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Article: CRISPRa-induced upregulation of human

Arockiaraj, Annie I / Johnson, Marie A / Munir, Anushe / Ekambaram, Prasanna / Lucas, Peter C / McAllister-Lucas, Linda M / Kemaladewi, Dwi U

bioRxiv : the preprint server for biology

2023

Abstract: Merosin-deficient congenital muscular dystrophy (MDC1A) is an autosomal recessive disorder caused by mutations in ... ...

Abstract	Merosin-deficient congenital muscular dystrophy (MDC1A) is an autosomal recessive disorder caused by mutations in the
Language	English
Publishing date	2023-03-07
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.06.531347
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Article ; Online: Canonical and Non-Canonical Roles of GRK2 in Lymphocytes.

Cheng, Jing / Lucas, Peter C / McAllister-Lucas, Linda M

Cells

2021 Volume 10, Issue 2

Abstract: ... Protein kinase A, G, C serine/threonine kinase family) kinase domain, and a C-terminal pleckstrin homology (PH ...

Abstract	G protein-coupled receptor kinase 2 (GRK2) is emerging as a key integrative signaling node in a variety of biological processes ranging from cell growth and proliferation to migration and chemotaxis. As such, GRK2 is now implicated as playing a role in the molecular pathogenesis of a broad group of diseases including heart failure, cancer, depression, neurodegenerative disease, and others. In addition to its long-known canonical role in the phosphorylation and desensitization of G protein-coupled receptors (GPCRs), recent studies have shown that GRK2 also modulates a diverse array of other molecular processes via newly identified GRK2 kinase substrates and via a growing number of protein-protein interaction binding partners. GRK2 belongs to the 7-member GRK family. It is a multidomain protein containing a specific N-terminal region (referred to as αN), followed by a regulator of G protein signaling homology (RH) domain, an AGC (Protein kinase A, G, C serine/threonine kinase family) kinase domain, and a C-terminal pleckstrin homology (PH) domain. GPCRs mediate the activity of many regulators of the immune system such as chemokines and leukotrienes, and thus GRK proteins may play key roles in modulating the lymphocyte response to these factors. As one of the predominant GRK family members expressed in immune cells, GRK2's canonical and noncanonical actions play an especially significant role in normal immune cell function as well as in the development and progression of disorders of the immune system. This review summarizes our current state of knowledge of the roles of GRK2 in lymphocytes. We highlight the diverse functions of GRK2 and discuss how ongoing investigation of GRK2 in lymphocytes may inform the development of new therapies for diseases associated with lymphocyte dysregulation.
MeSH term(s)	Animals ; G-Protein-Coupled Receptor Kinase 2/metabolism ; Humans ; Lymphocytes/metabolism ; Mice ; Signal Transduction
Chemical Substances	G-Protein-Coupled Receptor Kinase 2 (EC 2.7.11.16)
Language	English
Publishing date	2021-02-03
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10020307
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Article ; Online: The increasing importance of pathology in modern clinical trial conduct: OlympiA as a case in point.

Kalinowski, Lauren / Viale, Giuseppe / Domchek, Susan / Tutt, Andrew / Lucas, Peter C / Lakhani, Sunil R

Pathology

2022 Volume 54, Issue 5, Page(s) 511–516

MeSH term(s)	Clinical Trials as Topic ; Humans ; Pathology
Language	English
Publishing date	2022-06-29
Publishing country	England
Document type	Editorial
ZDB-ID	7085-3
ISSN	1465-3931 ; 0031-3025
ISSN (online)	1465-3931
ISSN	0031-3025
DOI	10.1016/j.pathol.2022.05.003
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Article ; Online: Remarkably rapid, recent diversification of Cochemiea and Mammillaria in the Baja California, Mexico region.

Breslin, Peter B / Wojciechowski, Martin F / Majure, Lucas C

American journal of botany

2022 Volume 109, Issue 9, Page(s) 1472–1487

Abstract: Premise: The Cactaceae of northwestern Mexico and the southwestern United States constitute a major component of the angiosperm biodiversity of the region. The Mammilloid clade, (Cactaceae, tribe Cacteae), composed of the genera Cochemiea, Coryphantha, ... ...

