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Summary Glioblastoma (GBM) may arise from astrocytes through a multistep process involving a progressive accumulation of mutations. We explored whether GBM-derived extracellular vesicles (EVs) may facilitate neoplastic transformation and malignant growth of astrocytes. We utilized conditioned media (CM) of cultured glioma cells, its sequential filtration, diverse cell-based assays, RNA sequencing, and metabolic assays to compare the effects of EV-containing and EV-depleted CM. GBM EVs facilitated the neoplastic growth of pre-transformed astrocytes but not normal human or mouse astrocytes. They induced proliferation, self-renewal, and colony formation of pre-transformed astrocytes and enhanced astrocytoma growth in a mouse allograft model. GBM EVs appear to reprogram astrocyte metabolism by inducing a shift in gene expression that may be partly associated with EV-mediated transfer of full-length mRNAs encoding ribosomal proteins, oxidative phosphorylation, and glycolytic factors. Our study suggests an EV/extracellular RNA (exRNA)-mediated mechanism that contributes to astrocyte transformation via metabolic reprograming and implicates horizontal mRNA transfer., Graphical Abstract, Highlights • Extracellular vesicles (EVs) shed by glioma cells are taken up by astrocytes • Glioma EVs facilitate astrocyte transformation and tumor growth • EVs reprogram glycolysis and oxidative phosphorylation of transformed astrocytes • mRNAs coding ribosomal proteins and other factors are dispersed via EVs, Biological Sciences; Cell Biology; Cancer

International audience; The Heat Shock Factors (HSFs) have been historically identified as a family of transcription factors that are activated and work in a stress-responsive manner, after exposure to a large variety of stimuli. However, they are also critical in normal conditions, in a life long manner, in a number of physiological processes that encompass gametogenesis, embryonic development and the integrity of adult organs and organisms. The importance of such roles is emphasized by the devastating impact of their deregulation on health, ranging from reproductive failure, neurodevelopmental disorders, cancer, and aging pathologies, including neurodegenerative disorders. Here, we provide an overview of the delicate choreography of the regulation of HSFs during neurodevelopment, at prenatal and postnatal stages. The regulation of HSFs acts at multiple layers and steps, and comprises the control of (i) HSF mRNA and protein levels, (ii) HSF activity in terms of DNA-binding and transcription, (iii) HSF homo- and hetero-oligomerization capacities, and (iv) HSF combinatory set of post-translational modifications. We also describe how these regulatory mechanisms operate in the normal developing brain and how their perturbation impact neurodevelopment under prenatal or perinatal stress conditions. In addition, we put into perspective the possible role of HSFs in the evolution of the vertebrate brains and the importance of the HSF pathway in a large variety of neurodevelopmental disorders.

Septic shock is characterized by an excessive inflammatory response depicted in a cytokine storm that results from invasive bacterial and viral infections. Non-canonical inflammasome activation is crucial in the development of septic shock promoting pyroptosis and pro-inflammatory cytokine production via caspase-11 and Gasdermin-D (GSDMD). Here, we show that NAD+treatment protected mice towards bacterial and LPS induced endotoxic shock by blocking the non-canonical inflammasome specifically. NAD+administration impeded systemic IL-1β and IL-18 production and GSDMD-mediated pyroptosis of macrophages via the IFN-β/STAT-1 signaling machinery. More importantly, NAD+administration not only improved casp-11-/-survival but rendered WT mice completely resistant to septic shock via the IL-10 signaling pathway that was independent from the non-canonical inflammasome. Here, we delineated a two-sided effect of NAD+blocking septic shock through a specific inhibition of the non-canonical inflammasome and promoting immune homeostasis via IL-10, underscoring its unique therapeutic potential.

Light absorption in graphene causes a significant change in electron temperature due to the low electronic heat capacity and weak electron-phonon coupling. This property makes graphene a beautiful material for hot-electron bolometers (HEB). However, along with the above advantages, a major challenge remains that, with weak electron-phonon scattering, the resistance is only weakly temperature dependent for pristine graphene. It is thus challenging to measure the electron temperature change due to incoming radiation power. In addition, thermally isolating graphene in order to achieve the small electron-phonon thermal conductance is difficult. To overcome this issue, stronger temperature dependence has been obtained either by using dual-gated bilayer graphene to create a tunable bandgap or by introducing defects to induce strong localization. Both schemes have successfully produced bolometric detection, with responsivities up to 2×105 V W−1 and a temperature coefficient for the resistance as high as 22 kΩ K−1 at 1.5 K. Here we use graphene quantum dots, where a bandgap is induced via quantum confinement and the graphene quantum dots device exhibits an extraordinarily high variation of resistance with temperature (higher than 430 MΩ K−1), leading to responsivities of 1 × 1010 V W−1.

