611 research outputs found
Einstein, Entropy, and Anomalies
This paper strengthens and defends the pluralistic implications of Einstein's successful, quantitative predictions of Brownian motion for a philosophical dispute about the nature of scientific advance that began between two prominent philosophers of science in the second half of the twentieth century (Thomas Kuhn and Paul Feyerabend). Kuhn promoted a monistic phase-model of scientific advance, according to which a paradigm driven `normal science' gives rise to its own anomalies, which then lead to a crisis and eventually a scientific revolution. Feyerabend stressed the importance of pluralism for scientific progress. He rejected Kuhn's model arguing that it fails to recognize the role that alternative theories can play in identifying exactly which phenomena are anomalous in the first place. On Feyerabend's account, Einstein's predictions allow for a crucial experiment between two incommensurable theories, and are an example of an anomaly that could refute the reigning paradigm only after the development of a competitor. Using Kuhn's specification of a disciplinary matrix to illustrate the incommensurability between the two paradigms, we examine the different research strategies available in this peculiar case. On the basis of our reconstruction, we conclude by rebutting some critics of Feyerabend's argument
Specific Human Astrocyte Subtype Revealed by Affinity Purified GFAP+1 Antibody; Unpurified Serum Cross-Reacts with Neurofilament-L in Alzheimer
The human GFAP splice variants GFAPÎ164 and GFAPÎexon6 both result in a GFAP protein isoform with a unique out-of-frame carboxy-terminus that can be detected by the GFAP+1 antibody. We previously reported that GFAP+1 was expressed in astrocytes and in degenerating neurons in Alzheimer's disease brains. In this study we aimed at further investigating the neuronal GFAP+1 expression and we started by affinity purifying the GFAP+1 antibody. The purified antibody resulted in a loss of neuronal GFAP+1 signal, although other antibodies directed against the amino- and carboxy-terminus of GFAPα still revealed GFAP-immunopositive neurons, as described before. With an in-depth analysis of a western blot, followed by mass spectrometry we discovered that the previously detected neuronal GFAP+1 expression was due to cross-reactivity of the antibody with neurofilament-L (NF-L). This was confirmed by double-label fluorescent immunohistochemistry and western blotting with the unpurified GFAP+1 antibody and an antibody against NF-L. Our data imply that NF-L can accumulate in some tangle-like structures in Alzheimer brains. More importantly, the purified GFAP+1 antibody clearly revealed a specific subtype of astrocytes in the adult human brain. These large astrocytes are present throughout the brain, e.g., along the subventricular zone, in the hippocampus, in the striatum and in the spinal cord of controls, Alzheimer, and Parkinson patients. The presence of a specific GFAP-isoform suggests a specialized function of these astrocytes
CCAAT/enhancer binding protein ÎČ expression is increased in the brain during HIV-1-infection and contributes to regulation of astrocyte tissue inhibitor of metalloproteinase-1
Human immunodeficiency virus (HIV)-1-associated neurocognitive disorders (HAND) associated with infection and activation of mononuclear phagocytes (MP) in the brain, occur late in disease. Infected/activated MP initiate neuroinflammation activating glial cells and ultimately disrupting neuronal function. Astrocytes secrete tissue inhibitor of metalloproteinase (TIMP)-1 in response to neural injury. Altered TIMP-1 levels are implicated in several CNS diseases. CCAAT enhancer-binding protein Ă (C/EBPĂ), a transcription factor, is expressed in rodent brains in response to neuroinflammation, implicating it in Alzheimerâs, Parkinsonâs, and HAND. Here, we report that C/EBPĂ mRNA levels are elevated and its isoforms differentially expressed in total brain tissue lysates of HIV-1-infected and HIV-1 encephalitis patients. In vitro, HAND-relevant stimuli additively induce C/EBPĂ nuclear expression in human astrocytes through 7 days of treatment. Over-expression of C/EBPĂ increases TIMP-1 promoter activity, mRNA, and protein levels in human astrocytes activated with interleukin-1Ă. Knockdown of C/EBPĂ with siRNA decreases TIMP-1 mRNA and protein levels. These data suggest that C/EBPĂ isoforms are involved in complex regulation of astrocyte TIMP-1 production during HIV-1 infection; however, further studies are required to completely understand their role during disease progression
