Partial Agonism through a Zinc-Ion Switch Constructed between Transmembrane Domains III and VII in the Tachykinin NK 1 Receptor

ABSTRACT Partly due to lack of detailed knowledge of the molecular recognition of ligands the structural basis for partial versus full agonism is not known. In the ␤ 2 -adrenergic receptor the agonist binding site has previously been structurally and functionally exchanged with an activating metal-ion site located between AspIII:08 -or a His residue introduced at this position in transmembrane domain (TM)-III-and a Cys residue substituted for AsnVII:06 in TM-VII. Here, this interhelical, bidentate metal-ion site is without loss of Zn 2ϩ affinity transferred to the tachykinin NK 1 receptor. In contrast to the similarly mutated ␤ 2 -adrenergic receptor, signal transduction-i.e., inositol phosphate turnover-could be stimulated by both Zn 2ϩ and by the natural agonist, Substance P in the mutated NK 1 receptor. The metal-ion acted as a 25% partial agonist through binding to the bidentate zinc switch located exactly one helical turn below the two previously identified interaction points for Substance P in, respectively, TM-III and -VII. The metal-ion chelator, phenantroline, which in the ␤ 2 -adrenergic receptor increased both the potency and the agonistic efficacy of Zn 2ϩ or Cu 2ϩ in complex with the chelator, also bound to the metal-ion site-engineered NK 1 receptor, but here the metal-ion chelator complex instead acted as a pure antagonist. It is concluded that signaling of even distantly related rhodopsin-like 7TM receptors can be activated through Zn 2ϩ coordination between metal-ion binding residues located at positions III:08 and VII:06. It is suggested that only partial agonism is obtained through this simple well defined metal-ion coordination due to lack of proper interactions with residues also in TM-VI. Mutational mapping and cross-linking experiments have provided much information concerning binding pockets for ligands in 7-transmembrane (TM) receptor

Информационно-коммуникационные технологии и их роль в управлении корпоративными отношениями (на примере ПАО "Сбербанк")

На данный момент информационно-коммуникационные технологии способны кардинально изменить способы функционирования различных институтов и государства в целом. Объединение информационных и коммуникационных технологий приводит к усовершенствованию традиционных отраслей экономики, разработке новых отраслей, услуг и продуктов, а также удовлетворению постоянно возникающих потребностей общества. Цель данного исследования – изучение информационно-коммуникационных технологий в ПАО "Сбербанк".Объект исследования – коммуникационная деятельность Публичного акционерного общества "Сбербанк России". Предмет исследования – механизмы, методы, процессы и роль информационно-коммуникационных технологий в управлении.At the moment, information and communication technologies are able to radically change the ways in which various institutions and the state as a whole function. The combination of information and communication technologies leads to the improvement of traditional sectors of the economy, the development of new industries, services and products, as well as to meet the ever-evolving needs of society. The purpose of this study is to study information and communication technologies in PAO "Sberbank"t. The subject of the study is the communication activity of the PAO "Sberbank of Russia". The subject of the research - mechanisms, methods, processes and the role of information and communication technologies in management

The Cannabinoid CB1 Antagonist TM38837 With Limited Penetrance to the Brain Shows Reduced Fear-Promoting Effects in Mice

Rimonabant was the first selective CB1 antagonist/inverse agonist introduced into clinical practice to treat obesity and metabolic-related disorders. It was withdrawn from market due to the notably increased rates of psychiatric side effects. We have evaluated TM38837, a novel, largely peripherally restricted CB1 antagonist, in terms of fear-promoting consequences of systemic vs. intracerebral injections. Different groups of male C57BL/6 N mice underwent auditory fear conditioning, followed by re-exposure to the tone. Mice were treated per os (p.o.) with TM38837 (10, 30, or 100 mg/kg), rimonabant (10 mg/kg; a brain penetrating CB1 antagonist/inverse agonist which served as a positive control), or vehicle, 2 h prior the tone presentation. Only the high dose of TM38837 (100 mg/kg) induced a significant increase in freezing behavior, similar to that induced by rimonabant (10 mg/kg) (p < 0.001). If injected into the brain both TM38837 (10 or 30 μg/mouse) and rimonabant (1 or 10 μg/mouse) caused a sustained fear response to the tone, which was more pronounced after rimonabant treatment. Taken together, TM38837 was at least one order of magnitude less effective in promoting fear responses than rimonabant. Given the equipotency of the two CB1 antagonists with regard to weight loss and metabolic syndrome-like symptoms in rodent obesity models, our results point to a critical dose range in which TM3887 might be beneficial for indications such as obesity and metabolic disorders with limited risk of fear-promoting effects

