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Article ; Online: Modelling electrified railway signalling misoperations during extreme space weather events in the UK.

Patterson, Cameron J / Wild, James A / Beggan, Ciarán D / Richardson, Gemma S / Boteler, David H

2024 Volume 14, Issue 1, Page(s) 1583

Abstract: Space weather has the potential to impact ground-based technologies on Earth, affecting many systems including railway signalling. This study uses a recently developed model to analyse the impact of geomagnetically induced currents on railway signalling ... ...

Abstract	Space weather has the potential to impact ground-based technologies on Earth, affecting many systems including railway signalling. This study uses a recently developed model to analyse the impact of geomagnetically induced currents on railway signalling systems in the United Kingdom during the March 1989 and October 2003 geomagnetic storms. The March 1989 storm is also scaled to estimate a 1-in-100 year and a 1-in-200 year extreme storm. Both the Glasgow to Edinburgh line, and the Preston to Lancaster section of the West Coast Main Line are modelled. No "right side" failures (when unoccupied sections appear occupied) are suggested to have occurred during either storm, and the total number of potential "wrong side" failures (when occupied sections appear clear) is low. However, the modelling indicates "right side" and "wrong side" failures are possible on both routes during the 1-in-100 year and 1-in-200 year extreme storms, with the Glasgow to Edinburgh line showing more total misoperations than the Preston to Lancaster section of the West Coast Main Line. A 1-in-100 year or 1-in-200 year extreme storm would result in misoperations over an extended period of time, with most occurring over a duration of 2-3 h either side of the peak of the storm.
Language	English
Publishing date	2024-01-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-51390-3
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Article ; Online: Endoplasmic Reticulum Stress-Regulated Chaperones as a Serum Biomarker Panel for Parkinson's Disease.

Mnich, Katarzyna / Moghaddam, Shirin / Browne, Patrick / Counihan, Timothy / Fitzgerald, Stephen P / Martin, Kenneth / Richardson, Ciaran / Samali, Afshin / Gorman, Adrienne M

Molecular neurobiology

2022 Volume 60, Issue 3, Page(s) 1476–1485

Abstract: Examination of post-mortem brain tissues has previously revealed a strong association between Parkinson's disease (PD) pathophysiology and endoplasmic reticulum (ER) stress. Evidence in the literature regarding the circulation of ER stress-regulated ... ...

Abstract	Examination of post-mortem brain tissues has previously revealed a strong association between Parkinson's disease (PD) pathophysiology and endoplasmic reticulum (ER) stress. Evidence in the literature regarding the circulation of ER stress-regulated factors released from neurons provides a rationale for investigating ER stress biomarkers in the blood to aid diagnosis of PD. The levels of ER stress-regulated proteins in serum collected from 29 PD patients and 24 non-PD controls were measured using enzyme-linked immunosorbent assays. A panel of four biomarkers, protein disulfide-isomerase A1, protein disulfide-isomerase A3, mesencephalic astrocyte-derived neurotrophic factor, and clusterin, together with age and gender had higher ability (area under the curve 0.64, sensitivity 66%, specificity 57%) and net benefit to discriminate PD patients from the non-PD group compared with other analyzed models. Addition of oligomeric and total α-synuclein to the model did not improve the diagnostic power of the biomarker panel. We provide evidence that ER stress-regulated proteins merit further investigation for their potential as diagnostic biomarkers of PD.
MeSH term(s)	Humans ; Parkinson Disease/diagnosis ; Parkinson Disease/metabolism ; Protein Disulfide-Isomerases/metabolism ; alpha-Synuclein/metabolism ; Endoplasmic Reticulum Stress/physiology ; Molecular Chaperones ; Neurons/metabolism
Chemical Substances	Protein Disulfide-Isomerases (EC 5.3.4.1) ; alpha-Synuclein ; Molecular Chaperones
Language	English
Publishing date	2022-12-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-022-03139-0
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Article ; Online: Inhibition of IRE1α RNase activity sensitizes patient-derived acute myeloid leukaemia cells to proteasome inhibitors.

