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BACKGROUND: Participation has been a key issue in gerontology, geriatric care policy and practice for several years now. The relationship between participation and space plays a role in the discussion about community orientation. So far, little attention has been paid to the relationship between participation and space within residential care facilities for older people. MATERIAL AND METHODS: Qualitative data from two studies on residential care facilities for older people were secondarily analyzed by a "supra-analysis" and using qualitative content analysis with respect to participation in relation to space and space in relation to participation. RESULTS: Almost all levels of the participation ladder considered can be found with respect to the co-design of spaces, although residents with dementia are granted fewer opportunities for participation. In addition, spaces can create conditions for participation through their arrangement. Reciprocal relationships are condensed in processes of space appropriation, design and planning. If there is no access to these processes, self-determined everyday life is limited. CONCLUSION: The results contribute to a spatially related development of participation concepts because they show in which spatial contexts participation is produced in institutional settings through the interaction of different actors and how it is distributed spatially. In order to promote participation in institutions, it is important to reflect on existing possibilities for spatial appropriation, design and planning against the background of institutional framework conditions.
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Instituciones de Vida Asistida , Geriatría , Humanos , AncianoRESUMEN
BACKGROUND: Research on age and ageing is starting to consider challenges related to climate change; however, most work focuses on reaction needs rather than action possibilities of older people. MATERIAL AND METHODS: Based on a scoping review of 39 papers from the scientific literature the construction of age(ing) in the context of climate change and sustainability were analyzed and constrictions were revealed. Following these considerations, a model of "sustainable age(ing) in times of climate change" is proposed, which enables successful, active and sustainable ageing to be reconciled. RESULTS: The scoping review shows that older people are often considered as a homogeneous, vulnerable group and more or less helpless in the face of climate change. In the context of sustainability, they are attributed the role of a central cause or as part of the solution for environmental crises. The focus is broadened and contradictions and ambivalences are reconciled in this model of sustainable age(ing). DISCUSSION: Climate change can only be dealt with together. Research on age and ageing can support this on the basis of the model of sustainable age(ing) by providing important contributions to handling climate change and (re)actions regarding environmental crises.
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The role of DNA methylation in cardiomyocyte physiology and cardiac disease remains a matter of controversy. We have recently provided evidence for an important role of DNMT3A in human cardiomyocyte cell homeostasis and metabolism, using engineered heart tissue (EHT) generated from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes carrying a knockout of the de novo DNA methyltransferase DNMT3A. Unlike isogenic control EHT, knockout EHT displayed morphological abnormalities such as lipid accumulations inside cardiomyocytes associated with impaired mitochondrial metabolism, as well as functional defects and impaired glucose metabolism. Here, we analyzed the role of DNMT3A in the setting of cardiac hypertrophy. We induced hypertrophic signaling by treatment with 50 nM endothelin-1 and 20 µM phenylephrine for one week and assessed EHT contractility, morphology, DNA methylation, and gene expression. While both knockout EHTs and isogenic controls showed the expected activation of the hypertrophic gene program, knockout EHTs were protected from hypertrophy-related functional impairment. Conversely, hypertrophic treatment prevented the metabolic consequences of a loss of DNMT3A, i.e. abolished lipid accumulation in cardiomyocytes likely by partial normalization of mitochondrial metabolism and restored glucose metabolism and metabolism-related gene expression of knockout EHT. Together, these data suggest an important role of DNA methylation not only for cardiomyocyte physiology, but also in the setting of cardiac disease.
