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Article: Roles of Chondroitin Sulfate Proteoglycans as Regulators of Skeletal Development.

Schwartz, Nancy B / Domowicz, Miriam S

Frontiers in cell and developmental biology

2022 Volume 10, Page(s) 745372

Abstract: The extracellular matrix (ECM) is critically important for most cellular processes including differentiation, morphogenesis, growth, survival and regeneration. The interplay between cells and the ECM often involves bidirectional signaling between ECM ... ...

Abstract	The extracellular matrix (ECM) is critically important for most cellular processes including differentiation, morphogenesis, growth, survival and regeneration. The interplay between cells and the ECM often involves bidirectional signaling between ECM components and small molecules, i.e., growth factors, morphogens, hormones, etc., that regulate critical life processes. The ECM provides biochemical and contextual information by binding, storing, and releasing the bioactive signaling molecules, and/or mechanical information that signals from the cell membrane integrins through the cytoskeleton to the nucleus, thereby influencing cell phenotypes. Using these dynamic, reciprocal processes, cells can also remodel and reshape the ECM by degrading and re-assembling it, thereby sculpting their environments. In this review, we summarize the role of chondroitin sulfate proteoglycans as regulators of cell and tissue development using the skeletal growth plate model, with an emphasis on use of naturally occurring, or created mutants to decipher the role of proteoglycan components in signaling paradigms.
Language	English
Publishing date	2022-04-08
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2022.745372
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Article: Chemistry and Function of Glycosaminoglycans in the Nervous System.

Schwartz, Nancy B / Domowicz, Miriam S

Advances in neurobiology

2022 Volume 29, Page(s) 117–162

Abstract: Proteoglycans, and especially their GAG components, participate in numerous biologically significant interactions with growth factors, chemokines, morphogens, guidance molecules, survival factors, and other extracellular and cell-surface components. ... ...

Abstract	Proteoglycans, and especially their GAG components, participate in numerous biologically significant interactions with growth factors, chemokines, morphogens, guidance molecules, survival factors, and other extracellular and cell-surface components. These interactions are often critical to the basic developmental processes of cellular proliferation and differentiation, as well as to both the onset of disease sequelae and prevention of disease progression. In many tissues, proteoglycans and especially their glycosaminoglycan (GAG) components are mediators of these processes. The GAG family is characterized by covalently linked repeating disaccharides forming long unbranched polysaccharide chains. Thus far in higher eukaryotes, the family consists of chondroitin sulfate (CS), heparin/heparan sulfate (HS), dermatan sulfate (DS), keratan sulfate (KS) and hyaluronan (HA). All GAG chains (except HA) are characteristically modified by varying amounts of esterified sulfate. One or more GAG chains are usually found in nature bound to polypeptide backbones in the form of proteoglycans; HA is the exception. In the nervous system, GAG/proteoglycan-mediated interactions participate in proliferation and synaptogenesis, neural plasticity, and regeneration. This review focuses on the structure, chemistry and function of GAGs in nervous system development, disease, function and injury response.
MeSH term(s)	Humans ; Glycosaminoglycans/metabolism ; Chondroitin Sulfates/chemistry ; Chondroitin Sulfates/metabolism ; Dermatan Sulfate ; Keratan Sulfate ; Hyaluronic Acid ; Heparitin Sulfate/metabolism ; Proteoglycans ; Heparin ; Disaccharides ; Sulfates/metabolism ; Nervous System
Chemical Substances	Glycosaminoglycans ; Chondroitin Sulfates (9007-28-7) ; Dermatan Sulfate (24967-94-0) ; Keratan Sulfate (9056-36-4) ; Hyaluronic Acid (9004-61-9) ; Heparitin Sulfate (9050-30-0) ; Proteoglycans ; Heparin (9005-49-6) ; Disaccharides ; Sulfates
Language	English
Publishing date	2022-10-18
Publishing country	United States
Document type	Review ; Journal Article
ISSN	2190-5215
ISSN	2190-5215
DOI	10.1007/978-3-031-12390-0_5
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Article ; Online: Roles of Chondroitin Sulfate Proteoglycans as Regulators of Skeletal Development

