ABSTRACT
The term 'digital resources' is increasingly used in educational research to describe the specific knowledge and skills that constitute teachers' professional digital competence. Educational policy documents, including the European Framework for the Digital Competence of Educators (DigCompEdu), deploy the term to reaffirm teachers' need for special skills in using digital resources. However, educational research literature presents inconsistent views of the term, restricting its effective use in further research and the promotion of associated skills among pre-service and in-service teachers. To clarify the term 'digital resources' and support future research related to its application especially in empirical research on teachers' professional digital competence, this systematic review aims to analyse the definitions of digital resources as a scientific term in 23 articles and to examine and compare the facets and aspects of digital resources. Finally, we derive a definition from the various perspectives and discuss the implications for the definition of digital resources as an aspect of teachers' professional digital competence.
ABSTRACT
A large body of evidence indicates that nitric oxide (NO) and cGMP contribute to central sensitization of pain pathways during inflammatory pain. Here, we investigated the distribution of cyclic nucleotide-gated (CNG) channels in the spinal cord, and identified the CNG channel subunit CNGA3 as a putative cGMP target in nociceptive processing. In situ hybridization revealed that CNGA3 is localized to inhibitory neurons of the dorsal horn of the spinal cord, whereas its distribution in dorsal root ganglia is restricted to non-neuronal cells. CNGA3 expression is upregulated in the superficial dorsal horn of the mouse spinal cord and in dorsal root ganglia following hindpaw inflammation evoked by zymosan. Mice lacking CNGA3 (CNGA3(-/-) mice) exhibited an increased nociceptive behavior in models of inflammatory pain, whereas their behavior in models of acute or neuropathic pain was normal. Moreover, CNGA3(-/-) mice developed an exaggerated pain hypersensitivity induced by intrathecal administration of cGMP analogs or NO donors. Our results provide evidence that CNGA3 contributes in an inhibitory manner to the central sensitization of pain pathways during inflammatory pain as a target of NO/cGMP signaling.
Subject(s)
Cyclic GMP/metabolism , Cyclic Nucleotide-Gated Cation Channels/metabolism , Inflammation/complications , Nitric Oxide/metabolism , Pain/etiology , Signal Transduction/physiology , Spinal Cord/metabolism , Analysis of Variance , Animals , Cyclic GMP/adverse effects , Cyclic GMP/analogs & derivatives , Cyclic GMP/pharmacology , Cyclic Nucleotide-Gated Cation Channels/deficiency , Cyclic Nucleotide-Gated Cation Channels/genetics , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Ganglia, Spinal/metabolism , Gene Expression Regulation/drug effects , Glial Fibrillary Acidic Protein/metabolism , Inflammation/chemically induced , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microdissection , Naphthalenes/metabolism , Natriuretic Peptides/adverse effects , Pain/drug therapy , Pain/pathology , Pain Measurement/drug effects , Pain Measurement/methods , Pain Perception/drug effects , Peripheral Nervous System Diseases/drug therapy , Peripheral Nervous System Diseases/pathology , Physical Stimulation/adverse effects , RNA, Messenger/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Stathmin/metabolism , Statistics, Nonparametric , Thionucleotides/pharmacology , Triazenes/pharmacology , Vesicular Inhibitory Amino Acid Transport Proteins/metabolismABSTRACT
Cyclic nucleotide-gated (CNG) channels, which are directly activated by cAMP and cGMP, have long been known to play a key role in retinal and olfactory signal transduction. Emerging evidence indicates that CNG channels are also involved in signaling pathways important for pain processing. Here, we found that the expression of the channel subunits CNGA2, CNGA3, CNGA4 and CNGB1 in dorsal root ganglia, and of CNGA2 in the spinal cord, is transiently altered after peripheral nerve injury in mice. Specifically, we show using in situ hybridization and quantitative real-time RT-PCR that CNG channels containing the CNGB1b subunit are localized to populations of sensory neurons and predominantly excitatory interneurons in the spinal dorsal horn. In CNGB1 knockout (CNGB1-/-) mice, neuropathic pain behavior is considerably attenuated whereas inflammatory pain behavior is normal. Finally, we provide evidence to support CNGB1 as a downstream mediator of cAMP signaling in pain pathways. Altogether, our data suggest that CNGB1-positive CNG channels specifically contribute to neuropathic pain processing after peripheral nerve injury.
