| 1. |
- Aksel Jacobsen, Freja, et al.
(författare)
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A Role for the Non-Receptor Tyrosine Kinase Abl2/Arg in Experimental Neuroinflammation
- 2018
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Ingår i: Journal of Neuroimmune Pharmacology. - New York, NY : Springer-Verlag New York. - 1557-1890 .- 1557-1904. ; 13:2, s. 265-276
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a neuroinflammatory degenerative disease, caused by activated immune cells infiltrating the CNS. The disease etiology involves both genetic and environmental factors. The mouse genetic locus, Eae27, linked to disease development in the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis, was studied in order to identify contributing disease susceptibility factors and potential drug targets for multiple sclerosis. Studies of an Eae27 congenic mouse strain, revealed that genetic variation within Eae27 influences EAE development. The Abl2 gene, encoding the non-receptor tyrosine kinase Arg, is located in the 4,1 megabase pair long Eae27 region. The Arg protein plays an important role in cellular regulation and is, in addition, involved in signaling through the B- and T-cell receptors, important for the autoimmune response. The presence of a single nucleotide polymorphism causing an amino acid change in a near actin-interacting domain of Arg, in addition to altered lymphocyte activation in the congenic mice upon immunization with myelin antigen, makes Abl2/Arg a candidate gene for EAE. Here we demonstrate that the non-synonymous SNP does not change Arg’s binding affinity for F-actin but suggest a role for Abl kinases in CNS inflammation pathogenesis by showing that pharmacological inhibition of Abl kinases ameliorates EAE, but not experimental arthritis. © 2018 The Author(s)
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| 2. |
- Funa, Keiko, 1949, et al.
(författare)
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The Roles of PDGF in Development and During Neurogenesis in the Normal and Diseased Nervous System
- 2014
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Ingår i: Journal of Neuroimmune Pharmacology. - : Springer Science and Business Media LLC. - 1557-1890 .- 1557-1904. ; 9:2, s. 168-181
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Forskningsöversikt (refereegranskat)abstract
- The four platelet-derived growth factor (PDGF) ligands and PDGF receptors (PDGFRs), alpha and beta (PDGFRA, PDGFRB), are essential proteins that are expressed during embryonic and mature nervous systems, i.e., in neural progenitors, neurons, astrocytes, oligodendrocytes, and vascular cells. PDGF exerts essential roles from the gastrulation period to adult neuronal maintenance by contributing to the regulation of development of preplacodal progenitors, placodal ectoderm, and neural crest cells to adult neural progenitors, in coordinating with other factors. In adulthood, PDGF plays critical roles for maintenance of many specific cell types in the nervous system together with vascular cells through controlling the blood brain barrier homeostasis. At injury or various stresses, PDGF modulates neuronal excitability through adjusting various ion channels, and affecting synaptic plasticity and function. Furthermore, PDGF stimulates survival signals, majorly PI3-K/Akt pathway but also other ways, rescuing cells from apoptosis. Studies imply an involvement of PDGF in dendrite spine morphology, being critical for memory in the developing brain. Recent studies suggest association of PDGF genes with neuropsychiatric disorders. In this review, we will describe the roles of PDGF in the nervous system, from the discovery to recent findings, in order to understand the broad spectrum of PDGF in the nervous system. Recent development of pharmacological and replacement therapies targeting the PDGF system is discussed.
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| 3. |
- Gisslén, Magnus, 1962, et al.
(författare)
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Defining and Evaluating HIV-Related Neurodegenerative Disease and Its Treatment Targets: A Combinatorial Approach to Use of Cerebrospinal Fluid Molecular Biomarkers
- 2007
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Ingår i: Journal of NeuroImmune Pharmacology. - : Springer Science and Business Media LLC. - 1557-1890 .- 1557-1904. ; 2:1, s. 112-119
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Tidskriftsartikel (refereegranskat)abstract
- There are a number of reasons that the accomplishments of clinical trials related to HIV-related neurodegenerative disease (HRND) and the AIDS dementia complex (ADC) have had such limited impact on clinical practice. These include: rapid evolution and progress in the treatment of systemic HIV infection that has quickly outpaced neurological efforts and has markedly reduced disease incidence; ethical constraints that (rightly) demand neurologically compromised patients receive the best available treatment before experimental therapeutics; complicated backgrounds and comorbidities of patients now most susceptible to HRND; and reluctance of general AIDS clinicians and drug companies to look beyond systemic or pivotal outcomes. However, the field has also been slow to adopt methods that better exploit advances in understanding of the pathogenesis of central nervous system (CNS) infection and brain injury, and that might circumvent some of these constraints. Using a simple model of pathogenesis, we propose an approach to characterizing patients, selecting treatment targets, and evaluating outcomes that emphasize a combination of cerebrospinal fluid (CSF) markers. This model begins by using three markers related to cardinal components of HRND: CNS HIV infection (measurement of CSF HIV RNA), intrathecal immunoactivation (CSF neopterin), and brain injury [CSF light chain neurofilament (NFL)]. Careful analysis of this and other marker combinations promises more rational trial design and more rapid progress in managing CNS HIV infection and HRND using both antiviral and adjuvant treatment approaches.