Creedican, Stuart / Robinson, Claire M / Mnich, Katarzyna / Islam, Md Nahidul / Szegezdi, Eva / Clifford, Ruth / Krawczyk, Janusz / Patterson, John B / FitzGerald, Stephen P / Summers, Mark / Richardson, Ciaran / Martin, Kenneth / Gorman, Adrienne M / Samali, Afshin

Journal of cellular and molecular medicine

2022 Volume 26, Issue 16, Page(s) 4629–4633

MeSH term(s)	Endoplasmic Reticulum Stress ; Endoribonucleases ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Proteasome Inhibitors/pharmacology ; Protein Serine-Threonine Kinases
Chemical Substances	Proteasome Inhibitors ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Endoribonucleases (EC 3.1.-)
Language	English
Publishing date	2022-07-13
Publishing country	England
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	2074559-X
ISSN	1582-4934 ; 1582-4934 ; 1582-1838
ISSN (online)	1582-4934
ISSN	1582-4934 ; 1582-1838
DOI	10.1111/jcmm.17479
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Article ; Online: Integrating inflammatory serum biomarkers into a risk calculator for prostate cancer detection.

Jalali, Amirhossein / Kitching, Michael / Martin, Kenneth / Richardson, Ciaran / Murphy, Thomas Brendan / FitzGerald, Stephen Peter / Watson, Ronald William / Perry, Antoinette Sabrina

Scientific reports

2021 Volume 11, Issue 1, Page(s) 2525

Abstract: Improved prostate cancer detection methods would avoid over-diagnosis of clinically indolent disease informing appropriate treatment decisions. The aims of this study were to investigate the role of a panel of Inflammation biomarkers to inform the need ... ...

Abstract	Improved prostate cancer detection methods would avoid over-diagnosis of clinically indolent disease informing appropriate treatment decisions. The aims of this study were to investigate the role of a panel of Inflammation biomarkers to inform the need for a biopsy to diagnose prostate cancer. Peripheral blood serum obtained from 436 men undergoing transrectal ultrasound guided biopsy were assessed for a panel of 18 inflammatory serum biomarkers in addition to Total and Free Prostate Specific Antigen (PSA). This panel was integrated into a previously developed Irish clinical risk calculator (IPRC) for the detection of prostate cancer and high-grade prostate cancer (Gleason Score ≥ 7). Using logistic regression and multinomial regression methods, two models (Logst-RC and Multi-RC) were developed considering linear and nonlinear effects of the panel in conjunction with clinical and demographic parameters for determination of the two endpoints. Both models significantly improved the predictive ability of the clinical model for detection of prostate cancer (from 0.656 to 0.731 for Logst-RC and 0.713 for Multi-RC) and high-grade prostate cancer (from 0.716 to 0.785 for Logst-RC and 0.767 for Multi-RC) and demonstrated higher clinical net benefit. This improved discriminatory power and clinical utility may allow for individualised risk stratification improving clinical decision making.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Biomarkers/blood ; Biopsy ; Early Detection of Cancer ; Humans ; Inflammation Mediators/blood ; Liquid Biopsy ; Male ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; Prostatic Neoplasms/blood ; Prostatic Neoplasms/diagnosis ; Prostatic Neoplasms/epidemiology ; ROC Curve ; Risk Assessment ; Risk Factors
Chemical Substances	Biomarkers ; Inflammation Mediators
Language	English
Publishing date	2021-01-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-81965-3
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Article ; Online: Integrating inflammatory serum biomarkers into a risk calculator for prostate cancer detection

Amirhossein Jalali / Michael Kitching / Kenneth Martin / Ciaran Richardson / Thomas Brendan Murphy / Stephen Peter FitzGerald / Ronald William Watson / Antoinette Sabrina Perry

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 8

Abstract: Abstract Improved prostate cancer detection methods would avoid over-diagnosis of clinically indolent disease informing appropriate treatment decisions. The aims of this study were to investigate the role of a panel of Inflammation biomarkers to inform ... ...

