Electrophysiology of glioma: a Rho GTPase-activating protein reduces tumor growth and spares neuron structure and function

Background. Glioblastomas are the most aggressive type of brain tumor. A successful treatment should aim at halting tumor growth and protecting neuronal cells to prevent functional deficits and cognitive deterioration. Here, we exploited a Rho GTPase-activating bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1), to interfere with glioma cell growth in vitro and vivo. We also investigated whether this toxin spares neuron structure and function in peritumoral areas. Methods. We performed a microarray transcriptomic and in-depth proteomic analysis to characterize the molecular changes triggered by CNF1 in glioma cells. We also examined tumor cell senescence and growth in vehicle-and CNF1-treated glioma-bearing mice. Electrophysiological and morphological techniques were used to investigate neuronal alterations in peritumoral cortical areas. Results. Administration of CNF1 triggered molecular and morphological hallmarks of senescence in mouse and human glioma cells in vitro. CNF1 treatment in vivo induced glioma cell senescence and potently reduced tumor volumes. In peritumoral areas of glioma-bearing mice, neurons showed a shrunken dendritic arbor and severe functional alterations such as increased spontaneous activity and reduced visual responsiveness. CNF1 treatment enhanced dendritic length and improved several physiological properties of pyramidal neurons, demonstrating functional preservation of the cortical network. Conclusions. Our findings demonstrate that CNF1 reduces glioma volume while at the same time maintaining the physiological and structural properties of peritumoral neurons. These data indicate a promising strategy for the development of more effective antiglioma therapies

How Water Interacts with the NOH Group: The Rotational Spectrum of the 1:1 N,N-diethylhydroxylamine·Water Complex

The rotational spectrum of the 1:1 N,N-diethylhydroxylamine-water complex has been investigated using pulsed jet Fourier transform microwave spectroscopy in the 6.5–18.5 GHz frequency region. The most stable conformer has been detected as well as the (Formula presented.) C monosubstituted isotopologues in natural abundance and the (Formula presented.) O enriched water species, allowing to determine the nitrogen nuclear quadrupole coupling constants and the molecular structure in the vibrational ground state. The molecule has a (Formula presented.) symmetry and the water lies in the (Formula presented.) symmetry plane forming two hydrogen bonds with the NOH frame with length: (Formula presented.) = 1.974 Å and (Formula presented.) = 2.096 Å. From symmetry-adapted perturbation theory calculations coupled to atoms in molecule approach, the corresponding interaction energy values are estimated to be 24 and 13 kJ·mol (Formula presented.), respectively. The great strength of the intermolecular interaction involving the nitrogen atom is in agreement with the high reactivity of hydroxylamine compounds at the nitrogen site

Study of MDT calibration constants using H8 testbeam data of year 2004

In year 2004 Atlas performed a long campaign of test beam data taking at the H8 Cern beam. Two sectors of the barrel and endcap regions of the Muon Spectrometer were exposed to the beam and large amount of data were collected in well defined and controlled operating conditions. This allowed a careful study on MDT drift properties. A better understanding of the calibration constants, of their definition and determination and of the criteria for their acceptance has been obtained. Systematic effects and time stability of the constants have also been studied

Progression of motor deficits in glioma-bearing mice: impact of CNF1 therapy at symptomatic stages

Glioblastoma (GBM) is the most aggressive type of brain tumor. In this context, animal models represent excellent tools for the early detection and longitudinal mapping of neuronal dysfunction, that are critical in the preclinical validation of new therapeutic strategies. In a mouse glioma model, we developed sensitive behavioral readouts that allow early recognizing and following neurological symptoms. We injected GL261 cells into the primary motor cortex of syngenic mice and we used a battery of behavioral tests to longitudinally monitor the dysfunction induced by tumor growth. Grip strength test revealed an early onset of functional deficit associated to the glioma growth, with a significant forelimb weakness appearing 9 days after tumor inoculation. A later deficit was observed in the rotarod and in the grid walk tasks. Using this model, we found reduced tumor growth and maintenance of behavioral functions following treatment with Cytotoxic Necrotizing Factor 1 (CNF1) at a symptomatic stage. Our data provide a detailed and precise examination of how tumor growth reverberates on the behavioral functions of glioma-bearing mice, providing normative data for the study of therapeutic strategies for glioma treatment. The reduced tumor volume and robust functional sparing observed in CNF1-treated, glioma-bearing mice strengthen the notion that CNF1 delivery is a promising strategy for glioma therapy