Nancy B. Schwartz / Miriam S. Domowicz

Frontiers in Cell and Developmental Biology, Vol

2022 Volume 10

Abstract	The extracellular matrix (ECM) is critically important for most cellular processes including differentiation, morphogenesis, growth, survival and regeneration. The interplay between cells and the ECM often involves bidirectional signaling between ECM components and small molecules, i.e., growth factors, morphogens, hormones, etc., that regulate critical life processes. The ECM provides biochemical and contextual information by binding, storing, and releasing the bioactive signaling molecules, and/or mechanical information that signals from the cell membrane integrins through the cytoskeleton to the nucleus, thereby influencing cell phenotypes. Using these dynamic, reciprocal processes, cells can also remodel and reshape the ECM by degrading and re-assembling it, thereby sculpting their environments. In this review, we summarize the role of chondroitin sulfate proteoglycans as regulators of cell and tissue development using the skeletal growth plate model, with an emphasis on use of naturally occurring, or created mutants to decipher the role of proteoglycan components in signaling paradigms.
Keywords	growth plate ; signaling factors ; chondrogenesis ; degradation ; regeneration ; proteoglycans ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
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Article ; Online: Proteoglycans in brain development and pathogenesis.

Schwartz, Nancy B / Domowicz, Miriam S

FEBS letters

2018 Volume 592, Issue 23, Page(s) 3791–3805

Abstract: Proteoglycans are diverse, complex extracellular/cell surface macromolecules composed of a central core protein with covalently linked glycosaminoglycan (GAG) chains; both of these components contribute to the growing list of important bio-active ... ...

Abstract	Proteoglycans are diverse, complex extracellular/cell surface macromolecules composed of a central core protein with covalently linked glycosaminoglycan (GAG) chains; both of these components contribute to the growing list of important bio-active functions attributed to proteoglycans. Increasingly, attention has been paid to the roles of proteoglycans in nervous tissue development due to their highly regulated spatio/temporal expression patterns, whereby they promote/inhibit neurite outgrowth, participate in specification and maturation of various precursor cell types, and regulate cell behaviors like migration, axonal pathfinding, synaptogenesis and plasticity. These functions emanate from both the environments proteoglycans create around cells by retaining ions and water or serving as scaffolds for cell shaping or motility, and from dynamic interactions that modulate signaling fields for cytokines, growth factors and morphogens, which may bind to either the protein or GAG portions. Also, genetic abnormalities impacting proteoglycan synthesis during critical steps of brain development and response to environmental insults and injuries, as well as changes in microenvironment interactions leading to tumors in the central nervous system, all suggest roles for proteoglycans in behavioral and intellectual disorders and malignancies.
MeSH term(s)	Animals ; Brain/cytology ; Brain/metabolism ; Brain Neoplasms/genetics ; Brain Neoplasms/metabolism ; Cell Movement/genetics ; Cell Plasticity/genetics ; Central Nervous System/cytology ; Central Nervous System/metabolism ; Gene Expression Profiling ; Humans ; Neurogenesis/genetics ; Proteoglycans/chemistry ; Proteoglycans/metabolism
Chemical Substances	Proteoglycans
Language	English
Publishing date	2018-03-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.13026
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Article ; Online: Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression.

Domowicz, Miriam S / Chan, Wen-Ching / Claudio-Vázquez, Patricia / Gonzalez, Tatiana / Schwartz, Nancy B

Journal of neuroinflammation

2021 Volume 18, Issue 1, Page(s) 262

Abstract: Background: Neuronal ceroid lipofuscinoses, (NCLs or Batten disease) are a group of inherited, early onset, fatal neurodegenerative diseases associated with mutations in 13 genes. All forms of the disease are characterized by lysosomal accumulation of ... ...