Atomically thin transition metal dichalcogenides (TMDs) are ideal candidates for ultrathin optoelectronics that are flexible and semitransparent. Photodetectors based on TMDs show remarkable performance, with responsivity and detectivity higher than 10

Intercellular communication within complex biological and pathological systems via extracellular vesicles (EVs) and secreted factors is a highly attractive area of research. However, cell models enabling investigation of such communication in vitro are limited. Commonly utilized is the supplementation of hyper-concentrated EVs or other extracellular factors to the recipient cell cultures. This approach requires purification of the secreted complexes and is confounded by the contamination of media components. Two-chamber co-cultures of donor and recipient cells separated by a pore membrane may represent a more physiological and better-controlled system for the investigation of intercellular communication. Yet, distinct culture conditions for different neural cell types often make them incompatible for co-culturing. Here we optimized short-term co-cultures of patient-derived low-passage glioma-initiating stem cells with normal cells of the brain microenvironment, such as primary neurons, astrocytes, microglia, and brain endothelial cells. We demonstrate the culture compatibility of these cell types and internalization of glioma-derived extracellular RNA by the normal recipient cells. The presented protocols are valuable for the investigation of intercellular communication between glioma brain tumor and cells of its microenvironment, including but not limited to the EVs-mediated communication.RESEARCH IN CONTEXTCell-to-cell communication is essential in normal physiology and implicated in disease; however, experimental systems for its modeling in vitro are limited. Particularly, the investigation of communication between brain tumors and normal cells of the brain microenvironment has been challenged by the lack of adequate culture models. Here we developed co-cultures of glioma stem cells with various types of normal brain cells, including primary neurons, astrocytes, microglia, and brain endothelial cells, and demonstrated their utility for the study of intercellular communication. Detection of proposed markers in the recipient cells confirmed RNA transfer in these co-cultures.

Atomically thin materials like semimetallic graphene and semiconducting transition metal dichalcogenides (TMDs) are an ideal platform for ultra-thin optoelectronic devices due to their direct bandgap (for monolayer thickness) and their considerable light absorption. For devices based on semiconducting TMDs, light detection occurs by optical excitation of charge carriers above the bandgap. For gapless graphene, light absorption causes a large increase in electron temperature, because of its small electronic heat capacity and weak electron-phonon coupling, making it suitable for hot-electron detectors. Here we show that, by nanostructuring graphene into quantum dots, we can exploit quantum confinement to achieve hot-electron bolometric detection. The graphene quantum dots are patterned from epitaxial graphene on SiC, with dot diameter ranging from 30 nm to 700 nm [1]. Nanostructuring greatly increases the temperature dependence of the electrical resistance, yielding detectors with extraordinary performance (responsivities of 1 × 10^(10) V W^(−1) and electrical noise-equivalent power, ∼2 × 10^(−16) W Hz^(−1/2) at 2.5 K). We will discuss how the dynamics of the charge carriers, namely the hot-electron cooling, affects the device operation and its power dependence. These detectors work in a very broad spectral range, from terahertz through telecom to ultraviolet radiation [2], with a design that is easily scalable for detector arrays. [1] El Fatimy, A. et al. , "Epitaxial graphene quantum dots for high-performance terahertz bolometers," Nature Nanotechnology 11, 335-338 (2016). [2] El Fatimy, A. et al. , "Ultra-broadband photodetectors based on epitaxial graphene quantum dots" Nanophotonics (2018).

Using in silico analysis of The Cancer Genome Atlas (TCGA), we identified microRNAs associated with glioblastoma (GBM) survival, and predicted their functions in glioma growth and progression. Inhibition of two “risky” miRNAs, miR-148a and miR-31, in orthotopic xenograft GBM mouse models suppressed tumor growth and thereby prolonged animal survival. Intracranial tumors treated with uncomplexed miR-148a and miR-31 antagomirs exhibited reduced proliferation, stem cell depletion, and normalized tumor vasculature. Growth-promoting functions of these two miRNAs were, in part, mediated by the common target, the factor inhibiting hypoxia-inducible factor 1 (FIH1), and the downstream pathways involving hypoxia-inducible factor HIF1α and Notch signaling. Therefore, miR-31 and miR-148a regulate glioma growth by maintaining tumor stem cells and their niche, and providing the tumor a way to activate angiogenesis even in a normoxic environment. This is the first study that demonstrates intratumoral uptake and growth-inhibiting effects of uncomplexed antagomirs in orthotopic glioma.

