1,375 research outputs found

    Direct primer walking on P1 plasmid DNA

    Get PDF

    Kainate Receptor-Mediated Modulation of Hippocampal Fast Spiking Interneurons in a Rat Model of Schizophrenia

    Get PDF
    Kainate receptor (KAR) subunits are believed to be involved in abnormal GABAergic neurotransmission in the hippocampus (HIPP) in schizophrenia (SZ) and bipolar disorder. Postmortem studies have shown changes in the expression of the GluR5/6 subunits of KARs in the stratum oriens (SO) of sectors CA2/3, where the basolateral amygdala (BLA) sends a robust projection. Previous work using a rat model of SZ demonstrated that BLA activation leads to electrophysiological changes in fast-spiking interneurons in SO of CA2/3. The present study explores KAR modulation of interneurons in CA2/3 in response to BLA activation. Intrinsic firing properties of these interneurons through KAR-mediated activity were measured with patch-clamp recordings from rats that received 15 days of picrotoxin infusion into the BLA. Chronic BLA activation induced changes in the firing properties of CA2/3 interneurons associated with modifications in the function of KARs. Specifically, the responsiveness of these interneurons to activation of KARs was diminished in picrotoxin-treated rats, while the after-hyperpolarization (AHP) amplitude was increased. In addition, we tested blockers of KAR subunits which have been shown to have altered gene expression in SO sector CA2/3 of SZ subjects. The GluR5 antagonist UBP296 further decreased AP frequency and increased AHP amplitude in picrotoxin-treated rats. Application of the GluR6/7 antagonist NS102 suggested that activation of GluR6/7 KARs may be required to maintain the high firing rates in SO interneurons in the presence of KA. Moreover, the GluR6/7 KAR-mediated signaling may be suppressed in PICRO-treated rats. Our findings indicate that glutamatergic activity from the BLA may modulate the firing properties of CA2/3 interneurons through GluR5 and GluR6/7 KARs. These receptors are expressed in GABAergic interneurons and play a key role in the synchronization of gamma oscillations. Modulation of interneuronal activity through KARs in response to amygdala activation may lead to abnormal oscillatory rhythms reported in SZ subjects

    How Prosecutors and Defense Attorneys Differ in Their Use of Neuroscience Evidence

    Get PDF
    Much of the public debate surrounding the intersection of neuroscience and criminal law is based on assumptions about how prosecutors and defense attorneys differ in their use of neuroscience evidence. For example, according to some commentators, the defense’s use of neuroscience evidence will abdicate criminals of all responsibility for their offenses. In contrast, the prosecution’s use of that same evidence will unfairly punish the most vulnerable defendants as unfixable future dangers to society. This “double- edged sword” view of neuroscience evidence is important for flagging concerns about the law’s construction of criminal responsibility and punishment: it demonstrates that the same information about the defendant can either be mitigating or aggravating depending on who is raising it. Yet empirical assessments of legal decisions reveal a far more nuanced reality, showing that public beliefs about the impact of neuroscience on the criminal law can often be wrong. This Article takes an evidence-based and multidisciplinary approach to examining how courts respond to neuroscience evidence in capital cases when the defense presents it to argue that the defendant’s mental state at the time of the crime was below the given legal requisite due to some neurologic or cognitive deficiency

    Popular attitudes to memory, the body, and social identity : the rise of external commemoration in Britain, Ireland, and New England

    Get PDF
    A comparative analysis of samples of external memorials from burial grounds in Britain, Ireland and New England reveals a widespread pattern of change in monument style and content, and exponential growth in the number of permanent memorials from the 18th century onwards. Although manifested in regionally distinctive styles on which most academic attention has so far been directed, the expansion reflects global changes in social relationships and concepts of memory and the body. An archaeological perspective reveals the importance of external memorials in articulating these changing attitudes in a world of increasing material consumption

    Controlled Localized Metal–Organic Framework Synthesis on Anion Exchange Membranes

    Get PDF
    Metal–organic framework (MOF) films can be used in various applications. In this work, we propose a method that can be used to synthesize MOF films localized on a single side of an anion exchange membrane, preventing the transport of the metal precursor via Donnan exclusion. This is advantageous compared to the related contra-diffusion method that results in the growth of a MOF film on both sides of the support, differing in quality on both sides. Our proposed method has the advantage that the synthesis conditions can potentially be tuned to create the optimal conditions for crystal growth on a single side. The localized growth of the MOF is governed by Donnan exclusion of the anion exchange membrane, preventing metal ions from passing to the other compartment, and this leads to a local control of the precursor stoichiometry. In this work, we show that our method can localize the growth of both Cu-BTC and ZIF-8 in water and in methanol, respectively, highlighting that this method can used for preparing a variety of MOF films with varying characteristics using soluble precursors at room temperature