Abstract	Background: Neuronal ceroid lipofuscinoses, (NCLs or Batten disease) are a group of inherited, early onset, fatal neurodegenerative diseases associated with mutations in 13 genes. All forms of the disease are characterized by lysosomal accumulation of fluorescent storage material, as well as profound neurodegeneration, but the relationship of the various genes' function to a single biological process is not obvious. In this study, we used a well-characterized mouse model of classical late infantile NCL (cLINCL) in which the tripeptidyl peptidase 1 (Tpp1) gene is disrupted by gene targeting, resulting in loss of detectable TPP1 activity and leading to progressive neurological phenotypes including ataxia, increased motor deficiency, and early death. Methods: In order to identify genes and pathways that may contribute to progression of the neurodegenerative process, we analyzed forebrain/midbrain and cerebellar transcriptional differences at 1, 2, 3 and 4 months of age in control and TPP1-deficient mice by global RNA-sequencing. Results: Progressive neurodegenerative inflammatory responses involving microglia, astrocytes and endothelial cells were observed, accompanied by activation of leukocyte extravasation signals and upregulation of nitric oxide production and reactive oxygen species. Several astrocytic (i.e., Gfap, C4b, Osmr, Serpina3n) and microglial (i.e., Ctss, Itgb2, Itgax, Lyz2) genes were identified as strong markers for assessing disease progression as they showed increased levels of expression in vivo over time. Furthermore, transient increased expression of choroid plexus genes was observed at 2 months in the lateral and fourth ventricle, highlighting an early role for the choroid plexus and cerebrospinal fluid in the disease pathology. Based on these gene expression changes, we concluded that neuroinflammation starts, for the most part, after 2 months in the Tpp1 Conclusions: These findings have led to a better understanding of cLINCL pathological onset and progression, which may aid in development of future therapeutic treatments for this disease.
MeSH term(s)	Animals ; Brain/pathology ; Disease Models, Animal ; Disease Progression ; Mice ; Mice, Knockout ; Neuronal Ceroid-Lipofuscinoses/genetics ; Neuronal Ceroid-Lipofuscinoses/pathology ; Transcriptome ; Tripeptidyl-Peptidase 1/genetics
Chemical Substances	Tpp1 protein, mouse ; Tripeptidyl-Peptidase 1
Language	English
Publishing date	2021-11-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-021-02302-z
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Article ; Online: The Role of

Jo, Stephanie Y / Domowicz, Miriam S / Henry, Judith G / Schwartz, Nancy B

JBMR plus

2019 Volume 4, Issue 2, Page(s) e10254

Abstract: Osteoarthritis and osteoporosis are widely prevalent and have far-reaching public health implications. There is increasing evidence that epigenetics, in particular, histone 3 lysine 79 ... ...

Abstract	Osteoarthritis and osteoporosis are widely prevalent and have far-reaching public health implications. There is increasing evidence that epigenetics, in particular, histone 3 lysine 79 methyltransferase
Language	English
Publishing date	2019-12-17
Publishing country	England
Document type	Journal Article
ISSN	2473-4039
ISSN (online)	2473-4039
DOI	10.1002/jbm4.10254
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Article: Chemistry and function of glycosaminoglycans in the nervous system.

Schwartz, Nancy B / Domowicz, Miriam S

Advances in neurobiology

2014 Volume 9, Page(s) 89–115

Abstract: The glycosaminoglycan (GAG) family is characterized by covalently linked repeating disaccharides forming long unbranched polysaccharide chains. Thus far in higher eukaryotes, the family consists of chondroitin sulfate (CS), heparin/heparan sulfate (HS), ... ...

Abstract	The glycosaminoglycan (GAG) family is characterized by covalently linked repeating disaccharides forming long unbranched polysaccharide chains. Thus far in higher eukaryotes, the family consists of chondroitin sulfate (CS), heparin/heparan sulfate (HS), dermatan sulfate (DS), and hyaluronan (HA). All GAG chains (except HA) are characteristically modified by varying amounts of esterified sulfate. One or more GAG chains are usually found in nature bound to polypeptide backbones in the form of proteoglycans; HA is the exception and is not synthesized covalently bound to a protein. Proteoglycans, and especially their GAG components, participate in numerous biologically significant interactions with growth factors, chemokines, morphogens, guidance molecules, survival factors, and other extracellular and cell-surface components. These interactions are often critical to the basic developmental processes of cellular proliferation and differentiation, as well as to both the onset of disease sequelae and the prevention of disease progression. In the nervous system, GAG/proteoglycan-mediated interactions participate in proliferation and synaptogenesis, neural plasticity, and regeneration. This review focuses on the structure, chemistry, and function of GAGs in nervous system development, disease, and injury response.
Language	English
Publishing date	2014
Publishing country	United States
Document type	Journal Article
ISSN	2190-5215
ISSN	2190-5215
DOI	10.1007/978-1-4939-1154-7_5
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Article: Proteoglycans in brain development and pathogenesis

Schwartz, Nancy B. / Domowicz, Miriam S.