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| 4. |
- Heldin, Carl-Henrik
(författare)
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Targeting the PDGF Signaling Pathway in the Treatment of Non-Malignant Diseases.
- 2014
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Ingår i: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. - : Springer Science and Business Media LLC. - 1557-1904. ; 9:2, s. 69-79
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factor (PDGF) is a family of mesenchymal mitogens with important functions during the embryonal development and in the control of tissue homeostasis in the adult. The PDGF isoforms exert their effects by binding to α-and β-tyrosine kinase receptors. Overactivity of PDGF signaling has been linked to the development of certain malignant and non-malignant diseases, including atherosclerosis and various fibrotic diseases. Different types of PDGF antagonists have been developed, including inhibitory monoclonal antibodies and DNA aptamers against PDGF isoforms and receptors, and receptor tyrosine kinase inhibitors. Beneficial effects have been recorded using such inhibitors in preclinical models and in patients with certain malignant as well as non-malignant diseases. The present communication summarizes the use of PDGF antagonists in the treatment of non-malignant diseases.
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| 5. |
- Kannan, SR, et al.
(författare)
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Infectivity of SARS-CoV-2: there Is Something More than D614G?
- 2020
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Ingår i: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. - : Springer Science and Business Media LLC. - 1557-1904. ; 15:4, s. 574-577
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 6. |
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| 7. |
- Nordström, Anders, et al.
(författare)
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Metabolomics : moving to the clinic.
- 2010
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Ingår i: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. - : Springer Science and Business Media LLC. - 1557-1904. ; 5:1, s. 4-17
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Tidskriftsartikel (refereegranskat)abstract
- Assessment of a biological system by means of global and non-targeted metabolite profiling--metabolomics or metabonomics--provides the investigator with molecular information that is close to the phenotype in question in the sense that metabolites are an ultimate product of gene, mRNA, and protein activity. Over the last few years, there has been a rapidly growing number of metabolomics applications aimed at finding biomarkers which could assist diagnosis, provide therapy guidance, and evaluate response to therapy for particular diseases. Also, within the fields of drug discovery, drug toxicology, and personalized pharmacology, metabolomics is emerging as a powerful tool. This review seeks to update the reader on analytical strategies, biomarker findings, and implications of metabolomics for the clinic. Particular attention is paid to recent biomarkers found related to neurological, cardiovascular, and cancer diseases. Moreover, the impact of metabolomics in the drug discovery and development process is examined.
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| 8. |
- Price, Richard W, et al.
(författare)
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Approach to Cerebrospinal Fluid (CSF) Biomarker Discovery and Evaluation in HIV Infection.
- 2013
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Ingår i: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. - : Springer Science and Business Media LLC. - 1557-1904. ; 8:5, s. 1147-1158
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Tidskriftsartikel (refereegranskat)abstract
- Central nervous system (CNS) infection is a nearly universal facet of systemic HIV infection that varies in character and neurological consequences. While clinical staging and neuropsychological test performance have been helpful in evaluating patients, cerebrospinal fluid (CSF) biomarkers present a valuable and objective approach to more accurate diagnosis, assessment of treatment effects and understanding of evolving pathobiology. We review some lessons from our recent experience with CSF biomarker studies. We have used two approaches to biomarker analysis: targeted, hypothesis-driven and non-targeted exploratory discovery methods. We illustrate the first with data from a cross-sectional study of defined subject groups across the spectrum of systemic and CNS disease progression and the second with a longitudinal study of the CSF proteome in subjects initiating antiretroviral treatment. Both approaches can be useful and, indeed, complementary. The first is helpful in assessing known or hypothesized biomarkers while the second can identify novel biomarkers and point to broad interactions in pathogenesis. Common to both is the need for well-defined samples and subjects that span a spectrum of biological activity and biomarker concentrations. Previously-defined guide biomarkers of CNS infection, inflammation and neural injury are useful in categorizing samples for analysis and providing critical biological context for biomarker discovery studies. CSF biomarkers represent an underutilized but valuable approach to understanding the interactions of HIV and the CNS and to more objective diagnosis and assessment of disease activity. Both hypothesis-based and discovery methods can be useful in advancing the definition and use of these biomarkers.