    Determination of the (3x3)-Sn/Ge(111) structure by photoelectron diffraction

    Full text link
    At a coverage of about 1/3 monolayer, Sn deposited on Ge(111) below 550 forms a metastable (sqrt3 x sqrt3)R30 phase. This phase continuously and reversibly transforms into a (3x3) one, upon cooling below 200 K. The photoemission spectra of the Sn 4d electrons from the (3x3)-Sn/Ge(111) surface present two components which are attributed to inequivalent Sn atoms in T4 bonding sites. This structure has been explored by photoelectron diffraction experiments performed at the ALOISA beamline of the Elettra storage ring in Trieste (Italy). The modulation of the intensities of the two Sn components, caused by the backscattering of the underneath Ge atoms, has been measured as a function of the emission angle at fixed kinetic energies and viceversa. The bond angle between Sn and its nearest neighbour atoms in the first Ge layer (Sn-Ge1) has been measured by taking polar scans along the main symmetry directions and it was found almost equivalent for the two components. The corresponding bond lengths are also quite similar, as obtained by studying the dependence on the photoelectron kinetic energy, while keeping the photon polarization and the collection direction parallel to the Sn-Ge1 bond orientation (bond emission). A clear difference between the two bonding sites is observed when studying the energy dependence at normal emission, where the sensitivity to the Sn height above the Ge atom in the second layer is enhanced. This vertical distance is found to be 0.3 Angstroms larger for one Sn atom out of the three contained in the lattice unit cell. The (3x3)-Sn/Ge(111) is thus characterized by a structure where the Sn atom and its three nearest neighbour Ge atoms form a rather rigid unit that presents a strong vertical distortion with respect to the underneath atom of the second Ge layer.Comment: 10 pages with 9 figures, added reference

    Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma.

    Get PDF
    Ewing's sarcoma is a malignant pediatric bone tumor with a poor prognosis for patients with metastatic or recurrent disease. Ewing's sarcoma cells are acutely hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibition and this is being evaluated in clinical trials, although the mechanism of hypersensitivity has not been directly addressed. PARP inhibitors have efficacy in tumors with BRCA1/2 mutations, which confer deficiency in DNA double-strand break (DSB) repair by homologous recombination (HR). This drives dependence on PARP1/2 due to their function in DNA single-strand break (SSB) repair. PARP inhibitors are also cytotoxic through inhibiting PARP1/2 auto-PARylation, blocking PARP1/2 release from substrate DNA. Here, we show that PARP inhibitor sensitivity in Ewing's sarcoma cells is not through an apparent defect in DNA repair by HR, but through hypersensitivity to trapped PARP1-DNA complexes. This drives accumulation of DNA damage during replication, ultimately leading to apoptosis. We also show that the activity of PARP inhibitors is potentiated by temozolomide in Ewing's sarcoma cells and is associated with enhanced trapping of PARP1-DNA complexes. Furthermore, through mining of large-scale drug sensitivity datasets, we identify a subset of glioma, neuroblastoma and melanoma cell lines as hypersensitive to the combination of temozolomide and PARP inhibition, potentially identifying new avenues for therapeutic intervention. These data provide insights into the anti-cancer activity of PARP inhibitors with implications for the design of treatment for Ewing's sarcoma patients with PARP inhibitors.Research in the M.J.G. laboratory is supported by grants from the Wellcome Trust (086357 and 102696/Z/13/Z; http://www.wellcome.ac.uk/Funding). Research in the S.P.J. laboratory is funded by Cancer Research UK Program Grant C6/A11224 (http://www.cancerresearchuk.org/funding-for-researchers/our-funding-schemes), the European Research Council (http://erc.europa.eu/funding-and-grants)and the European Community Seventh Framework Program grant agreement no. HEALTH-F2-2010-259893 (DDResponse). Core infrastructure funding was provided by Cancer Research UK Grant C6946/A14492 and Wellcome Trust Grant WT092096. S.P.J. receives a salary from the University of Cambridge, supplemented by Cancer Research UK. J.T. was funded by the European Community Seventh Framework Program grant agreement no. HEALTH-F2-2010-259893 (DDResponse). U.M. is supported by a Cancer Research UK Clinician Scientist Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pone.014098

    Induction of the GABA Cell Phenotype: An In Vitro Model for Studying Neurodevelopmental Disorders

    Get PDF
    Recent studies of the hippocampus have suggested that a network of genes is associated with the regulation of the GAD67 (GAD1) expression and may play a role in γ-amino butyric acid (GABA) dysfunction in schizophrenia (SZ) and bipolar disorder (BD). To obtain a more detailed understanding of how GAD67 regulation may result in GABAergic dysfunction, we have developed an in vitro model in which GABA cells are differentiated from the hippocampal precursor cell line, HiB5. Growth factors, such as PDGF, and BDNF, regulate the GABA phenotype by inducing the expression of GAD67 and stimulating the growth of cellular processes, many with growth cones that form appositions with the cell bodies and processes of other GAD67-positive cells. These changes are associated with increased expression of acetylated tubulin, microtubule-associated protein 2 (MAP2) and the post-synaptic density protein 95 (PSD95). The addition of BDNF, together with PDGF, increases the levels of mRNA and protein for GAD67, as well as the high affinity GABA uptake protein, GAT1. These changes are associated with increased concentrations of GABA in the cytoplasm of “differentiated” HiB5 neurons. In the presence of Ca2+ and K+, newly synthesized GABA is released extracellularly. When the HiB5 cells appear to be fully differentiated, they also express GAD65, parvalbumin and calbindin, and GluR subtypes as well as HDAC1, DAXX, PAX5, Runx2, associated with GAD67 regulation. Overall, these results suggest that the HiB5 cells can differentiate into functionally mature GABA neurons in the presence of gene products that are associated with GAD67 regulation in the adult hippocampus
    corecore