FEBS letters. 2018 Dec., v. 592, no. 23

2018

Abstract	Proteoglycans are diverse, complex extracellular/cell surface macromolecules composed of a central core protein with covalently linked glycosaminoglycan (GAG) chains; both of these components contribute to the growing list of important bio‐active functions attributed to proteoglycans. Increasingly, attention has been paid to the roles of proteoglycans in nervous tissue development due to their highly regulated spatio/temporal expression patterns, whereby they promote/inhibit neurite outgrowth, participate in specification and maturation of various precursor cell types, and regulate cell behaviors like migration, axonal pathfinding, synaptogenesis and plasticity. These functions emanate from both the environments proteoglycans create around cells by retaining ions and water or serving as scaffolds for cell shaping or motility, and from dynamic interactions that modulate signaling fields for cytokines, growth factors and morphogens, which may bind to either the protein or GAG portions. Also, genetic abnormalities impacting proteoglycan synthesis during critical steps of brain development and response to environmental insults and injuries, as well as changes in microenvironment interactions leading to tumors in the central nervous system, all suggest roles for proteoglycans in behavioral and intellectual disorders and malignancies.
Keywords	brain ; chemical bonding ; cytokines ; glycosaminoglycans ; neurites ; pathogenesis ; proteoglycans ; synaptogenesis
Language	English
Dates of publication	2018-12
Size	p. 3791-3805.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	REVIEW
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.13026
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Article ; Online: Global Brain Transcriptome Analysis of a Tpp1 Neuronal Ceroid Lipofuscinoses Mouse Model.

Domowicz, Miriam S / Chan, Wen-Ching / Claudio-Vázquez, Patricia / Henry, Judith G / Ware, Christopher B / Andrade, Jorge / Dawson, Glyn / Schwartz, Nancy B

ASN neuro

2019 Volume 11, Page(s) 1759091419843393

Abstract: In humans, homozygous mutations in the TPP1 gene results in loss of tripeptidyl peptidase 1 (TPP1) enzymatic activity, leading to late infantile neuronal ceroid lipofuscinoses disease. Using a mouse model that targets the Tpp1 gene and recapitulates the ... ...

Abstract	In humans, homozygous mutations in the TPP1 gene results in loss of tripeptidyl peptidase 1 (TPP1) enzymatic activity, leading to late infantile neuronal ceroid lipofuscinoses disease. Using a mouse model that targets the Tpp1 gene and recapitulates the pathology and clinical features of the human disease, we analyzed end-stage (4 months) transcriptional changes associated with lack of TPP1 activity. Using RNA sequencing technology, Tpp1 expression changes in the forebrain/midbrain and cerebellum of 4-month-old homozygotes were compared with strain-related controls. Transcriptional changes were found in 510 and 1,550 gene transcripts in forebrain/midbrain and cerebellum, respectively, from Tpp1-deficient brain tissues when compared with age-matched controls. Analysis of the differentially expressed genes using the Ingenuity™ pathway software, revealed increased neuroinflammation activity in microglia and astrocytes that could lead to neuronal dysfunction, particularly in the cerebellum. We also observed upregulation in the production of nitric oxide and reactive oxygen species; activation of leukocyte extravasation signals and complement pathways; and downregulation of major transcription factors involved in control of circadian rhythm. Several of these expression changes were confirmed by independent quantitative polymerase chain reaction and histological analysis by mRNA in situ hybridization, which allowed for an in-depth anatomical analysis of the pathology and provided independent confirmation of at least two of the major networks affected in this model. The identification of differentially expressed genes has revealed new lines of investigation for this complex disorder that may lead to novel therapeutic targets.
MeSH term(s)	Aminopeptidases/genetics ; Animals ; Brain/metabolism ; Brain/pathology ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics ; Disease Models, Animal ; Gene Expression Regulation/physiology ; Mice ; Mutation ; Neuronal Ceroid-Lipofuscinoses/genetics ; Neuronal Ceroid-Lipofuscinoses/metabolism ; Neuronal Ceroid-Lipofuscinoses/pathology ; Serine Proteases/genetics ; Transcriptome/physiology
Chemical Substances	Serine Proteases (EC 3.4.-) ; Aminopeptidases (EC 3.4.11.-) ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (EC 3.4.14.-) ; tripeptidyl-peptidase 1 (EC 3.4.14.9)
Language	English
Publishing date	2019-04-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2485467-0
ISSN	1759-0914 ; 1759-0914
ISSN (online)	1759-0914
ISSN	1759-0914
DOI	10.1177/1759091419843393
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Article ; Online: 3D high spectral and spatial resolution imaging of ex vivo mouse brain.