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| 9. |
- Persson, Lennart, et al.
(författare)
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Cannibalism in a size-structured population : energy extraction and control
- 2004
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Ingår i: Ecological Monographs. - : Wiley. - 0012-9615 .- 1557-7015. ; 74:1, s. 135-157
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Tidskriftsartikel (refereegranskat)abstract
- Recent size-structured cannibalistic models point to the importance of the energy gain by cannibals and also show that this gain may result in the emergence of giant individuals. We use a combination of a 10-year field study of a perch (Perca fluviatilis) population and quantitative within-season modeling of individual and population-level dynamics to investigate which mechanisms are most likely to drive the dynamics of the studied perch population. We focused on three main aspects to explain observed discrepancies between earlier model predictions and data: (1) introduction of more than one shared resource between cannibals and victims, (2) whether or not several victim age cohorts are necessary to allow giant growth, and (3) the intensity of inter-cohort competition between young-of-the-year (YOY) perch and 1-yr-old perch. At the start of the study period, the perch population was dominated by “stunted” perch individuals, and recruitment of perch to an age of 1-yr-old was negligible. Following a major death in adult perch, strong recruitments of perch to 1-yr-old were thereafter observed for a number of years. As 1-yr-olds these successful recruiters subsequently starved to death due to competition with the new YOY. The few surviving adult perch accelerated substantially in growth and became “giants.” At the end of the study period, the perch population moved back to the situation with stunted individuals. There was a high agreement between observed diets of cannibalistic perch and those predicted by the model for both the stunted and the giant phases. Analyses of growth rates showed that cannibalistic perch could become giants on a diet of YOY perch only, but that a supplement with the second shared resource (macroinvertebrates) was needed to reach the observed sizes. Modeling of growth and diet in the giant phase showed an exploitative competitive effect of YOY perch on 1-yr-old perch, but a restriction in habitat use of 1-yr-old perch had to be assumed to yield the observed growth rate and diet. The resource dynamics of zooplankton and macroinvertebrates were both accurately predicted by the model. Also, YOY perch mortality was accurately predicted and, furthermore, suggested that one of the trawling methods used may underestimate the number of YOY perch when they increase in size. We conclude that the presence of a second shared resource and the restricted habitat use and absence of cannibalistic consumption by 1-yr-old perch individuals are two important mechanisms to explain the discrepancy between model predictions and data. Our results also point to the fact that that the dynamics observed may be explained by complex dynamics not involving the presence of a giant and dwarf cycle.
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| 10. |
- Bokhorst, Stef Frederik
(författare)
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The spatial structure of Antarctic biodiversity
- 2014
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Ingår i: Ecological Monographs. - : Wiley. - 0012-9615 .- 1557-7015. ; 84, s. 203-244
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Forskningsöversikt (refereegranskat)abstract
- Patterns of environmental spatial structure lie at the heart of the most fundamental and familiar patterns of diversity on Earth. Antarctica contains some of the strongest environmental gradients on the planet and therefore provides an ideal study ground to test hypotheses on the relevance of environmental variability for biodiversity. To answer the pivotal question, "How does spatial variation in physical and biological environmental properties across the Antarctic drive biodiversity?" we have synthesized current knowledge on environmental variability across terrestrial, freshwater, and marine Antarctic biomes and related this to the observed biotic patterns. The most important physical driver of Antarctic terrestrial communities is the availability of liquid water, itself driven by solar irradiance intensity. Patterns of biota distribution are further strongly influenced by the historical development of any given location or region, and by geographical barriers. In freshwater ecosystems, free water is also crucial, with further important influences from salinity, nutrient availability, oxygenation, and characteristics of ice cover and extent. In the marine biome there does not appear to be one major driving force, with the exception of the oceanographic boundary of the Polar Front. At smaller spatial scales, ice cover, ice scour, and salinity gradients are clearly important determinants of diversity at habitat and community level. Stochastic and extreme events remain an important driving force in all environments, particularly in the context of local extinction and colonization or recolonization, as well as that of temporal environmental variability. Our synthesis demonstrates that the Antarctic continent and surrounding oceans provide an ideal study ground to develop new biogeographical models, including life history and physiological traits, and to address questions regarding biological responses to environmental variability and change.
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