The rockefeller university

Abuse and addiction to prescription opioids such as oxycodone (a short-acting Mu opioid receptor (MOP-r) agonist) in adolescence is a pressing public health issue. We have previously shown differences in oxycodone self-administration behaviors between adolescent and adult C57BL/6J mice and expression of striatal neurotransmitter receptor genes, in areas involved in reward. In this study, we aimed to determine whether oxycodone self-administration differentially affects genes regulating synaptic plasticity in the hippocampus of adolescent compared to adult mice, since the hippocampus may be involved in learning aspects associated with chronic drug self administration. Hippocampus was isolated for mRNA analysis from mice that had self administered oxycodone (0.25 mg/kg/infusion) 2 h/day for 14 consecutive days or from yoked saline controls. Gene expression was analyzed with real-time polymerase chain reaction (PCR) using a commercially available "synaptic plasticity'' PCR array containing 84 genes. We found that adolescent and adult control mice significantly differed in the expression of several genes in the absence of oxycodone exposure, including those coding for mitogenactivated protein kinase, calcium/calmodulin-dependent protein kinase II gamma subunit, glutamate receptor, ionotropic AMPA2 and metabotropic 5. Chronic oxycodone self administration increased proviral integration site 1 (Pim1) and thymoma viral proto-oncogene 1 mRNA levels compared to controls in both age groups. Both Pim1 and cadherin 2 mRNAs showed a significant combined effect of Drug Condition and Age x Drug Condition. Furthermore, the mRNA levels of both cadherin 2 and cAMP response element modulators showed an experiment-wise significant difference between oxycodone and saline control in adult but not in adolescent mice. Overall, this study demonstrates for the first time that chronic oxycodone self-administration differentially alters synaptic plasticity gene expression in the hippocampus of adolescent and adult mice. (C) 2014 Published by Elsevier Ltd. on behalf of IBRO.

Arc is a unique immediate early gene whose expression is induced as synapses are being modified during learning. The uniqueness comes from the fact that newly synthesized Arc mRNA is rapidly transported throughout dendrites where it localizes near synapses that were recently activated. Here, we summarize aspects of Arc mRNA translation in dendrites in vivo, focusing especially on features of its expression that are paradoxical or that donot fit in with current models of how Arc protein operates. Findings from in vivo studies that donot quite fit include: (1) Following induction of LIP in vivo, Arc mRNA and protein localize near active synapses, but are also distributed throughout dendrites. In contrast, Arc mRNA localizes selectively near active synapses when stimulation is continued as Arc mRNA is transported into dendrites; (2) Strong induction of Arc expression as a result of a seizure does not lead to a rundown of synaptic efficacy in vivo as would be predicted by the hypothesis that high levels of Arc cause glutamate receptor endocytosis and LTD. (3) Arc protein is synthesized in the perinuclear cytoplasm rapidly after transcriptional activation, indicating that at least a pool of Arc mRNA is not translationally repressed to allow for dendritic delivery; (4) Increases in Arc mRNA in dendrites are not paralleled by increases in levels of exon junction complex (EJC) proteins. These results of studies of mRNA trafficking in neurons in vivo provide a new perspective on the possible roles of Arc in activity-dependent synaptic modifications.

A measurement of the W boson helicity is presented, where the W boson originates from the decay of a top quark produced in pp collisions. The event selection, optimized for reconstructing a single top quark in the final state, requires exactly one isolated lepton (muon or electron) and exactly two jets, one of which is likely to originate from the hadronization of a bottom quark. The analysis is performed using data recorded at a center-of-mass energy of 8 TeV with the CMS detector at the CERN LHC in 2012. The data sample corresponds to an integrated luminosity of 19.7 fb(-1). The measured helicity fractions are F-L = 0.298 +/- 0.028 (stat) +/- 0.032(syst), F-0 = 0.720 +/- 0.039 (stat) +/- 0.037(syst), and F-R = -0.018 +/- 0.019 (stat) +/- 0.011(syst). These results are used to set limits on the real part of the tWb anomalous couplings, g(L) and g(R).

The myenteric plexus of the enteric nervous system controls the movement of smooth muscles in the gastrointestinal system. They extend their axons between two peripheral smooth muscle layers to form a tubular meshwork arborizing the gut wall. How a tubular axonal meshwork becomes established without invading centrally toward the gut epithelium has not been addressed. We provide evidence here that sonic hedgehog (Shh) secreted from the gut epithelium prevents central projections of enteric axons, thereby forcing their peripheral tubular distribution. Exclusion of enteric central projections by Shh requires its binding partner growth arrest specific gene 1 (Gas1) and its signaling component smoothened (Smo) in enteric neurons. Using enteric neurons differentiated from neurospheres in vitro, we show that enteric axon growth is not inhibited by Shh. Rather, when Shh is presented as a point source, enteric axons turn away from it in a Gas1-dependent manner. Of the Gai proteins that can couple with Smo, G protein alpha Z (Gnaz) is found in enteric axons. Knockdown and dominant negative inhibition of Gnaz dampen the axon-repulsive response to Shh, and Gnaz mutant intestines contain centrally projected enteric axons. Together, our data uncover a previously unsuspected mechanism underlying development of centrifugal tubular organization and identify a previously unidentified effector of Shh in axon guidance.