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Cardiomegalia/etiología , Cardiomegalia/metabolismo , ADN (Citosina-5-)-Metiltransferasas/deficiencia , Metabolismo Energético , Contracción Miocárdica , Miocitos Cardíacos/metabolismo , Transducción de Señal , Biomarcadores , Cardiomegalia/fisiopatología , Metilación de ADN , ADN Metiltransferasa 3A , Epigénesis Genética , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Mitocondrias Cardíacas/genética , Mitocondrias Cardíacas/metabolismo , Contracción Miocárdica/genéticaRESUMEN
BACKGROUND: DNA methylation acts as a mechanism of gene transcription regulation. It has recently gained attention as a possible therapeutic target in cardiac hypertrophy and heart failure. However, its exact role in cardiomyocytes remains controversial. Thus, we knocked out the main de novo DNA methyltransferase in cardiomyocytes, DNMT3A, in human induced pluripotent stem cells. Functional consequences of DNA methylation-deficiency under control and stress conditions were then assessed in human engineered heart tissue from knockout human induced pluripotent stem cell-derived cardiomyocytes. METHODS: DNMT3A was knocked out in human induced pluripotent stem cells by CRISPR/Cas9gene editing. Fibrin-based engineered heart tissue was generated from knockout and control human induced pluripotent stem cell-derived cardiomyocytes. Development and baseline contractility were analyzed by video-optical recording. Engineered heart tissue was subjected to different stress protocols, including serum starvation, serum variation, and restrictive feeding. Molecular, histological, and ultrastructural analyses were performed afterward. RESULTS: Knockout of DNMT3A in human cardiomyocytes had three main consequences for cardiomyocyte morphology and function: (1) Gene expression changes of contractile proteins such as higher atrial gene expression and lower MYH7/MYH6 ratio correlated with different contraction kinetics in knockout versus wild-type; (2) Aberrant activation of the glucose/lipid metabolism regulator peroxisome proliferator-activated receptor gamma was associated with accumulation of lipid vacuoles within knockout cardiomyocytes; (3) Hypoxia-inducible factor 1α protein instability was associated with impaired glucose metabolism and lower glycolytic enzyme expression, rendering knockout-engineered heart tissue sensitive to metabolic stress such as serum withdrawal and restrictive feeding. CONCLUSION: The results suggest an important role of DNA methylation in the normal homeostasis of cardiomyocytes and during cardiac stress, which could make it an interesting target for cardiac therapy.
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ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN/genética , Epigenómica/métodos , Regulación de la Expresión Génica/genética , Miocitos Cardíacos/metabolismo , Ingeniería de Tejidos/métodos , Cardiomegalia/patología , ADN Metiltransferasa 3A , HumanosRESUMEN
BACKGROUND: The study of housing and living spaces has always played a central role in sociogerontological research. For example, living environments are seen as essential influencing factors on the quality of life and personal well-being (or the lack of it) of older people. The study of the relationship between space and age(ing) is dominated by psychologically influenced environmental gerontological approaches and social area-oriented research. While environmental perspectives in gerontology focus in particular on perceptions, experiences and affects to identify the relationships between space and age(ing), social area-oriented research tends to focus on social inequalities and strategies of participation. OBJECTIVE: The results of ecogerontological approaches to affects and social area-oriented research on social inequalities are combined by means of a praxiological approach. A relational understanding of space and age is developed, which is able to focus on affects and is also sensitive to spatial exclusions based on social inequalities and which also have an affective component. This combination enables new insights into a gerontological designation of the relationship between space and age(ing). RESULTS AND CONCLUSION: Such a remapping of age(ing) makes it possible to formulate other research questions regarding constructions of space through age or age through space and to provide impulses for gerontological research perspectives that take the complex interplay of humans, artefacts and spatial arrangements into account and explore the consequences for individual persons and also for their living spaces.