Abstract	Abstract Improved prostate cancer detection methods would avoid over-diagnosis of clinically indolent disease informing appropriate treatment decisions. The aims of this study were to investigate the role of a panel of Inflammation biomarkers to inform the need for a biopsy to diagnose prostate cancer. Peripheral blood serum obtained from 436 men undergoing transrectal ultrasound guided biopsy were assessed for a panel of 18 inflammatory serum biomarkers in addition to Total and Free Prostate Specific Antigen (PSA). This panel was integrated into a previously developed Irish clinical risk calculator (IPRC) for the detection of prostate cancer and high-grade prostate cancer (Gleason Score ≥ 7). Using logistic regression and multinomial regression methods, two models (Logst-RC and Multi-RC) were developed considering linear and nonlinear effects of the panel in conjunction with clinical and demographic parameters for determination of the two endpoints. Both models significantly improved the predictive ability of the clinical model for detection of prostate cancer (from 0.656 to 0.731 for Logst-RC and 0.713 for Multi-RC) and high-grade prostate cancer (from 0.716 to 0.785 for Logst-RC and 0.767 for Multi-RC) and demonstrated higher clinical net benefit. This improved discriminatory power and clinical utility may allow for individualised risk stratification improving clinical decision making.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: Biomarkers During Recovery From AKI and Prediction of Long-term Reductions in Estimated GFR.

Wilson, Michelle / Packington, Rebecca / Sewell, Helen / Bartle, Rebecca / McCole, Eibhlin / Kurth, Mary Jo / Richardson, Ciaran / Shaw, Sue / Akani, Aleli / Banks, Rosamonde E / Selby, Nicholas M

American journal of kidney diseases : the official journal of the National Kidney Foundation

2021 Volume 79, Issue 5, Page(s) 646–656.e1

Abstract: Rationale & objective: The effects of acute kidney injury (AKI) on long-term kidney function, cardiovascular disease, and mortality are well documented. We aimed to identify biomarkers for the estimation of risk of new or worsening chronic kidney ... ...

Abstract	Rationale & objective: The effects of acute kidney injury (AKI) on long-term kidney function, cardiovascular disease, and mortality are well documented. We aimed to identify biomarkers for the estimation of risk of new or worsening chronic kidney disease (CKD) following AKI. Study design: Prospective cohort study. Setting & participants: Adults from a single clinical center who experienced AKI between May 2013 and May 2016 and survived until 3 years after the hospitalization during which AKI occurred. Participants included those with and without preexisting CKD. Predictors: Panel of 11 plasma biomarkers measured 3 months after hospitalization. Outcome: Kidney disease progression, defined as a≥25% decrease in estimated glomerular filtration rate (eGFR) combined with worsening CKD stage, assessed 3 years after the occurrence of AKI. Analytical approach: Associations between biomarkers and kidney disease progression were evaluated in multivariable logistic regression models. Importance of predictor variables was assessed by constructing multiple decision trees, with penalized least absolute shrinkage and selection operator logistic regression for variable selection used to produce multivariable models. Results: A total of 500 patients were studied. Soluble tumor necrosis factor receptor (sTNFR) 1, sTNFR2, cystatin C, neutrophil gelatinase-associated lipocalin, 3-month eGFR, and urinary albumin-creatinine ratio were independently associated with kidney disease progression and were more important than AKI severity or duration. A multivariable model containing sTNFR1, sTNFR2, cystatin C, and eGFR discriminated between those with and without kidney disease progression (area under the curve, 0.79 [95% CI, 0.70-0.83]). Optimizing the cutoff point to maximize utility as a "rule-out" test to identify those at low risk increased the sensitivity of the model to 95% and its negative predictive value to 92%. Limitations: Lack of external validation cohort. Analyses limited to patients who survived for 3 years after AKI. Mixed population of patients with and without baseline CKD. Conclusions: A panel of plasma biomarkers measured 3 months after discharge from a hospitalization complicated by AKI provides a potential opportunity to identify patients who are at very low risk of incident or worsening CKD. Further study is required to determine its clinical utility through independent prospective validation.
MeSH term(s)	Acute Kidney Injury/etiology ; Adult ; Biomarkers ; Creatinine ; Cystatin C ; Disease Progression ; Female ; Glomerular Filtration Rate ; Humans ; Lipocalin-2 ; Male ; Prospective Studies ; Renal Insufficiency, Chronic/complications
Chemical Substances	Biomarkers ; Cystatin C ; Lipocalin-2 ; Creatinine (AYI8EX34EU)
Language	English
Publishing date	2021-10-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604539-x
ISSN	1523-6838 ; 0272-6386
ISSN (online)	1523-6838
ISSN	0272-6386
DOI	10.1053/j.ajkd.2021.08.017
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Article: The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway.

