The Nucleotide Exchange Factor Ric-8A is a Chaperone for the Conformationally Dynamic Nucleotide-Free State of G Alpha I1

Heterotrimeric G protein alpha subunits are activated upon exchange of GDP for GTP at the nucleotide binding site of G alpha, catalyzed by guanine nucleotide exchange factors (GEFs). In addition to transmembrane G protein-coupled receptors (GPCRs), which act on G protein heterotrimers, members of the family cytosolic proteins typified by mammalian Ric-8A are GEFs for Gi/q/12/13-class G alpha subunits. Ric-8A binds to G alpha.GDP, resulting in the release of GDP. The Ric-8A complex with nucleotide-free G alpha i1 is stable, but dissociates upon binding of GTP to G alpha i1. To gain insight into the mechanism of Ric-8A-catalyzed GDP release from G alpha i1, experiments were conducted to characterize the physical state of nucleotide-free G alpha i1 (hereafter referred to as G alpha i1[]) in solution, both as a monomeric species, and in the complex with Ric-8A. We found that Ric-8A-bound, nucleotide-free G alpha i1 is more accessible to trypsinolysis than G alpha i1.GDP, but less so than G alpha i1[] alone. The TROSY-HSQC spectrum of [N-15]G alpha i1[] bound to Ric-8A shows considerable loss of peak intensity relative to that of [N-15]G alpha i1.GDP. Hydrogen-deuterium exchange in G alpha i1[] bound to Ric-8A is 1.5-fold more extensive than in G alpha i1.GDP. Differential scanning calorimetry shows that both Ric-8A and G alpha i1.GDP undergo cooperative, irreversible unfolding transitions at 47 degrees and 52 degrees, respectively, while nucleotide-free G alpha i1 shows a broad, weak transition near 35 degrees. The unfolding transition for Ric-8A: G alpha i1[] is complex, with a broad transition that peaks at 50 degrees, suggesting that both Ric-8A and G alpha i1[] are stabilized within the complex, relative to their respective free states. The C-terminus of G alpha i1 is shown to be a critical binding element for Ric-8A, as is also the case for GPCRs, suggesting that the two types of GEF might promote nucleotide exchange by similar mechanisms, by acting as chaperones for the unstable and dynamic nucleotide-free state of G alpha

Trajectories of long-term exposure to anticholinergic and sedative drugs: A latent class growth analysis

Introduction: A variety of drugs, which are frequently prescribed to older people, have anticholinergic and sedative effects whereby they may impair cognitive and physical function. Although substantial inter-individual variation in anticholinergic and sedative exposure has been documented, little is known about subpopulations with distinct trajectories of exposure. Methods: Data from the Longitudinal Aging Study Amsterdam (LASA), an ongoing Dutch population-based cohort study, collected over 20 years (1992-2012) at seven occasions, were analyzed. On each occasion, cumulative anticholinergic and sedative exposure was quantified with the Drug Burden Index, a linear additive pharmacological dose-response model. The most likely number of trajectories were empirically derived with Latent Class Growth Analysis using "Goodness of fit" statistics. Trajectories were then compared on physical and cognitive function. Results: A total of 763 participants completed all follow-ups (61% women; mean age 83, ±6). "Goodness of fit" statistics (Bayesian In-formation Criterion = 22916, Bootstrapped Likelihood Ratio Test of 3 vs. 2 classes = 514.12

Drug burden index and cognitive and physical function in aged care residents: a longitudinal study