Abstract	Premise: The Cactaceae of northwestern Mexico and the southwestern United States constitute a major component of the angiosperm biodiversity of the region. The Mammilloid clade, (Cactaceae, tribe Cacteae), composed of the genera Cochemiea, Coryphantha, Cumarinia, Mammillaria, and Pelecyphora is especially species rich. We sought to understand the timing, geographical and climate influences correlated with expansion of the Mammilloid clade, through the Sonoran Desert into Baja California. Methods: We reconstructed the historical biogeography of the Mammilloid clade, using Bayesian and maximum likelihood methods, based on a strongly supported molecular phylogeny. We also estimated divergence times, the timing of emergence of key characters, and diversification rates and rate shifts of the Mammilloid clade. Results: We found that the most recent common ancestor of Cochemiea arrived in the Cape region of Baja California from the Sonoran Desert region approximately 5 million years ago, coinciding with the timing of peninsular rifting from the mainland, suggesting dispersal and vicariance as causes of species richness and endemism. The diversification rate for Cochemiea is estimated to be approximately 12 times that of the mean background diversification rate for angiosperms. Divergence time estimation shows that many of the extant taxa in Cochemiea and Baja California Mammillaria emerged from common ancestors 1 million to 200,000 years ago, having a mid-Pleistocene origin. Conclusions: Cochemiea and Mammillaria of the Baja California region are examples of recent, rapid diversification. Geological and climatic forces at multiple spatial and temporal scales are correlated with the western distributions of the Mammilloid clade.
MeSH term(s)	Bayes Theorem ; Cactaceae/genetics ; Geography ; Mexico ; Phylogeny
Language	English
Publishing date	2022-09-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2935-x
ISSN	1537-2197 ; 0002-9122
ISSN (online)	1537-2197
ISSN	0002-9122
DOI	10.1002/ajb2.16048
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Article ; Online: Canonical and Non-Canonical Roles of GRK2 in Lymphocytes

Jing Cheng / Peter C. Lucas / Linda M. McAllister-Lucas

Cells, Vol 10, Iss 307, p

2021 Volume 307

Abstract: ... Protein kinase A, G, C serine/threonine kinase family) kinase domain, and a C-terminal pleckstrin homology (PH ...

Abstract	G protein-coupled receptor kinase 2 (GRK2) is emerging as a key integrative signaling node in a variety of biological processes ranging from cell growth and proliferation to migration and chemotaxis. As such, GRK2 is now implicated as playing a role in the molecular pathogenesis of a broad group of diseases including heart failure, cancer, depression, neurodegenerative disease, and others. In addition to its long-known canonical role in the phosphorylation and desensitization of G protein-coupled receptors (GPCRs), recent studies have shown that GRK2 also modulates a diverse array of other molecular processes via newly identified GRK2 kinase substrates and via a growing number of protein-protein interaction binding partners. GRK2 belongs to the 7-member GRK family. It is a multidomain protein containing a specific N-terminal region (referred to as αN), followed by a regulator of G protein signaling homology (RH) domain, an AGC (Protein kinase A, G, C serine/threonine kinase family) kinase domain, and a C-terminal pleckstrin homology (PH) domain. GPCRs mediate the activity of many regulators of the immune system such as chemokines and leukotrienes, and thus GRK proteins may play key roles in modulating the lymphocyte response to these factors. As one of the predominant GRK family members expressed in immune cells, GRK2′s canonical and noncanonical actions play an especially significant role in normal immune cell function as well as in the development and progression of disorders of the immune system. This review summarizes our current state of knowledge of the roles of GRK2 in lymphocytes. We highlight the diverse functions of GRK2 and discuss how ongoing investigation of GRK2 in lymphocytes may inform the development of new therapies for diseases associated with lymphocyte dysregulation.
Keywords	lymphocyte ; GPCR ; cell signaling ; lymphoma ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2021-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Dealing With Nonproportional Hazards in Coronary Revascularisation Studies.

Godoy, Lucas C / Ko, Dennis T / Farkouh, Michael E / Shah, Baiju R / Austin, Peter C

The Canadian journal of cardiology

2023 Volume 39, Issue 11, Page(s) 1651–1660

Abstract: The Cox proportional hazards model is one of the most popular statistical tools to model time to event outcomes without the need for specifying the hazards or survival time distributions. The Cox model requires that the ratio of the hazards of the ... ...

Abstract	The Cox proportional hazards model is one of the most popular statistical tools to model time to event outcomes without the need for specifying the hazards or survival time distributions. The Cox model requires that the ratio of the hazards of the occurrence of the outcome for any 2 individuals remains constant during the entire follow-up. Studies comparing coronary revascularisation strategies, however, might be prone to violations of proportionality by the crossing of the hazard functions over time. Early increases in the risk of cardiovascular outcomes are commonly observed when comparing coronary artery bypass grafting vs percutaneous coronary intervention, whereas decreased risk might be observed later during the follow-up. The same is valid for comparisons between invasive vs conservative coronary revascularisation strategies. In these situations, the statistical power of the Cox model is reduced, and hazard ratios might not be an informative summary measure of treatment effect. In this article, we discuss methods to identify and account for nonproportionality. We illustrate the use of these methods in a case study based on reconstructed data from a coronary revascularisation clinical trial. And finally, we review the cardiovascular literature to estimate how the proportionality assumption has been reported in coronary revascularisation studies recently.
MeSH term(s)	Humans ; Treatment Outcome ; Coronary Artery Bypass ; Percutaneous Coronary Intervention/methods ; Proportional Hazards Models ; Heart ; Coronary Artery Disease/surgery
Language	English
Publishing date	2023-07-17
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	632813-1
ISSN	1916-7075 ; 0828-282X
ISSN (online)	1916-7075
ISSN	0828-282X
DOI	10.1016/j.cjca.2023.07.014
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Article ; Online: The Great Immune Escape: Understanding the Divergent Immune Response in Breast Cancer Subtypes.