Richardson, Ciaran / Alessi, Dario R

Journal of cell science

2008 Volume 121, Issue Pt 20, Page(s) 3293–3304

Abstract: It has recently been shown that the WNK [with-no-K(Lys)] kinases (WNK1, WNK2, WNK3 and WNK4) have vital roles in the control of salt homeostasis and blood pressure. This Commentary focuses on recent findings that have uncovered the backbone of a novel ... ...

Abstract	It has recently been shown that the WNK [with-no-K(Lys)] kinases (WNK1, WNK2, WNK3 and WNK4) have vital roles in the control of salt homeostasis and blood pressure. This Commentary focuses on recent findings that have uncovered the backbone of a novel signal-transduction network that is controlled by WNK kinases. Under hyperosmotic or hypotonic low-Cl- conditions, WNK isoforms are activated, and subsequently phosphorylate and activate the related protein kinases SPAK and OSR1. SPAK and OSR1 phosphorylate and activate ion co-transporters that include NCC, NKCC1 and NKCC2, which are targets for the commonly used blood-pressure-lowering thiazide-diuretic and loop-diuretic drugs. The finding that mutations in WNK1, WNK4, NCC and NKCC2 cause inherited blood-pressure syndromes in humans highlights the importance of these enzymes. We argue that these new findings indicate that SPAK and OSR1 are promising drug targets for the treatment of hypertension, because inhibiting these enzymes would reduce NCC and NKCC2 activity and thereby suppress renal salt re-absorption. We also discuss unresolved and controversial questions in this field of research.
MeSH term(s)	Absorption/drug effects ; Absorption/genetics ; Animals ; Blood Pressure/genetics ; Chlorides/metabolism ; Genetic Diseases, Inborn/drug therapy ; Genetic Diseases, Inborn/genetics ; Genetic Diseases, Inborn/metabolism ; Humans ; Hypertension/drug therapy ; Hypertension/genetics ; Hypertension/metabolism ; Intracellular Signaling Peptides and Proteins ; Ion Channels/genetics ; Ion Channels/metabolism ; Ion Transport/drug effects ; Ion Transport/genetics ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Kidney/metabolism ; Minor Histocompatibility Antigens ; Mutation ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Sodium Chloride Symporter Inhibitors/therapeutic use ; Sodium Potassium Chloride Symporter Inhibitors/therapeutic use ; Syndrome ; WNK Lysine-Deficient Protein Kinase 1
Chemical Substances	Chlorides ; Intracellular Signaling Peptides and Proteins ; Ion Channels ; Isoenzymes ; Minor Histocompatibility Antigens ; Sodium Chloride Symporter Inhibitors ; Sodium Potassium Chloride Symporter Inhibitors ; OXSR1 protein, human (EC 2.7.1.-) ; WNK2 protein, human (EC 2.7.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; STK39 protein, human (EC 2.7.11.1) ; WNK Lysine-Deficient Protein Kinase 1 (EC 2.7.11.1) ; WNK1 protein, human (EC 2.7.11.1) ; WNK3 protein, human (EC 2.7.11.1) ; WNK4 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2008-10-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.029223
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Article ; Online: United Kingdom: Health System Review.

Cylus, Jonathan / Richardson, Erica / Findley, Lisa / Longley, Marcus / O'Neill, Ciaran / Steel, David

Health systems in transition

2015 Volume 17, Issue 5, Page(s) 1–126

Abstract: This analysis of the United Kingdom health system reviews recent developments in organization and governance, health financing, health care provision, health reforms and health system performance. It provides an overview of how the national health ... ...