Objectives: Anticholinergic/antimuscarinic and sedative medications (eg, benzodiazepines) have been found to be associated with poorer cognitive and physical function and mobility impairment in older age. However, previous studies were mostly conducted among community-dwelling older individuals and had often a cross-sectional design. Accordingly, our aim was to examine longitudinal associations between cumulative exposure to anticholinergic and sedative medications and cognitive and physical function among residents from aged care homes.Design: Longitudinal study.Setting and Participants: A total of 4624 residents of Dutch aged care homes of whom data were collected between June 2005 and April 2014.Methods: Outcome measures were collected with the Long-Term Care Facilities assessment from the international Residential Assessment Instrument (interRAI-LTCF) and included the Cognitive Performance Scale, the Activities of Daily Living (ADL) Hierarchy scale, a timed 4-meter walk test, distance walked, hours of physical activity, and days being outside. Cumulative exposure to anticholinergic and sedative medications was calculated with the Drug Burden Index (DBI), a linear additive pharmacological dose-response model. Associations were examined with linear mixed models to take the potential dependence of observations into account (ie, data were collected at repeated assessment occasions of residents who were clustered in aged care homes). Analyses were adjusted for sex, age, dementia, comorbidity (neurological, psychiatric, cardiovascular, oncological, and pulmonary), fractures, depressive symptoms, and medications excluded from the DBI.Results: We observed significant longitudinal associations between a higher DBI and poorer ADLs, fewer hours of physical activity, and fewer days being outside. We found no significant longitudinal association between a higher DBI and poorer cognitive function.Conclusions and Implications: Over time, cumulative exposure to anticholinergic and sedative medications is associated with poorer physical but not cognitive function in aged care residents. Careful monitoring of aged care residents with high cumulative anticholinergic and sedative medication exposure is needed. (C) 2020 Published by Elsevier Inc. on behalf of AMDA - The Society for Post-Acute and Long-Term Care Medicine.Clinical Pharmacy and Toxicolog

IL-1α Signaling Is Critical for Leukocyte Recruitment after Pulmonary Aspergillus fumigatus Challenge

Aspergillus fumigatus is a mold that causes severe pulmonary infections. Our knowledge of how A. fumigatus growth is controlled in the respiratory tract is developing, but still limited. Alveolar macrophages, lung resident macrophages, and airway epithelial cells constitute the first lines of defense against inhaled A. fumigatus conidia. Subsequently, neutrophils and inflammatory CCR2+ monocytes are recruited to the respiratory tract to prevent fungal growth. However, the mechanism of neutrophil and macrophage recruitment to the respiratory tract after A. fumigatus exposure remains an area of ongoing investigation. Here we show that A. fumigatus pulmonary challenge induces expression of the inflammasome-dependent cytokines IL-1β and IL-18 within the first 12 hours, while IL-1α expression continually increases over at least the first 48 hours. Strikingly, Il1r1-deficient mice are highly susceptible to pulmonary A. fumigatus challenge exemplified by robust fungal proliferation in the lung parenchyma. Enhanced susceptibility of Il1r1-deficient mice correlated with defects in leukocyte recruitment and anti-fungal activity. Importantly, IL-1α rather than IL-1β was crucial for optimal leukocyte recruitment. IL-1α signaling enhanced the production of CXCL1. Moreover, CCR2+ monocytes are required for optimal early IL-1α and CXCL1 expression in the lungs, as selective depletion of these cells resulted in their diminished expression, which in turn regulated the early accumulation of neutrophils in the lung after A. fumigatus challenge. Enhancement of pulmonary neutrophil recruitment and anti-fungal activity by CXCL1 treatment could limit fungal growth in the absence of IL-1α signaling. In contrast to the role of IL-1α in neutrophil recruitment, the inflammasome and IL-1β were only essential for optimal activation of anti-fungal activity of macrophages. As such, Pycard-deficient mice are mildly susceptible to A. fumigatus infection. Taken together, our data reveal central, non-redundant roles for IL-1α and IL-1β in controlling A. fumigatus infection in the murine lung

Concurrent use of prescription drugs and herbal medicinal products in older adults: A systematic review

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The use of herbal medicinal products (HMPs) is common among older adults. However, little is known about concurrent use with prescription drugs as well as the potential interactions associated with such combinations. Objective Identify and evaluate the literature on concurrent prescription and HMPs use among older adults to assess prevalence, patterns, potential interactions and factors associated with this use. Methods Systematic searches in MEDLINE, PsycINFO, EMBASE, CINAHL, AMED, Web of Science and Cochrane from inception to May 2017 for studies reporting concurrent use of prescription medicines with HMPs in adults (≥65 years). Quality was assessed using the Joanna Briggs Institute checklists. The Evidence for Policy and Practice Information and Co-ordinating Centre (EPPI-Centre) three stage approach to mixed method research was used to synthesise data. Results Twenty-two studies were included. A definition of HMPs or what was considered HMP was frequently missing. Prevalence of concurrent use by older adults varied widely between 5.3% and 88.3%. Prescription medicines most combined with HMPs were antihypertensive drugs, beta blockers, diuretics, antihyperlipidemic agents, anticoagulants, analgesics, antihistamines, antidiabetics, antidepressants and statins. The HMPs most frequently used were: ginkgo, garlic, ginseng, St John’s wort, Echinacea, saw palmetto, evening primrose oil and ginger. Potential risks of bleeding due to use of ginkgo, garlic or ginseng with aspirin or warfarin was the most reported herb-drug interaction. Some data suggests being female, a lower household income and less than high school education were associated with concurrent use. Conclusion Prevalence of concurrent prescription drugs and HMPs use among older adults is substantial and potential interactions have been reported. Knowledge of the extent and manner in which older adults combine prescription drugs will aid healthcare professionals can appropriately identify and manage patients at risk.Peer reviewedFinal Published versio

