Endocannabinoid Signaling in Embryonic Neuronal Motility and Cell-Cell Contact - Role of mGluR5 and TRPC3 Channels

Cell-cell communication plays a central role in the guidance of migrating neuronal precursor cells during the development of the cerebral cortex. Endocannabinoids (eCBs) have previously been shown to be one of the central factors regulating neuronal migration. In this study the effects of eCBs on different parameters, expected to affect embryonic cortical neuronal motility have been analyzed in neurosphere-derived neuroblasts using time-lapse microscopy. Increased endogenous production of the endocannabinoid 2-arachidonyl glycerol (2-AG) causes bursts of neuroblast motility. The neuroblasts move longer distances and show a low frequency of turning, and the number of neuron-neuron contacts are reduced. Similar changes occur interfering with the function of the metabotropic glutamate receptor 5 (mGluR5) or its transducer canonical transient receptor potential channel 3 (TRPC3) or the neuregulin receptor ErbB4. Blocking of 2-AG production reverses these effects. The data suggest that eCB-regulated neuronal motility is controlled by mGluR5/TRPC3 activity possibly via NRG/ErbB4 signaling. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.Peer reviewe

Regulation of radial glial process growth by glutamate via mGluR5/TRPC3 and neuregulin/ErbB4

Radial glial cells play an essential role through their function as guides for neuronal migration during development. Disruption of metabotropic glutamate receptor 5 (mGluR5) function retards the growth of radial glial processes in vitro. Neuregulins (NRG) are activated by proteolytic cleavage and regulate (radial) glial maintenance via ErbB3/ErbB4 receptors. We show here that blocking ErbB4 disrupts radial process extension. Soluble NRG acting on ErbB4 receptors is able to promote radial process extension in particular where process elongation has been impeded by blockade of mGluR5, the nonselective cation channel canonical transient receptor potential 3 (TRPC3), or matrix metalloproteases (MMP). NRG does not restore retarded process growth caused by ErbB4 blockade. Stimulation of muscarinic receptors restores process elongation due to mGluR5 blockade but not that caused by TRPC3, MMP or ErbB4 blockade suggesting that muscarinic receptors can replace mGluR5 with respect to radial process extension. Additionally, NRG/ErbB4 causes Ca2+ mobilization in a population of cells through cooperation with ErbB1 receptors. Our results indicate that mGluR5 promotes radial process growth via NRG activation by a mechanism involving TRPC3 channels and MMPs. Thus neurotransmitters acting on G-protein coupled receptors could play a central role in the maintenance of the radial glial scaffold through activation of NRG/ErbB4 signaling.Peer reviewe

High-fidelity state detection and tomography of a single ion Zeeman qubit

We demonstrate high-fidelity Zeeman qubit state detection in a single trapped 88 Sr+ ion. Qubit readout is performed by shelving one of the qubit states to a metastable level using a narrow linewidth diode laser at 674 nm followed by state-selective fluorescence detection. The average fidelity reached for the readout of the qubit state is 0.9989(1). We then measure the fidelity of state tomography, averaged over all possible single-qubit states, which is 0.9979(2). We also fully characterize the detection process using quantum process tomography. This readout fidelity is compatible with recent estimates of the detection error-threshold required for fault-tolerant computation, whereas high-fidelity state tomography opens the way for high-precision quantum process tomography

Competence acquisition for single-incision laparoscopic cholecystectomy

BACKGROUND AND OBJECTIVES: Within the past few years, there has been a push for an even more minimally invasive approach to biliary disease with the adoption of single-incision laparoscopic cholecystectomy. We sought to compare 4 individual surgeon experiences to define whether there exists a learning curve for performing single-incision laparoscopic cholecystectomy. METHODS: We performed a retrospective review 290 single-incision laparoscopic cholecystectomies performed by a group of general surgeons, with varying levels of experience and training, at 3 institutions between May 2008 and September 2010. The procedure times were recorded for each single-incision laparoscopic cholecystectomy, ordered chronologically for each surgeon, and subsequently plotted on a graph. The patients were also combined into cohorts of 5 and 10 cases to further evaluate for signs of improvement in operative efficiency. RESULTS: Of the 4 surgeons involved in the study, only 1 (surgeon 4, laparoscopic fellowship trained with \u3c5 \u3eyears\u27 experience) confirmed the presence of a learning curve, reaching proficiency within the first 15 cases performed. The other surgeons had more variable procedure times, which did not show a distinct trend. When we evaluated the cases by cohorts of 5 cases, surgeon 4 had a significant difference between the first and last cohort. Increased body mass index resulted in a slightly longer operative time (P \u3c .0063). The conversion rate to multiport laparoscopic surgery was 3.1%. CONCLUSIONS: Our results indicate that among experienced general surgeons, there does not seem to be a significant learning curve when transitioning from conventional laparoscopic cholecystectomy to single-incision laparoscopic cholecystectomy. The least experienced surgeon in the group, surgeon 4, appeared to reach proficiency after 15 cases. Greater than 5 years of experience in laparoscopic surgery appears to provide surgeons with a sufficient skill set to obviate the need for a single-incision laparoscopic cholecystectomy learning curve

Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss

Genome-wide analyses have identified thousands of long noncoding RNAs (lncRNAs). Malat1 (metastasis-associated lung adenocarcinoma transcript 1) is among the most abundant lncRNAs whose expression is altered in numerous cancers. Here we report that genetic loss or systemic knockdown of Malat1 using antisense oligonucleotides (ASOs) in the MMTV (mouse mammary tumor virus)-PyMT mouse mammary carcinoma model results in slower tumor growth accompanied by significant differentiation into cystic tumors and a reduction in metastasis. Furthermore, Malat1 loss results in a reduction of branching morphogenesis in MMTV-PyMT- and Her2/neu-amplified tumor organoids, increased cell adhesion, and loss of migration. At the molecular level, Malat1 knockdown results in alterations in gene expression and changes in splicing patterns of genes involved in differentiation and protumorigenic signaling pathways. Together, these data demonstrate for the first time a functional role of Malat1 in regulating critical processes in mammary cancer pathogenesis. Thus, Malat1 represents an exciting therapeutic target, and Malat1 ASOs represent a potential therapy for inhibiting breast cancer progression

Hyperpolarized Long-T1 Silicon Nanoparticles for Magnetic Resonance Imaging

Silicon nanoparticles are experimentally investigated as a potential hyperpolarized, targetable MRI imaging agent. Nuclear T_1 times at room temperature for a variety of Si nanoparticles are found to be remarkably long (10^2 to 10^4 s) - roughly consistent with predictions of a core-shell diffusion model - allowing them to be transported, administered and imaged on practical time scales without significant loss of polarization. We also report surface functionalization of Si nanoparticles, comparable to approaches used in other biologically targeted nanoparticle systems.Comment: supporting material here: http://marcuslab.harvard.edu/Aptekar_hyper1_sup.pd

Structural and biochemical characterization of a mitochondrial peroxiredoxin from Plasmodium falciparum

Plasmodium falciparum possesses a single mitochondrion with a functional electron transport chain. During respiration, reactive oxygen species are generated that need to be removed to protect the organelle from oxidative damage. In the absence of catalase and glutathione peroxidase, the parasites rely primarily on peroxiredoxin-linked systems for protection. We have analysed the biochemical and structural features of the mitochondrial peroxiredoxin and thioredoxin of P. falciparum. The mitochondrial localization of both proteins was confirmed by expressing green fluorescent protein fusions in parasite erythrocytic stages. Recombinant protein was kinetically characterized using the cytosolic and the mitochondrial thioredoxin (PfTrx1 and PfTrx2 respectively). The peroxiredoxin clearly preferred PfTrx2 to PfTrx1 as a reducing partner, reflected by the K(M) values of 11.6 μM and 130.4 μM respectively. Substitution of the two dyads asparagine-62/tyrosine-63 and phenylalanine-139/alanine-140 residues by aspartate-phenylalaine and valine-serine, respectively, reduced the K(M) for Trx1 but had no effect on the K(M) of Trx2 suggesting some role for these residues in the discrimination between the two substrates. Solution studies suggest that the protein exists primarily in a homodecameric form. The crystal structure of the mitochondrial peroxiredoxin reveals a fold typical of the 2-Cys class peroxiredoxins and a dimeric form with an intermolecular disulphide bridge between Cys67 and Cys187. These results show that the mitochondrial peroxiredoxin of P. falciparum occurs in both dimeric and decameric forms when purified under non-reducing conditions

Lightweight composite fighting cover prototype development program

The U.S. Army Field Assistance Science and Technology Program requested Oak Ridge National Laboratory (ORNL) to demonstrate the use of lightweight composite materials in construction of overhead covers for reinforced infantry fighting positions. In recent years, ORNL researchers have designed and tested several concepts for lightweight ballistic protection structures, and they have developed numerous prototype composite structures for military and civilian applications. In the current program, composite panel designs and materials are tested and optimized to meet anticipated static and dynamic load conditions for the overhead cover structure. Ten prototype composite covers were built at ORNL for use in Army field tests. Each composite cover has a nominal surface area of 12 ft[sup 2] and a nominal weight of 8 lb. Four of the prototypes are made with folding sections to improve their handling characteristics. The composite covers exhibit equivalent performance in Army field tests to covers made with conventional materials that weigh four times as much