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Article ; Online: IL-33 supplementation improves uterine artery resistance and maternal hypertension in response to placental ischemia.

Wang, Xi / Shields, Corbin / Tardo, Geilda / Peacock, Greg / Hester, Emily / Anderson, Marissa / Williams, Jan M / Cornelius, Denise C

American journal of physiology. Heart and circulatory physiology

2024 Volume 326, Issue 4, Page(s) H1006–H1016

Abstract: Preeclampsia (PE), a leading cause of maternal/fetal morbidity and mortality, is a hypertensive pregnancy disorder with end-organ damage that manifests after 20 wk of gestation. PE is characterized by chronic immune activation and endothelial dysfunction. ...

Abstract	Preeclampsia (PE), a leading cause of maternal/fetal morbidity and mortality, is a hypertensive pregnancy disorder with end-organ damage that manifests after 20 wk of gestation. PE is characterized by chronic immune activation and endothelial dysfunction. Clinical studies report reduced IL-33 signaling in PE. We use the Reduced Uterine Perfusion Pressure (RUPP) rat model, which mimics many PE characteristics including reduced IL-33, to identify mechanisms mediating PE pathophysiology. We hypothesized that IL-33 supplementation would improve blood pressure (BP), inflammation, and oxidative stress (ROS) during placental ischemia. We implanted intraperitoneal mini-osmotic pumps infusing recombinant rat IL-33 (1 µg/kg/day) into normal pregnant (NP) and RUPP rats from
MeSH term(s)	Animals ; Female ; Pregnancy ; Rats ; Blood Pressure/drug effects ; Dietary Supplements ; Disease Models, Animal ; Hypertension/drug therapy ; Inflammation/metabolism ; Interleukin-33/pharmacology ; Ischemia/metabolism ; Placenta/blood supply ; Pre-Eclampsia/drug therapy ; Pre-Eclampsia/metabolism ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Uterine Artery/drug effects ; Uterine Artery/metabolism
Chemical Substances	Interleukin-33 ; Reactive Oxygen Species
Language	English
Publishing date	2024-02-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	603838-4
ISSN	1522-1539 ; 0363-6135
ISSN (online)	1522-1539
ISSN	0363-6135
DOI	10.1152/ajpheart.00045.2024
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Article ; Online: Inhibition of Caspase 1 Reduces Blood Pressure, Cytotoxic NK Cells, and Inflammatory T-Helper 17 Cells in Placental Ischemic Rats.

Shields, Corbin A / Tardo, Geilda A / Wang, Xi / Peacock, Gregory / Robbins, Marcus / Glenn, Hannah / Wilson, Rachel / Williams, Jan M / Cornelius, Denise C

International journal of molecular sciences

2024 Volume 25, Issue 2

Abstract: Preeclampsia (PE) is characterized by maternal hypertension, fetal growth restriction (FGR), and increased inflammation and populations of cytotoxic NK cells (cNKs) and inflammatory T-Helper 17 cells (TH17s). Both cytotoxic NK cells and TH17 cells are ... ...

Abstract	Preeclampsia (PE) is characterized by maternal hypertension, fetal growth restriction (FGR), and increased inflammation and populations of cytotoxic NK cells (cNKs) and inflammatory T-Helper 17 cells (TH17s). Both cytotoxic NK cells and TH17 cells are heavily influenced via IL-1β signaling. Caspase 1 activity leads to the release of the inflammatory cytokine IL-1β, which is increased in women with PE. Therefore, we tested the hypothesis that the inhibition of Caspase 1 with VX-765 in rats with reduced uterine perfusion pressure (RUPP) will attenuate PE pathophysiology. On gestation day (GD) 14, timed pregnant Sprague-Dawley rats underwent the RUPP or Sham procedure and were separated into groups that received either vehicle or VX-765 (50 mg/kg/day i.p.). On GD19, MAP was measured via carotid catheter and blood and tissues were collected. Bio-Plex and flow cytometry analysis were performed on placental tissues. Placental IL-1β was increased in the RUPP rats vs. the Sham rats and treatment with VX-765 reduced IL-1β in the RUPP rats. Caspase 1 inhibition reduced placental cNKs and TH17s in RUPP rats compared to vehicle-treated RUPP rats. Increased MAP was observed in RUPP rats compared with Sham rats and was reduced in RUPP + VX-765 rats. Placental reactive oxygen species (ROS) were elevated in RUPP rats compared to Sham rats. VX-765 administration reduced ROS in treated RUPP rats. Caspase 1 inhibition increased the number of live pups, yet had no effect on fetal weight or placental efficiency in the treated groups. In conclusion, Caspase 1 inhibition reduces placental IL-1β, inflammatory TH17 and cNK populations, and reduces MAP in RUPP rats. These data suggest that Caspase 1 is a key contributor to PE pathophysiology. This warrants further investigation of Caspase 1 as a potential therapeutic target to improve maternal outcomes in PE.
MeSH term(s)	Animals ; Female ; Humans ; Pregnancy ; Rats ; Antineoplastic Agents ; Blood Pressure ; Caspase 1/metabolism ; Killer Cells, Natural ; Placenta ; Pre-Eclampsia/drug therapy ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Th17 Cells
Chemical Substances	Antineoplastic Agents ; Caspase 1 (EC 3.4.22.36) ; Reactive Oxygen Species ; belnacasan (00OLE78529)
Language	English
Publishing date	2024-01-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25020863
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Article ; Online: VASCULAR AND RENAL MECHANISMS OF PREECLAMPSIA.

Wang, Xi / Shields, Corbin A / Ekperikpe, Ubong / Amaral, Lorena M / Williams, Jan Michael / Cornelius, Denise C

Current opinion in physiology

2023 Volume 33

Abstract: Preeclampsia (PE) is a multisystem obstetric disorder that affects 2-10% of pregnancies worldwide and it is a leading cause of maternal and fetal morbidity and mortality. The etiology of PE development is not clearly delineated, but since delivery of the ...

Abstract	Preeclampsia (PE) is a multisystem obstetric disorder that affects 2-10% of pregnancies worldwide and it is a leading cause of maternal and fetal morbidity and mortality. The etiology of PE development is not clearly delineated, but since delivery of the fetus and placenta often leads to symptom resolution in the most cases of PE, it is hypothesized that the placenta is the inciting factor of the disease. Current management strategies for PE focus on treating the maternal symptoms to stabilize the mother in an attempt to prolong the pregnancy. However, the efficacy of this management strategy is limited. Therefore, identification of novel therapeutic targets and strategies is needed. Here, we provide a comprehensive overview of the current state of knowledge regarding mechanisms of vascular and renal pathophysiology during PE and discuss potential therapeutic targets directed at improving maternal vascular and renal function.
Language	English
Publishing date	2023-03-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2918626-2
ISSN	2468-8673 ; 2468-8681
ISSN (online)	2468-8673
ISSN	2468-8681
DOI	10.1016/j.cophys.2023.100655
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Article ; Online: Does Using a Stacking Ensemble Method to Combine Multiple Base Learners Within a Database Improve Model Transportability?

Yang, Cynthia / Fridgeirsson, Egill A / Kors, Jan A / Reps, Jenna M / Rijnbeek, Peter R / Wong, Jenna / Williams, Ross D

Studies in health technology and informatics

2023 Volume 302, Page(s) 129–130

Abstract: We investigated a stacking ensemble method that combines multiple base learners within a database. The results on external validation across four large databases suggest a stacking ensemble could improve model transportability. ...

Abstract	We investigated a stacking ensemble method that combines multiple base learners within a database. The results on external validation across four large databases suggest a stacking ensemble could improve model transportability.
MeSH term(s)	Databases, Factual
Language	English
Publishing date	2023-05-19
Publishing country	Netherlands
Document type	Journal Article
ISSN	1879-8365
ISSN (online)	1879-8365
DOI	10.3233/SHTI230080
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Article ; Online: Neutralizing MIP3

Ekperikpe, Ubong S / Poudel, Bibek / Shields, Corbin A / Mandal, Sautan / Cornelius, Denise C / Williams, Jan M

The Journal of pharmacology and experimental therapeutics

2022 Volume 384, Issue 3, Page(s) 445–454

Abstract: Recently, we reported that the early progression of renal injury in obese Dahl salt-sensitive leptin receptor mutant ( ... ...

Abstract	Recently, we reported that the early progression of renal injury in obese Dahl salt-sensitive leptin receptor mutant (SS
MeSH term(s)	Rats ; Animals ; Rats, Inbred Dahl ; Pediatric Obesity/metabolism ; Insulin Resistance ; Receptors, Leptin/metabolism ; Receptors, Leptin/therapeutic use ; Kidney ; Kidney Diseases/metabolism ; Proteinuria/metabolism ; Sodium Chloride, Dietary/metabolism ; Inflammation/metabolism ; Hypertension/drug therapy ; Blood Pressure
Chemical Substances	Receptors, Leptin ; Sodium Chloride, Dietary
Language	English
Publishing date	2022-12-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.122.001298
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Article ; Online: Chronic treatment with IL-25 increases renal M2 macrophages and reduces renal injury in obese Dahl salt-sensitive rats during the prepubescent stage.

Poudel, Bibek / Ekperikpe, Ubong S / Mandal, Sautan / Wilson, Gregory E / Shields, Corbin A / Cornelius, Denise C / Williams, Jan M

American journal of physiology. Renal physiology

2023 Volume 325, Issue 1, Page(s) F87–F98

Abstract: Recently, we have reported that the early progression of proteinuria in the obese Dahl salt-sensitive (SS) leptin receptor mutant ( ... ...

Abstract	Recently, we have reported that the early progression of proteinuria in the obese Dahl salt-sensitive (SS) leptin receptor mutant (SS
MeSH term(s)	Rats ; Animals ; Rats, Inbred Dahl ; Interleukin-17/pharmacology ; Kidney/pathology ; Kidney Diseases/pathology ; Proteinuria/pathology ; Obesity/complications ; Obesity/pathology ; Sodium Chloride, Dietary/pharmacology ; Macrophages/pathology
Chemical Substances	Interleukin-17 ; Sodium Chloride, Dietary
Language	English
Publishing date	2023-05-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00209.2022
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Article ; Online: Patient Perceptions of e-Visits: Qualitative Study of Older Adults to Inform Health System Implementation.

Judson, Timothy J / Subash, Meera / Harrison, James D / Yeager, Jan / Williams, Aimée M / Grouse, Carrie K / Byron, Maria

JMIR aging

2023 Volume 6, Page(s) e45641

Abstract: Background: Electronic visits (e-visits) are billable, asynchronous patient-initiated messages that require at least five minutes of medical decision-making by a provider. Unequal use of patient portal tools like e-visits by certain patient populations ... ...

Abstract	Background: Electronic visits (e-visits) are billable, asynchronous patient-initiated messages that require at least five minutes of medical decision-making by a provider. Unequal use of patient portal tools like e-visits by certain patient populations may worsen health disparities. To date, no study has attempted to qualitatively assess perceptions of e-visits in older adults. Objective: In this qualitative study, we aimed to understand patient perceptions of e-visits, including their perceived utility, barriers to use, and care implications, with a focus on vulnerable patient groups. Methods: We conducted a qualitative study using in-depth structured individual interviews with patients from diverse backgrounds to assess their knowledge and perceptions surrounding e-visits as compared with unbilled portal messages and other visit types. We used content analysis to analyze interview data. Results: We conducted 20 interviews, all in adults older than 65 years. We identified 4 overarching coding categories or themes. First, participants were generally accepting of the concept of e-visits and willing to try them. Second, nearly two-thirds of the participants voiced a preference for synchronous communication. Third, participants had specific concerns about the name "e-visit" and when to choose this type of visit in the patient portal. Fourth, some participants indicated discomfort using or accessing technology for e-visits. Financial barriers to the use of e-visits was not a common theme. Conclusions: Our findings suggest that older adults are generally accepting of the concept of e-visits, but uptake may be limited due to their preference for synchronous communication. We identified several opportunities to improve e-visit implementation.
Language	English
Publishing date	2023-05-26
Publishing country	Canada
Document type	Journal Article
ISSN	2561-7605
ISSN (online)	2561-7605
DOI	10.2196/45641
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Article: Chronic Inflammatory Enteropathy and Low-Grade Intestinal T-Cell Lymphoma Are Associated with Altered Microbial Tryptophan Catabolism in Cats.

Barko, Patrick C / Williams, David A / Wu, Yu-An / Steiner, Joerg M / Suchodolski, Jan S / Gal, Arnon / Marsilio, Sina

Animals : an open access journal from MDPI

2023 Volume 14, Issue 1

Abstract: Chronic inflammatory enteropathy (CIE) and low-grade intestinal T-cell lymphoma (LGITL) are common chronic enteropathies (CE) in cats. Enteric microbiota dysbiosis is implicated in the pathogenesis of CE; however, the mechanisms of host-microbiome ... ...

