383 research outputs found
Increased expression of axogenesis-related genes and mossy fibre length in dentate granule cells from adult HuD overexpressor mice
The neuronal RNA-binding protein HuD plays a critical role in the post-transcriptional regulation of short-lived mRNAs during the initial establishment and remodelling of neural connections. We have generated transgenic mice overexpressing this protein (HuD-Tg) in adult DGCs (dentate granule cells) and shown that their mossy fibres contain high levels of GAP-43 (growth-associated protein 43) and exhibit distinct morphological and electrophysiological properties. To investigate the basis for these changes and identify other molecular targets of HuD, DGCs from HuD-Tg and control mice were collected by LCM (laser capture microscopy) and RNAs analysed using DNA microarrays. Results show that 216 known mRNAs transcripts and 63 ESTs (expressed sequence tags) are significantly up-regulated in DGCs from these transgenic mice. Analyses of the 3′-UTRs (3′-untranslated regions) of these transcripts revealed an increased number of HuD-binding sites and the presence of several known instability-conferring sequences. Among these, the mRNA for TTR (transthyretin) shows the highest level of up-regulation, as confirmed by qRT–PCR (quantitative reverse transcription–PCR) and ISH (in situ hybridization). GO (gene ontology) analyses of up-regulated transcripts revealed a large over-representation of genes associated with neural development and axogenesis. In correlation with these gene expression changes, we found an increased length of the infrapyramidal mossy fibre bundle in HuD-Tg mice. These results support the notion that HuD stabilizes a number of developmentally regulated mRNAs in DGCs, resulting in increased axonal elongation
Sequence learning in Associative Neuronal-Astrocytic Network
The neuronal paradigm of studying the brain has left us with limitations in
both our understanding of how neurons process information to achieve biological
intelligence and how such knowledge may be translated into artificial
intelligence and its most brain-derived branch, neuromorphic computing.
Overturning our fundamental assumptions of how the brain works, the recent
exploration of astrocytes is revealing that these long-neglected brain cells
dynamically regulate learning by interacting with neuronal activity at the
synaptic level. Following recent experimental evidence, we designed an
associative, Hopfield-type, neuronal-astrocytic network and analyzed the
dynamics of the interaction between neurons and astrocytes. We show that
astrocytes were sufficient to trigger transitions between learned memories in
the neuronal component of the network. Further, we mathematically derived the
timing of the transitions that was governed by the dynamics of the
calcium-dependent slow-currents in the astrocytic processes. Overall, we
provide a brain-morphic mechanism for sequence learning that is inspired by,
and aligns with, recent experimental findings. To evaluate our model, we
emulated astrocytic atrophy and showed that memory recall becomes significantly
impaired after a critical point of affected astrocytes was reached. This
brain-inspired and brain-validated approach supports our ongoing efforts to
incorporate non-neuronal computing elements in neuromorphic information
processing.Comment: 8 pages, 5 figure
Computational prediction of neural progenitor cell fates
Understanding how stem and progenitor cells choose between alternative cell fates is a major challenge in developmental biology. Efforts to tackle this problem have been hampered by the scarcity of markers that can be used to predict cell division outcomes. Here we present a computational method, based on algorithmic information theory, to analyze dynamic features of living cells over time. Using this method, we asked whether rat retinal progenitor cells (RPCs) display characteristic phenotypes before undergoing mitosis that could foretell their fate. We predicted whether RPCs will undergo a self-renewing or terminal division with 99% accuracy, or whether they will produce two photoreceptors or another combination of offspring with 87% accuracy. Our implementation can segment, track and generate predictions for 40 cells simultaneously on a standard computer at 5 min per frame. This method could be used to isolate cell populations with specific developmental potential, enabling previously impossible investigations.The computational aspects of this work were supported by the Center for Subsurface Sensing and
Imaging Systems (NSF Grant EEC-9986821), by the Rensselaer Polytechnic Institute and by the
University of Wisconsin-Milwaukee. This work was supported by grants from the Canadian Institutes of Health Research and the
Foundation Fighting Blindness – Canada (to M.C). M.C. is a CIHR New Investigator and a W.K.