Foxley, Sean / Domowicz, Miriam / Karczmar, Gregory S / Schwartz, Nancy

Medical physics

2015 Volume 42, Issue 3, Page(s) 1463–1472

Abstract: Purpose: Widely used MRI methods show brain morphology both in vivo and ex vivo at very high resolution. Many of these methods (e.g., T2*-weighted imaging, phase-sensitive imaging, or susceptibility-weighted imaging) are sensitive to local magnetic ... ...

Abstract	Purpose: Widely used MRI methods show brain morphology both in vivo and ex vivo at very high resolution. Many of these methods (e.g., T2-weighted imaging, phase-sensitive imaging, or susceptibility-weighted imaging) are sensitive to local magnetic susceptibility gradients produced by subtle variations in tissue composition. However, the spectral resolution of commonly used methods is limited to maintain reasonable run-time combined with very high spatial resolution. Here, the authors report on data acquisition at increased spectral resolution, with 3-dimensional high spectral and spatial resolution MRI, in order to analyze subtle variations in water proton resonance frequency and lineshape that reflect local anatomy. The resulting information compliments previous studies based on T2 and resonance frequency. Methods: The proton free induction decay was sampled at high resolution and Fourier transformed to produce a high-resolution water spectrum for each image voxel in a 3D volume. Data were acquired using a multigradient echo pulse sequence (i.e., echo-planar spectroscopic imaging) with a spatial resolution of 50 × 50 × 70 μm(3) and spectral resolution of 3.5 Hz. Data were analyzed in the spectral domain, and images were produced from the various Fourier components of the water resonance. This allowed precise measurement of local variations in water resonance frequency and lineshape, at the expense of significantly increased run time (16-24 h). Results: High contrast T2-weighted images were produced from the peak of the water resonance (peak height image), revealing a high degree of anatomical detail, specifically in the hippocampus and cerebellum. In images produced from Fourier components of the water resonance at -7.0 Hz from the peak, the contrast between deep white matter tracts and the surrounding tissue is the reverse of the contrast in water peak height images. This indicates the presence of a shoulder in the water resonance that is not present at +7.0 Hz and may be specific to white matter anatomy. Moreover, a frequency shift of 6.76 ± 0.55 Hz was measured between the molecular and granular layers of the cerebellum. This shift is demonstrated in corresponding spectra; water peaks from voxels in the molecular and granular layers are consistently 2 bins apart (7.0 Hz, as dictated by the spectral resolution) from one another. Conclusions:* High spectral and spatial resolution MR imaging has the potential to accurately measure the changes in the water resonance in small voxels. This information can guide optimization and interpretation of more commonly used, more rapid imaging methods that depend on image contrast produced by local susceptibility gradients. In addition, with improved sampling methods, high spectral and spatial resolution data could be acquired in reasonable run times, and used for in vivo scans to increase sensitivity to variations in local susceptibility.
MeSH term(s)	Animals ; Brain/cytology ; Fourier Analysis ; Imaging, Three-Dimensional/methods ; Magnetic Resonance Imaging/methods ; Mice ; Water
Chemical Substances	Water (059QF0KO0R)
Language	English
Publishing date	2015-03-17
Publishing country	United States
Document type	Journal Article ; Research Support, American Recovery and Reinvestment Act ; Research Support, N.I.H., Extramural
ZDB-ID	188780-4
ISSN	2473-4209 ; 0094-2405
ISSN (online)	2473-4209
ISSN	0094-2405
DOI	10.1118/1.4908203
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