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Afecto , Envejecimiento/psicología , Viviendas para Ancianos , Calidad de Vida , Anciano , Anciano de 80 o más Años , Entorno Construido , Geriatría , Disparidades en el Estado de Salud , Vivienda , Humanos , Factores Socioeconómicos , Conducta EspacialRESUMEN
BACKGROUND: Heart failure is associated with altered gene expression and DNA methylation. De novo DNA methylation is associated with gene silencing, but its role in cardiac pathology remains incompletely understood. We hypothesized that inhibition of DNA methyltransferases (DNMT) might prevent the deregulation of gene expression and the deterioration of cardiac function under pressure overload (PO). To test this hypothesis, we evaluated a DNMT inhibitor in PO in rats and analysed DNA methylation in cardiomyocytes. METHODS AND RESULTS: Young male Wistar rats were subjected to PO by transverse aortic constriction (TAC) or to sham surgery. Rats from both groups received solvent or 12.5â¯mg/kg body weight of the non-nucleosidic DNMT inhibitor RG108, initiated on the day of the intervention. After 4â¯weeks, we analysed cardiac function by MRI, fibrosis with Sirius Red staining, gene expression by RNA sequencing and qPCR, and DNA methylation by reduced representation bisulphite sequencing (RRBS). RG108 attenuated the ~70% increase in heart weight/body weight ratio of TAC over sham to 47% over sham, partially rescued reduced contractility, diminished the fibrotic response and the downregulation of a set of genes including Atp2a2 (SERCA2a) and Adrb1 (beta1-adrenoceptor). RG108 was associated with significantly lower global DNA methylation in cardiomyocytes by ~2%. The differentially methylated pathways were "cardiac hypertrophy", "cell death" and "xenobiotic metabolism signalling". Among these, "cardiac hypertrophy" was associated with significant methylation differences in the group comparison sham vs. TAC, but not significant between sham+RG108 and TAC+RG108 treatment, suggesting that RG108 partially prevented differential methylation. However, when comparing TAC and TAC+RG108, the pathway cardiac hypertrophy was not significantly differentially methylated. CONCLUSIONS: DNMT inhibitor treatment is associated with attenuation of cardiac hypertrophy and moderate changes in cardiomyocyte DNA methylation. The potential mechanistic link between these two effects and the role of non-myocytes need further clarification.
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Cardiomegalia/genética , Cardiomegalia/fisiopatología , ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , Metilación de ADN/efectos de los fármacos , Metilación de ADN/genética , Ftalimidas/farmacología , Triptófano/análogos & derivados , Análisis de Varianza , Animales , Islas de CpG/genética , Modelos Animales de Enfermedad , Fibrosis , Regulación de la Expresión Génica , Insuficiencia Cardíaca/metabolismo , Imagen por Resonancia Magnética , Masculino , Miocardio/patología , Miocitos Cardíacos/metabolismo , Ratas , Ratas Wistar , Análisis de Secuencia de ARN , Arterias Torácicas/cirugía , Triptófano/farmacología , Función VentricularRESUMEN
In this paper, I develop features of a material gerontology which are summarised in the concept of "distributed age(ing);" that is, age(ing) that is distributed across and co-constituted through meanings, roles, and identities, as well as human and non-human forms of materiality, their productive dimensions and their relations to each other. The starting point is the critique of the human-centredness of gerontological approaches and, thus, the lack of a systematic conceptual consideration of non-human forms of materiality and agency in the context of age(ing). To overcome this problem, I propose the following shifts in perspective that are inspired by actor-network theory: from human-centredness to the recognition and consideration of the material diversity of age(ing); from the critique of subject/object dualism to the symmetrisation of materialities; from the seemingly given ontology of the ageing body to the re-ontologisation of age(ing); from the critique of intentional and causal determinants to embodiment and relationality; from linearity and chronology to the plural temporalities of age(ing). I will explain these features in more detail by using breathing as an example. I will show that the concept of distributed age(ing) allows for both the generation of new insights on age(ing) by asking how, where and when age(ing) takes place and reflection on presumptions, determinants and reductions of approaches belonging to social and cultural gerontology.
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Geriatría , Humanos , EnvejecimientoRESUMEN
BACKGROUND AND OBJECTIVE: The progesterone receptor (PR) is a ligand-activated transcription factor existing in two isoforms, A (PRA) and B (PRB), resulting from alternative promoter usage. It has long been speculated that genetic variants of PR are associated with the risk for various benign and malignant diseases, but data from clinical trials and in-vitro studies remain contradictory. The most extensively studied variant is termed PROGINS and consists of an intronic 320-bp Alu insertion and two coding (Ser344Thr, Val660Leu) and one silent single nucleotide polymorphism in complete linkage disequilibrium (allele frequency in Caucasians 9-19%). Our study aimed at elucidating the functional consequences of the PROGINS-associated single nucleotide polymorphisms of PRA and PRB (i.e. Thr344 and Leu660) as compared with wild-type PR (Ser344, Val660). METHODS: The two PRA and two PRB full-length receptor variants were expressed by adenovirus in the PR-negative human breast cancer cell line T47D-Y and assayed with respect to transactivational properties, c-src activation, combined net mRNA and protein stability and hormone-binding characteristics. RESULTS: In all experiments the wild-type PR and the PROGINS variant were undistinguishable. CONCLUSION: Though there still might be tissue specific effects of the variants, our data indicate that these common PR variants do not functionally differ, which may provide a basis to explain the heterogeneous outcome of association studies.
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Expresión Génica , Polimorfismo Genético , Receptores de Progesterona/genética , Elementos Alu/genética , Neoplasias de la Mama/genética , Línea Celular Tumoral , Femenino , Expresión Génica/efectos de los fármacos , Frecuencia de los Genes , Haplotipos , Humanos , Desequilibrio de Ligamiento , Progesterona/farmacología , Regiones Promotoras Genéticas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estabilidad Proteica/efectos de los fármacos , Estabilidad del ARN/efectos de los fármacos , Receptores de Progesterona/metabolismoRESUMEN
Mechanical unloading (MU) by implantation of left ventricular assist devices (LVAD) has become clinical routine. This procedure has been shown to reverse cardiac pathological remodeling, with the underlying molecular mechanisms incompletely understood. Most studies thus far were performed in non-standardized human specimens or MU of healthy animal hearts. Our study investigates cardiac remodeling processes in sham-operated healthy rat hearts and in hearts subjected to standardized pathological pressure overload by transverse aortic constriction (TAC) prior to MU by heterotopic heart transplantation (hHTx/MU). Rats underwent sham or TAC surgery. Disease progression was monitored by echocardiography prior to MU by hHTx/MU. Hearts after TAC or TAC combined with hHTx/MU were removed and analyzed by histology, western immunoblot and gene expression analysis. TAC surgery resulted in cardiac hypertrophy and impaired cardiac function. TAC hearts revealed significantly increased cardiac myocyte diameter and mild fibrosis. Expression of hypertrophy associated genes after TAC was higher compared to hearts after hHTx/MU. While cardiac myocyte cell diameter regressed to the level of sham-operated controls in all hearts subjected to hHTx/MU, fibrotic remodeling was significantly exacerbated. Transcription of pro-fibrotic and apoptosis-related genes was markedly augmented in all hearts after hHTx/MU. Sarcomeric proteins involved in excitation-contraction coupling displayed significantly lower phosphorylation levels after TAC and significantly reduced total protein levels after hHTx/MU. Development of myocardial fibrosis, cardiac myocyte atrophy and loss of sarcomeric proteins was observed in all hearts that underwent hHTX/MU regardless of the disease state. These results may help to explain the clinical experience with low rates of LVAD removal due to lack of myocardial recovery.
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Fibrosis/cirugía , Trasplante de Corazón , Miocitos Cardíacos/patología , Animales , Cardiomegalia/patología , Cardiomegalia/cirugía , Modelos Animales de Enfermedad , Fibrosis/patología , Cardiopatías , Corazón Auxiliar , Masculino , Ratas , Trasplante HeterotópicoRESUMEN
OBJECTIVE: RGS proteins (regulators of G protein signalling) negatively regulate G protein function as GTPase activating proteins. By controlling heterotrimeric G proteins they may regulate myocardial hypertrophy and contractility. We investigated the expression of RGS proteins in the human heart and whether they take part in the pathophysiological changes of heart failure. METHODS AND RESULTS: Using RNase protection assays (RPAs) RGS2, 3L, 3S, 4, 5 and 6 were identified in the myocardium from terminally failing human hearts with dilated (DCM, n=22) or ischemic (ICM, n=18) cardiomyopathy and from nonfailing donor hearts (NF, n=9). With reverse transcriptase polymerase chain reaction in addition mRNA of RGS1, 9, 12, 14 and 16 were detectable. Compared to NF in failing LV myocardium RGS4 mRNA and protein was upregulated 2-3-fold (mRNA, 10(-21) mol/microg+/-S.E.M.: NF: 22+/-5, DCM: 51+/-10*, ICM: 37+/-8; P<0.05 vs. DCM+ICM, *P<0.05 vs. NF, P<0.05 vs. DCM+ICM; protein, % of NF+/-S.E.M.: NF: 100+/-35, DCM 266+/-60*, ICM: 205+/-64, n=5, *P<0.05 vs. NF). In contrast, RGS2, 3L, 3S, 5, 6, and 16 protein and mRNA levels did not vary between failing and NF hearts. In order to investigate the impact of RGS4 on Gq/11 mediated signalling, PLC activity was measured in human LV membranes. Recombinant RGS4 blunted the endothelin-1 (ET-1) stimulated PLC activity. When overexpressed by adenoviral mediated gene transfer in rabbit ventricular myocytes RGS4 abolished the inotropic effect of ET-1. CONCLUSION: The upregulation of RGS4 in failing human myocardium diminishes Gq/11-mediated signalling and can be involved in the desensitization of Gq/11-mediated positive inotropic effects.