Stell Scholar of the Foundation Fighting Blindness – Canada
Tissue print of prostate biopsy: a novel tool in the diagnostic procedure of prostate cancer
<p>Abstract</p> <p>Background</p> <p>Nowadays, the histological examination of prostate core needle biopsies is still regarded as the gold standard in the diagnosis of prostate cancer (PCa). We investigated if the tissue print of core needle biopsy (biopsy print) could be used as adjunctive molecular investigative procedures in conjunction with routine histological examination of biopsy to improve PCa diagnosis.</p> <p>Methods</p> <p>The direct contact of PCa core biopsy to nitrocellulose membrane resulted in the release of a cellular micropeel that was used for downstream analytical procedures.</p> <p>Results</p> <p>By zymogram print-phoresis we demonstrated that matrix metalloproteases MMP-2 and MMP-9 could be visualized in biopsy prints and that the gelatinolytic activity was positively correlated with immunohistochemistry analysis of the same markers in matched bioptic specimens. Moreover, we compared the ability to detect the PCa-associated hypermethylation of GSTP1 promoter in DNA extracted from biopsy prints with those of the corresponding core needle biopsies. Biopsy prints demonstrated the same specificity of biopsies in detecting PCa (50%) while the sensitivity and the positive predictive value were lower than biopsies (56% vs 78% and 63% vs 70%, respectively).</p> <p>Conclusions</p> <p>Biopsy print, combining a molecular point of view to the routinely hystopathological analysis of prostate biopsies, should be a useful tool to improve the diagnosis of PCa.</p
Mesenchymal stromal-cell transplants induce oligodendrocyte progenitor migration and remyelination in a chronic demyelination model.
Demyelinating disorders such as leukodystrophies and multiple sclerosis are neurodegenerative diseases characterized by the progressive loss of myelin that may lead toward a chronic demyelination of the brain¿s white matter, impairing normal axonal conduction velocity and ultimately causing neurodegeneration. Current treatments modifying the pathological mechanisms are capable of ameliorating the disease; however, frequently, these therapies are not sufficient to repress the progressive demyelination into a chronic condition and permanent loss of function. To this end, we analyzed the effect that bone marrowderived mesenchymal stromal cell (BM-MSC) grafts exert in a chronically demyelinated mouse brain. As a result, oligodendrocyte progenitors were recruited surrounding the graft due to the expression of various trophic signals by the grafted MSCs. Although there was no significant reaction in the non-grafted side, in the grafted regions oligodendrocyte progenitors were detected. These progenitors were derived from the nearby tissue as well as from the neurogenic niches, including the subependymal zone and dentate gyrus. Once near the graft site, the cells matured to myelinating oligodendrocytes. Finally, electrophysiological studies demonstrated that axonal conduction velocity was significantly increased in the grafted side of the fimbria. In conclusion, we demonstrate here that in chronic demyelinated white matter, BM-MSC transplantation activates oligodendrocyte progenitors and induces remyelination in the tissue surrounding the stem cell graft
Human disc cells in monolayer vs 3D culture: cell shape, division and matrix formation
BACKGROUND: The relationship between cell shape, proliferation, and extracellular matrix (ECM) production, important aspects of cell behavior, is examined in a little-studied cell type, the human annulus cell from the intervertebral disc, during monolayer vs three-dimensional (3D) culture. RESULTS: Three experimental studies showed that cells respond specifically to culture microenvironments by changes in cell shape, mitosis and ECM production: 1) Cell passages showed extensive immunohistochemical evidence of Type I and II collagens only in 3D culture. Chondroitin sulfate and keratan sulfate were abundant in both monolayer and 3D cultures. 2) Cells showed significantly greater proliferation in monolayer in the presence of platelet-derived growth factor compared to cells in 3D. 3) Cells on Matrigel™-coated monolayer substrates became rounded and formed nodular colonies, a finding absent during monolayer growth. CONCLUSIONS: The cell's in vivo interactions with the ECM can regulate shape, gene expression and other cell functions. The shape of the annulus cell changes markedly during life: the young, healthy disc contains spindle shaped cells and abundant collagen. With aging and degeneration, many cells assume a strikingly different appearance, become rounded and are surrounded by unusual accumulations of ECM products. In vitro manipulation of disc cells provides an experimental window for testing how disc cells from given individuals respond when they are grown in environments which direct cells to have either spindle- or rounded-shapes. In vitro assessment of the response of such cells to platelet-derived growth factor and to Matrigel™ showed a continued influence of cell shape even in the presence of a growth factor stimulus. These findings contribute new information to the important issue of the influence of cell shape on cell behavior