Forebrain Engraftment by Human Glial Progenitor Cells Enhances Synaptic Plasticity and Learning in Adult Mice
SummaryHuman astrocytes are larger and more complex than those of infraprimate mammals, suggesting that their role in neural processing has expanded with evolution. To assess the cell-autonomous and species-selective properties of human glia, we engrafted human glial progenitor cells (GPCs) into neonatal immunodeficient mice. Upon maturation, the recipient brains exhibited large numbers and high proportions of both human glial progenitors and astrocytes. The engrafted human glia were gap-junction-coupled to host astroglia, yet retained the size and pleomorphism of hominid astroglia, and propagated Ca2+ signals 3-fold faster than their hosts. Long-term potentiation (LTP) was sharply enhanced in the human glial chimeric mice, as was their learning, as assessed by Barnes maze navigation, object-location memory, and both contextual and tone fear conditioning. Mice allografted with murine GPCs showed no enhancement of either LTP or learning. These findings indicate that human glia differentially enhance both activity-dependent plasticity and learning in mice.Video Abstrac
Escargot maintains stemness and suppresses differentiation in Drosophila intestinal stem cells
Snail family transcription factors are expressed in various stem cell types, but their function in maintaining stem cell identity is unclear. In the adult Drosophila midgut, the Snail homolog Esg is expressed in intestinal stem cells (ISCs) and their transient undifferentiated daughters, termed enteroblasts (EB). We demonstrate here that loss of esg in these progenitor cells causes their rapid differentiation into enterocytes (EC) or enteroâendocrine cells (EE). Conversely, forced expression of Esg in intestinal progenitor cells blocks differentiation, locking ISCs in a stem cell state. Cell typeâspecific transcriptome analysis combined with DamâID binding studies identified Esg as a major repressor of differentiation genes in stem and progenitor cells. One critical target of Esg was found to be the POUâdomain transcription factor, Pdm1, which is normally expressed specifically in differentiated ECs. Ectopic expression of Pdm1 in progenitor cells was sufficient to drive their differentiation into ECs. Hence, Esg is a critical stem cell determinant that maintains stemness by repressing differentiationâpromoting factors, such as Pdm1
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PATH-38. ROSETTE-FORMING GLIONEURONAL TUMOR IS DEFINED BY FGFR1 ACTIVATING ALTERATIONS WITH FREQUENT ACCOMPANYING PI3K AND MAPK PATHWAY MUTATIONS
Abstract
BACKGROUND
Rosette-forming glioneuronal tumor (RGNT) is an uncommon CNS tumor originally described in the fourth ventricle characterized by a low-grade glial neoplasm admixed with a rosette-forming neurocytic component.
METHODS
We reviewed clinicopathologic features of 42 patients with RGNT. Targeted next-generation sequencing was performed, and genome-wide methylation profiling is underway.
RESULTS
The 20 male and 22 female patients had a mean age of 25 years (range 3â47) at time of diagnosis. Tumors were located within or adjacent to the lateral ventricle (n=16), fourth ventricle (15), third ventricle (9), and spinal cord (2). All 31 tumors assessed to date contained FGFR1 activating alterations, either in-frame gene fusion, kinase domain tandem duplication, or hotspot missense mutation in the kinase domain (p.N546 or p.K656). While 7 of these 31 tumors harbored FGFR1 alterations as the solitary pathogenic event, 24 contained additional pathogenic alterations within PI3-kinase or MAP kinase pathway genes: 5 with additional PIK3CA and NF1 mutations, 4 with PIK3CA mutation, 3 with PIK3R1 mutation (one of which also contained focal RAF1 amplification), 5 with PTPN11 mutation (one with additional PIK3R1 mutation), and 2 with NF1 deletion. The other 5 cases demonstrated anaplastic features including hypercellularity and increased mitotic activity. Among these anaplastic cases, 3 harbored inactivating ATRX mutations and two harbored CDKN2A homozygous deletion, in addition to the FGFR1 alterations plus other PI3-kinase and MAP kinase gene mutations seen in those RGNT without anaplasia.
