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Article ; Online: Inflammation as a Regulator of the Airway Surface Liquid pH in Cystic Fibrosis.

Rehman, Tayyab / Welsh, Michael J

2023 Volume 12, Issue 8

Abstract: The airway surface liquid (ASL) is a thin sheet of fluid that covers the luminal aspect of the airway epithelium. The ASL is a site of several first-line host defenses, and its composition is a key factor that determines respiratory fitness. Specifically, ...

Abstract	The airway surface liquid (ASL) is a thin sheet of fluid that covers the luminal aspect of the airway epithelium. The ASL is a site of several first-line host defenses, and its composition is a key factor that determines respiratory fitness. Specifically, the acid-base balance of ASL has a major influence on the vital respiratory defense processes of mucociliary clearance and antimicrobial peptide activity against inhaled pathogens. In the inherited disorder cystic fibrosis (CF), loss of cystic fibrosis transmembrane conductance regulator (CFTR) anion channel function reduces HCO
MeSH term(s)	Humans ; Cystic Fibrosis/pathology ; Cystic Fibrosis Transmembrane Conductance Regulator ; Respiratory Mucosa/pathology ; Inflammation/pathology ; Hydrogen-Ion Concentration
Chemical Substances	Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
Language	English
Publishing date	2023-04-07
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; 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/cells12081104
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Article ; Online: A model for stimulation of enzyme activity by a competitive inhibitor based on the interaction of terazosin and phosphoglycerate kinase 1.

Riley, Mitchell J / Mitchell, Colleen C / Ernst, Sarah E / Taylor, Eric B / Welsh, Michael J

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

2024 Volume 121, Issue 9, Page(s) e2318956121

Abstract: The drug terazosin (TZ) binds to and can enhance the activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and can increase ATP levels. That finding prompted studies of TZ in Parkinson's disease (PD) in which decreased neuronal energy ... ...

Abstract	The drug terazosin (TZ) binds to and can enhance the activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and can increase ATP levels. That finding prompted studies of TZ in Parkinson's disease (PD) in which decreased neuronal energy metabolism is a hallmark feature. TZ was neuroprotective in cell-based and animal PD models and in large epidemiological studies of humans. However, how TZ might increase PGK1 activity has remained a perplexing question because structural data revealed that the site of TZ binding to PGK1 overlaps with the site of substrate binding, predicting that TZ would competitively inhibit activity. Functional data also indicate that TZ is a competitive inhibitor. To explore the paradoxical observation of a competitive inhibitor increasing enzyme activity under some conditions, we developed a mass action model of TZ and PGK1 interactions using published data on PGK1 kinetics and the effect of varying TZ concentrations. The model indicated that TZ-binding introduces a bypass pathway that accelerates product release. At low concentrations, TZ binding circumvents slow product release and increases the rate of enzymatic phosphotransfer. However, at high concentrations, TZ inhibits PGK1 activity. The model explains stimulation of enzyme activity by a competitive inhibitor and the biphasic dose-response relationship for TZ and PGK1 activity. By providing a plausible mechanism for interactions between TZ and PGK1, these findings may aid development of TZ or other agents as potential therapeutics for neurodegenerative diseases. The results may also have implications for agents that interact with the active site of other enzymes.
MeSH term(s)	Humans ; Animals ; Phosphoglycerate Kinase/metabolism ; Prazosin/pharmacology ; Prazosin/analogs & derivatives ; Parkinson Disease/drug therapy ; Glycolysis
Chemical Substances	Terazosin (8L5014XET7) ; Phosphoglycerate Kinase (EC 2.7.2.3) ; Prazosin (XM03YJ541D)
Language	English
Publishing date	2024-02-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2318956121
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Zs.A 1148: Show issues

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Article ; Online: Data on Sea turtle relative abundance in nearshore waters adjacent to the Mississippi River delta, Gulf of Mexico, United States.

