Direct vascular contact is a hallmark of cerebral astrocytes

Astrocytes establish extensive networks via gap junctions that allow each astrocyte to connect indirectly to the vasculature. However, the proportion of astrocytes directly associated with blood vessels is unknown. Here, we quantify structural contacts of cortical astrocytes with the vasculature in vivo. We show that all cortical astrocytes are connected to at least one blood vessel. Moreover, astrocytes contact more vessels in deeper cortical layers where vessel density is known to be higher. Further examination of different brain regions reveals that only the hippocampus, which has the lowest vessel density of all investigated brain regions, harbors single astrocytes with no apparent vascular connection. In summary, we show that almost all gray matter astrocytes have direct contact to the vasculature. In addition to the glial network, a direct vascular access may represent a complementary pathway for metabolite uptake and distribution

Decoupling astrocytes in adult mice impairs synaptic plasticity and spatial learning

The mechanisms by which astrocytes modulate neural homeostasis, synaptic plasticity, and memory are still poorly explored. Astrocytes form large intercellular networks by gap junction coupling, mainly composed of two gap junction channel proteins, connexin 30 (Cx30) and connexin 43 (Cx43). To circumvent developmental perturbations and to test whether astrocytic gap junction coupling is required for hippocampal neural circuit function and behavior, we generate and study inducible, astrocyte-specific Cx30 and Cx43 double knockouts. Surprisingly, disrupting astrocytic coupling in adult mice results in broad activation of astrocytes and microglia, without obvious signs of pathology. We show that hippocampal CA1 neuron excitability, excitatory synaptic transmission, and long-term potentiation are significantly affected. Moreover, behavioral inspection reveals deficits in sensorimotor performance and a complete lack of spatial learning and memory. Together, our findings establish that astrocytic connexins and an intact astroglial network in the adult brain are vital for neural homeostasis, plasticity, and spatial cognition

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

Demonstration of surface electron rejection with interleaved germanium detectors for dark matter searches

The following article appeared in Applied Physics Letters 103.16 (2013): 164105 and may be found at http://scitation.aip.org/content/aip/journal/apl/100/26/10.1063/1.4729825The SuperCDMS experiment in the Soudan Underground Laboratory searches for dark matter with a 9-kg array of cryogenic germanium detectors. Symmetric sensors on opposite sides measure both charge and phonons from each particle interaction, providing excellent discrimination between electron and nuclear recoils, and between surface and interior events. Surface event rejection capabilities were tested with two 210 Pb sources producing ∼130 beta decays/hr. In ∼800 live hours, no events leaked into the 8–115 keV signal region, giving upper limit leakage fraction 1.7 × 10−5 at 90% C.L., corresponding to < 0.6 surface event background in the future 200-kg SuperCDMS SNOLAB experiment.This work is supported in part by the National Science Foundation (Grant Nos. AST-9978911, NSF-0847342, PHY-1102795,NSF-1151869, PHY-0542066, PHY-0503729, PHY-0503629, PHY-0503641, PHY-0504224, PHY-0705052,PHY-0801708, PHY-0801712, PHY-0802575, PHY-0847342, PHY-0855299, PHY-0855525, and PHY-1205898), by the Department of Energy (Contract Nos. DE-AC03-76SF00098, DE-FG02-92ER40701, DE-FG02-94ER40823,DE-FG03-90ER40569, DE-FG03-91ER40618, and DESC0004022),by NSERC Canada (Grant Nos. SAPIN 341314 and SAPPJ 386399), and by MULTIDARK CSD2009-00064 and FPA2012-34694. Fermilab is operated by Fermi Research Alliance, LLC under Contract No. De-AC02-07CH11359, while SLAC is operated under Contract No. DE-AC02-76SF00515 with the United States Department of Energy

Molecular basis of USP7 inhibition by selective small-molecule inhibitors

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice

A system to detect the onset of epileptic seizures

During prolonged EEG monitoring of epileptic patients, the continuous recording may be marked where seizures are likely to have taken place. Several methods of automatic seizure detection exist, but few can operate as an on-line seizure alert system. Proposed is a seizure detection system that can be used in real-time to alert medical staff to the onset of a patient seizure and hence improve clinical diagnosis. Proposed is a system based on the seizure probability of a section of EEG. Final operation features a user-tuneable threshold to exploit the trade-off between sensitivity and detection delay and an acceptable false detection rate.The system was designed using 307 hours of scalp EEG including a total of 56 seizures in 13 patients. Wavelet decomposition, feature extraction and data segmentation were employed to compute the a priori probabilities required for the Bayesian formulation used in training, testing and operation.Results based on the analysis of separate testing data (354 hours of scalp EEG including 74 seizures in 15 patients) show an average sensitivity of 70.5% and a false detection rate of 0.25/hr. This average sensitivity is based on the successful detection of 47 of the 74 seizures with a mean detection delay of 10.8s and a delay of 10 seconds or less in 31 of these (66% of detections).The system is considered to be preliminary and results are promising enough to encourage further work on probability-based seizure detection. The tuning mechanism was also seen to add value to the use of the system

Ineffective correction of PPARγ signaling in cystic fibrosis airway epithelial cells undergoing repair

Peroxisome proliferator-activated receptor gamma (PPARγ) represents a potential target to treat airway mucus hypersecretion in cystic fibrosis (CF). We aimed to determine if PPARγ is altered in CF human airway epithelial cells (HAECs), if PPARγ contributes to mucin expression and HAEC differentiation, and if PPARγ ligand therapy corrects the CF phenotype. To this end, well-differentiated CF and NCF HAEC primary cultures were wounded to monitor the expression of key genes involved in PPARγ activation and mucus homeostasis, and to evaluate the effect of a PPARγ agonist, at different times of repair. Hydroxyprostaglandin dehydrogenase (HPGD) converts prostaglandin E2 to 15-keto PGE2 (15kPGE2), an endogenous PPARγ ligand. Interestingly, PPARγ and HPGD expression dramatically decreased in CF HAECs. These changes were accompanied by an increase in the expression of MUC5B. The correlation between PPARγ and MUC5B was confirmed in an airway epithelial cell line after CFTR knock-down. Exposure of HAECs to 15kPGE2 did not correct the CF phenotype but revealed a defect in the process of basal cell (BC) differentiation. The HPGD/PPARγ axis is deregulated in primary HAEC cultures from CF patients, which may impact the maturation of BCs to differentiated luminal cells. Importantly, PPARγ therapy was inefficient in correcting the CF defect

Bleeding risk and safety profile related to the use of eptifibatide: a current review

INTRODUCTION: Eptifibatide is a glycoprotein IIb/IIIa inhibitor that blocks the final common pathway of platelet aggregation. Its major adverse effect is bleeding. Balancing its safety and efficacy is paramount for its appropriate usage. AREAS COVERED: The development of eptifibatide and its mechanism of action are explored. Clinical trials evaluating its efficacy and safety in a variety of clinical settings, as well as newer dosing regimens, are discussed. Readers will be able to understand the bleeding risks of eptifibatide in specific patient populations. EXPERT OPINION: The risk of bleeding with eptifibatide needs to be weighed against the potential benefits. Understanding which patients are at higher risk of bleeding will help the clinician make appropriate decisions

ALAMBIC, a simulation tool to assess the red-oils hazards in reprocessing facilities

International audienceIn the French nuclear industry, the reprocessing of spent nuclear fuel is based on the PUREX aqueous process (“Plutonium Uranium Refining by EXtraction”). The main involved compounds are an organic mixture of hydrocarbon diluted tri-n-butyl phosphate (TBP) as well as a nitric acid solution used to dissolve the spent fuel. Even if the neat TBP is thermally stable, an extended contact with an acid solution (nitric acid and extractable heavy metal nitrates) forms a mixture called red-oils due to reaction at elevated temperature between involved species. These complex reactions and the formation of unstable by-products can lead to a thermal runaway in the plants’ evaporators potentially followed by an explosion, a containment failure and a radioactive release into the environment [1]. In the past, these phenomena have been responsible of several significant accidents such as, two accidents in the United States at Savannah River plant (1953 and 1975) and more recently one accident in Russia at Tomsk (1993). This raises the question of exothermicity of reactions involving extractant TBP, its diluent (hydrogenated tetra-propylene, HTP) and their by-products and calls for a better knowledge of underlying thermochemical phenomena. In the context of safety reviews regarding the French reprocessing plants at La Hague, one of the important risks concerning the evaporators is the explosion risk due to the red-oils compounds formation. Therefore, in order to simulate the behaviour of reactant solutions in evaporators during an accidental transient due to a thermal runaway, a simulation tool, ALAMBIC, is being developed at IRSN to support, in the next future, safety analyses. Its aim will be to simulate the thermal degradation of TBP in contact with nitric acid/uranyl nitrate solution and thus investigate the conditions leading to violent thermal runaways. This tool is built from modules of the ASTEC software package (Accident Source Term Evaluation Code) [2], one able to simulate the thermal-hydraulic behaviour coupled with another one to calculate the chemical evolution. For the latter, several key data are mandatory as the thermodynamic properties of species in aqueous and organic liquids or the kinetics rate laws of TBP and by-products degradations. Before addressing the chemical kinetics, a study based on quantum chemical methods has been started to fill the lack of knowledge regarding the standard heat of formation of n-butyl phosphate species [3]. Similarly, efforts have been recently continued towards the uranyl nitrate complex because the potential by-products are not as evident as TBP-nitric acid system. We will first introduce the safety controls useful for safety reviews applied to evaporators in reprocessing facilities. Then, a highlight will be made on the recent theoretical results obtained about the reaction pathways of uranyl nitrate complexes. Finally the state of progress of ALAMBIC simulation tool will be presented.References1. V.N. Usachev et al., Radiochemistry 45, 1 (2003).2. L. Chailan et al., Overview of ASTEC code and models for Evaluation of Severe Accidents in Water CooledReactors, IAEA Technical Meeting, Vienna (Austria), October, 9-12, 20173. M. Saab et al., J. Chem. Phys. 146, 244312 (2017