c-Myc induced changes in higher order rDNA structure accompany growth factor stimulation of quiescent cells

Human c-Myc is believed to be a high level coordinator of protein synthesis capacity and cell growth rate, capable of activating transcription by all three nuclear RNA Polymerases. Direct activation of rDNA transcription by c-Myc is functionally conserved in rat cells, despite high divergence in non-coding rDNA sequences, suggesting that this coordinating role is likely to be a general within mammals. Upon re-feeding of starved cells, c-Myc activity enhances the efficiency of RNA Polymerase I and SL1/TIF-1B recruitment to the rDNA and rapidly induces higher order gene loop structures in rDNA chromatin that juxtapose upstream and downstream rDNA sequences. Furthermore c-Myc induced gene-loop formation in rDNA genes occurs independently of rDNA transcription, implying that it may be an early step in the re-programming of quiescent cells as they enter the growth cycle

Radio and Millimeter Monitoring of Sgr A*: Spectrum, Variability, and Constraints on the G2 Encounter

We report new observations with the Very Large Array, Atacama Large Millimeter Array, and Submillimeter Array at frequencies from 1.0 to 355 GHz of the Galactic Center black hole, Sagittarius A*. These observations were conducted between October 2012 and November 2014. While we see variability over the whole spectrum with an amplitude as large as a factor of 2 at millimeter wavelengths, we find no evidence for a change in the mean flux density or spectrum of Sgr A* that can be attributed to interaction with the G2 source. The absence of a bow shock at low frequencies is consistent with a cross-sectional area for G2 that is less than $2 \times 10^{29}$ cm$^2$. This result fits with several model predictions including a magnetically arrested cloud, a pressure-confined stellar wind, and a stellar photosphere of a binary merger. There is no evidence for enhanced accretion onto the black hole driving greater jet and/or accretion flow emission. Finally, we measure the millimeter wavelength spectral index of Sgr A* to be flat; combined with previous measurements, this suggests that there is no spectral break between 230 and 690 GHz. The emission region is thus likely in a transition between optically thick and thin at these frequencies and requires a mix of lepton distributions with varying temperatures consistent with stratification.Comment: Accepted for publication in Ap

A Bima Array Survey of Molecules in Comets Linear (C/2002 T7) and Neat (C/2001 Q4)

We present an interferometric search for large molecules, including methanol, methyl cyanide, ethyl cyanide, ethanol, and methyl formate in comets LINEAR (C/2002 T7) and NEAT (C/2001 Q4) with the Berkeley-Illinois-Maryland Association (BIMA) array. In addition, we also searched for transitions of the simpler molecules CS, SiO, HNC, HN13C and 13CO . We detected transitions of methanol and CS around Comet LINEAR and one transition of methanol around Comet NEAT within a synthesized beam of ~20''. We calculated the total column density and production rate of each molecular species using the variable temperature and outflow velocity (VTOV) model described by Friedel et al.(2005).Considering the molecular production rate ratios with respect to water, Comet T7 LINEAR is more similar to Comet Hale-Bopp while Comet Q4 NEAT is more similar to Comet Hyakutake. It is unclear, however, due to such a small sample size, whether there is a clear distinction between a Hale-Bopp and Hyakutake class of comet or whether comets have a continuous range of molecular production rate ratios.Comment: Accepted for Publication in the Astrophysical Journa

Precision Measurement of the Proton and Deuteron Spin Structure Functions g2 and Asymmetries A2

We have measured the spin structure functions g2p and g2d and the virtual photon asymmetries A2p and A2d over the kinematic range 0.02 < x < 0.8 and 0.7 < Q^2 < 20 GeV^2 by scattering 29.1 and 32.3 GeV longitudinally polarized electrons from transversely polarized NH3 and 6LiD targets. Our measured g2 approximately follows the twist-2 Wandzura-Wilczek calculation. The twist-3 reduced matrix elements d2p and d2n are less than two standard deviations from zero. The data are inconsistent with the Burkhardt-Cottingham sum rule if there is no pathological behavior as x->0. The Efremov-Leader-Teryaev integral is consistent with zero within our measured kinematic range. The absolute value of A2 is significantly smaller than the sqrt[R(1+A1)/2] limit.Comment: 12 pages, 4 figures, 2 table

