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Article: Incidentally Discovered Ochronosis Explaining Decades of Chronic Pain.

Reyes, Aaron / Hashemi, Leila

Federal practitioner : for the health care professionals of the VA, DoD, and PHS

2020 Volume 37, Issue 1, Page(s) 48–52

Abstract: Although commonly detected early in life, alkaptonuria, a rare congenital metabolic disorder, can be challenging to diagnosis and treat in older patients. ...

Abstract	Although commonly detected early in life, alkaptonuria, a rare congenital metabolic disorder, can be challenging to diagnosis and treat in older patients.
Language	English
Publishing date	2020-02-10
Publishing country	United States
Document type	Journal Article
ISSN	1078-4497
ISSN	1078-4497
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Cardiac Cell Therapy with Pluripotent Stem Cell-Derived Cardiomyocytes: What Has Been Done and What Remains to Do?

Selvakumar, Dinesh / Reyes, Leila / Chong, James J H

Current cardiology reports

2022 Volume 24, Issue 5, Page(s) 445–461

Abstract: Purpose of review: Exciting pre-clinical data presents pluripotent stem cell-derived cardiomyocytes (PSC-CM) as a novel therapeutic prospect following myocardial infarction, and worldwide clinical trials are imminent. However, despite notable advances, ... ...

Abstract	Purpose of review: Exciting pre-clinical data presents pluripotent stem cell-derived cardiomyocytes (PSC-CM) as a novel therapeutic prospect following myocardial infarction, and worldwide clinical trials are imminent. However, despite notable advances, several challenges remain. Here, we review PSC-CM pre-clinical studies, identifying key translational hurdles. We further discuss cell production and characterization strategies, identifying markers that may help generate cells which overcome these barriers. Recent findings: PSC-CMs can robustly repopulate infarcted myocardium with functional, force generating cardiomyocytes. However, current differentiation protocols produce immature and heterogenous cardiomyocytes, creating related issues such as arrhythmogenicity, immunogenicity and poor engraftment. Recent efforts have enhanced our understanding of cardiovascular developmental biology. This knowledge may help implement novel differentiation or gene editing strategies that could overcome these limitations. PSC-CMs are an exciting therapeutic prospect. Despite substantial recent advances, limitations of the technology remain. However, with our continued and increasing biological understanding, these issues are addressable, with several worldwide clinical trials anticipated in the coming years.
MeSH term(s)	Cell Differentiation ; Cell- and Tissue-Based Therapy ; Humans ; Induced Pluripotent Stem Cells ; Myocardium ; Myocytes, Cardiac ; Pluripotent Stem Cells
Language	English
Publishing date	2022-03-11
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2055373-0
ISSN	1534-3170 ; 1523-3782
ISSN (online)	1534-3170
ISSN	1523-3782
DOI	10.1007/s11886-022-01666-9
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Article ; Online: Enhancing bacterial survival through phenotypic heterogeneity.

Reyes Ruiz, Leila M / Williams, Caitlin L / Tamayo, Rita

PLoS pathogens

2020 Volume 16, Issue 5, Page(s) e1008439

MeSH term(s)	Bacteria/genetics ; Bacteria/metabolism ; Bacteria/pathogenicity ; Biological Variation, Population/genetics ; Biological Variation, Population/physiology ; Gene Expression Regulation, Bacterial/genetics ; Phenotype
Language	English
Publishing date	2020-05-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7366
ISSN (online)	1553-7374
ISSN	1553-7366
DOI	10.1371/journal.ppat.1008439
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Article ; Online: The Clinical Pathophysiology of Chronic Systemic Sclerosis.

Reyes, Aaron / Hashemi, Leila

Federal practitioner : for the health care professionals of the VA, DoD, and PHS

2017 Volume 35, Issue 5, Page(s) 36–43

Abstract: Primary care providers should monitor disease progression in the skin and in the pulmonary, renal, cardiac, and gastrointestinal systems in patients with systemic sclerosis, a rare autoimmune and connective tissue disease. ...

Abstract	Primary care providers should monitor disease progression in the skin and in the pulmonary, renal, cardiac, and gastrointestinal systems in patients with systemic sclerosis, a rare autoimmune and connective tissue disease.
Language	English
Publishing date	2017-12-12
Publishing country	United States
Document type	Journal Article
ISSN	1945-337X
ISSN (online)	1945-337X
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Article ; Online: A cryptic transcription factor regulates Caulobacter adhesin development.