Two-dimensional materials such as graphene and transition metal dichalcogenides (TMDs) are ideal candidates to create ultra-thin electronics suitable for flexible substrates. Although optoelectronic devices based on TMDs have demonstrated remarkable performance, scalability is still a significant issue. Most devices are created using techniques that are not suitable for mass production, such as mechanical exfoliation of monolayer flakes and patterning by electron-beam lithography. Here we show that large-area MoS

MicroRNAs (miRNA) regulate fundamental biological processes, including neuronal plasticity, stress response, and survival. Here, we describe a neuroprotective function of miR-132, the miRNA most significantly downregulated in neurons in Alzheimer’s disease. We demonstrate that miR-132 protects primary mouse and human wild-type neurons and more vulnerable Tau-mutant neurons against amyloid β-peptide (Aβ) and glutamate excitotoxicity. It lowers the levels of total, phosphorylated, acetylated, and cleaved forms of Tau implicated in tauopathies, promotes neurite elongation and branching, and reduces neuronal death. Similarly, miR-132 attenuates PHF-Tau pathology and neurodegeneration, and enhances long-term potentiation in the P301S Tau transgenic mice. The neuroprotective effects are mediated by direct regulation of the Tau modifiers acetyltransferase EP300, kinase GSK3β, RNA-binding protein Rbfox1, and proteases Calpain 2 and Caspases 3/7. These data suggest miR-132 as a master regulator of neuronal health and indicate that miR-132 supplementation could be of therapeutic benefit for the treatment of Tau-associated neurodegenerative disorders. Electronic supplementary material The online version of this article (10.1007/s00401-018-1880-5) contains supplementary material, which is available to authorized users.

The opening of a quantum confinement gap in nanostructured graphene yields extremely sensitive photodetectors, with electrical noise equivalent power lower than 10−15 W Hz−0.5 at temperatures below 3 K, for detection of radiation in a very broad frequency range, including ultraviolet, visible and terahertz. Here we demonstrate the operation of these detectors in the presence of magnetic field as high as 7 T, paving the way to in situ spectroscopy of molecular nanomagnets.

OBJECTIVE To investigate miR-155 in the SOD1 mouse model and human sporadic and familial amyotrophic lateral sclerosis (ALS).

Atomically thin transition metal dichalcogenides (TMDs) are ideal candidates for ultrathin optoelectronics that is flexible and semitransparent. Photodetectors based on TMDs show remarkable performance, with responsivity and detectivity higher than 10^3 A/W and 10^12 Jones, respectively, but they are plagued by response times as slow as several tens of seconds. Although it is well established that gas adsorbates such as water and oxygen create charge traps and significantly increase both the responsivity and the response time, the underlying mechanism is still unclear. Here we study the influence of adsorbates on MoS2 photodetectors under ambient conditions, vacuum and illumination at different wavelengths. We show that, for wavelengths sufficiently short to excite electron-hole pairs in the MoS2, light illumination causes desorption of water and oxygen molecules. The change in the molecular gating provided by the physisorbed molecules is the dominant contribution to the device photoresponse in ambient conditions.

Two-dimensional materials such as graphene and transition metal dichalcogenides (TMDs) are ideal candidates to create ultra-thin electronics suitable for flexible substrates. Although optoelectronic devices based on TMDs have demonstrated remarkable performance, scalability is still a significant issue. Most devices are created using techniques that are not suitable for mass production, such as mechanical exfoliation of monolayer flakes and patterning by electron-beam lithography. Here we show that large-area MoS2 grown by chemical vapor deposition and patterned by photolithography yields highly sensitive photodetectors, with record shot-noise-limited detectivities of 8.7 X 10^14 Jones in ambient condition and even higher when sealed with a protective layer. These detectivity values are higher than the highest values reported for photodetectors based on exfoliated MoS2. We study MoS2 devices with gold electrodes and graphene electrodes. The devices with graphene electrodes have a tunable band alignment and are especially attractive for scalable ultra-thin flexible optoelectronics.