Subject(s)
Cyclic AMP , Cyclic Nucleotide-Gated Cation Channels/genetics , Nerve Tissue Proteins/genetics , Neuralgia/psychology , Pain/chemically induced , Pain/psychology , Animals , Cyclic Nucleotide-Gated Cation Channels/biosynthesis , Ganglia, Spinal/metabolism , Ganglia, Spinal/pathology , Inflammation/chemically induced , Inflammation/pathology , Injections, Spinal , Mice, Inbred C57BL , Mice, Knockout , Neuralgia/pathology , Pain/pathology , Postural Balance/drug effects , Signal Transduction/drug effects , Spinal Cord Injuries/metabolism , Spinal Cord Injuries/pathologyABSTRACT
A large body of evidence indicates that the release of nitric oxide (NO) is crucial for the central sensitization of pain pathways during both inflammatory and neuropathic pain. Here, we investigated the distribution of NO-sensitive guanylyl cyclase (NO-GC) in the spinal cord and in dorsal root ganglia, and we characterized the nociceptive behavior of mice deficient in NO-GC (GC-KO mice). We show that NO-GC is distinctly expressed in neurons of the mouse dorsal horn, whereas its distribution in dorsal root ganglia is restricted to non-neuronal cells. GC-KO mice exhibited a considerably reduced nociceptive behavior in models of inflammatory or neuropathic pain, but their responses to acute pain were not impaired. Moreover, GC-KO mice failed to develop pain sensitization induced by intrathecal administration of drugs releasing NO or carbon monoxide. Surprisingly, during spinal nociceptive processing, cGMP produced by NO-GC may activate signaling pathways different from cGMP-dependent protein kinase I (cGKI), whereas cGKI can be activated by natriuretic peptide receptor-B dependent cGMP production. Together, our results provide evidence that NO-GC is crucially involved in the central sensitization of pain pathways during inflammatory and neuropathic pain.
Subject(s)
Cyclic GMP/biosynthesis , Ganglia, Spinal/metabolism , Guanylate Cyclase/metabolism , Inflammation/physiopathology , Neuralgia/metabolism , Pain/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Spinal Cord/metabolism , Animals , Behavior, Animal , Carbon Monoxide/metabolism , Cyclic GMP-Dependent Protein Kinase Type I , Cyclic GMP-Dependent Protein Kinases/metabolism , Female , Guanylate Cyclase/deficiency , Inflammation/metabolism , Male , Mice , Mice, Knockout , Neuralgia/etiology , Neuralgia/physiopathology , Neuralgia/psychology , Nociceptors/physiopathology , Pain/etiology , Pain/psychology , Receptors, Cytoplasmic and Nuclear/deficiency , Signal Transduction , Soluble Guanylyl Cyclase , Tissue DistributionABSTRACT
Unravelling the factors that can positively influence remyelination is one of the major challenges in multiple sclerosis research. Expression of the chemokine receptor CXCR2 on oligodendrocytes both in vitro and in MS lesions has suggested a possible role for CXCR2 in the recruitment of oligodendrocyte precursor cells (OPC). To investigate the function of CXCR2 during remyelination in vivo, we studied this receptor in cuprizone-induced demyelination and subsequent remyelination. We found that CXCR2 is constitutively expressed on OPC, whereas on macrophages/microglia CXCR2 is upregulated upon activation during demyelination. Hence, the expression of CXCR2 is differentially regulated in oligodendrocytes and macrophages/microglia. Furthermore, we subjected CXCR2-/- mice to the cuprizone model demonstrating that remyelination was not altered in comparison to wildtype controls. In addition, the number of OPC and the amount of microglial accumulation were similar in both CXCR2-/- and wildtype animals during the whole demyelination and remyelination process. These results suggest that despite expression on OPC and microglia CXCR2 plays only a minor role during remyelination.
