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Introduction: Neural stem cells (NSCs) are essential for both embryonic development and adult neurogenesis, and their dysregulation causes a number of neurodevelopmental disorders, such as epilepsy and autism spectrum disorders. NSC proliferation and differentiation in the developing brain is a complex process controlled by various intrinsic and extrinsic stimuli. The mammalian target of rapamycin (mTOR) regulates proliferation and differentiation, among other cellular functions, and disruption in the mTOR pathway can lead to severe nervous system development deficits. In this study, we investigated the effect of inhibition of the mTOR pathway by rapamycin (Rapa) on NSC proliferation and differentiation. Methods: The NSC cultures were treated with Rapa for 1, 2, 6, 24, and 48 h. The effect on cellular functions was assessed by immunofluorescence staining, western blotting, and proliferation/metabolic assays. Results: mTOR inhibition suppressed NSC proliferation/metabolic activity as well as S-Phase entry by as early as 1 h of Rapa treatment and this effect persisted up to 48 h of Rapa treatment. In a separate experiment, NSCs were differentiated for 2 weeks after treatment with Rapa for 24 or 48 h. Regarding the effect on neuronal and glial differentiation (2 weeks post-treatment), this was suppressed in NSCs deficient in mTOR signaling, as evidenced by downregulated expression of NeuN, MAP2, and GFAP. We assume that the prolonged effect of mTOR inhibition is realized due to the effect on cytoskeletal proteins. Discussion: Here, we demonstrate for the first time that the mTOR pathway not only regulates NSC proliferation but also plays an important role in NSC differentiation into both neuronal and glial lineages. [ABSTRACT FROM AUTHOR]

Our knowledge of the institutional features of local government in Canadian cities is surprisingly fragmentary. The academic literature has long identified dominant tendencies in Canadian local institutions, but systematic empirical data has been missing. In this article, we address this gap in knowledge in two ways. We introduce the Canadian Municipal Attributes Portal (CMAP), a new open-access database that contains information on dozens of institutional features of local government for nearly 100 of the most populous municipalities in Canada. We then propose a new multidimensional index of authority concentration, which is designed to capture variation in the local structure of decision-making authority in a systematic and nuanced manner. We apply this index to a systematic pan-Canadian subsample of 65 CMAP municipalities. The result is a rich portrait of institutional variety, one that both corroborates and substantially extends our current understanding of the shape of municipal institutions in Canadian cities. [ABSTRACT FROM AUTHOR]

The paper deals with an improved algorithm for estimating errors during approximate symbolic analysis. A linear system can be solved symbolically. However, the size of the resulting formula grows exponentially with the matrix size. The approximate symbolic analysis omits insignificant terms of the exact formula to decrease its size, which, on the other hand, limits the validity of the approximate result. The proposed algorithm estimates, in a computationally feasible way, the approximation error over a region of system parameters. This makes it possible to maintain the validity of the results even if the tolerances of the system parameters are defined. The method is based on the first-order approximation of error functions. The algorithm is demonstrated using the SNAP symbolic analyzer, which has been developed by the authors.

NMDA receptors (NMDARs) are ionotropic glutamate receptors that play a key role in excitatory neurotransmission. The number and subtype of surface NMDARs are regulated at several levels, including their externalization, internalization, and lateral diffusion between the synaptic and extrasynaptic regions. Here, we used novel anti-GFP (green fluorescent protein) nanobodies conjugated to either the smallest commercially available quantum dot 525 (QD525) or the several nanometer larger (and thus brighter) QD605 (referred to as nanoGFP-QD525 and nanoGFP-QD605, respectively). Targeting the yellow fluorescent protein-tagged GluN1 subunit in rat hippocampal neurons, we compared these two probes to a previously established larger probe, a rabbit anti-GFP IgG together with a secondary IgG conjugated to QD605 (referred to as antiGFP-QD605). The nanoGFP-based probes allowed faster lateral diffusion of the NMDARs, with several-fold increased median values of the diffusion coefficient (D). Using thresholded tdTomato-Homer1c signals to mark synaptic regions, we found that the nanoprobe-based D values sharply increased at distances over 100 nm from the synaptic edge, while D values for antiGFP-QD605 probe remained unchanged up to a 400 nm distance. Using the nanoGFP-QD605 probe in hippocampal neurons expressing the GFP-GluN2A, GFP-GluN2B, or GFP-GluN3A subunits, we detected subunit-dependent differences in the synaptic localization of NMDARs, D value, synaptic residence time, and synaptic-extrasynaptic exchange rate. Finally, we confirmed the applicability of the nanoGFP-QD605 probe to study differences in the distribution of synaptic NMDARs by comparing to data obtained with nanoGFPs conjugated to organic fluorophores, using universal point accumulation imaging in nanoscale topography and direct stochastic optical reconstruction microscopy. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a complex disease with an unknown etiology. Available treatments, limited to cholinesterase inhibitors and N-methyl-d-aspartate receptor (NMDAR) antagonists, provide symptomatic relief only. As single-target therapies have not proven effective, rational specific-targeted combination into a single molecule represents a more promising approach for treating AD, and is expected to yield greater benefits in alleviating symptoms and slowing disease progression. In the present study, we designed, synthesized, and biologically evaluated 24 novel N-methylpropargylamino-quinazoline derivatives. Initially, compounds were thoroughly inspected by in silico techniques determining their oral and CNS availabilities. We tested, in vitro, the compounds' effects on cholinesterases and monoamine oxidase A/B (MAO-A/B), as well as their impacts on NMDAR antagonism, dehydrogenase activity, and glutathione levels. In addition, we inspected selected compounds for their cytotoxicity on undifferentiated and differentiated neuroblastoma SH-SY5Y cells. We collectively highlighted II-6h as the best candidate endowed with a selective MAO-B inhibition profile, NMDAR antagonism, an acceptable cytotoxicity profile, and the potential to permeate through BBB. The structure-guided drug design strategy applied in this study imposed a novel concept for rational drug discovery and enhances our understanding on the development of novel therapeutic agents for treating AD. [ABSTRACT FROM AUTHOR]

Is the Right to the City (RTTC) still a useful framework for a transformative urban politics? Given recent scholarly criticism of its real-world applications and appropriations, in this paper, we argue that the transformative promise in the RTTC lies beyond its role as a framework for oppositional struggle, and in its normative ends. Building upon Henri Lefebvre's original writing on the subject, we develop a "radical-cooperative" conception of the RTTC. Such a view, which is grounded in the lived experiences of the current city, envisions an urban society in which inhabitants can pursue their material and social needs through self-governed cooperation across social difference. Growing and diversifying spaces and sectors of urban life that are decoupled from global capitalism are, we argue, necessary to create space for this inclusionary politics. While grassroots action is essential to this process, so is multi-scalar support from the state. [ABSTRACT FROM AUTHOR]

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