Welsh, Ryan C / Witherington, Blair E / Guertin, Jeffrey R / Mott, Cody R / Bresette, Michael J

Data in brief

2023 Volume 47, Page(s) 108984

Abstract: We measured the relative abundance of sea turtles using standardized transect surveys conducted during the summer and fall of 2013 in neritic waters surrounding the Mississippi River delta in Louisiana, USA. Data comprise sea turtle locations, ... ...

Abstract	We measured the relative abundance of sea turtles using standardized transect surveys conducted during the summer and fall of 2013 in neritic waters surrounding the Mississippi River delta in Louisiana, USA. Data comprise sea turtle locations, observation circumstances, and environmental covariates recorded at the beginning of each transect and at the time of each turtle observation. Turtles were recorded by species and size class, as well as location in the water column and the distance the turtle was from the transect line. Transects were performed on an 8.2 meter vessel with two observers atop a 4.5 meter elevated platform, with vessel speed standardized at ∼15 km/hr. These data are the first to describe relative abundance of sea turtles observed from small vessels in this region. Detection of turtles <45 cm SSCL and data detail are greater than aerial surveys. The data serve to inform resource managers and researchers regarding these protected marine species.
Language	English
Publishing date	2023-02-14
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2786545-9
ISSN	2352-3409 ; 2352-3409
ISSN (online)	2352-3409
ISSN	2352-3409
DOI	10.1016/j.dib.2023.108984
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Article ; Online: Mitochondrial uncoupling proteins protect human airway epithelial ciliated cells from oxidative damage.

Jain, Akansha / Kim, Bo Ram / Yu, Wenjie / Moninger, Thomas O / Karp, Philip H / Wagner, Brett A / Welsh, Michael J

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

2024 Volume 121, Issue 10, Page(s) e2318771121

Abstract: Apical cilia on epithelial cells defend the lung by propelling pathogens and particulates out of the respiratory airways. Ciliated cells produce ATP that powers cilia beating by densely grouping mitochondria just beneath the apical membrane. However, ... ...

Abstract	Apical cilia on epithelial cells defend the lung by propelling pathogens and particulates out of the respiratory airways. Ciliated cells produce ATP that powers cilia beating by densely grouping mitochondria just beneath the apical membrane. However, this efficient localization comes at a cost because electrons leaked during oxidative phosphorylation react with molecular oxygen to form superoxide, and thus, the cluster of mitochondria creates a hotspot for oxidant production. The relatively high oxygen concentration overlying airway epithelia further intensifies the risk of generating superoxide. Thus, airway ciliated cells face a unique challenge of producing harmful levels of oxidants. However, surprisingly, highly ciliated epithelia produce less reactive oxygen species (ROS) than epithelia with few ciliated cells. Compared to other airway cell types, ciliated cells express high levels of mitochondrial uncoupling proteins, UCP2 and UCP5. These proteins decrease mitochondrial protonmotive force and thereby reduce production of ROS. As a result, lipid peroxidation, a marker of oxidant injury, decreases. However, mitochondrial uncoupling proteins exact a price for decreasing oxidant production; they decrease the fraction of mitochondrial respiration that generates ATP. These findings indicate that ciliated cells sacrifice mitochondrial efficiency in exchange for safety from damaging oxidation. Employing uncoupling proteins to prevent oxidant production, instead of relying solely on antioxidants to decrease postproduction oxidant levels, may offer an advantage for targeting a local area of intense ROS generation.
MeSH term(s)	Humans ; Reactive Oxygen Species/metabolism ; Mitochondrial Uncoupling Proteins/metabolism ; Superoxides/metabolism ; Ion Channels/metabolism ; Oxidative Stress ; Adenosine Triphosphate/metabolism ; Epithelial Cells/metabolism ; Oxidants/pharmacology ; Oxygen/metabolism ; Mitochondrial Proteins/metabolism
Chemical Substances	Reactive Oxygen Species ; Mitochondrial Uncoupling Proteins ; Superoxides (11062-77-4) ; Ion Channels ; Adenosine Triphosphate (8L70Q75FXE) ; Oxidants ; Oxygen (S88TT14065) ; Mitochondrial Proteins
Language	English
Publishing date	2024-02-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2318771121
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Article ; Online: Use of Glycolysis-Enhancing Drugs and Risk of Parkinson's Disease.