Abstract	Chronic inflammatory enteropathy (CIE) and low-grade intestinal T-cell lymphoma (LGITL) are common chronic enteropathies (CE) in cats. Enteric microbiota dysbiosis is implicated in the pathogenesis of CE; however, the mechanisms of host-microbiome interactions are poorly understood in cats. Microbial indole catabolites of tryptophan (MICT) are gut bacterial catabolites of tryptophan that are hypothesized to regulate intestinal inflammation and mucosal barrier function. MICTs are decreased in the sera of humans with inflammatory bowel disease and previous studies identified altered tryptophan metabolism in cats with CE. We sought to determine whether MICTs were decreased in cats with CE using archived serum samples from cats with CIE (
Language	English
Publishing date	2023-12-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606558-7
ISSN	2076-2615
ISSN	2076-2615
DOI	10.3390/ani14010067
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Article ; Online: Tunable force transduction through the

Williams-Jones, Daniel P / Webby, Melissa N / Press, Cara E / Gradon, Jan M / Armstrong, Sophie R / Szczepaniak, Joanna / Kleanthous, Colin

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

2023 Volume 120, Issue 47, Page(s) e2306707120

Abstract: The outer membrane (OM) of Gram-negative bacteria is not energised and so processes requiring a driving force must connect to energy-transduction systems in the inner membrane (IM). Tol (Tol-Pal) and Ton are related, proton motive force- (PMF-) coupled ... ...

Abstract	The outer membrane (OM) of Gram-negative bacteria is not energised and so processes requiring a driving force must connect to energy-transduction systems in the inner membrane (IM). Tol (Tol-Pal) and Ton are related, proton motive force- (PMF-) coupled assemblies that stabilise the OM and import essential nutrients, respectively. Both rely on proton-harvesting IM motor (stator) complexes, which are homologues of the flagellar stator unit Mot, to transduce force to the OM through elongated IM force transducer proteins, TolA and TonB, respectively. How PMF-driven motors in the IM generate mechanical work at the OM via force transducers is unknown. Here, using cryoelectron microscopy, we report the 4.3Å structure of the
MeSH term(s)	Escherichia coli/metabolism ; Escherichia coli Proteins/metabolism ; Cryoelectron Microscopy ; Cell Membrane/metabolism ; Membrane Proteins/metabolism
Chemical Substances	Escherichia coli Proteins ; Membrane Proteins
Language	English
Publishing date	2023-11-16
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.2306707120
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Article ; Online: RNA to Rule Them All: Critical Steps in Lassa Virus Ribonucleoparticle Assembly and Recruitment.

Sänger, Lennart / Williams, Harry M / Yu, Dingquan / Vogel, Dominik / Kosinski, Jan / Rosenthal, Maria / Uetrecht, Charlotte

Journal of the American Chemical Society

2023 Volume 145, Issue 51, Page(s) 27958–27974

Abstract: Lassa virus is a negative-strand RNA virus with only four structural proteins that causes periodic outbreaks in West Africa. The nucleoprotein (NP) encapsidates the viral genome, forming ribonucleoprotein complexes (RNPs) together with the viral RNA and ... ...

Abstract	Lassa virus is a negative-strand RNA virus with only four structural proteins that causes periodic outbreaks in West Africa. The nucleoprotein (NP) encapsidates the viral genome, forming ribonucleoprotein complexes (RNPs) together with the viral RNA and the L protein. RNPs must be continuously restructured during viral genome replication and transcription. The Z protein is important for membrane recruitment of RNPs, viral particle assembly, and budding and has also been shown to interact with the L protein. However, the interaction of NP, viral RNA, and Z is poorly understood. Here, we characterize the interactions between Lassa virus NP, Z, and RNA using structural mass spectrometry. We identify the presence of RNA as the driver for the disassembly of ring-like NP trimers, a storage form, into monomers to subsequently form higher order RNA-bound NP assemblies. We locate the interaction site of Z and NP and demonstrate that while NP binds Z independently of the presence of RNA, this interaction is pH-dependent. These data improve our understanding of RNP assembly, recruitment, and release in Lassa virus.
MeSH term(s)	Lassa virus/genetics ; Lassa virus/metabolism ; Ribonucleoproteins/chemistry ; Nucleoproteins ; Virus Assembly ; RNA, Viral/genetics ; RNA, Viral/metabolism
Chemical Substances	Ribonucleoproteins ; Nucleoproteins ; RNA, Viral
Language	English
Publishing date	2023-12-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.3c07325
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