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Proteínas de Unión al GTP , Proteínas Activadoras de GTPasa , Regulación de la Expresión Génica , Insuficiencia Cardíaca/metabolismo , Contracción Miocárdica/fisiología , Miocardio/metabolismo , Proteínas RGS/genética , Animales , Western Blotting , Estudios de Casos y Controles , Femenino , Expresión Génica , Ventrículos Cardíacos , Humanos , Persona de Mediana Edad , Miocardio/química , Proteínas/análisis , Proteínas RGS/análisis , Proteínas RGS/metabolismo , ARN Mensajero/análisis , Conejos , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
To date, feminist approaches to neurosciences have evaluated the debates surrounding practices of knowledge production within and research results of contemporary brain research. Consequently, neurofeminist scholars have critically examined gendered impacts of neuroscientific research. Feminist neuroscientists also develop research approaches for a more gender-appropriate neuroscientific research on several levels. Based on neurofeminist critique feminist neuroscientists aim to enrich neuroscientific work by offering methodological suggestions for a more differentiated setup of categories and experimental designs, for reflective result presentations and interpretations as well as for the analysis of result validity. Reframing neuro-epistemologies by including plasticity concepts works to uncover social influences on the gendered development of the brain and of behavior. More recently, critical work on contemporary neurocultures has highlighted the entanglements of neuroscientific research within society and the implications of 'neurofacts' for gendered cultural symbolisms, social practices, and power relations. Not least, neurofeminism critically analyses the portrayal of neuro-knowledge in popular media. This article presents on overview on neurofeminist debates and on current approaches of feminist neurosciences. The authors conclude their review by calling for a more gender-appropriate research approach that takes into account both its situatedness and reflections on the neuroscientific agenda, but also questions neurofeminist discourse in regards to uses and misuses of its concepts.
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AIMS: Atorvastatin blunts the response of cardiomyocytes to catecholamines by reducing isoprenylation of G gamma subunits. We examined whether atorvastatin exerts similar effects in vivo and protects the rat heart from harmful effects of catecholamines. METHODS AND RESULTS: Rats were treated with atorvastatin (1 or 10 mg/kg x day) or H(2)O for 14 days per gavage. All three animal groups were subjected to restraint stress on day 10 and to infusions of isoprenaline (ISO; 1 mg/kg x day) or NaCl via minipumps for the last 4 days. Heart rate was measured by telemetry, left ventricular atrial natriuretic peptide (ANP) transcript levels by RT-PCR, and left atrial contractile function in organ baths. Heart rate was similar in all six study groups. In animals pre-treated with water, infusion of ISO induced an increase in heart-to-body weight ratio (HW/BW) by approximately 20%, an increase in ANP mRNA by approximately 350%, and a reduction in the inotropic effect of isoprenaline in left atrium by approximately 50%. In animals pre-treated with high-dose atorvastatin, the effects of ISO on HW/BW, ANP, and left atrial force were approximately 40, 50, and 40% smaller, respectively. Low dose atorvastatin had similar, albeit smaller effects. Atorvastatin treatment of NaCl-infused rats had only marginal effects. In cardiac homogenates from atorvastatin-treated rats (both NaCl- and ISO-infused), G gamma and G alpha(s) were partially translocated from the membrane to the cytosol. CONCLUSION: In the rat heart, treatment with atorvastatin results in translocation of cardiac membrane G gamma and G alpha(s) to the cytosol. This mechanism might contribute to protecting the heart from harm induced by chronic isoprenaline infusion without affecting heart rate.