency aiming at inspiring a novel research agenda on collective climate action.
MeSH term(s)	Emotions ; Humans ; Social Identification
Language	English
Publishing date	2021-05-15
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2831565-0
ISSN	2352-2518 ; 2352-250X ; 2352-250X
ISSN (online)	2352-2518 ; 2352-250X
ISSN	2352-250X
DOI	10.1016/j.copsyc.2021.05.001
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