Onkar, Sayali S / Carleton, Neil M / Lucas, Peter C / Bruno, Tullia C / Lee, Adrian V / Vignali, Dario A A / Oesterreich, Steffi

Cancer discovery

2023 Volume 13, Issue 1, Page(s) 23–40

Abstract: Breast cancer, the most common type of cancer affecting women, encompasses a collection of histologic (mainly ductal and lobular) and molecular subtypes exhibiting diverse clinical presentation, disease trajectories, treatment options, and outcomes. ... ...

Abstract	Breast cancer, the most common type of cancer affecting women, encompasses a collection of histologic (mainly ductal and lobular) and molecular subtypes exhibiting diverse clinical presentation, disease trajectories, treatment options, and outcomes. Immunotherapy has revolutionized treatment for some solid tumors but has shown limited promise for breast cancers. In this review, we summarize recent advances in our understanding of the complex interactions between tumor and immune cells in subtypes of breast cancer at the cellular and microenvironmental levels. We aim to provide a perspective on opportunities for future immunotherapy agents tailored to specific features of each subtype of breast cancer. Significance: Although there are currently over 200 ongoing clinical trials testing immunotherapeutics, such as immune-checkpoint blockade agents, these are largely restricted to the triple-negative and HER2+ subtypes and primarily focus on T cells. With the rapid expansion of new in vitro, in vivo, and clinical data, it is critical to identify and highlight the challenges and opportunities unique for each breast cancer subtype to drive the next generation of treatments that harness the immune system.
MeSH term(s)	Female ; Humans ; Breast Neoplasms/pathology ; Immunotherapy ; Immunity ; Triple Negative Breast Neoplasms/therapy ; Triple Negative Breast Neoplasms/pathology
Language	English
Publishing date	2023-08-17
Publishing country	United States
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-22-0475
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Article ; Online: Light regulates xylem cell differentiation via PIF in Arabidopsis.

Ghosh, Shraboni / Nelson, Joseph F / Cobb, Geoffrey M C / Etchells, J Peter / de Lucas, Miguel

Cell reports

2022 Volume 40, Issue 3, Page(s) 111075

Abstract: The balance between cell proliferation and differentiation in the cambium defines the formation of plant vascular tissues. As cambium cells proliferate, subsets of daughter cells differentiate into xylem or phloem. TDIF-PXY/TDR signaling is central to ... ...

Abstract	The balance between cell proliferation and differentiation in the cambium defines the formation of plant vascular tissues. As cambium cells proliferate, subsets of daughter cells differentiate into xylem or phloem. TDIF-PXY/TDR signaling is central to this process. TDIF, encoded by CLE41 and CLE44, activates PXY/TDR receptors to maintain proliferative cambium. Light and water are necessary for photosynthesis; thus, vascular differentiation must occur upon light perception to facilitate the transport of water and minerals to the photosynthetic tissues. However, the molecular mechanism controlling vascular differentiation in response to light remains elusive. In this study we show that the accumulation of PIF transcription factors in the dark promotes TDIF signaling and inhibits vascular cell differentiation. On the contrary, PIF inactivation by light leads to a decay in TDIF activity, which induces vascular cell differentiation. Our study connects light to vascular differentiation and highlights the importance of this crosstalk to fine-tune water transport.
MeSH term(s)	Arabidopsis/metabolism ; Arabidopsis Proteins/genetics ; Arabidopsis Proteins/metabolism ; Cell Differentiation ; Gene Expression Regulation, Plant ; Oligopeptides/genetics ; Water ; Xylem/metabolism
Chemical Substances	Arabidopsis Proteins ; Oligopeptides ; Water (059QF0KO0R)
Language	English
Publishing date	2022-07-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.111075
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Article ; Online: Azithromycin Augments Bacterial Uptake and Anti-Inflammatory Macrophage Polarization in Cystic Fibrosis.

