Title: Agonist-biased signalling at the histamine H 4 receptor: JNJ7777120 recruits beta-arrestin without activating G proteins

Abstract -248 words Introduction -584 word

Estimation of dietary flavonoid intake and cognitive performance in older adults with Alzheimer\u27s type dementia

Abstract presented at The Nutrition Society of Australia and Nutrition Society of New Zealand 2013 Joint Annual Scientific Meeting, 4-6 December 2013, Brisbane, Australi

Abrupt stratospheric vortex weakening associated with North Atlantic anticyclonic wave breaking

The sudden stratospheric warming (SSW) of 12 February 2018 was not forecast by any extended-range model beyond 12 days. From early February, all forecast models that com prise the subseasonal-to-seasonal (S2S) database abruptly transitioned from indicating a strong stratospheric polar vortex (SPV) to a high likelihood of a major SSW. We demonstrate that this forecast evolution was associated with the track and intensity of a cyclone in the north-east Atlantic, with an associated anticyclonic Rossby wave break, which was not well-forecast. The wave break played a pivotal role in building the Ural high, which existing literature has shown was a precursor of the 2018 SSW. The track of the cyclone built an anomalously strong sea-level pressure dipole between Scandinavia and Greenland (termed the S-G dipole) which we use as a diagnostic of the wave break. Forecasts which did not capture the magnitude of this event had the largest errors in the SPV strength and did not show enhanced vertical wave activity. A composite of similarly strong wintertime (November{March) S-G dipoles in reanalysis shows associated anticyclonic wave breaking leading to significantly enhanced vertical wave activity and a weakened SPV in the following days, which occured in 35% of the 15-day periods preceding observed major SSWs. Our results indicate a particular transient trigger for weakening the SPV, complementing existing results on the importance of tropospheric blocking for disruptions to the Northern Hemisphere extratropical stratospheric circulation

Functional desensitization of the β 2 adrenoceptor is not dependent on agonist efficacy

© 2015 John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. Chronic treatment with β2 adrenoceptor agonists is recommended as a first-line maintenance therapy for chronic obstructive pulmonary disease (COPD). However, a potential consequence of long-term treatment may be the loss of functional response (tachyphylaxis) over time. In this study, we have investigated the tendency of such agonists, with a range of efficacies, to develop functional desensitization to cAMP responses in primary human bronchial smooth muscle cells following prolonged agonist exposure. The data show that upon repeat exposure, all agonists produced functional desensitization to the same degree and rate. In addition, β2 adrenoceptor internalization and β-arrestin-2 recruitment were monitored using β2·eGFP visualization and the PathHunter™ β-arrestin-2 assay, respectively. All agonists were capable of causing robust receptor internalization and β-arrestin-2 recruitment, the rate of which was influenced by agonist efficacy, as measured in those assays. In summary, although a relationship exists between agonist efficacy and the rate of both receptor internalization and β-arrestin-2 recruitment, there is no correlation between agonist efficacy and the rate or extent of functional desensitization

Agonist-Biased Signaling at the Histamine H 4 Receptor: JNJ7777120 Recruits ␤-Arrestin without Activating G Proteins

