Myosin V Regulates Spatial Localization of Different Forms of Neurotransmitter Release in Central Synapses

Synaptic active zone (AZ) contains multiple specialized release sites for vesicle fusion. The utilization of release sites is regulated to determine spatiotemporal organization of the two main forms of synchronous release, uni-vesicular (UVR) and multi-vesicular (MVR). We previously found that the vesicle-associated molecular motor myosin V regulates temporal utilization of release sites by controlling vesicle anchoring at release sites in an activity-dependent manner. Here we show that acute inhibition of myosin V shifts preferential location of vesicle docking away from AZ center toward periphery, and results in a corresponding spatial shift in utilization of release sites during UVR. Similarly, inhibition of myosin V also reduces preferential utilization of central release sites during MVR, leading to more spatially distributed and temporally uniform MVR that occurs farther away from the AZ center. Using a modeling approach, we provide a conceptual framework that unites spatial and temporal functions of myosin V in vesicle release by controlling the gradient of release site release probability across the AZ, which in turn determines the spatiotemporal organization of both UVR and MVR. Thus myosin V regulates both temporal and spatial utilization of release sites during two main forms of synchronous release.

The evolution of eloquent located low-grade gliomas surgical approaches, their natural history and molecular classification

Low-grade glioma is characterized by slow growth, infiltrative pattern through white matter tracts and progression to a malignant tumour type. The traditional classification is newly replaced by molecular stratification. This reorganisation gathers glioma with similar prognosis and treatment protocols. The preferential location of that tumour in eloquent areas constituted, over time, a real challenge regarding the best surgical approach. Because of the high risk of postoperative neurological deficits initially a more conservative management was adopted. Once with the development of preoperative and intraoperative functional assessment techniques, a higher degree of resection was possible in the limits of cortico-subcortical eloquence, being well known that this is a statistically significant factor for survival. We present in this paper the natural evolution of low-grade glioma, their new molecular classification, prognostic factors and the various approach proposed for eloquent ones.

Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma

Both the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have been associated with progression and resistance to therapies in glioblastoma, but their specific contribution remained unknown. By long-term tracking of tumor cell fate and dynamics in the live mouse brain, differential therapeutic responses in both niches are determined. Both the PVN, a preferential location of long-term quiescent glioma cells, and network integration facilitate resistance against cytotoxic effects of radiotherapy and chemotherapy—independently of each other, but with additive effects. Perivascular glioblastoma cells are particularly able to actively repair damage to tumor regions. Population of the PVN and resistance in it depend on proficient NOTCH1 expression. In turn, NOTCH1 downregulation induces resistant multicellular networks by TM extension. Our findings identify NOTCH1 as a central switch between the PVN and network niche in glioma, and demonstrate robust cross-compensation when only one niche is targeted.

How Insertion of a Single Tryptophan in the N-Terminus of a Cecropin A-Melittin Hybrid Peptide Changes Its Antimicrobial and Biophysical Profile

In the era of antibiotic resistance, there is an urgent need for efficient antibiotic therapies to fight bacterial infections. Cationic antimicrobial peptides (CAMP) are promising lead compounds given their membrane-targeted mechanism of action, and high affinity towards the anionic composition of bacterial membranes. We present a new CAMP, W-BP100, derived from the highly active BP100, holding an additional tryptophan at the N-terminus. W-BP100 showed a broader antibacterial activity, demonstrating a potent activity against Gram-positive strains. Revealing a high partition constant towards anionic over zwitterionic large unilamellar vesicles and inducing membrane saturation at a high peptide/lipid ratio, W-BP100 has a preferential location for hydrophobic environments. Contrary to BP100, almost no aggregation of anionic vesicles is observed around saturation conditions and at higher concentrations no aggregation is observed. With these results, it is possible to state that with the incorporation of a single tryptophan to the N-terminus, a highly active peptide was obtained due to the π–electron system of tryptophan, resulting in negatively charged clouds, that participate in cation–π interactions with lysine residues. Furthermore, we propose that W-BP100 action can be achieved by electrostatic interactions followed by peptide translocation.

