Notes

Gut Microbiota-Mediated Modulation regarding Cancers Development and also Treatments Efficacy.
The elucidation of the mechanisms ruling SOD1 localization and misplacing might shed light on peculiar ALS features such as cell selectivity and late onset. More importantly, these studies might disclose novel targets for therapeutic intervention in familial ALS as well as non-genetic forms. Finally, pharmacological or genetic manipulation aimed to prevent or counteract the intracellular shifting of mutant SOD1 could be effective for other neurodegenerative disorders featuring the toxic accumulation of misfolded proteins.Small RhoGTPases, such as Cdc42 and RhoA, are key players in integrating external cues and intracellular signaling pathways that regulate growth cone (GC) motility. Indeed, Cdc42 is involved in actin polymerization and filopodia formation, whereas RhoA induces GC collapse and neurite retraction through actomyosin contraction. In this study we employed Förster Resonance Energy Transfer (FRET) microscopy to study the spatio-temporal dynamics of Cdc42 and RhoA in GCs in response to local Semaphorin-3A (Sema3A) stimulation obtained with lipid vesicles filled with Sema3A and positioned near the selected GC using optical tweezers. We found that Cdc42 and RhoA were activated at the leading edge of NG108-15 neuroblastoma cells during spontaneous cycles of protrusion and retraction, respectively. The release of Sema3A brought to a progressive activation of RhoA within 30 s from the stimulus in the central region of the GC that collapsed and retracted. In contrast, the same stimulation evoked waves of Cdc42 activation propagating away from the stimulated region. A more localized stimulation obtained with Sema3A coated beads placed on the GC, led to Cdc42 active waves that propagated in a retrograde manner with a mean period of 70 s, and followed by GC retraction. Therefore, Sema3A activates both Cdc42 and RhoA with a complex and different spatial-temporal dynamics.Experience-dependent plasticity is the ability of brain circuits to undergo molecular, structural and functional changes as a function of neural activity. Neural activity continuously shapes our brain during all the stages of our life, from infancy through adulthood and beyond. Epigenetic modifications of histone proteins and DNA seem to be a leading molecular mechanism to modulate the transcriptional changes underlying the fine-tuning of synaptic connections and circuitry rewiring during activity-dependent plasticity. The recent discovery that cytosine methylation is an epigenetic mark particularly dynamic in brain cells has strongly increased the interest of neuroscientists in understanding the role of covalent modifications of DNA in activity-induced remodeling of neuronal circuits. Here, we provide an overview of the role of DNA methylation and hydroxylmethylation in brain plasticity both during adulthood, with emphasis on learning and memory related processes, and during postnatal development, focusing specifically on experience-dependent plasticity in the visual cortex.Retinitis pigmentosa (RP) is a progressive retinal dystrophy that causes visual impairment and eventual blindness. Retinal prostheses are the best currently available vision-restoring treatment for RP, but only restore crude vision. One possible contributing factor to the poor quality of vision achieved with prosthetic devices is the pathological retinal ganglion cell (RGC) hyperactivity that occurs in photoreceptor dystrophic disorders. Gap junction blockade with meclofenamic acid (MFA) was recently shown to diminish RGC hyperactivity and improve the signal-to-noise ratio (SNR) of RGC responses to light flashes and electrical stimulation in the rd10 mouse model of RP. We sought to extend these results to spatiotemporally patterned optogenetic stimulation in the faster-degenerating rd1 model and compare the effectiveness of a number of drugs known to disrupt rd1 hyperactivity. We crossed rd1 mice with a transgenic mouse line expressing the light-sensitive cation channel channelrhodopsin2 (ChR2) in RGCs, allowing them to be stimulated directly using high-intensity blue light. We used 60-channel ITO multielectrode arrays to record ChR2-mediated RGC responses from wholemount, ex-vivo retinas to full-field and patterned stimuli before and after application of MFA, 18-β-glycyrrhetinic acid (18BGA, another gap junction blocker) or flupirtine (Flu, a Kv7 potassium channel opener). All three drugs decreased spontaneous RGC firing, but 18BGA and Flu also decreased the sensitivity of RGCs to optogenetic stimulation. Nevertheless, all three drugs improved the SNR of ChR2-mediated responses. MFA also made it easier to discern motion direction of a moving bar from RGC population responses. Our results support the hypothesis that reduction of pathological RGC spontaneous activity characteristic in retinal degenerative disorders may improve the quality of visual responses in retinal prostheses and they provide insights into how best to achieve this for optogenetic prostheses.Previous studies have shown that the pial microcirculation remodeling improves neurological outcome after middle cerebral artery occlusion (MCAO), accompanied by higher expression of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS), modulating in vivo angiogenesis. This study was aimed to assess the effects of bone marrow mesenchymal stem cells (BM-MSCs) infused after MCAO on rat pial microcirculation. Animals were subjected to 2 h MCAO followed by BM-MSCs infusion into internal carotid artery. Pial microcirculation was observed at different reperfusion times by fluorescence microscopy. Geometric characteristics of arteriolar