ABSTRACT The G i/o -coupled histamine H 4 receptor is highly expressed in hemopoietic cells and is a promising new target for the treatment of chronic inflammatory diseases. 1-[(5-Chloro-1H-indol-2-yl)carbonyl]-4-methyl-piperazine (JNJ7777120) has been described as a selective antagonist at the H 4 receptor and is widely used to characterize the physiological role of the H 4 receptor. We have investigated the pharmacological properties of JNJ7777120 using two distinct downstream signaling measurements, G protein activation and ␤-arrestin recruitment. The H 4 receptor agonists histamine and clobenpropit, but not JNJ7777120, were able to induce [ 35 S]GTP␥S binding in membranes prepared from U2OS-H 4 cells. Thioperamide, a dual H 3 /H 4 receptor antagonist, and JNJ7777120 were both able to inhibit the [ 35 S]GTP␥S binding induced by clobenpropit. Agonists and antagonists specific for other members of the histamine receptor family had no effect in this assay format. Histamine and clobenpropit increased ␤-arrestin recruitment to the H 4 receptor in a concentration-dependent manner. This ␤-arrestin recruitment could be inhibited by preincubation with thioperamide. We were surprised to find that preincubation with the H 4 -selective antagonist JNJ7777120 potentiated rather than antagonized the response to a submaximal concentration of clobenpropit. JNJ7777120 treatment alone resulted in an increase in ␤-arrestin recruitment, which again could be inhibited by preincubation with thioperamide. Schild analysis demonstrated competitive antagonism between thioperamide and both clobenpropit and JNJ7777120. Histamine and clobenpropit had comparable potencies for both [ 35 S]GTP␥S binding and ␤-arrestin recruitment, suggesting little difference in the levels of receptor reserve between the two assays. In conclusion, we have demonstrated that JNJ7777120 recruits ␤-arrestin to the H 4 receptor, independent of G protein activation

Dietary flavonoid intake and cognitive performance in older adults with Alzheimer\u27s type dementia

Background: Dietary flavonoid intake and intake of flavonoid subclasses has been associated with improved cognitive performance. However, the association between flavonoid intake and cognitive performance in older adults with Alzheimer\u27s type dementia has not been investigated. Objectives: To estimate dietary total flavonoid intake and intake of flavonoid subclasses in older adults with Alzheimer\u27s type dementia and assess the relationship of flavonoid intake with measures of cognition. Design: Cross sectional analysis. Setting: Community dwelling older adults in NSW, Australia. Participants: Older adults (+65y) with mild to moderate dementia (n=49). Measurements: A 24h diet recall was collected with help from a carer and used to estimate flavonoid intake. A battery of cognitive tasks assessed cognitive performance of several cognitive domains. Results: Pearson and spearman correlation coefficients identified an association between flavonoid intake and executive function (r=0.319, p=0.025). After controlling for depression, the relationship was reduced. Conclusion: The identified association between cognitive functioning, depression and flavonoid intake in older adults with Alzheimer\u27s type dementia warrants further research in a larger sample

The Population of Weak Mg II Absorbers I. A Survey of 26 QSO HIRES/Keck Spectra

We present a search for "weak" MgII absorbers [those with W_r(2796) < 0.3 A in the HIRES/Keck spectra of 26 QSOs. We found 30, of which 23 are newly discovered. The spectra are 80% complete to W_r(2796) = 0.02 A and have a cumulative redshift path of ~17.2 for the redshift range 0.4 < z < 1.4. The number of absorbers per unit redshift, dN/dz, is seen to increase as the equivalent width threshold is decreased; we obtained dN/dz = 1.74+/-0.10 for our 0.02 <= W_r(2796) < 0.3 A sample. The equivalent width distribution follows a power law with slope -1.0; there is no turnover down to W_r(2796) = 0.02 A at = 0.9. Weak absorbers comprise at least 65% of the total MgII absorption population, which outnumbers Lyman limit systems (LLS) by a factor of 3.8+/-1.1; the majority of weak MgII absorbers must arise in sub-LLS environments. Tentatively, we predict that ~5% of the Lyman-alpha forest clouds with W_r(1215) > 0.1 A will have detectable MgII absorption to W_r,min(2796) = 0.02 A and that this is primarily a high-metallicity selection effect (Z/Z_sun] > -1). This implies that MgII absorbing structures figure prominently as tracers of sub-LLS environments where gas has been processed by stars. We compare the number density of W_r(2796) > 0.02 A absorbers with that of both high and low surface brightness galaxies and find a fiducial absorber size of 35h^-1 to 63h^-1 kpc, depending upon the assumed galaxy population and their absorption properties. The individual absorbing "clouds" have W_r(2796) <= 0.15 A and their narrow (often unresolved) line widths imply temperatures of ~25,000 K. We measured W_r(1548) from CIV in FOS/HST archival spectra and, based upon comparisons with FeII, found a range of ionization conditions (low, high, and multi-phase) in absorbers selected by weak MgII.Comment: Accepted Version: 43 pages, PostScript figures embedded; accepted to ApJ; updated version includes analysis of CIV absorptio