A germanate transparent conductive oxide

Wide bandgap conductors such as In2O3 and ZnO are used as transparent conducting oxides (TCOs). To date, TCOs are realized using post transition metal cations with largely spread s-orbitals such as In3+, Sn4+, Zn2+ and Cd2+. On the other hand, no good electronic conductor has been realized in oxides of Al, Si and Ge. Here we report the conversion of an oxide of Ge into a good electronic conductor by employing the concept of superdegeneracy. We find that cubic SrGeO3, synthesized under high pressure, displays a direct bandgap of 3.5 eV, a carrier mobility of 12 cm2(Vs)−1, and conductivities of 3 Scm−1 (DC) and 400 Scm−1 (optical conductivity). This is the first Ge-based electronic conductive oxide, and expands the family of TCOs from ionic oxides to covalent oxides

Архетип свобода у контексті французької політичної теорії та історії

Розглянуто сучасні підходи щодо аналізу політичної ментальності. У межах політологічного аналізу окреслено коло проблем, які потребують вирішення з використанням підходів психології. Зроблено висновок про те, що архетип “свобода” становить важливий елемент політичної ментальності французів.Modern approaches of analysis of political mentality are considered. Within the limits of political science analysis outlined circle of problems which need decision with the use of approaches of psychology. A conclusion is done that archetype freedom makes the important element of political mentality of French’s

Development of a Core Outcome Set for effectiveness trials aimed at optimising prescribing in older adults in care homes

Background: Prescribing medicines for older adults in care homes is known to be sub-optimal. Whilst trials testing interventions to optimise prescribing in this setting have been published, heterogeneity in outcome reporting has hindered comparison of interventions, thus limiting evidence synthesis. The aim of this study was to develop a core outcome set (COS), a list of outcomes which should be measured and reported, as a minimum, for all effectiveness trials involving optimising prescribing in care homes. The COS was developed as part of the Care Homes Independent Pharmacist Prescribing Study (CHIPPS). Methods: A long-list of outcomes was identified through a review of published literature and stakeholder input. Outcomes were reviewed and refined prior to entering a two-round online Delphi exercise and then distributed via a web link to the CHIPPS Management Team, a multidisciplinary team including pharmacists, doctors and Patient Public Involvement representatives (amongst others), who comprised the Delphi panel. The Delphi panellists (n = 19) rated the importance of outcomes on a 9-point Likert scale from 1 (not important) to 9 (critically important). Consensus for an outcome being included in the COS was defined as ≥70% participants scoring 7–9 and <15% scoring 1–3. Exclusion was defined as ≥70% scoring 1–3 and <15% 7–9. Individual and group scores were fed back to participants alongside the second questionnaire round, which included outcomes for which no consensus had been achieved. Results: A long-list of 63 potential outcomes was identified. Refinement of this long-list of outcomes resulted in 29 outcomes, which were included in the Delphi questionnaire (round 1). Following both rounds of the Delphi exercise, 13 outcomes (organised into seven overarching domains: medication appropriateness, adverse drug events, prescribing errors, falls, quality of life, all-cause mortality and admissions to hospital (and associated costs)) met the criteria for inclusion in the final COS. Conclusions: We have developed a COS for effectiveness trials aimed at optimising prescribing in older adults in care homes using robust methodology. Widespread adoption of this COS will facilitate evidence synthesis between trials. Future work should focus on evaluating appropriate tools for these key outcomes to further reduce heterogeneity in outcome measurement in this context