Microglia are the immune cells of the brain. They play a dual role by promoting homeostatic functions in the healthy brain, but acquiring dysregulated properties in neurodegenerative and neuroinflammatory diseases. How this switch in the microglia phenotype is executed on the molecular level is still[for full text, please go to the a.m. URL], Joint-Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN) and the Scandinavian Neuropathological Society (SNS)

MicroRNA-132 is markedly downregulated in Alzheimer's disease (AD) and related tauopathies, and its levels are closely associated with tau pathology in AD. Whether and how miR-132 contributes to pathology in these neurodegenerative diseases remains unclear. Here, we show that miR-132 and its paralogue miR-212 directly regulate the expression of neuronal nitric oxide synthase (NOS1) through the primate-specific binding site. Inhibition of miR-132 in primary human neurons and neural cells leads to increased NOS1 levels and triggers excessive production of nitric oxide, followed by aberrant S-nitrosylation (SNO) of specific proteins associated with neurodegeneration and tau pathology, such as cyclin-dependent kinase 5, dynamin-related protein 1, and glyceraldehyde-3-phosphate dehydrogenase. This, in turn, increases tau phosphorylation at disease associated Ser396, Ser404, and Ser202 sites, and impairs neural viability. Our findings indicate that downregulation of miR-132/212 disturbs the balance of S-nitrosylation and induces tau phosphorylation in a NOS1-dependent way, and thereby may contribute to the pathogenesis of AD and other tauopathies.

Glioblastoma (GBM) brain tumor remains among the most lethal and incurable human diseases. Oncogenic microRNA-10b (miR-10b) is strongly and universally upregulated in GBM, and its inhibition by antisense oligonucleotides (ASOs) reduces the growth of heterogeneous glioma cells; therefore, miR-10b represents a unique therapeutic target for GBM. Here we explored the effects of miR-10b gene editing on GBM. Using the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system, we investigated effects of miR-10b gene editing on the growth of cultured human glioma cells, tumor-initiating stem-like cells, and mouse GBM xenografts, as well as the oncogene-induced transformation of normal astrocytes. We show that GBM is strictly "addicted" to miR-10b and that miR-10b gene ablation is lethal for glioma cell cultures and established intracranial tumors. miR-10b loss-of-function mutations lead to the death of glioma, but not other cancer cell lines. We have not detected escaped proliferative clones of GBM cells edited in the miR-10b locus. Finally, neoplastic transformation of normal astrocytes was abolished by the miR-10b-editing vectors. This study demonstrates the feasibility of gene editing for brain tumors in vivo and suggests virus-mediated miR-10b gene ablation as a promising therapeutic approach that permanently eliminates the key regulator essential for tumor growth and survival.

SMN1, the causative gene for spinal muscular atrophy (SMA), plays a housekeeping role in the biogenesis of small nuclear RNA ribonucleoproteins. SMN is also present in granular foci along axonal projections of motoneurons, which are the predominant cell type affected in the pathology. These so-called RNA granules mediate the transport of specific mRNAs along neurites and regulate mRNA localization, stability, as well as local translation. Recent work has provided evidence suggesting that SMN may participate in the assembly of RNA granules, but beyond that, the precise nature of its role within these structures remains unclear. Here, we demonstrate that SMN associates with polyribosomes and can repress translation in an in vitro translation system. We further identify the arginine methyltransferase CARM1 as an mRNA that is regulated at the translational level by SMN and find that CARM1 is abnormally up-regulated in spinal cord tissue from SMA mice and in severe type I SMA patient cells. We have previously characterized a novel regulatory pathway in motoneurons involving the SMN-interacting RNA-binding protein HuD and CARM1. Thus, our results suggest the existence of a potential negative feedback loop in this pathway. Importantly, an SMA-causing mutation in the Tudor domain of SMN completely abolished translational repression, a strong indication for the functional significance of this novel SMN activity in the pathology.

Resonant frequencies of the two-dimensional plasma in field effect transistors (FETs) increase with the reduction of the channel dimensions and can reach the terahertz (THz) range for micrometer and sub-micrometer channel lengths. Nonlinearity of the gated electron gas in the transistor channel can be used for the detection of THz radiation. The possibility of tuneable narrow band detection in sub-THz and THz range, related to plasma resonances, has been demonstrated for nanometre gate length transistors at cryogenic temperatures. At room temperatures the plasma oscillations are usually strongly damped, but field effect transistors can still operate as an efficient broadband detectors in the THz range. We present an overview of experimental results on THz detection by field effect transistors made of III-V and Si materials, The material issue is discussed and first room applications of FETs for imaging at frequencies above 1 THz are demonstrated. (© 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

The results evaluated the efficiency of all used algal extracts with high significant differences and could be arranged dissentingly as Dictyota linearis > Dictyota dichotoma var. dichotoma > Dictyopteris membranacea > Padina pavonica (Dictyotaceae). The methanolic used algal extracts of spring and summer were more efficient without significant difference while the algal extractions of autumn came at the second rank with significant difference. The used fungi were Aspergillus niger, Aspergillus flavus, Penicilium parasiticus, Fusarium oxysporum, Fusarium solani and Candida utilis. All of them were affected by all used algal extracts without significant difference.