The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: A randomised placebo-controlled study

We evaluated the effect of gefapixant on cough reflex sensitivity to evoked tussive challenge.In this phase 2, double-blind, two-period study, patients with chronic cough (CC) and healthy volunteers (HV) were randomised to single-dose gefapixant 100 mg or placebo in a crossover fashion. Sequential inhalational challenges with ATP, citric acid, capsaicin and distilled water were performed 1, 3 and 5 h after dosing. Mean concentrations evoking ≥2 coughs (C2) and ≥5 coughs (C5) post dose versus baseline were co-primary endpoints. Objective cough frequency (coughs·h−1) over 24 h and a cough severity visual analogue scale (VAS) were assessed in CC patients. Adverse events were monitored.24 CC patients and 12 HV were randomised (mean age 61 and 38 years, respectively). The cough challenge threshold increased for ATP by 4.7-fold (C2, p≤0.001) and 3.7-fold (C5, p=0.007) for gefapixant versus placebo in CC patients; in HV, C2 and C5 increased 2.4-fold (C2, p=0.113; C5, p=0.003). The distilled water C2 and C5 thresholds increased significantly (

Environmental correlates of geographic divergence in a phenotypic trait: A case study using bat echolocation

Divergence in phenotypic traits may arise from the interaction of different evolutionary forces, including different kinds of selection (e.g., ecological), genetic drift, and phenotypic plasticity. Sensory systems play an important role in survival and reproduction, and divergent selection on such systems may result in lineage diversification. Such diversification could be largely influenced by selection in different environments as a result of isolation by environment (IbE). We investigated this process using geographic variation in the resting echolocation frequency of the horseshoe bat species, Rhinolophus damarensis, as a test case. Bats were sampled along a latitudinal gradient ranging from 16°S to 32°S in the arid western half of southern Africa. We measured body size and peak resting frequencies (RF) from handheld individual bats. Three hypotheses for the divergence in RF were tested: (1) James’ Rule, (2) IbE, and (3) genetic drift through isolation by distance (IbD) to isolate the effects of body size, local climatic conditions, and geographic distance, respectively, on the resting frequency of R. damarensis. Our results did not support genetic drift because there was no correlation between RF variation and geographic distance. Our results also did not support James’ Rule because there was no significant relationship between (1) geographic distances and RF, (2) body size and RF, or (3) body size and climatic variables. Instead, we found support for IbE in the form of a correlation between RF and both region and annual mean temperature, suggesting that RF variation may be the result of environmental discontinuities. The environmental discontinuities coincided with previously reported genetic divergence. Climatic gradients in conjunction with environmental discontinuities could lead to local adaptation in sensory signals and directed dispersal such that gene flow is restricted, allowing lineages to diverge. However, our study cannot exclude the role of processes like phenotypic plasticity in phenotypic variation

Precision Measurement of the Proton and Deuteron Spin Structure Functions g\u3csub\u3e2\u3c/sub\u3e and Asymmetries A\u3csub\u3e2\u3c/sub\u3e

We have measured the spin struction functions g2(p) and g(2)(d) and the virtual photon asymmetries A(2)(p) and A(2)(d) over the kinetmatic range 0.02 less than or equal to x less than or equal to 0.8 and 0.7 less than or equal to Q2 less than or equal to 20 GeV2 by scattering 29.1 and 32.3 GeV longitudinally polarized electrons from transversely polarized NH3 and (LiD)-Li-6 targets. Our measured g2 approximately follows the twist-2 Wandzura-Wilczek calculation. The twist-3 reduced matrix elements d(2)(p) and d(2)(n) are less than two standard deviations from zero. The data are inconsistent with the Burkhardt-Cottingham sum rule if there is no pathological behavior as x --\u3e 0. The Efremov-Leader-Teryaev integral is consistent with zero within our measured kinematic range. The absolute value of A2 is significantly smaller than the A2 \u3c √ R(1 +A1)/2 limit