Simmering, Jacob E / Welsh, Michael J / Schultz, Jordan / Narayanan, Nandakumar S

Movement disorders : official journal of the Movement Disorder Society

2022 Volume 37, Issue 11, Page(s) 2210–2216

Abstract: Background: Terazosin (TZ) and closely related α1-adrenergic receptor antagonists (doxazosin [DZ] and alfuzosin [AZ]) enhance glycolysis and reduce neurodegeneration in animal models. Observational evidence in humans from several databases supports this ...

Abstract	Background: Terazosin (TZ) and closely related α1-adrenergic receptor antagonists (doxazosin [DZ] and alfuzosin [AZ]) enhance glycolysis and reduce neurodegeneration in animal models. Observational evidence in humans from several databases supports this finding; however, a recent study has suggested that tamsulosin, the comparator medication, increases the risk of Parkinson's disease. Aims: We consider a different comparison group of men taking 5α-reductase inhibitors (5ARIs) as a new, independent comparison allowing us to both obtain new estimates of the association between TZ/DZ/AZ and Parkinson's disease outcomes and validate tamsulosin as an active comparator. Methods: Using the Truven Health Analytics Marketscan database, we identified men without Parkinson's disease, newly started on TZ/DZ/AZ, tamsulosin, or 5ARIs. We followed these matched cohorts to compare the hazard of developing Parkinson's disease. We conducted sensitivity analyses using variable duration of lead-in to mitigate biases introduced by prodromal disease. Results: We found that men taking TZ/DZ/AZ had a lower hazard of Parkinson's disease than men taking tamsulosin (hazard ratio (HR) = 0.71, 95% CI [confidence interval]: 0.65-0.77, n = 239,888) and lower than men taking 5ARIs (HR = 0.84, 95% CI: 0.75-0.94, n = 129,116). We found the TZ/DZ/AZ versus tamsulosin HR to be essentially unchanged with up to 5 years of lead-in time; however, the TZ/DZ/AZ versus 5ARI effect became attenuated with longer lead-in durations. Conclusions: These data suggest that men using TZ/DZ/AZ have a somewhat lower risk of developing Parkinson's disease than those using tamsulosin and a slightly lower risk than those using 5ARIs. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
MeSH term(s)	Male ; Animals ; Humans ; Tamsulosin/therapeutic use ; Parkinson Disease/drug therapy ; Parkinson Disease/epidemiology ; Parkinson Disease/etiology ; Prostatic Hyperplasia/complications ; Prostatic Hyperplasia/drug therapy ; 5-alpha Reductase Inhibitors/therapeutic use ; Glycolysis
Chemical Substances	Tamsulosin (G3P28OML5I) ; 5-alpha Reductase Inhibitors
Language	English
Publishing date	2022-08-22
Publishing country	United States
Document type	Observational Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	607633-6
ISSN	1531-8257 ; 0885-3185
ISSN (online)	1531-8257
ISSN	0885-3185
DOI	10.1002/mds.29184
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Zs.A 2555: 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.MO 238: Show issues

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Article ; Online: Pulmonary neuroendocrine cells sense succinate to stimulate myoepithelial cell contraction.

Yu, Wenjie / Moninger, Thomas O / Rector, Michael V / Stoltz, David A / Welsh, Michael J

Developmental cell

2022 Volume 57, Issue 18, Page(s) 2221–2236.e5

Abstract: Pulmonary neuroendocrine cells (PNECs) are rare airway cells with potential sensory capacity linked to vagal neurons and immune cells. How PNECs sense and respond to external stimuli remains poorly understood. We discovered PNECs located within pig and ... ...