Tarique, Abdullah A / Tuladhar, Neeraj / Kelk, Dean / Begum, Nelufa / Lucas, Richard M / Luo, Lin / Stow, Jennifer L / Wainwright, Claire E / Bell, Scott C / Sly, Peter D / Fantino, Emmanuelle

Cells

2024 Volume 13, Issue 2

Abstract: Background: Azithromycin (AZM) is widely being used for treating patients with cystic fibrosis (pwCF) following clinical trials demonstrating improved lung function and fewer incidents of pulmonary exacerba-tions. While the precise mechanisms remain ... ...

Abstract	Background: Azithromycin (AZM) is widely being used for treating patients with cystic fibrosis (pwCF) following clinical trials demonstrating improved lung function and fewer incidents of pulmonary exacerba-tions. While the precise mechanisms remain elusive, immunomodulatory actions are thought to be involved. We previously reported impaired phagocytosis and defective anti-inflammatory M2 macrophage polarization in CF. This study systematically analyzed the effect of AZM on the functions of unpolarized and M1/M2 polarized macrophages in CF. Methods: Monocytes, isolated from the venous blood of patients with CF (pwCF) and healthy controls (HCs), were differentiated into monocyte-derived macrophages (MDMs) and subsequently infected with Results: Following AZM treatment, both HC and CF MDMs exhibited a significant increase in Conclusions: This study highlights the cellular functions and molecular targets of AZM which may involve an improved uptake of both Gram-positive and Gram-negative bacteria, restored anti-inflammatory macrophage polarization in CF. This may in turn shape the reduced lung inflammation observed in clinical trials. In addition, we confirmed the role of ERK1/2 activation for bacterial uptake.
MeSH term(s)	Humans ; Azithromycin/pharmacology ; Gram-Negative Bacteria ; Anti-Bacterial Agents/pharmacology ; Cystic Fibrosis/drug therapy ; Escherichia coli ; Staphylococcus aureus ; Gram-Positive Bacteria ; Macrophages ; Anti-Inflammatory Agents/pharmacology
Chemical Substances	Azithromycin (83905-01-5) ; Anti-Bacterial Agents ; Anti-Inflammatory Agents
Language	English
Publishing date	2024-01-16
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells13020166
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Article ; Online: Fatty acid elongases 1-3 have distinct roles in mitochondrial function, growth, and lipid homeostasis in Trypanosoma cruzi.

Pagura, Lucas / Dumoulin, Peter C / Ellis, Cameron C / Mendes, Maria T / Estevao, Igor L / Almeida, Igor C / Burleigh, Barbara A

The Journal of biological chemistry

2023 Volume 299, Issue 6, Page(s) 104715

Abstract: Trypanosomatids are a diverse group of uniflagellate protozoan parasites that include globally relevant pathogens such as Trypanosoma cruzi, the causative agent of Chagas disease. Trypanosomes lack the fatty acid synthase system typically used for de ... ...

Abstract	Trypanosomatids are a diverse group of uniflagellate protozoan parasites that include globally relevant pathogens such as Trypanosoma cruzi, the causative agent of Chagas disease. Trypanosomes lack the fatty acid synthase system typically used for de novo fatty acid (FA) synthesis in other eukaryotes. Instead, these microbes have evolved a modular FA elongase (ELO) system comprised of individual ELO enzymes (ELO1-4) that can operate processively to generate long chain- and very long chain-FAs. The importance of ELO's for maintaining lipid homeostasis in trypanosomatids is currently unclear, given their ability to take up and utilize exogenous FAs for lipid synthesis. To assess ELO function in T. cruzi, we generated individual KO lines, Δelo1, Δelo2, and Δelo3, in which the genes encoding ELO1-3 were functionally disrupted in the parasite insect stage (epimastigote). Using unbiased lipidomic and metabolomic analyses, in combination with metabolic tracing and biochemical approaches, we demonstrate that ELO2 and ELO3 are required for global lipid homeostasis, whereas ELO1 is dispensable for this function. Instead, ELO1 activity is needed to sustain mitochondrial activity and normal growth in T. cruzi epimastigotes. The cross-talk between microsomal ELO1 and the mitochondrion is a novel finding that, we propose, merits further examination of the trypanosomatid ELO pathway as critical for central metabolism.
MeSH term(s)	Humans ; Trypanosoma cruzi/genetics ; Trypanosoma cruzi/metabolism ; Fatty Acid Elongases/metabolism ; Chagas Disease/genetics ; Chagas Disease/metabolism ; Homeostasis ; Mitochondria/genetics ; Mitochondria/metabolism ; Lipids
Chemical Substances	Fatty Acid Elongases (EC 2.3.1.-) ; Lipids
Language	English
Publishing date	2023-04-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.104715
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