The Spatial, Ionization, and Kinematic Conditions of the z=1.39 Damped Ly-alpha Absorber in Q0957+561 A,B

We examined the sizes of the absorption clouds in a z=1.3911 damped Ly-alpha absorber (DLA) in the double image lensed quasar Q0957+561 A,B (separation 135 pc at the absorber redshift). Using HIRES/Keck spectra, we studied the MgII 2796,2803 doublet, FeII multiplet, and MgI 2853 transition in absorption. We defined six "clouds" in the system of sightline A and seven clouds in the system of sightline B. An examination of the N(v) profiles, using the apparent optical depth method, reveals no clear physical connection between the clouds in A and those in B. The observed column density ratios of all clouds is log[N(MgI)/N(FeII)] ~ -2 across the full velocity range in both systems and also spatially (in both sightlines). This is a remarkable uniformity not seen in Lyman limit systems. The uniformity of the cloud properties suggests that the multiple clouds are not part of a "halo". Based upon photoionization modeling, we constrain the ionization parameters in the range -6.2 < log(U) < -5.1, where the range brackets known abundance ratio and dust depletion patterns. The inferred cloud properties are densities of 2 < n_H < 20 cm^-3, and line of sight sizes of 1 < D < 25 pc. The masses of the clouds in system A are 10 < M/M_sun < 1000 and in system B are 1 < M/M_sun < 60 for spherical clouds. For planar clouds, the upper limits are 400 M_sun and 160 M_sun for A and B, respectively. We favor a model of the absorber in which the DLA region itself is a single cloud in thiscomplex, which could be a parcel of gas in a galactic ISM. A spherical cloud of ~10 pc would be limited to one of the sightlines (A) and imply a covering factor less than 0.1 for the DLA complex. We infer that the DLA cloud properties are consistent with those of lower density, cold clouds in the Galactic interstellar medium.Comment: Accepted for publication in the Astrophysical Journal; final versio

The Physical Conditions of Intermediate Redshift MgII Absorbing Clouds from Voigt Profile Analysis

[Slightly Abridged] We present a detailed statistical analysis of the column densities, N, and Doppler parameters, b, of MgII absorbing clouds at redshifts 0.4<z<1.2. We use the HIRES/Keck data and Voigt profile (VP) fitting results presented by Churchill & Vogt (Paper I). The sample is comprised of 175 clouds from 23 systems along 18 quasar lines of sight. In order to understand whether inferred conditions could be "false", we performed extensive simulations of our VP analyses. In brief, we find: (1) N(FeII) and N(MgII) are correlated at the 9-sigma level. There is a 5-sigma anti-correlation between N(MgI)/N(MgII) and N(MgII). (2) Power-law fits to the distributions of N(MgII), N(FeII), and N(MgI) yielded power-law slopes of -1.6, -1.7, and -2.0. (3) The modes of the Doppler parameter distributions were ~5 km/s for MgII and FeII and ~7 km/s for MgI. The clouds are consistent with being thermally broadened, with temperatures in the 30-40,000K range. (4) A two-component Gaussian model to the velocity two-point correlation function yielded velocity dispersions of 54 km/s and 166 km/s. The narrow component has roughly twice the amplitude of the broader component. The width and amplitude of the broader component decreases as equivalent width increases. (5) From photoionization models we find that the column density ratios are most consistent with photoionization by the extragalactic background, as opposed to stars. Based upon N(MgI)/N(MgII), it appears that at least two-phase ionization models are required to explain the data.Comment: Accepted to the Astronomical Journal (January 2003