Connexin channels and phospholipids: association and modulation

<p>Abstract</p> <p>Background</p> <p>For membrane proteins, lipids provide a structural framework and means to modulate function. Paired connexin hemichannels form the intercellular channels that compose gap junction plaques while unpaired hemichannels have regulated functions in non-junctional plasma membrane. The importance of interactions between connexin channels and phospholipids is poorly understood.</p> <p>Results</p> <p>Endogenous phospholipids most tightly associated with purified connexin26 or connexin32 hemichannels or with junctional plaques in cell membranes, those likely to have structural and/or modulatory effects, were identified by tandem electrospray ionization-mass spectrometry using class-specific interpretative methods. Phospholipids were characterized by headgroup class, charge, glycerol-alkyl chain linkage and by acyl chain length and saturation. The results indicate that specific endogenous phospholipids are uniquely associated with either connexin26 or connexin32 channels, and some phospholipids are associated with both. Functional effects of the major phospholipid classes on connexin channel activity were assessed by molecular permeability of hemichannels reconstituted into liposomes. Changes to phospholipid composition(s) of the liposome membrane altered the activity of connexin channels in a manner reflecting changes to the surface charge/potential of the membrane and, secondarily, to cholesterol content. Together, the data show that connexin26 and connexin32 channels have a preference for tight association with unique anionic phospholipids, and that these, independent of headgroup, have a positive effect on the activity of both connexin26 and connexin32 channels. Additionally, the data suggest that the likely in vivo phospholipid modulators of connexin channel structure-function that are connexin isoform-specific are found in the cytoplasmic leaflet. A modulatory role for phospholipids that promote negative curvature is also inferred.</p> <p>Conclusion</p> <p>This study is the first to identify (endogenous) phospholipids that tightly associate with connexin channels. The finding that specific phospholipids are associated with different connexin isoforms suggests connexin-specific regulatory and/or structural interactions with lipid membranes. The results are interpreted in light of connexin channel function and cell biology, as informed by current knowledge of lipid-protein interactions and membrane biophysics. The intimate involvement of distinct phospholipids with different connexins contributes to channel structure and/or function, as well as plaque integrity, and to modulation of connexin channels by lipophilic agents.</p

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Prevalence, years lived with disability, and trends in anaemia burden by severity and cause, 1990-2021: findings from the Global Burden of Disease Study 2021

Background Anaemia is a major health problem worldwide. Global estimates of anaemia burden are crucial for developing appropriate interventions to meet current international targets for disease mitigation. We describe the prevalence, years lived with disability, and trends of anaemia and its underlying causes in 204 countries and territories. Methods We estimated population-level distributions of haemoglobin concentration by age and sex for each location from 1990 to 2021. We then calculated anaemia burden by severity and associated years lived with disability (YLDs). With data on prevalence of the causes of anaemia and associated cause-specific shifts in haemoglobin concentrations, we modelled the proportion of anaemia attributed to 37 underlying causes for all locations, years, and demographics in the Global Burden of Disease Study 2021. Findings In 2021, the global prevalence of anaemia across all ages was 24·3% (95% uncertainty interval [UI] 23·9–24·7), corresponding to 1·92 billion (1·89–1·95) prevalent cases, compared with a prevalence of 28·2% (27·8–28·5) and 1·50 billion (1·48–1·52) prevalent cases in 1990. Large variations were observed in anaemia burden by age, sex, and geography, with children younger than 5 years, women, and countries in sub-Saharan Africa and south Asia being particularly affected. Anaemia caused 52·0 million (35·1–75·1) YLDs in 2021, and the YLD rate due to anaemia declined with increasing Socio-demographic Index. The most common causes of anaemia YLDs in 2021 were dietary iron deficiency (cause-specific anaemia YLD rate per 100 000 population: 422·4 [95% UI 286·1–612·9]), haemoglobinopathies and haemolytic anaemias (89·0 [58·2–123·7]), and other neglected tropical diseases (36·3 [24·4–52·8]), collectively accounting for 84·7% (84·1–85·2) of anaemia YLDs. Interpretation Anaemia remains a substantial global health challenge, with persistent disparities according to age, sex, and geography. Estimates of cause-specific anaemia burden can be used to design locally relevant health interventions aimed at improving anaemia management and prevention. Funding Bill & Melinda Gates Foundation

Early postnatal perturbation of inhibitory transmission in the vestibular nucleus governs the expression of spatial map and spatial navigation behaviors

Conference Theme: A Decade of Positive Agin

Reelaborando o viver: o papel do grupo no cotidiano de mulheres idosas Rediseñando el vivir: el papel de los grupos en el cotidiano de mujeres ancianas Redrawing the living: the role of groups in the quotidian of elderly women

Objetiva-se compreender a motivação que impulsiona mulheres idosas a procurarem grupos de convivência, analisar e pontuar a apreensão de estratégias que contribuam para a reelaboração e reinvenção de saberes e fazeres em seus cotidianos. Estudo descritivo-exploratório com abordagem qualitativa realizado durante o primeiro semestre de 2007, com 14 mulheres de 60 anos ou mais, participantes há mais de 1 ano do grupo de convivência para idosos denominado Projeto Gugu, ofertado na cidade de Niterói/RJ. O trabalho de campo efetivou-se por meio de observação participante e de entrevistas. Os dados gerados possibilitaram a produção de categorias que expressam a significância do grupo como cenário de redimensionamento do processo de envelhecimento, de resgate e ampliação da sociabilidade e de vínculos afetivos. Conclui-se que cenários como o estudado podem recriar formas de conceber e viver o envelhecimento, tornando-o ativo e alargando a possibilidade de inclusão social.<br>El objetivo es comprender la motivación que impulsa a las mujeres mayores a buscar grupos de apoyo, analizar y puntuar la toma de estrategias que contribuyan a la reconversión y la reinvención de conocimientos y prácticas en sus vidas cotidianas. Estudio descriptivo-exploratorio con enfoque cualitativo realizado durante el primer semestre de 2007, con 14 mujeres de 60 años o más, participantes de más de 1 año de grupo de apoyo para la tercera edad llamado Proyecto Gugu, ofrecido en la ciudad de Niterói, RJ. El trabajo de campo se llevó a cabo a través de la observación participante y entrevistas. Los datos obtenidos permitieron la producción de las categorías que expresan la importancia del grupo como una configuración para redimensionar el proceso de envejecimiento, de recuperación y expansión de la sociabilidad y lazos afectivos. Concluye-se que, los escenarios estudiados pueden volver a crear formas de diseño y el envejecimiento, lo que activa y amplía la posibilidad de la inclusión social.<br>It aims to understand the motivation that drives elderly women to seek support groups, analyze and score the seizure of strategies that contribute to the redevelopment and reinvention of knowledge and practices in their daily lives. A descriptive and exploratory qualitative approach performed during the first half of 2007, with 14 women aged 60 years or more, participants for more than 1 year of support group for seniors called Project Gugu, offered in the city of Niterói, RJ. The field work was accomplished through participant observation and interviews. Data generated enabled the production of categories that express the significance of the group as a setting for resizing of the aging process, of recovery and expansion of sociability and bonds. It is concluded that as the scenarios studied can recreate forms of design and the aging, making it active and expanding the possibility of social inclusion