Subject(s)
Cuprizone/toxicity , Demyelinating Diseases/metabolism , Myelin Sheath/physiology , Neuroglia/metabolism , Neuroglia/physiology , Receptors, Interleukin-8B/biosynthesis , Animals , Demyelinating Diseases/chemically induced , Demyelinating Diseases/pathology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Mutant Strains , Myelin Sheath/drug effects , Myelin Sheath/pathology , Neuroglia/drug effects , Neuroglia/pathology , Receptors, Interleukin-8B/physiology , Stem Cells/drug effects , Stem Cells/metabolism , Stem Cells/pathology , Stem Cells/physiologyABSTRACT
The effect of interferon-beta (IFN-beta) for the treatment of multiple sclerosis (MS) is thought to be mediated by the modulation of immune cells. In addition, it has been shown that glial cells may be influenced by IFN-beta and a role during remyelination has been suggested. However, the mechanism is not yet clear and there are conflicting data. We have therefore systematically investigated proliferation, differentiation, toxicity, and cytoprotection of IFN-beta on oligodendroglia, both as a direct effect and mediated indirectly via other glial cells. Differentiation of oligodendrocyte progenitor cells (OPC) was significantly (p<0.01) inhibited by IFN-beta only when cultured in the presence with astrocytes and microglia. Proliferation was not changed, neither was IFN-beta toxic. There was no cytoprotective effect of IFN-beta on oligodendroglia injury induced by H2O2, NO, complement, or glutamate. Similarly, there was no cytoprotective effect mediated via treatment of astrocytes with IFN-beta. These data demonstrate that IFN-beta is neither toxic nor cytoprotective for oligodendrocytes. In summary, the only effect of IFN-beta was the inhibition of differentiation of OPC mediated indirectly via other glial cells. In vivo experiments will show how this effect may influence remyelination.
Subject(s)
Interferon-beta/pharmacology , Myelin Sheath/drug effects , Nerve Fibers, Myelinated/drug effects , Nerve Regeneration/drug effects , Oligodendroglia/drug effects , Animals , Animals, Newborn , Astrocytes/drug effects , Astrocytes/immunology , Cell Communication/drug effects , Cell Communication/immunology , Cell Differentiation/drug effects , Cell Differentiation/immunology , Cells, Cultured , Coculture Techniques , Cytoprotection/drug effects , Cytoprotection/immunology , Cytotoxins/antagonists & inhibitors , Microglia/drug effects , Microglia/immunology , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , Multiple Sclerosis/physiopathology , Myelin Sheath/immunology , Myelin Sheath/metabolism , Nerve Fibers, Myelinated/immunology , Nerve Fibers, Myelinated/metabolism , Nerve Regeneration/physiology , Oligodendroglia/immunology , Oligodendroglia/metabolism , Rats , Rats, Sprague-Dawley , Stem Cells/drug effects , Stem Cells/immunology , Stem Cells/metabolismABSTRACT
Myelination in the central nervous system requires an accurate interplay between oligodendrocyte precursor cells (OPC) and axons. By as yet not fully understood mechanisms, OPC proliferate, migrate to the axon to be myelinated and finally differentiate into mature oligodendrocytes. The recent finding that OPC express CXC chemokine receptors led us to the investigation of the expression and functional importance of CC chemokine receptors. Using RT-PCR, we show that primary OPC from neonatal rats express CCR3, while CCR1, CCR2, CCR4, CCR5, and CCR7 are not expressed. Immunofluorescence staining of OPC could further demonstrate protein expression of CCR3. A rise of intracellular Ca2+ upon stimulation with the appropriate ligand CCL11 showed that this receptor is functional. Moreover, CCL11 led to a concentration specific increase in proliferation, inhibition of migration, and augmentation of differentiation in primary OPC. Thus, CCR3 may influence the process of myelination. This is of general importance for both developmental tissue patterning and for repair processes in demyelinating diseases like multiple sclerosis.
Subject(s)
Myelin Sheath/metabolism , Oligodendroglia/metabolism , Receptors, Chemokine/biosynthesis , Stem Cells/metabolism , Animals , Cell Differentiation/immunology , Cell Movement/immunology , Cell Proliferation , Cells, Cultured , Chemokine CCL11 , Chemokines, CC/metabolism , Immunohistochemistry , Oligodendroglia/cytology , RNA, Messenger/analysis , Rats , Rats, Sprague-Dawley , Receptors, CCR3 , Reverse Transcriptase Polymerase Chain Reaction , Stem Cells/cytologyABSTRACT
Migration, proliferation, and differentiation of oligodendrocyte precursor cells are essential for the assembly of myelin in the central nervous system. Knowledge on the regulation of these precursor cells is therefore of great importance for the understanding of developmental myelination and remyelination in demyelinating diseases. Here, we show that primary rat oligodendrocyte precursor cells express the chemokine receptor CXCR4. Stimulation with the ligand CXCL12 (SDF-1 alpha) leads to intracellular Ca elevation. Furthermore, 10 ng/ml CXCL12 augmented differentiation of precursors into mature oligodendrocytes. Migration toward growth factor conditioned medium was inhibited by CXCL12, while proliferation was only slightly modulated. The effect of CXCL12 on both migration and differentiation was blocked using a G protein antagonist. These data suggest a role for CXCL12 and oligodendroglial CXCR4 receptors during developmental myelination and repair in demyelinating diseases of the central nervous system.
Subject(s)
Chemokines, CXC/pharmacology , Oligodendroglia/immunology , Receptors, CXCR4/genetics , Animals , Animals, Newborn , Base Sequence , Calcium/physiology , Cell Differentiation , Cells, Cultured , Chemokine CXCL12 , DNA Primers , Glial Fibrillary Acidic Protein/genetics , Oligodendroglia/drug effects , Polymerase Chain Reaction , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Interferon-beta (IFN-beta) is a pleiotropic cytokine that is known to modulate the immune response in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS). Spontaneous remyelination and repair mechanisms in MS are mostly insufficient and contribute to clinical disability. Here, we investigated whether IFN-beta has a potential in modifying the extent of de- and remyelination in a toxic model of CNS demyelination induced by the copper chelator cuprizone. IFN-beta deficient (k/o) mice showed an accelerated spontaneous remyelination. However, the amount of remyelination after 6 weeks did not differ between the two groups. Demyelination in IFN-beta k/o mice was paralleled by a diminished astrocytic and microglia response as compared with wildtype controls, whereas the accelerated remyelination was paralleled by an increased number of oligodendrocyte precursor cells (OPC) within the demyelinated lesion at the beginning of the remyelination phase. We hypothesize that the absence of IFN-beta leads to more efficient recruitment and proliferation of OPC already during demyelination, thus allowing early remyelination. These results demonstrate that IFN-beta is able to alter remyelination in the absence of an immune-mediated demyelination.
Subject(s)
Interferon-beta/genetics , Multiple Sclerosis/immunology , Myelin Sheath/immunology , Animals , Astrocytes/immunology , Astrocytes/metabolism , Axons/immunology , Axons/metabolism , Axons/pathology , Chelating Agents/toxicity , Cuprizone/toxicity , Disease Models, Animal , Gliosis/immunology , Gliosis/metabolism , Gliosis/physiopathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microglia/immunology , Microglia/metabolism , Microscopy, Electron, Transmission , Multiple Sclerosis/genetics , Multiple Sclerosis/metabolism , Myelin Sheath/metabolism , Myelin Sheath/pathology , Recovery of Function/genetics , Recovery of Function/immunologyABSTRACT
The transcription factor hypoxia-inducible factor-1 (HIF-1) is critical for erythropoietin and other factors involved in the adaptation of the organism to hypoxic stress. Conflicting results have been published regarding the role of the mitochondrial electron transport chain (ETC) in the regulation of HIF-1alpha. We assessed cellular hypoxia by pimonidazole staining and blotting of the O2-labile HIF-1 alpha-subunit in human osteosarcoma cell cultures (U2OS and 143B). In conventional, gas-impermeable cell culture dishes, ETC inhibitors had no effect on pimonidazole staining or HIF-1alpha abundance in a 20% O2 atmosphere; both parameters were undetectable. Pimonidazole staining and HIF activity were substantial in 0.1% O2 irrespective of ETC inhibition. At an intermediate oxygen concentration (3% O2) pimonidazole staining and HIF-alpha expression were detectable but strongly reduced after ETC inhibition in conventional cell cultures. All effects of ETC inhibition on HIF-1alpha regulation were eliminated in gas-permeable dishes. As shown in a 143B subclone deficient in mitochondrial DNA (206rho0), genetic inactivation of the ETC led to similar responses with respect to HIF-1alpha regulation as ETC inhibitors. Our data demonstrate that reduction of oxygen consumption reduces the O2 gradient in conventional cell cultures, causing elevation of the cellular O2 concentration, which leads to degradation of HIF-alpha.