Ontogenetic Development of Neurophysiological Mechanisms Underlying Language Processing

During the last 20 years, new data on the neurophysiological mechanisms underlying different types of cognitive activity, especially speech and its ontogenetic formation, were obtained in the Laboratory of Children’s Neurophysiology headed by Prof. M.N. Tsitseroshin. Using the analysis of the spatial-temporal structure of regional interactions of cortical bioelectric potentials (so-called functional connectivity), we investigated how specific language levels, such as phonology, grammar, and semantics, are represented in the brain. The data obtained in children vs. adults indicate that the speech perception and production require joint and extremely coordinated activities of both hemispheres, along with the obligatory and differentiated involvement of “classic” speech centers in the left hemisphere, especially Wernicke’s area. Another line of our research is to explore the differences, which arise during verbal processing in adults and children with impaired vs. non-impaired speech, particularly with alalia, dysarthria and stuttering, using behavioral and EEG data. Our data obtained in children vs. adults allow assessing the degree of maturity in the organization of the central processes of maintaining the studied types of verbal activity in children of different ages. These data allow expanding modern concepts about the brain mechanisms of verbal activity in children in the norm and pathology

Induction of cancer-specific cytotoxicity towards human prostate and skin cells using quercetin and ultrasound

Bioflavonoids, such as quercetin, have recently emerged as a new class of chemotherapeutic drugs for the treatment of various cancer types, but are marred by their low potency and poor selectivity. We report that a short application of low-frequency ultrasound selectively sensitises prostate and skin cancer cells against quercetin. Pretreatment of cells with ultrasound (20 kHz, 2 W cm−2, 60 s) selectively induced cytotoxicity in skin and prostate cancer cells, while having minimal effect on corresponding normal cell lines. About 90% of the viable skin cancer cell population was lost within 48 h after ultrasound-quercetin (50 μM) treatment. Ultrasound reduced the LC50 of quercetin for skin cancer cells by almost 80-fold, while showing no effect on LC50 for nonmalignant skin cells

Genome-Wide Screen for Mycobacterium tuberculosis Genes That Regulate Host Immunity

In spite of its highly immunogenic properties, Mycobacterium tuberculosis (Mtb) establishes persistent infection in otherwise healthy individuals, making it one of the most widespread and deadly human pathogens. Mtb's prolonged survival may reflect production of microbial factors that prevent even more vigorous immunity (quantitative effect) or that divert the immune response to a non-sterilizing mode (qualitative effect). Disruption of Mtb genes has produced a list of several dozen candidate immunomodulatory factors. Here we used robotic fluorescence microscopy to screen 10,100 loss-of-function transposon mutants of Mtb for their impact on the expression of promoter-reporter constructs for 12 host immune response genes in a mouse macrophage cell line. The screen identified 364 candidate immunoregulatory genes. To illustrate the utility of the candidate list, we confirmed the impact of 35 Mtb mutant strains on expression of endogenous immune response genes in primary macrophages. Detailed analysis focused on a strain of Mtb in which a transposon disrupts Rv0431, a gene encoding a conserved protein of unknown function. This mutant elicited much more macrophage TNFα, IL-12p40 and IL-6 in vitro than wild type Mtb, and was attenuated in the mouse. The mutant list provides a platform for exploring the immunobiology of tuberculosis, for example, by combining immunoregulatory mutations in a candidate vaccine strain

Nuclear Factor-Kappa B Family Member RelB Inhibits Human Immunodeficiency Virus-1 Tat-Induced Tumor Necrosis Factor-Alpha Production

Human Immunodeficiency Virus-1 (HIV-1)-associated neurocognitive disorder (HAND) is likely neuroinflammatory in origin, believed to be triggered by inflammatory and oxidative stress responses to cytokines and HIV protein gene products such as the HIV transactivator of transcription (Tat). Here we demonstrate increased messenger RNA for nuclear factor-kappa B (NF-κB) family member, transcription factor RelB, in the brain of doxycycline-induced Tat transgenic mice, and increased RelB synthesis in Tat-exposed microglial cells. Since genetic ablation of RelB in mice leads to multi-organ inflammation, we hypothesized that Tat-induced, newly synthesized RelB inhibits cytokine production by microglial cells, possibly through the formation of transcriptionally inactive RelB/RelA complexes. Indeed, tumor necrosis factor-alpha (TNFα) production in monocytes isolated from RelB deficient mice was significantly higher than in monocytes isolated from RelB expressing controls. Moreover, RelB overexpression in microglial cells inhibited Tat-induced TNFα synthesis in a manner that involved transcriptional repression of the TNFα promoter, and increased phosphorylation of RelA at serine 276, a prerequisite for increased RelB/RelA protein interactions. The Rel-homology-domain within RelB was necessary for this interaction. Overexpression of RelA itself, in turn, significantly increased TNFα promoter activity, an effect that was completely blocked by RelB overexpression. We conclude that RelB regulates TNFα cytokine synthesis by competitive interference binding with RelA, which leads to downregulation of TNFα production. Moreover, because Tat activates both RelB and TNFα in microglia, and because Tat induces inflammatory TNFα synthesis via NF-κB, we posit that RelB serves as a cryoprotective, anti-inflammatory, counter-regulatory mechanism for pathogenic NF-κB activation. These findings identify a novel regulatory pathway for controlling HIV-induced microglial activation and cytokine production that may have important therapeutic implications for the management of HAND

Unveiling transport properties of Co2MnSi Heusler epitaxial thin films with ultra-low magnetic damping

International audienceThe family of Co-based Heusler compounds contains promising candidates for spintronic applications regarding their predicted Half-Metal-Magnetic nature, ultra-low magnetic damping coefficients, high curie temperatures and tunable electronic properties. Here we focused on the transport properties of Co2MnSi thin films with thickness in the range of 4-44 nm exhibiting magnetic damping in the 10-4 range. The goals of this study are to examine the impact of the peculiar electronic band structure on the transport properties, to identify the temperature-dependent scattering process, and to extract robust conduction parameters to exploit this material in magnetoelectric devices. In order to undoubtedly correlate all results, the full study has been performed on the same series of samples. Scanning transmission electron microscopy experiments were performed to check the chemically-ordered L21 phase in our films, and also allowed us to identify misfit dislocations generated at the interface with the substrate. The variation of the resistivity with film thickness was measured at different temperatures. The results are examined under the Fuchs and Sondheimer model which allowed us to extract the electron mean free path in Co2MnSi in the temperature range 5-300 K. Values for the residual resistivity, Debye temperature, and distance between the Fermi energy and the conduction band for minority spins were obtained from the fit of the resistivity versus temperatures curves. A negative AMR ratio was measured for all the samples which confirmed the Half-metallic nature of the Co2MnSi films. The determination of the ordinary Hall coefficient alloys allowed us to extract the carrier concentration and carrier mobility and their dependency on the temperature. Finally, scaling of the anomalous Hall coefficient with the longitudinal resistivity was performed indicating that skew scattering is the dominant temperature-dependent scattering mechanism in our films