Extracellular matrix inhibits structural and functional plasticity of dendritic spines in the adult visual cortex

Brain cells are immersed in a complex structure forming the extracellular matrix. The composition of the matrix gradually matures during postnatal development, as the brain circuitry reaches its adult form. The fully developed extracellular environment stabilizes neuronal connectivity and decreases cortical plasticity as highlighted by the demonstration that treatments degrading the matrix are able to restore synaptic plasticity in the adult brain. The mechanisms through which the matrix inhibits cortical plasticity are not fully clarified. Here we show that a prominent component of the matrix, chondroitin sulfate proteoglycans (CSPGs), restrains morphological changes of dendritic spines in the visual cortex of adult mice. By means of in vivo and in vitro two-photon imaging and electrophysiology, we find that after enzymatic digestion of CSPGs, cortical spines become more motile and express a larger degree of structural and functional plasticity

The role of preclinical models in creatine transporter deficiency: Neurobiological mechanisms, biomarkers and therapeutic development

Creatine (Cr) Transporter Deficiency (CTD) is an X-linked metabolic disorder, mostly caused by missense mutations in the SLC6A8 gene and presenting with intellectual disability, autistic behavior, and epilepsy. There is no effective treatment for CTD and patients need lifelong assistance. Thus, the research of novel intervention strategies is a major scientific challenge. Animal models are an excellent tool to dissect the disease pathogenetic mechanisms and drive the preclinical development of therapeutics. This review illustrates the current knowledge about Cr metabolism and CTD clinical aspects, with a focus on mainstay diagnostic and therapeutic options. Then, we discuss the rodent models of CTD characterized in the last decade, comparing the phenotypes expressed within clinically relevant domains and the timeline of symptom development. This analysis highlights that animals with the ubiquitous deletion/mutation of SLC6A8 genes well recapitulate the early onset and the complex pathological phenotype of the human condition. Thus, they should represent the preferred model for preclinical efficacy studies. On the other hand, brain-and cell-specific conditional mutants are ideal for understanding the basis of CTD at a cellular and molecular level. Finally, we explain how CTD models might provide novel insight about the pathogenesis of other disorders, including cancer

The AGILE real-time analysis pipelines in the multi-messenger era

In the multi-messenger era, space and ground-based observatories usually develop real-time analysis (RTA) pipelines to rapidly detect transient events and promptly share information with the scientific community to enable follow-up observations. These pipelines can also react to science alerts shared by other observatories through networks such as the Gamma-Ray Coordinates Network (GCN) and the Astronomer's Telegram (ATels). AGILE is a space mission launched in 2007 to study X-ray and gamma-ray phenomena. This contribution presents the technologies used to develop two types of AGILE pipelines using the RTApipe framework and an overview of the main scientific results. The first type performs automated analyses on new AGILE data to detect transient events and automatically sends AGILE notices to the GCN network. Since May 2019, this pipeline has sent more than 50 automated notices with a few minutes delay since data arrival. The second type of pipeline reacts to multi-messenger external alerts (neutrinos, gravitational waves, GRBs, and other transients) received through the GCN network and performs hundreds of analyses searching for counterparts in all AGILE instruments' data. The AGILE Team uses these pipelines to perform fast follow-up of science alerts reported by other facilities, which resulted in the publishing of several ATels and GCN circulars.Comment: 8 pages, 3 figures, Proceedings of the 37th International Cosmic Ray Conference (ICRC 2021), Berlin, German