CONCLUSION
Independent of ventricular location, RGNT is defined by FGFR1 activating mutations or rearrangements, which are frequently accompanied by mutations involving PIK3CA, PIK3R1, PTPN11, NF1, and KRAS. Whereas pilocytic astrocytoma and ganglioglioma are characterized by solitary activating MAP kinase pathway alterations (e.g. BRAF fusion or mutation), RGNT are genetically more complex with dual PI3K-Akt-mTOR and Ras-Raf-MAPK pathway activation. Rare anaplastic examples may show additional ATRX and/or CDKN2A inactivation
Reduction in Phencyclidine Induced Sensorimotor Gating Deficits in the Rat Following Increased System Xc â Activity in the Medial Prefrontal Cortex
Rationale: Aspects of schizophrenia, including deficits in sensorimotor gating, have been linked to glutamate dysfunction and/or oxidative stress in the prefrontal cortex. System xc â, a cystineâglutamate antiporter, is a poorly understood mechanism that contributes to both cellular antioxidant capacity and glutamate homeostasis.
Objectives: Our goal was to determine whether increased system xc â activity within the prefrontal cortex would normalize a rodent measure of sensorimotor gating.
Methods: In situ hybridization was used to map messenger RNA (mRNA) expression of xCT, the active subunit of system xc â, in the prefrontal cortex. Prepulse inhibition was used to measure sensorimotor gating; deficits in prepulse inhibition were produced using phencyclidine (0.3â3 mg/kg, sc). N-Acetylcysteine (10â100 ÎŒM) and the system xc â inhibitor (S)-4-carboxyphenylglycine (CPG, 0.5 ÎŒM) were used to increase and decrease system xc â activity, respectively. The uptake of 14C-cystine into tissue punches obtained from the prefrontal cortex was used to assay system xc â activity.
Results: The expression of xCT mRNA in the prefrontal cortex was most prominent in a lateral band spanning primarily the prelimbic cortex. Although phencyclidine did not alter the uptake of 14C-cystine in prefrontal cortical tissue punches, intraprefrontal cortical infusion of N-acetylcysteine (10â100 ÎŒM) significantly reduced phencyclidine- (1.5 mg/kg, sc) induced deficits in prepulse inhibition. N-Acetylcysteine was without effect when coinfused with CPG (0.5 ÎŒM), indicating an involvement of system xc â.
Conclusions: These results indicate that phencyclidine disrupts sensorimotor gating through system xc â independent mechanisms, but that increasing cystineâglutamate exchange in the prefrontal cortex is sufficient to reduce behavioral deficits produced by phencyclidine
Employing an open-source tool to assess astrocyte tridimensional structure
Astrocytes display important features that allow them to maintain a close dialog with neurons, ultimately impacting brain function. The complex morphological structure of astrocytes is crucial to the role of astrocytes in brain networks. Therefore, assessing morphologic features of astrocytes will help provide insights into their physiological relevance in healthy and pathological conditions. Currently available tools that allow the tridimensional reconstruction of astrocytes present a number of disadvantages, including the need for advanced computational skills and powerful hardware, and are either time-consuming or costly. In this study, we optimized and validated the FIJI-ImageJ, Simple Neurite Tracer (SNT) plugin, an open-source software that aids in the reconstruction of GFAP-stained structure of astrocytes. We describe (1) the loading of confocal microscopy Z-stacks, (2) the selection criteria, (3) the reconstruction process, and (4) the post-reconstruction analysis of morphological features (process length, number, thickness, and arbor complexity). SNT allows the quantification of astrocyte morphometric parameters in a simple, efficient, and semi-automated manner. While SNT is simple to learn, and does not require advanced computational skills, it provides reproducible results, in different brain regions or pathophysiological states.The authors acknowledge funding from national funds through the FCTâFoundation for Science and Technologyâproject (PTDC/SAU-NSC/118194/2010) to G.T., V.M.S., S.G.G. and J.F.O., and fellowships (SFRH/BD/89714/2012 to V.M.S., SFRH/BPD/97281/2013 to J.F.O., SFRH/BD/101298/2014 to S.G.G., PD/BD/114120/2015 to S.P.N, and PD/BD/127822/2016 to G.T.); Marie Curie Fellowship FP7-PEOPLE-2010-IEF 273936 and BIAL Foundation Grants and 207/14 to J.F.O.; QREN and FEDER funds through Operational program for competitiveness factorsâCOMPETE, âON.2 SR&TD Integrated ProgramâNORTE-07-0124-FEDER-000021â; National and European funds through FCT, and FEDER through COMPETE (PEst-C/SAU/LA0026/2011 and FCOMP-01-0124-FEDER-022724; PEst-C/SAU/LA0026/2013 and FCOMP-01-0124-FEDER-037298, respectively)info:eu-repo/semantics/publishedVersio
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