McLaughlin, Maeve / Hershey, David M / Reyes Ruiz, Leila M / Fiebig, Aretha / Crosson, Sean

PLoS genetics

2022 Volume 18, Issue 10, Page(s) e1010481

Abstract: Alphaproteobacteria commonly produce an adhesin that is anchored to the exterior of the envelope at one cell pole. In Caulobacter crescentus this adhesin, known as the holdfast, facilitates attachment to solid surfaces and cell partitioning to air-liquid ...

Abstract	Alphaproteobacteria commonly produce an adhesin that is anchored to the exterior of the envelope at one cell pole. In Caulobacter crescentus this adhesin, known as the holdfast, facilitates attachment to solid surfaces and cell partitioning to air-liquid interfaces. An ensemble of two-component signal transduction (TCS) proteins controls C. crescentus holdfast biogenesis by indirectly regulating expression of HfiA, a potent inhibitor of holdfast synthesis. We performed a genetic selection to discover direct hfiA regulators that function downstream of the adhesion TCS system and identified rtrC, a hypothetical gene. rtrC transcription is directly activated by the adhesion TCS regulator, SpdR. Though its primary structure bears no resemblance to any defined protein family, RtrC binds and regulates dozens of sites on the C. crescentus chromosome via a pseudo-palindromic sequence. Among these binding sites is the hfiA promoter, where RtrC functions to directly repress transcription and thereby activate holdfast development. Either RtrC or SpdR can directly activate transcription of a second hfiA repressor, rtrB. Thus, environmental regulation of hfiA transcription by the adhesion TCS system is subject to control by an OR-gated type I coherent feedforward loop; these regulatory motifs are known to buffer gene expression against fluctuations in regulating signals. We have further assessed the functional role of rtrC in holdfast-dependent processes, including surface adherence to a cellulosic substrate and formation of pellicle biofilms at air-liquid interfaces. Strains harboring insertional mutations in rtrC have a diminished adhesion profile in a competitive cheesecloth binding assay and a reduced capacity to colonize pellicle biofilms in select media conditions. Our results add to an emerging understanding of the regulatory topology and molecular components of a complex bacterial cell adhesion control system.
MeSH term(s)	Transcription Factors/genetics ; Transcription Factors/metabolism ; Gene Expression Regulation, Bacterial ; Caulobacter/metabolism ; Adhesins, Bacterial/genetics ; Adhesins, Bacterial/metabolism ; Caulobacter crescentus/metabolism ; Bacterial Adhesion/genetics ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism
Chemical Substances	Transcription Factors ; Adhesins, Bacterial ; Bacterial Proteins
Language	English
Publishing date	2022-10-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1010481
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Article ; Online: Enhancing bacterial survival through phenotypic heterogeneity.

Leila M Reyes Ruiz / Caitlin L Williams / Rita Tamayo

PLoS Pathogens, Vol 16, Iss 5, p e

2020 Volume 1008439

Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-05-01T00:00:00Z
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: Characterization of the cellular effects of myeloperoxidase-derived oxidants on H9c2 cardiac myoblasts.

Reyes, Leila / Hawkins, Clare L / Rayner, Benjamin S

Archives of biochemistry and biophysics

2019 Volume 665, Page(s) 132–142

Abstract: Oxidative stress is a major hallmark of cardiac ischemia/reperfusion (I/R) injury, which is in part due to the release of the enzyme myeloperoxidase (MPO) from activated infiltrating leukocytes, and the subsequent production of the oxidants hypochlorous ... ...

Abstract	Oxidative stress is a major hallmark of cardiac ischemia/reperfusion (I/R) injury, which is in part due to the release of the enzyme myeloperoxidase (MPO) from activated infiltrating leukocytes, and the subsequent production of the oxidants hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). Although exposure of various cell types to either oxidant is known to cause cellular dysfunction within a variety of pathological settings, the precise role of HOCl and HOSCN in the initiation of tissue damage evident following cardiac I/R injury remains unclear. In this study, we have employed the use of the cardiac myoblast cell line H9c2 as a model for cardiac myocytes and demonstrate that exposure to either oxidant elicits a dose-dependent increase in cytosolic calcium accumulation, depletion of the cellular thiol pool, reduction of glutathione (GSH) levels and loss of mitochondrial inner trans-membrane potential, concomitant with increased necrotic cell death. H9c2 cell recovery from the initial oxidant exposure involves the initiation of cell survival signalling pathways centred around Nrf2-antioxidant response element (ARE) and activator protein 1 (AP-1) activation, with cell survival accompanied by restoration of mitochondrial function following exposure to HOSCN, but not HOCl. These data highlight the cellular responses elicited by HOCl and HOSCN in cardiac myocytes furthering our understanding of the pathogenesis of oxidant injury following cardiac I/R injury.
MeSH term(s)	Animals ; Cell Line ; Glutathione/metabolism ; Hypochlorous Acid/metabolism ; Myoblasts, Cardiac/metabolism ; Oxidants/metabolism ; Oxidative Stress ; Peroxidase/metabolism ; Rats ; Signal Transduction ; Thiocyanates/metabolism
Chemical Substances	Oxidants ; Thiocyanates ; hypothiocyanous acid ; Hypochlorous Acid (712K4CDC10) ; Peroxidase (EC 1.11.1.7) ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2019-03-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	523-x
ISSN	1096-0384 ; 0003-9861
ISSN (online)	1096-0384
ISSN	0003-9861
DOI	10.1016/j.abb.2019.03.004
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Article ; Online: Regulation of bacterial surface attachment by a network of sensory transduction proteins.

Reyes Ruiz, Leila M / Fiebig, Aretha / Crosson, Sean

PLoS genetics

2019 Volume 15, Issue 5, Page(s) e1008022

Abstract: Bacteria are often attached to surfaces in natural ecosystems. A surface-associated lifestyle can have advantages, but shifts in the physiochemical state of the environment may result in conditions in which attachment has a negative fitness impact. ... ...

Abstract	Bacteria are often attached to surfaces in natural ecosystems. A surface-associated lifestyle can have advantages, but shifts in the physiochemical state of the environment may result in conditions in which attachment has a negative fitness impact. Therefore, bacteria employ numerous mechanisms to control the transition from an unattached to a sessile state. The Caulobacter crescentus protein HfiA is a potent developmental inhibitor of the secreted polysaccharide adhesin known as the holdfast, which enables permanent attachment to surfaces. Multiple environmental cues influence expression of hfiA, but mechanisms of hfiA regulation remain largely undefined. Through a forward genetic selection, we have discovered a multi-gene network encoding a suite of two-component system (TCS) proteins and transcription factors that coordinately control hfiA transcription, holdfast development and surface adhesion. The hybrid HWE-family histidine kinase, SkaH, is central among these regulators and forms heteromeric complexes with the kinases, LovK and SpdS. The response regulator SpdR indirectly inhibits hfiA expression by activating two XRE-family transcription factors that directly bind the hfiA promoter to repress its transcription. This study provides evidence for a model in which a consortium of environmental sensors and transcriptional regulators integrate environmental cues at the hfiA promoter to control the attachment decision.
MeSH term(s)	Adhesins, Bacterial/genetics ; Adhesins, Bacterial/metabolism ; Bacterial Adhesion ; Caulobacter crescentus/genetics ; Caulobacter crescentus/metabolism ; Ecosystem ; Environment ; Gene Expression Regulation, Bacterial ; Gene Regulatory Networks ; Gene-Environment Interaction ; Histidine Kinase/genetics ; Histidine Kinase/metabolism ; Polysaccharides, Bacterial/genetics ; Polysaccharides, Bacterial/metabolism ; Promoter Regions, Genetic ; Protein Binding ; Signal Transduction/genetics ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcription, Genetic
Chemical Substances	Adhesins, Bacterial ; Polysaccharides, Bacterial ; Transcription Factors ; bacterial adhesins, polysaccharide ; Histidine Kinase (EC 2.7.13.1)
Language	English
Publishing date	2019-05-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1008022
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Coordinated modulation of multiple processes through phase variation of a c-di-GMP phosphodiesterase in Clostridioides difficile.

Reyes Ruiz, Leila M / King, Kathleen A / Agosto-Burgos, Christian / Gamez, Isabella S / Gadda, Nicole C / Garrett, Elizabeth M / Tamayo, Rita

PLoS pathogens

2022 Volume 18, Issue 7, Page(s) e1010677

Abstract: The opportunistic nosocomial pathogen Clostridioides difficile exhibits phenotypic heterogeneity through phase variation, a stochastic, reversible process that modulates expression. In C. difficile, multiple sequences in the genome undergo inversion ... ...

Abstract	The opportunistic nosocomial pathogen Clostridioides difficile exhibits phenotypic heterogeneity through phase variation, a stochastic, reversible process that modulates expression. In C. difficile, multiple sequences in the genome undergo inversion through site-specific recombination. Two such loci lie upstream of pdcB and pdcC, which encode phosphodiesterases (PDEs) that degrade the signaling molecule c-di-GMP. Numerous phenotypes are influenced by c-di-GMP in C. difficile including cell and colony morphology, motility, colonization, and virulence. In this study, we aimed to assess whether PdcB phase varies, identify the mechanism of regulation, and determine the effects on intracellular c-di-GMP levels and regulated phenotypes. We found that expression of pdcB is heterogeneous and the orientation of the invertible sequence, or 'pdcB switch', determines expression. The pdcB switch contains a promoter that when properly oriented promotes pdcB expression. Expression is augmented by an additional promoter upstream of the pdcB switch. Mutation of nucleotides at the site of recombination resulted in phase-locked strains with significant differences in pdcB expression. Characterization of these mutants showed that the pdcB locked-ON mutant has reduced intracellular c-di-GMP compared to the locked-OFF mutant, consistent with increased and decreased PdcB activity, respectively. These alterations in c-di-GMP had concomitant effects on multiple known c-di-GMP regulated processes, indicating that phase variation of PdcB allows C. difficile to coordinately diversify multiple phenotypes in the population to enhance survival.
MeSH term(s)	Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Biofilms ; Clostridioides difficile/enzymology ; Clostridioides difficile/genetics ; Cyclic GMP/analogs & derivatives ; Cyclic GMP/metabolism ; Gene Expression Regulation, Bacterial ; Phase Variation ; Phosphoric Diester Hydrolases/genetics ; Phosphoric Diester Hydrolases/metabolism
Chemical Substances	Bacterial Proteins ; bis(3',5')-cyclic diguanylic acid (61093-23-0) ; Phosphoric Diester Hydrolases (EC 3.1.4.-) ; Cyclic GMP (H2D2X058MU)
Language	English
Publishing date	2022-07-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1010677
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Article ; Online: Impact of European Union Label Changes for Fluoroquinolone-Containing Medicinal Products for Systemic and Inhalation Use: Post-Referral Prescribing Trends.

Ly, Nelly F / Flach, Clare / Lysen, Thom S / Markov, Emanuil / van Ballegooijen, Hanne / Rijnbeek, Peter / Duarte-Salles, Talita / Reyes, Carlen / John, Luis H / Karimi, Leila / Reich, Christian / Salek, Sam / Layton, Deborah

Drug safety

2023 Volume 46, Issue 4, Page(s) 405–416

Abstract: Introduction: Concerns of the persistence and severity of the adverse effects of fluoroquinolones, mainly involving the nervous system, muscles and joints, resulted in the 2018 referral procedure led by the European Medicines Agency (EMA). They advised ... ...

Abstract	Introduction: Concerns of the persistence and severity of the adverse effects of fluoroquinolones, mainly involving the nervous system, muscles and joints, resulted in the 2018 referral procedure led by the European Medicines Agency (EMA). They advised to stop prescribing fluoroquinolones for infections of mild severity or of a presumed self-limiting course and for prevention of infections, plus to restrict prescriptions in cases of milder infections where other treatment options are available, and restrict in at-risk populations. We aimed to examine whether the impact of EMA regulatory interventions implemented throughout 2018-2019 had an impact on fluoroquinolone prescribing rates. Methods: A retrospective population-based cohort study was conducted using electronic health care records from six European countries between 2016 and 2021. We analysed monthly incident fluoroquinolone use rates overall and for each fluoroquinolone active substance through flexible modelling via segmented regression to detect time points of trend changes, in monthly percentage change (MPC). Results: The incidence of fluoroquinolone use ranged from 0.7 to 8.0/1000 persons per month over all calendar years. While changes in fluoroquinolone prescriptions were observed over time across countries, these were inconsistent and did not seem to be temporally related to EMA interventions (e.g., Belgium: February/May 2018, MPC - 33.3%, 95% confidence interval [CI] - 35.9 to - 30.7; Germany: February/May 2019, MPC - 12.6%, 95% CI - 13.7 to - 11.6]; UK: January/April 2016, MPC - 4.9%, 95% CI - 6.2 to - 3.6). Conclusion: The regulatory action associated with the 2018 referral did not seem to have relevant effects on fluoroquinolone prescribing in primary care.
MeSH term(s)	Humans ; Fluoroquinolones/adverse effects ; Anti-Bacterial Agents/adverse effects ; European Union ; Retrospective Studies ; Cohort Studies
Chemical Substances	Fluoroquinolones ; Anti-Bacterial Agents
Language	English
Publishing date	2023-03-28
Publishing country	New Zealand
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1018059-x
ISSN	1179-1942 ; 0114-5916
ISSN (online)	1179-1942
ISSN	0114-5916
DOI	10.1007/s40264-023-01286-4
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