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

Evaluation of a Brief Sodium Screener in Two Samples

The Sodium Screener© (SS©), as developed by NutritionQuest (Berkeley, CA, USA), was designed to reduce the burden of repeated dietary or urinary sodium measurements, but the accuracy of daily sodium intake estimates has not been reported. Associations were examined between sodium intakes derived from the SS© scores and repeated 24-h recalls (24DR) in two studies with different administration modes. In one study, 102 registered dietitians (RD) completed three Automated Self-Administered 24DRs (ASA24©), version 2014, followed by the SS©; both were self-administered and web-based. In the second sample, (the Study of Household Purchasing Patterns, Eating, and Recreation or SHoPPER), trained dietitians conducted 24DR interviews with 69 community-dwelling adults in their homes; all the community adults then completed a paper-based SS© at the final visit. In the RD study, SS©-predicted sodium intakes were 2604 ± 990 (mean ± Standard deviation (SD)), and ASA24© sodium intakes were 3193 ± 907 mg/day. In the SHoPPER sample, corresponding values were 3338 ± 1310 mg/day and 2939 ± 1231 mg/day, respectively. SS© -predicted and recall sodium estimates were correlated in the RD study (r = 0.381, p = 0.0001) and in the SHoPPER (r = 0.430, p = 0.0002). Agreement between the SS© and 24-h recalls was poor when classifying individuals as meeting the dietary sodium guidelines of 2300 mg/day or not (RD study: kappa = 0.080, p = 0.32; SHoPPER: kappa = 0.207, p = 0.08). Based on repeated 24DR either in person or self-reported online as the criterion for estimating daily sodium intakes, the SS© may require additional modifications

A Conceptual Model for Navigating a Career Path in Medical School Leadership

There is a paucity of literature providing guidance to physicians hoping to attain a position as a medical school dean. Realizing this gap, the Society for Academic Emergency Medicine (SAEM) Faculty Development Committee organized an educational session focused on offering faculty guidance for obtaining a position in medical school leadership. The session involved panelists who are nationally known leaders in medical school administration and was successfully presented at the SAEM 2018 annual meeting in Indianapolis, Indiana. Knowledge and perspective gained both during this session and through literature review was analyzed using a conceptual thinking skills framework. This process offered insights that promoted the development of a conceptual model informed by current evidence and expert insight and rooted in educational, economic, and cognitive theory. This model provides a step‐by‐step guide detailing a process that physicians can use to create a plan for professional development that is informed, thoughtful, and individualized to their own needs to optimize their future chances of advancing to a career in medical school leadership.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146843/1/aet210212.pd

Lapatinib Plus Capecitabine in Women with HER-2–Positive Advanced Breast Cancer: Final Survival Analysis of a Phase III Randomized Trial

The article presents final analyses of overall survival from a phase III trial of lapatinib and capecitabine in patients with human epidermal growth factor receptor 2–positive locally advanced or metastatic breast cancer that progressed following prior therapy including trastuzumab

Phenoconversion from probable rapid eye movement sleep behavior disorder to mild cognitive impairment to dementia in a population-based sample

© 2017 The Authors Introduction Rapid eye movement sleep behavior disorder (RBD) is strongly associated with synucleinopathies. In 2012, we reported an increased risk of mild cognitive impairment (MCI) and Parkinson disease (PD) in cognitively normal Olmsted County, Minnesota, residents, aged 70 to 89 years with probable RBD. Here, we examine their progression to dementia and other neurodegenerative phenotypes. Methods Fifteen participants with RBD who were diagnosed with either MCI or PD were longitudinally followed, and their subsequent clinical courses were reviewed. Results Over 6.4 ± 2.9 years, six of the 14 participants with MCI developed additional neurodegenerative signs, five of whom had Lewy body disease features. Four of them progressed to dementia at a mean age 84.8 ± 4.9 years, three of whom met the criteria for probable dementia with Lewy bodies. One subject with PD developed MCI, but not dementia. Discussion Our findings from the population-based sample of Olmsted County, Minnesota, residents suggest that a substantial number of RBD patients tend to develop overt synucleinopathy features over time, and RBD patients who develop MCI and subsequent dementia have clinical features most consistent with dementia with Lewy bodies

Efficacy of a Soft Release Strategy for Translocating Scaled Quail in the Rolling Plains of Texas

Scaled Quail (Callipepla squamata) populations have become locally extinct and spatially fragmented in the Rolling Plains ecoregion of Texas. Translocating Scaled Quail from core to declining populations could augment populations or re-establishing extinct populations. Although translocations of scaled quail have been attempted in Texas, none have been documented and none have attempted to identify best practices. Release strategy (i.e., hard or soft release) is a factor that can influence the success of a translocation. Our objective was to compare daily apparent survival of scaled quail translocated to the Rolling Plains between 2 release treatment groups: hard- and soft-release. We estimated a daily apparent survival rate (DASR) for radio-marked hens during the breeding season as a function of age, release treatment, and a time trend. We found evidence of a positive effect of the soft release treatment and higher DASR in adult hens. Overall, DASR of translocated hens was low compared to reported estimates of survival in established resident populations. Using a soft release strategy and translocating a greater proportion of adults may improve future translocation success for scaled quail

Genes and lipids that impact uptake and assimilation of exogenous coenzyme Q in Saccharomyces cerevisiae.

Coenzyme Q (CoQ) is an essential player in the respiratory electron transport chain and is the only lipid-soluble antioxidant synthesized endogenously in mammalian and yeast cells. In humans, genetic mutations, pathologies, certain medical treatments, and aging, result in CoQ deficiencies, which are linked to mitochondrial, cardiovascular, and neurodegenerative diseases. The only strategy available for these patients is CoQ supplementation. CoQ supplements benefit a small subset of patients, but the poor solubility of CoQ greatly limits treatment efficacy. Consequently, the efficient delivery of CoQ to the mitochondria and restoration of respiratory function remains a major challenge. A better understanding of CoQ uptake and mitochondrial delivery is crucial to make this molecule a more efficient and effective therapeutic tool. In this study, we investigated the mechanism of CoQ uptake and distribution using the yeast Saccharomyces cerevisiae as a model organism. The addition of exogenous CoQ was tested for the ability to restore growth on non-fermentable medium in several strains that lack CoQ synthesis (coq mutants). Surprisingly, we discovered that the presence of CoQ biosynthetic intermediates impairs assimilation of CoQ into a functional respiratory chain in yeast cells. Moreover, a screen of 40 gene deletions considered to be candidates to prevent exogenous CoQ from rescuing growth of the CoQ-less coq2Δ mutant, identified six novel genes (CDC10, RTS1, RVS161, RVS167, VPS1, and NAT3) as necessary for efficient trafficking of CoQ to mitochondria. The proteins encoded by these genes represent essential steps in the pathways responsible for transport of exogenously supplied CoQ to its functional sites in the cell, and definitively associate CoQ distribution with endocytosis and intracellular vesicular trafficking pathways conserved from yeast to human cells

A bacterial quorum-sensing precursor induces mortality in the marine coccolithophore, Emiliania huxleyi

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Frontiers in Microbiology 7 (2016): 59, doi:10.3389/fmicb.2016.00059.Interactions between phytoplankton and bacteria play a central role in mediating biogeochemical cycling and food web structure in the ocean. However, deciphering the chemical drivers of these interspecies interactions remains challenging. Here, we report the isolation of 2-heptyl-4-quinolone (HHQ), released by Pseudoalteromonas piscicida, a marine gamma-proteobacteria previously reported to induce phytoplankton mortality through a hitherto unknown algicidal mechanism. HHQ functions as both an antibiotic and a bacterial signaling molecule in cell–cell communication in clinical infection models. Co-culture of the bloom-forming coccolithophore, Emiliania huxleyi with both live P. piscicida and cell-free filtrates caused a significant decrease in algal growth. Investigations of the P. piscicida exometabolome revealed HHQ, at nanomolar concentrations, induced mortality in three strains of E. huxleyi. Mortality of E. huxleyi in response to HHQ occurred slowly, implying static growth rather than a singular loss event (e.g., rapid cell lysis). In contrast, the marine chlorophyte, Dunaliella tertiolecta and diatom, Phaeodactylum tricornutum were unaffected by HHQ exposures. These results suggest that HHQ mediates the type of inter-domain interactions that cause shifts in phytoplankton population dynamics. These chemically mediated interactions, and other like it, ultimately influence large-scale oceanographic processes.This research was support through funding from the Gordon and Betty Moore Foundation through Grant GBMF3301 to MJ and TM; NIH grant from the National Institute of Allergy and Infectious Disease (NIAID – 1R21Al119311-01) to TM and KW; the National Science Foundation (OCE – 1313747) and US National Institute of Environmental Health Science (P01-ES021921) through the Oceans and Human Health Program to BM. Additional financial support was provided to TM from the Flatley Discovery Lab

Long receptor residence time of C26 contributes to super agonist activity at the human β2 adrenoceptor

Super agonists produce greater functional responses than endogenous agonists in the same assay, and their unique pharmacology is the subject of increasing interest and debate. We propose that receptor residence time and the duration of receptor signaling contribute to the pharmacology of super agonism. We have further characterized the novel β2 adrenoceptor agonist C26 (7-[(R)-2-((1R,2R)-2-benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone), which displays higher intrinsic activity than the endogenous ligand adrenaline in cAMP accumulation, β-arrestin-2 recruitment, and receptor internalization assays. C26 recruited β-arrestin-2, and internalized the Green Fluorescent Protein (GFP)-taggedβ2 adrenoceptor at a slow rate, with half-life (t1/2) values of 0.78 ± 0.1 and 0.78 ± 0.04 hours, respectively. This was compared with 0.31 ± 0.04 and 0.34 ± 0.01 hours for adrenaline-mediated β-arrestin-2 recruitment and GFP-β2 internalization, respectively. The slower rate for C26 resulted in levels of β-arrestin-2 recruitment increasing up to 4-hour agonist incubation, at which point the intrinsic activity was determined to be 124.3 ± 0.77% of the adrenaline response. In addition to slow functional kinetics, C26 displayed high affinity with extremely slow receptor dissociation kinetics, giving a receptor residence half-life of 32.7 minutes at 37°C, which represents the slowest dissociation rate we have observed for any β2 adrenoceptor agonist tested to date. In conclusion, we propose that the gradual accumulation of long-lived active receptor complexes contributes to the increased intrinsic activity of C26 over time. This highlights the need to consider the temporal aspects of agonist binding and signaling when characterizing ligands as super agonists