Measurements of the Q2Q^2-Dependence of the Proton and Neutron Spin Structure Functions g1p and g1n

The structure functions g1p and g1n have been measured over the range 0.014 < x < 0.9 and 1 < Q2 < 40 GeV2 using deep-inelastic scattering of 48 GeV longitudinally polarized electrons from polarized protons and deuterons. We find that the Q2 dependence of g1p (g1n) at fixed x is very similar to that of the spin-averaged structure function F1p (F1n). From a NLO QCD fit to all available data we find $\Gamma_1^p - \Gamma_1^n =0.176 \pm 0.003 \pm 0.007$ at Q2=5 GeV2, in agreement with the Bjorken sum rule prediction of 0.182 \pm 0.005.Comment: 17 pages, 3 figures. Submitted to Physics Letters

The Distribution, Excitation and Formation of Cometary Molecules: Methanol, Methyl Cyanide and Ethylene Glycol

We present an interferometric and single dish study of small organic species toward Comets C/1995 O1 (Hale-Bopp) and C/2002 T7 (LINEAR) using the BIMA interferometer at 3 mm and the ARO 12m telescope at 2 mm. For Comet Hale-Bopp, both the single-dish and interferometer observations of CH3OH indicate an excitation temperature of 105+/-5 K and an average production rate ratio Q(CH3OH)/Q(H2O)~1.3% at ~1 AU. Additionally, the aperture synthesis observations of CH3OH suggest a distribution well described by a spherical outflow and no evidence of significant extended emission. Single-dish observations of CH3CN in Comet Hale-Bopp indicate an excitation temperature of 200+/-10 K and a production rate ratio of Q(CH3CN)/Q(H2O)~0.017% at ~1 AU. The non-detection of a previously claimed transition of cometary (CH2OH)2 toward Comet Hale-Bopp with the 12m telescope indicates a compact distribution of emission, D<9'' (<8500 km). For the single-dish observations of Comet T7 LINEAR, we find an excitation temperature of CH3OH of 35+/-5 K and a CH3OH production rate ratio of Q(CH3OH)/Q(H2O)~1.5% at ~0.3 AU. Our data support current chemical models that CH3OH, CH3CN and (CH2OH)2 are parent nuclear species distributed into the coma via direct sublimation off cometary ices from the nucleus with no evidence of significant production in the outer coma.Comment: accepted for publication in Ap

Production, characterization, and antigen specificity of recombinant 62-71-3, a candidate monoclonal antibody for rabies prophylaxis in humans

Rabies kills many people throughout the developing world every year. The murine monoclonal antibody (mAb) 62-71-3 was recently identified for its potential application in rabies postexposure prophylaxis (PEP). The purpose here was to establish a plant-based production system for a chimeric mouse-human version of mAb 62-71-3, to characterize the recombinant antibody and investigate at a molecular level its interaction with rabies virus glycoprotein. Chimeric 62-71-3 was successfully expressed in Nicotiana benthamiana. Glycosylation was analyzed by mass spectroscopy; functionality was confirmed by antigen ELISA, as well as rabies and pseudotype virus neutralization. Epitope characterization was performed using pseudotype virus expressing mutagenized rabies glycoproteins. Purified mAb demonstrated potent viral neutralization at 500 IU/mg. A critical role for antigenic site I of the glycoprotein, as well as for two specific amino acid residues (K226 and G229) within site I, was identified with regard to mAb 62-71-3 neutralization. Pseudotype viruses expressing glycoprotein from lyssaviruses known not to be neutralized by this antibody were the controls. The results provide the molecular rationale for developing 62-71-3 mAb for rabies PEP; they also establish the basis for developing an inexpensive plant-based antibody product to benefit low-income families in developing countries.—Both, L., van Dolleweerd, C., Wright, E., Banyard, A. C., Bulmer-Thomas, B., Selden, D., Altmann, F., Fooks, A. R., Ma, J. K.-C. Production, characterization, and antigen specificity of recombinant 62-71-3, a candidate monoclonal antibody for rabies prophylaxis in humans