Myosin V regulates spatial localization of different forms of neurotransmitter release in central synapses

SUMMARYSynaptic active zone (AZ) contains multiple specialized release sites for vesicle fusion. The utilization of release sites is regulated to determine spatiotemporal organization of the two main forms of synchronous release, uni-vesicluar (UVR) and multi-vesicular (MVR). We previously found that the vesicle-associated molecular motor myosin V regulates temporal utilization of release sites by controlling vesicle anchoring at release sites (Maschi et al, 2018). Here we show that acute inhibition of myosin V shifts preferential location of vesicle docking away from AZ center towards periphery, and results in a corresponding spatial shift in utilization of release sites during UVR. Similarly, inhibition of myosin V also reduces preferential utilization of central release sites during MVR, leading to more spatially distributed and temporally uniform MVR that occurs farther away from the AZ center. Thus myosin V regulates both temporal and spatial utilization of release sites during two main forms of synchronous release.

Tumor cell plasticity, heterogeneity and resistance in crucial microenvironmental niches in glioma

Both the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have been associated with progression and resistance to therapies in glioblastoma, but their specific contribution remained unknown. By long-term tracking of tumor cell fate and dynamics in the live mouse brain, differential therapeutic responses in both niches could be determined. Both the PVN, a preferential location of long-term quiescent glioma cells, and network integration facilitated resistance against cytotoxic effects of radiotherapy and chemotherapy - independently of each other, but with additive effects. Perivascular glioblastoma cells were particularly able to actively repair damage to tumor regions. Population of the PVN and resistance in it depended on proficient NOTCH1 expression. In turn, NOTCH1 downregulation induced resistant multicellular networks by TM extension. Our findings identify NOTCH1 as a central switch between the PVN and network niche in glioma, and demonstrate robust cross-compensation when only one niche is targeted.

Last Glacial Maximum landscape and Epigravettian horse hunting strategy in Central Europe: The case of Stránská skála IV

With the end of MIS3, the unity of larger Gravettian settlements based predominantly on mammoth exploitation split into a mosaic of smaller Epigravettian sites with specific behaviors and economies. Based on C14 chronology, the site of Stránská skála IV (together with Grubgraben, Ságvár and Kašov), correlates with a brief warm period after the Last Glacial Maximum around 22 ka calBP. We detected two main accumulations of predominantly horse bones under a rock cliff suggesting that the site was not a regular settlement but rather a specialised hunting site. No features or hearths were recovered. Lithic raw materials were imported from long distances, and the horse hunting strategy profitted from the specific geographic qualitites of the site. Preferential location of Epigravettian sites in secluded valleys is a pattern generally recognized in Moravia and usually explained as a response to the harsh MIS2 climates.

Preferential location of zirconium dopants in cerium dioxide nanoparticles and the effects of doping on their reducibility: a DFT study

Zirconium doping dramatically facilitates O vacancy formation in ceria nanoparticles not only at the surface but also in four-coordinated inner O positions, which enhances O mobility. In mixed nanoparticles zirconium tends to occupy inner sites.

Large anterior temporal Virchow–Robin spaces: Evaluating MRI features over the years—Our experience and literature review

Dilated Virchow–Robin spaces (VRSs) are expansions of the normal perivascular spaces with a short axis greater than 2 mm or, according to some authors, greater than 3 mm. They are usually documented at the basal ganglia, at the convexity white matter (WM) and centrum semiovale, and at the mesencephalon. The anterior temporal WM is a recently described preferential location for large (≥5 mm) VRSs. The aim of our study was to evaluate the magnetic resonance imaging (MRI) features and their modifications during a long-term follow-up period (≥24 months) of the anterior temporal VRSs with a retrospective analysis among all brain MRI studies performed at our institution between January 2010 and January 2017. In our study, the presence and the stability of characteristic MRI features certainly increased our diagnostic confidence allowing us to continue conservative approach while the surrounding signal change, as reported in the literature, should not in itself prompt alternative diagnoses to be entertained.