Abstract	Pulmonary neuroendocrine cells (PNECs) are rare airway cells with potential sensory capacity linked to vagal neurons and immune cells. How PNECs sense and respond to external stimuli remains poorly understood. We discovered PNECs located within pig and human submucosal glands, a tissue that produces much of the mucus that defends the lung. These PNECs sense succinate, an inflammatory molecule in liquid lining the airway surface. The results indicate that succinate migrates down the submucosal gland duct to the acinus, where it triggers apical succinate receptors, causing PNECs to release ATP. The short-range ATP signal stimulates the contraction of myoepithelial cells wrapped tightly around the submucosal glands. Succinate-triggered gland contraction may complement the action of neurotransmitters that induce mucus release but not gland contraction to promote mucus ejection onto the airway surface. These findings identify a local circuit in which rare PNECs within submucosal glands sense an environmental cue to orchestrate the function of airway glands.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Animals ; Humans ; Lung/metabolism ; Mucus/metabolism ; Neuroendocrine Cells ; Succinic Acid/metabolism ; Swine
Chemical Substances	Adenosine Triphosphate (8L70Q75FXE) ; Succinic Acid (AB6MNQ6J6L)
Language	English
Publishing date	2022-09-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2054967-2
ISSN	1878-1551 ; 1534-5807
ISSN (online)	1878-1551
ISSN	1534-5807
DOI	10.1016/j.devcel.2022.08.010
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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: AJRCCM: 100-Year Anniversary. Progress along the Pathway of Discovery Leading to Treatment and Cure of Cystic Fibrosis.

Ramsey, Bonnie W / Welsh, Michael J

American journal of respiratory and critical care medicine

2017 Volume 195, Issue 9, Page(s) 1092–1099

Language	English
Publishing date	2017-05-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.201702-0266ED
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Article ; Online: Novel multiparametric MRI detects improved future liver remnant quality post-dual vein embolization.

Sundaravadanan, Senthil / Welsh, Fenella Ks / Sethi, Pulkit / Noorani, Shaheen / Cresswell, Ben A / Connell, John J / Knapp, Sina K / Núñez, Luis / Brady, J Michael / Banerjee, Rajarshi / Rees, Myrddin

HPB : the official journal of the International Hepato Pancreato Biliary Association

2024

Abstract: Background: Optimisation of the future liver remnant (FLR) is crucial to outcomes of extended liver resections. This study aimed to assess the quality of the FLR before and after dual vein embolization (DVE) by quantitative multiparametric MRI.: ... ...

Abstract	Background: Optimisation of the future liver remnant (FLR) is crucial to outcomes of extended liver resections. This study aimed to assess the quality of the FLR before and after dual vein embolization (DVE) by quantitative multiparametric MRI. Methods: Of 100 patients with liver metastases recruited in a clinical trial (Precision1:NCT04597710), ten consecutive patients with insufficient FLR underwent quantitative multiparametric MRI pre- and post-DVE (right portal and hepatic vein). FLR volume, liver fibro-inflammation (corrected T1) scores and fat percentage (proton density fat fraction, PDFF) were determined. Patient metrics were compared by Wilcoxon signed-rank test and statistical analysis done using R software. Results: All patients underwent uncomplicated DVE with improvement in liver remnant health, median 37 days after DVE: cT1 scores reduced from median (interquartile range) 790 ms (753-833 ms) to 741 ms (708-760 ms) p = 0.014 [healthy range <795 ms], as did PDFF from 11% (4-21%), to 3% (2-12%) p = 0.017 [healthy range <5.6%]. There was a significant increase in median (interquartile range) FLR volume from 33% (30-37%)% to 49% (44-52%), p = 0.002. Conclusion: This non-invasive and reproducible MRI technique showed improvement in volume and quality of the FLR after DVE. This is a significant advance in our understanding of how to prevent liver failure in patients undergoing major liver surgery.
Language	English
Publishing date	2024-02-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2131251-5
ISSN	1477-2574 ; 1365-182X
ISSN (online)	1477-2574
ISSN	1365-182X
DOI	10.1016/j.hpb.2024.02.008
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Zs.A 6326: Show issues