Gender Differences in Publication Output: Towards an Unbiased Metric of Research Performance
We examined the publication records of a cohort of 168 life scientists in the field of ecology and evolutionary biology to assess gender differences in research performance. Clear discrepancies in publication rate between men and women appear very early in their careers and this has consequences for the subsequent citation of their work. We show that a recently proposed index designed to rank scientists fairly is in fact strongly biased against female researchers, and advocate a modified index to assess men and women on a more equitable basis
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Neurotoxic reactive astrocytes are induced by activated microglia
Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1α, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes are abundant in various human neurodegenerative diseases including Alzheimer’s, Huntington’s and Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis. Taken together these findings help to explain why CNS neurons die after axotomy, strongly suggest that A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders, and provide opportunities for the development of new treatments for these diseases.This work was supported by grants from the National Institutes of Health (R01 AG048814, B.A.B.; RO1 DA15043, B.A.B.; P50 NS38377, V.L.D. and T.M.D.) Christopher and Dana Reeve Foundation (B.A.B.), the Novartis Institute for Biomedical Research (B.A.B.), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (B.A.B.), the JPB Foundation (B.A.B., T.M.D.), the Cure Alzheimer’s Fund (B.A.B.), the Glenn Foundation (B.A.B.), the Esther B O’Keeffe Charitable Foundation (B.A.B.), the Maryland Stem Cell Research Fund (2013-MSCRFII-0105-00, V.L.D.; 2012-MSCRFII-0268-00, T.M.D.; 2013-MSCRFII-0105-00, T.M.D.; 2014-MSCRFF-0665, M.K.). S.A.L. was supported by a postdoctoral fellowship from the Australian National Health and Medical Research Council (GNT1052961), and the Glenn Foundation Glenn Award. L.E.C. was funded by a Merck Research Laboratories postdoctoral fellowship (administered by the Life Science Research Foundation). W.-S.C. was supported by a career transition grant from NEI (K99EY024690). C.J.B. was supported by a postdoctoral fellowship from Damon Runyon Cancer Research Foundation (DRG-2125-12). L.S. was supported by a postdoctoral fellowship from the German Research Foundation (DFG, SCHI 1330/1-1)
Oligodendrocyte Development in the Absence of Their Target Axons In Vivo
Oligodendrocytes form myelin around axons of the central nervous system, enabling saltatory conduction. Recent work has established that axons can regulate certain aspects of oligodendrocyte development and myelination, yet remarkably oligodendrocytes in culture retain the ability to differentiate in the absence of axons and elaborate myelin sheaths around synthetic axon-like substrates. It remains unclear the extent to which the life-course of oligodendrocytes requires the presence of, or signals derived from axons in vivo. In particular, it is unclear whether the specific axons fated for myelination regulate the oligodendrocyte population in a living organism, and if so, which precise steps of oligodendrocyte-cell lineage progression are regulated by target axons. Here, we use live-imaging of zebrafish larvae carrying transgenic reporters that label oligodendrocyte-lineage cells to investigate which aspects of oligodendrocyte development, from specification to differentiation, are affected when we manipulate the target axonal environment. To drastically reduce the number of axons targeted for myelination, we use a previously identified kinesin-binding protein (kbp) mutant, in which the first myelinated axons in the spinal cord, reticulospinal axons, do not fully grow in length, creating a region in the posterior spinal cord where most initial targets for myelination are absent. We find that a 73% reduction of reticulospinal axon surface in the posterior spinal cord of kbp mutants results in a 27% reduction in the number of oligodendrocytes. By time-lapse analysis of transgenic OPC reporters, we find that the reduction in oligodendrocyte number is explained by a reduction in OPC proliferation and survival. Interestingly, OPC specification and migration are unaltered in the near absence of normal axonal targets. Finally, we find that timely differentiation of OPCs into oligodendrocytes does not depend at all on the presence of target axons. Together, our data illustrate the power of zebrafish for studying the entire life-course of the oligodendrocyte lineage in vivo in an altered axonal environment
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