networks, permeability increase, leukocyte adhesion, perfused capillary density, VEGF, and endothelial nitric oxide synthase (e-NOS) expression were evaluated. Green fluorescent protein (GFP)-BM-MSCs were used to evaluate their distribution and cell phenotype development during reperfusion. BM-MSCs stimulated a geometric rearrangement of pial networks with formation of new anastomotic vessels sprouting from preexistent arterioles in the penumbra at 7-14-28 days of reperfusion. At the same time VEGF and eNOS expression increased. GFP-BM-MSCs appear to be involved in endothelial and smooth muscle cell programming in the infarcted area. In conclusion, transient MCAO induced pial vascular remodeling characterized by arteriolar anastomotic arcades (originated from preexistent arterioles in penumbra area) able to overlap the ischemic core supplying blood to the neuronal tissue. BM-MSCs appear to accelerate angiogenic processes facilitating new vessel formation; this mechanism was promoted by an increase in VEGF and eNOS expression.Oligodendrocytes myelinate neuronal axons in the central nervous system (CNS) facilitating rapid transmission of action potentials by saltatory conduction. Myelin basic protein (MBP) is an essential component of myelin and its absence results in severe hypomyelination in the CNS of rodents. Mbp mRNA is not translated immediately after exit from the nucleus in the cytoplasm, but is transported to the plasma membrane in RNA transport granules in a translationally silenced state. We have previously identified the small non-coding RNA 715 (sncRNA715) as an inhibitor of Mbp translation associated with RNA granules. Argonaute (Ago) proteins and small RNAs form the minimal core of the RNA induced silencing complex and together recognize target mRNAs to be translationally inhibited or degraded. Recently, tyrosine phosphorylation of Ago2 was reported to be a regulator of small RNA binding. The oligodendroglial non-receptor tyrosine kinase Fyn is activated by neuronal signals and stimulates the translation of Mbp mRNA at the axon-glial contact site. Here we analyzed the expression of Ago proteins in oligodendrocytes, if they associate with Mbp mRNA transport granules and are tyrosine phosphorylated by Fyn. We show that all Ago proteins (Ago1-4) are expressed by oligodendrocytes and that Ago2 colocalizes with hnRNP A2 in granular cytoplasmic structures. Ago2 associates with hnRNP A2, Mbp mRNA, sncRNA715 and Fyn kinase and is tyrosine phosphorylated in response to Fyn activity. Our findings suggest an involvement of Ago2 in the translational regulation of Mbp. The identification of Ago proteins as Fyn targets will foster further research to understand in more molecular detail how Fyn activity regulates Mbp translation.Holometabolous insects, including Drosophila melanogaster, undergo complete metamorphosis that includes a pupal stage. During metamorphosis, the Drosophila nervous system undergoes massive remodeling and growth, that include cell death and large-scale axon and synapse elimination as well as neurogenesis, developmental axon regrowth, and formation of new connections. Neuronal remodeling is an essential step in the development of vertebrate and invertebrate nervous systems. Research on the stereotypic remodeling of Drosophila mushroom body (MB) γ neurons has contributed to our knowledge of the molecular mechanisms of remodeling but our knowledge of the cellular mechanisms remain poorly understood. A major hurdle in understanding various dynamic processes that occur during metamorphosis is the lack of time-lapse resolution. The pupal case and opaque fat bodies that enwrap the central nervous system (CNS) make live-imaging of the central brain in-vivo impossible. We have established an ex vivo long-term brain culture system that supports the development and neuronal remodeling of pupal brains. By optimizing culture conditions and dissection protocols, we have observed development in culture at kinetics similar to what occurs in vivo. selleck chemicals Using this new method, we have obtained the first time-lapse sequence of MB γ neurons undergoing remodeling in up to a single cell resolution. We found that axon pruning is initiated by blebbing, followed by one-two nicks that seem to initiate a more widely spread axon fragmentation. As such, we have set up some of the tools and methodologies needed for further exploration of the cellular mechanisms of neuronal remodeling, not limited to the MB. The long-term ex vivo brain culture system that we report here could be used to study dynamic aspects of neurodevelopment of any Drosophila neuron.Midbody release from proliferative neural progenitor cells is tightly associated with the neuronal commitment of neural progenitor cells during the progression of neurogenesis in the mammalian cerebral cortex. While the central portion of the midbody, a cytoplasmic bridge between nascent daughter cells, is engulfed by one of the daughter cell by most cells in vitro, it is shown to be released into the extracellular cerebrospinal fluid (CF) in vivo in mouse embryos. Several proteins have been involved in midbody release; however, few studies have addressed the participation of the plasma membrane's lipids in this process. Here, we show by Shotgun Lipidomic analysis that phosphatydylserine (PS), among other lipids, is enriched in the released midbodies compared to lipoparticles and cellular membranes, both collected from the CF of the developing mouse embryos. Moreover, the developing mouse embryo neural progenitor cells released two distinct types of midbodies carrying either internalized PS or externalized PS on their membrane.
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