Effects of Place of Articulation Changes on Auditory Neural Activity: A Magnetoencephalography Study

In casual speech, phonemic segments often assimilate such that they adopt features from adjacent segments, a typical feature being their place of articulation within the vocal tract (e.g., labial, coronal, velar). Place assimilation (e.g., from coronal /n/ to labial /m/: rainbow→*raimbow) alters the surface form of words. Listeners' ability to perceptually compensate for such changes seems to depend on the phonemic context, on whether the adjacent segment (e.g., the /b/ in “rainbow”) invites the particular change. Also, some assimilations occur frequently (e.g., /n/→/m/), others are rare (e.g., /m/→/n/). We investigated the effects of place assimilation, its contextual dependency, and its frequency on the strength of auditory evoked mismatch negativity (MMN) responses, using pseudowords. Results from magnetoencephalography (MEG) revealed that the MMN was modulated both by the frequency and contextual appropriateness of assimilations

The Impact of Acute Psychosocial Stress on Magnetoencephalographic Correlates of Emotional Attention and Exogenous Visual Attention

Stress-induced acute activation of the cerebral catecholaminergic systems has often been found in rodents. However, little is known regarding the consequences of this activation on higher cognitive functions in humans. Theoretical inferences would suggest increased distractibility in the sense of increased exogenous attention and emotional attention. The present study investigated the influence of acute stress responses on magnetoencephalographic (MEG) correlates of visual attention. Healthy male subjects were presented emotional and neutral pictures in three subsequent MEG recording sessions after being exposed to a TSST-like social stressor, intended to trigger a HPA-response. The subjects anticipation of another follow-up stressor was designed to sustain the short-lived central catecholaminergic stress reactions throughout the ongoing MEG recordings. The heart rate indicates a stable level of anticipatory stress during this time span, subsequent cortisol concentrations and self-report measures of stress were increased. With regard to the MEG correlates of attentional functions, we found that the N1m amplitude remained constantly elevated during stressor anticipation. The magnetic early posterior negativity (EPNm) was present but, surprisingly, was not at all modulated during stressor anticipation. This suggests that a general increase of the influence of exogenous attention but no specific effect regarding emotional attention in this time interval. Regarding the time course of the effects, an influence of the HPA on these MEG correlates of attention seems less likely. An influence of cerebral catecholaminergic systems is plausible, but not definite

Covid-19: Szenarien für Herbst/Winter 2022 – und darüber hinaus

Die vergangenen Monate haben dynamische Entwicklungen der Pandemie verdeutlicht. Als Folge dessen kam es quasi zeitgleich in Österreich im ersten Quartal des Jahres 2022 neben dem Beschluss äußerst restriktiver Vorgaben wie der Impfpflicht auch wieder zur Aufhebung fast aller Schutzmaßnahmen im Zusammenhang mit der COVID-19-Pandemie. Die letzten beiden Jahre haben gezeigt, wie dynamisch und rasch sich die Situation phasenweise in der Pandemie ändern kann. Jede Phase erfordert – und je länger die Pandemie andauert, umso mehr – verstärkt interdisziplinäre Zugänge und klare Zielsetzungen für Public Health Interventionen. Dies ist einerseits im Sinne einer verständlichen Kommunikation gegenüber der allgemeinen Bevölkerung wichtig, und andererseits im Sinne einer effektiven Bekämpfung der Ausbreitung der Pandemie unbedingt erforderlich

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI <18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For schoolaged children and adolescents, we report thinness (BMI <2 SD below the median of the WHO growth reference) and obesity (BMI >2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit