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Mycobacterium tuberculosis infection continues to cause substantial human suffering. New chemotherapeutic strategies, which require insight into the pathways essential for M. tuberculosis pathogenesis, are imperative. We previously reported that depletion of the CarD protein in mycobacteria compromises viability, resistance to oxidative stress and fluoroquinolones, and pathogenesis. CarD associates with the RNA polymerase (RNAP), but it has been unknown which of the diverse functions of CarD are mediated through the RNAP; this question must be answered to understand the CarD mechanism of action. Herein, we describe the interaction between the M. tuberculosis CarD and the RNAP beta subunit and identify point mutations that weaken this interaction. The characterization of mycobacterial strains with attenuated CarD/RNAP beta interactions demonstrates that the CarD/RNAP beta association is required for viability and resistance to oxidative stress but not for fluoroquinolone resistance. Weakening the CarD/RNAP beta interaction also increases the sensitivity of mycobacteria to rifampin and streptomycin. Surprisingly, depletion of the CarD protein did not affect sensitivity to rifampin. These findings define the CarD/RNAP interaction as a new target for chemotherapeutic intervention that could also improve the efficacy of rifampin treatment of tuberculosis. In addition, our data demonstrate that weakening the CarD/RNAP beta interaction does not completely phenocopy the depletion of CarD and support the existence of functions for CarD independent of direct RNAP binding.

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40pb(-1) of data collected in pp collisions at root s = 7TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum p(T) larger than a few GeV/c is above 95% over the whole region of pseudorapidity covered by the CMS muon system, vertical bar eta vertical bar < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with p(T) above a few GeV/c is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with p(T) below 100GeV/c and, using cosmic rays, it is shown to be better than 10% in the central region up to p(T) = 1TeV/c. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.

Memories are remarkably persistent, but rely on transient signaling. The prion-like properties of CPEB suggested a solution to this problem. The paper by Kruttner et al. (2012) in this issue of Neuron demonstrates that the prion-like domain of Drosophila CPEB functions independently of its RNA-binding domain for memory.

Addictive diseases, including addiction to heroin, prescription opioids, or cocaine, pose massive personal and public health costs. Addictions are chronic relapsing diseases of the brain caused by drug-induced direct effects and persisting neuroadaptations at the epigenetic, mRNA, neuropeptide, neurotransmitter, or protein levels. These neuroadaptations, which can be specific to drug type, and their resultant behaviors are modified by various internal and external environmental factors, including stress responsivity, addict mindset, and social setting. Specific gene variants, including variants encoding pharmacological target proteins or genes mediating neuroadaptations, also modify vulnerability at particular stages of addiction. Greater understanding of these interacting factors through laboratory-based and translational studies have the potential to optimize early interventions for the therapy of chronic addictive diseases and to reduce the burden of relapse. Here, we review the molecular neurobiology and genetics of opiate addiction, including heroin and prescription opioids, and cocaine addiction.

We present a precision measurement of the top-quark mass using the full sample of Tevatron root s = 1.96 TeV proton-antiproton collisions collected by the CDF II detector, corresponding to an integrated luminosity of 8.7 fb(-1). Using a sample of t (t) over bar candidate events decaying into the lepton + jets channel, we obtain distributions of the top-quark masses and the invariant mass of two jets from the W boson decays from data. We then compare these distributions to templates derived from signal and background samples to extract the top-quark mass and the energy scale of the calorimeter jets with in situ calibration. The likelihood fit of the templates from signal and background events to the data yields the single most-precise measurement of the top-quark mass, M-top = 172.85 +/- 0.71(stat) +/- 0.85(syst) GeV/c(2).

Background: The understanding of how general anesthetics act on individual cells and on global brain function has increased significantly during the last decade. What remains poorly understood is how anesthetics act at intermediate scales. Several major theories emphasize the importance of neuronal groups, sets of strongly connected neurons that fire in a time-locked fashion, in all aspects of brain function, particularly as a necessary substrate of consciousness. The authors have undertaken computer modeling to determine how (a) over tilde -aminobutyric acid receptor type A (GABA(A)) receptor potentiating agents such as propofol may influence the dynamics of neuronal group formation and ongoing activity. Methods: A computer model of a cortical network with connections modified by synaptic plasticity was examined. At baseline, the model spontaneously formed neuronal groups. Direct effects of GABA(A) receptor potentiation and indirect effects on input drive were then examined to study their effects on this process. Results: Potentiation of GABA(A) inhibition and input drive reduction reduced the firing frequency of inhibitory and excitatory neurons in a dose-dependent manner. The diminution in spiking rates led to dramatic reductions in the firing frequency of neuronal groups. Simulated electroencephalographic output from the model at baseline exhibits gamma and theta rhythmicity. The direct and indirect GABA(A) effects reduce the amplitude of these underlying rhythms and modestly slow the gamma rhythm. Conclusions: GABA(A) facilitation both directly and indirectly inhibits the ability of neurons to form groups spontaneously. A lack of group formation is consistent with some theories of anesthetic-induced loss of memory formation and consciousness.

A search is presented for charge-asymmetric production of a W' boson that has been proposed to accommodate the forward-backward asymmetry observed in the production of top-antitop quark pairs at the Tevatron. The new heavy W' boson would be produced in association with a top quark and would decay into top and down quarks. The data correspond to an integrated luminosity of 5.0 fb(-1) in pp collisions at a center-of-mass energy of 7 TeV, recorded by the CMS detector at the LHC. No significant excess above the standard model expectations is observed, and, from a combination of the electron-plus-jets and muon-plus-jets channels, a 95% confidence level lower limit of 840 GeV/c(2) is set on the W' boson mass for a W' boson model with values for coupling constants to top and down quarks g(L) = 0 and g(R) = 2. In addition, a kinematic reconstruction of the W' resonance mass using the inherent charge asymmetry of this model finds no indication of the presence of W' events in the data. (C) 2012 CERN. Published by Elsevier B.V. All rights reserved.

Cancer, as well as other human disorders, has long been considered to result from the consequence of genetic mutations in key regulatory genes that reside in pathways controlling proliferation, cellular differentiation, DNA damage and repair. In the case of cancer, mutations are well documented to arise in key oncogenes and critically important tumor-suppressor genes as part of the disease progression process. In addition to more accepted, genetic mutations, a rapidly increasing body of evidence supports the general view that profound alterations also occur in 'epigenes', whose products serve to define the 'epigenetic landscape' of tumor cells. Aberrant changes in epigenetic mechanisms such as DNA methylation, histone modifications and expression of micro RNAs play an important role in cancer and contribute to malignant transitions. Here we review recent studies linking epigenetic mechanisms to epithelial-to-mesenchymal transition as defined in normal processes, as well as abnormal transitions that lead to oncogensis. (C) 2012 Elsevier Ltd. All rights reserved.

Genetically encoded calcium indicators (GECIs) are powerful tools for systems neuroscience. Recent efforts in protein engineering have significantly increased the performance of GECIs. The state-of-the art single-wavelength GECI, GCaMP3, has been deployed in a number of model organisms and can reliably detect three or more action potentials in short bursts in several systems in vivo. Through protein structure determination, targeted mutagenesis, high-throughput screening, and a battery of in vitro assays, we have increased the dynamic range of GCaMP3 by severalfold, creating a family of "GCaMP5" sensors. We tested GCaMP5s in several systems: cultured neurons and astrocytes, mouse retina, and in vivo in Caenorhabditis chemosensory neurons, Drosophila larval neuromuscular junction and adult antennal lobe, zebrafish retina and tectum, and mouse visual cortex. Signal-to-noise ratio was improved by at least 2- to 3-fold. In the visual cortex, two GCaMP5 variants detected twice as many visual stimulus-responsive cells as GCaMP3. By combining in vivo imaging with electrophysiology we show that GCaMP5 fluorescence provides a more reliable measure of neuronal activity than its predecessor GCaMP3. GCaMP5 allows more sensitive detection of neural activity in vivo and may find widespread applications for cellular imaging in general.

An inclusive search for the standard model Higgs boson using the four-lepton final state in proton-antiproton collisions produced by the Tevatron at root s = 1.96 TeV is conducted. The data are recorded by the CDF II detector and correspond to an integrated luminosity of 9.7 fb(-1). Three distinct Higgs decay modes, namely ZZ, WW, and tau tau, are simultaneously probed. Nine potential signal events are selected and found to be consistent with the background expectation. We set a 95% credibility limit on the production cross section times the branching ratio and subsequent decay to the four-lepton final state for hypothetical Higgs boson masses between 120 GeV/c(2) and 300 GeV/c(2).