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Article ; Online: Association Between Clinician-Level Factors and Patient Outcomes in Virtual and In-Person Outpatient Treatment for Substance Use Disorders: Multilevel Analysis.

Welsh, Justine W / Sitar, Siara I / Parks, Michael J / Patton, Samantha C / Braughton, Jacqueline E / Waller, Lance A / Ngo, Quyen M

JMIR human factors

2023 Volume 10, Page(s) e48701

Abstract: Background: The use of virtual treatment services increased dramatically during the COVID-19 pandemic. Unfortunately, large-scale research on virtual treatment for substance use disorder (SUD), including factors that may influence outcomes, has not ... ...

Abstract	Background: The use of virtual treatment services increased dramatically during the COVID-19 pandemic. Unfortunately, large-scale research on virtual treatment for substance use disorder (SUD), including factors that may influence outcomes, has not advanced with the rapidly changing landscape. Objective: This study aims to evaluate the link between clinician-level factors and patient outcomes in populations receiving virtual and in-person intensive outpatient services. Methods: Data came from patients (n=1410) treated in a virtual intensive outpatient program (VIOP) and an in-person intensive outpatient program (IOP), who were discharged between January 2020 and March 2021 from a national treatment organization. Patient data were nested by treatment providers (n=58) examining associations with no-shows and discharge with staff approval. Empathy, comfort with technology, perceived stress, resistance to change, and demographic covariates were examined at the clinician level. Results: The VIOP (β=-5.71; P=.03) and the personal distress subscale measure (β=-6.31; P=.003) were negatively associated with the percentage of no-shows. The VIOP was positively associated with discharges with staff approval (odds ratio [OR] 2.38, 95% CI 1.50-3.76). Clinician scores on perspective taking (β=-9.22; P=.02), personal distress (β=-9.44; P=.02), and male clinician gender (β=-6.43; P=.04) were negatively associated with in-person no-shows. Patient load was positively associated with discharge with staff approval (OR 1.04, 95% CI 1.02-1.06). Conclusions: Overall, patients in the VIOP had fewer no-shows and a higher rate of successful discharge. Few clinician-level characteristics were significantly associated with patient outcomes. Further research is necessary to understand the relationships among factors such as clinician gender, patient load, personal distress, and patient retention.
MeSH term(s)	Humans ; Male ; Outpatients ; Multilevel Analysis ; Pandemics ; Substance-Related Disorders/therapy ; Ambulatory Care
Language	English
Publishing date	2023-11-03
Publishing country	Canada
Document type	Journal Article
ISSN	2292-9495
ISSN (online)	2292-9495
DOI	10.2196/48701
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Article ; Online: Sustaining Lifelong Competency of Surgeons: Multimodality Empowerment Personal and Institutional Strategy.

Rosengart, Todd K / Chen, Jennifer H / Gantt, Nancy L / Angelos, Peter / Warshaw, Andrew L / Rosen, Jennifer E / Perrier, Nancy D / Kaups, Krista L / Doherty, Gerard M / Zoumpou, Theofano / Ashley, Stanley W / Doscher, William / Welsh, David / Savarise, Mark / Sutherland, Michael J / Sidawy, Anton N / Kopelan, Adam M

Journal of the American College of Surgeons

2024

Language	English
Publishing date	2024-04-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	1181115-8
ISSN	1879-1190 ; 1072-7515
ISSN (online)	1879-1190
ISSN	1072-7515
DOI	10.1097/XCS.0000000000001066
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