The following summarizes the key points addressed during a tutorial session on the Micromechanics of Hearing that took place at the 12th International Workshop on the Mechanics of Hearing held at Cape Sounio, Greece, in June 2014. The tutorial was intended to present an overview of basic ideas and to address topics of current interest relevant to the Workshop. The session was recorded, and the audio file and accompanying visual content of the presentation can be found in the Mechanics of Hearing Digital Library (www.mechanicsofhearing.org).

An isospectral matrix reduction is a procedure that reduces the size of a matrix while maintaining its eigenvalues up to a known set. As to not violate the fundamental theorem of algebra, the reduced matrices have rational functions as entries. Because isospectral reductions can preserve the spectrum of a matrix, they are fundamentally different from say the restriction of a matrix to an invariant subspace. We show that the notion of pseudospectrum can be extended to a wide class of matrices with rational function entries and that the pseudospectrum of such matrices shrinks with isospectral reductions. Hence, the eigenvalues of a reduced matrix are more robust to entry-wise perturbations than the eigenvalues of the original matrix. Moreover, the isospectral reductions considered here are more general than those considered elsewhere. We also introduce the notion of an inverse pseudospectrum (or pseudoresonances), which indicates how stable the poles of a rational function valued matrix are to entry-wise perturbations. Illustrations of these concepts are given for mass-spring networks. Copyright (c) 2014 John Wiley & Sons, Ltd.

The genus Sphaerocetum Fikacek, 2010 is reviewed on the basis of specimens collected from mixed ant nests shared by Camponotus Mayr, 1861 and Crematogaster Lund, 1831 ants in Peninsular Malaysia. Two new species, S. arboreum, sp. nov. and S. hortulanum, sp. nov., are described. A larva of S. arboreum was collected in the same nest as the adults, implying that it is likely that the entire life cycle takes place inside the ant nest; its association with adults was confirmed by cox1 sequences. It is described in detail and represents the first known larva of the tribe Protosternini. Fragments of four genes (cox1, cox2, 18S and 28S) were amplified for S. arboreum and combined with previously generated data in order to test the position of the genus within the subfamily Sphaeridiinae. The analyses revealed Sphaerocetum as a sister taxon to Protosternum Sharp, 1890, corroborating the monophyly of the tribe Protosternini. Bayesian analysis revealed an alternative hypothesis of the phylogenetic position of the tribe, indicating that Protosternini is a sister-group to Omicrini. This position is supported by the chaetotaxy of the maxillary stipes of the larva, which lacks the increased number of stout setae on the inner face present in all other Sphaeridiinae larvae except Omicrini.

The antibody gene mutator activation-induced cytidine deaminase (AID) promiscuously damages oncogenes, leading to chromosomal translocations and tumorigenesis. Why nonimmunoglobulin loci are susceptible to AID activity is unknown. Here, we study AID-mediated lesions in the context of nuclear architecture and the B cell regulome. We show that AID targets are not randomly distributed across the genome but are predominantly grouped within super-enhancers and regulatory clusters. Unexpectedly, in these domains, AID deaminates active promoters and eRNA(+) enhancers interconnected in some instances over megabases of linear chromatin. Using genome editing, we demonstrate that 3D-linked targets cooperate to recruit AID-mediated breaks. Furthermore, a comparison of hypermutation in mouse B cells, AID-induced kataegis in human lymphomas, and translocations in MEFs reveals that AID damages different genes in different cell types. Yet, in all cases, the targets are predominantly associated with topological complex, highly transcribed super-enhancers, demonstrating that these compartments are key mediators of AID recruitment.

The dementia of Alzheimer's disease (AD) results primarily from degeneration of neurons that furnish glutamatergic corticocortical connections that subserve cognition. Although neuron death is minimal in the absence of AD, age-related cognitive decline does occur in animals as well as humans, and it decreases quality of life for elderly people. Age-related cognitive decline has been linked to synapse loss and/or alterations of synaptic proteins that impair function in regions such as the hippocampus and prefrontal cortex. These synaptic alterations are likely reversible, such that maintenance of synaptic health in the face of aging is a critically important therapeutic goal. Here, we show that riluzole can protect against some of the synaptic alterations in hippocampus that are linked to age-related memory loss in rats. Riluzole increases glutamate uptake through glial transporters and is thought to decrease glutamate spillover to extrasynaptic NMDA receptors while increasing synaptic glutamatergic activity. Treated aged rats were protected against age-related cognitive decline displayed in nontreated aged animals. Memory performance correlated with density of thin spines on apical dendrites in CA1, although not with mushroom spines. Furthermore, riluzole-treated rats had an increase in clustering of thin spines that correlated with memory performance and was specific to the apical, but not the basilar, dendrites of CA1. Clustering of synaptic inputs is thought to allow nonlinear summation of synaptic strength. These findings further elucidate neuroplastic changes in glutamatergic circuits with aging and advance therapeutic development to prevent and treat agerelated cognitive decline.

Matrix metalloproteinase-2 (MMP-2) is involved in several physiological mechanisms, including wound healing and tumor progression. We show that MMP-2 directly stimulates dendritic cells (DCs) to both upregulate OX40L on the cell surface and secrete inflammatory cytokines. The mechanism underlying DC activation includes physical association with Toll-like receptor-2 (TLR2), leading to NF-kappa B activation, OX40L upregulation on DCs, and ensuing TH2 differentiation. Significantly, MMP-2 polarizes T cells toward type 2 responses in vivo, in a TLR2-dependent manner. MMP-2-dependent type 2 polarization may represent a key immune regulatory mechanism for protection against a broad array of disorders, such as inflammatory, infectious, and autoimmune diseases, which can be hijacked by tumors to evade immunity.