Abstract	This analysis of the United Kingdom health system reviews recent developments in organization and governance, health financing, health care provision, health reforms and health system performance. It provides an overview of how the national health services operate in the four nations that make up the United Kingdom, as responsibility for organizing health financing and services was devolved from 1997. With devolution, the health systems in the United Kingdom have diverged in the details of how services are organized and paid for, but all have maintained national health services which provide universal access to a comprehensive package of services that are mostly free at the point of use. These health services are predominantly financed from general taxation and 83.5% of total health expenditure in the United Kingdom came from public sources in 2013. Life expectancy has increased steadily across the United Kingdom, but health inequalities have proved stubbornly resistant to improvement, and the gap between the most deprived and the most privileged continues to widen, rather than close. The United Kingdom faces challenges going forward, including how to cope with the needs of an ageing population, how to manage populations with poor health behaviours and associated chronic conditions, how to meet patient expectations of access to the latest available medicines and technologies, and how to adapt a system that has limited resources to expand its workforce and infrastructural capacity so it can rise to these challenges.
MeSH term(s)	Delivery of Health Care/economics ; Delivery of Health Care/organization & administration ; Health Care Reform/organization & administration ; Health Facilities/statistics & numerical data ; Health Manpower/organization & administration ; Health Manpower/statistics & numerical data ; Health Services Research ; Health Status Disparities ; Humans ; Information Dissemination ; Information Services/organization & administration ; Life Expectancy ; National Health Programs/economics ; National Health Programs/organization & administration ; Quality of Health Care/organization & administration ; Socioeconomic Factors ; United Kingdom
Language	English
Publishing date	2015
Publishing country	Denmark
Document type	Journal Article
ZDB-ID	2233748-9
ISSN	1817-6127 ; 1817-6119
ISSN (online)	1817-6127
ISSN	1817-6119
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Article ; Online: Design and Synthesis of Functionally Active 5-Amino-6-Aryl Pyrrolopyrimidine Inhibitors of Hematopoietic Progenitor Kinase 1.

Gallego, Rebecca A / Bernier, Louise / Chen, Hui / Cho-Schultz, Sujin / Chung, Loanne / Collins, Michael / Del Bel, Matthew / Elleraas, Jeff / Costa Jones, Cinthia / Cronin, Ciaran N / Edwards, Martin / Fang, Xu / Fisher, Timothy / He, Mingying / Hoffman, Jacqui / Huo, Ruiduan / Jalaie, Mehran / Johnson, Eric / Johnson, Ted W /

Journal of medicinal chemistry

2023 Volume 66, Issue 7, Page(s) 4888–4909

Abstract: Immune activating agents represent a valuable class of therapeutics for the treatment of cancer. An area of active research is expanding the types of these therapeutics that are available to patients via targeting new biological mechanisms. Hematopoietic ...

Abstract	Immune activating agents represent a valuable class of therapeutics for the treatment of cancer. An area of active research is expanding the types of these therapeutics that are available to patients via targeting new biological mechanisms. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of immune signaling and a target of high interest for the treatment of cancer. Herein, we present the discovery and optimization of novel amino-6-aryl pyrrolopyrimidine inhibitors of HPK1 starting from hits identified via virtual screening. Key components of this discovery effort were structure-based drug design aided by analyses of normalized
MeSH term(s)	Humans ; Protein Serine-Threonine Kinases/metabolism ; Signal Transduction ; Pyrroles/pharmacology
Chemical Substances	hematopoietic progenitor kinase 1 (EC 2.7.1.11) ; pyrrolopyrimidine ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Pyrroles
Language	English
Publishing date	2023-03-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.2c02038
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Article: The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway

Richardson, Ciaran / Alessi, Dario R

Journal of cell science. 2008 Oct. 15, v. 121, no. 20

2008

Abstract	It has recently been shown that the WNK [with-no-K(Lys)] kinases (WNK1, WNK2, WNK3 and WNK4) have vital roles in the control of salt homeostasis and blood pressure. This Commentary focuses on recent findings that have uncovered the backbone of a novel signal-transduction network that is controlled by WNK kinases. Under hyperosmotic or hypotonic low-Cl⁻ conditions, WNK isoforms are activated, and subsequently phosphorylate and activate the related protein kinases SPAK and OSR1. SPAK and OSR1 phosphorylate and activate ion co-transporters that include NCC, NKCC1 and NKCC2, which are targets for the commonly used blood-pressure-lowering thiazide-diuretic and loop-diuretic drugs. The finding that mutations in WNK1, WNK4, NCC and NKCC2 cause inherited blood-pressure syndromes in humans highlights the importance of these enzymes. We argue that these new findings indicate that SPAK and OSR1 are promising drug targets for the treatment of hypertension, because inhibiting these enzymes would reduce NCC and NKCC2 activity and thereby suppress renal salt re-absorption. We also discuss unresolved and controversial questions in this field of research.
Language	English
Dates of publication	2008-1015
Size	p. 3293-3304.
Publishing place	The Company of Biologists Limited
Document type	Article
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
Database	NAL-Catalogue (AGRICOLA)

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