O Brasil na nova cartografia global da religião

Este artigo analisa as mudanças sociais, econômicas, culturais e religiosas que fizeram do Brasil um polo importante de produção do sagrado numa emergente cartografia global. Esta cartografia é policêntrica e entrecortada por uma miríade de redes transnacionais e multi-direcionais que facilitam o rápido movimento de pessoas, ideias, imagens, capitais e mercadorias. Entre os vetores que vamos examinar estão: imigrantes brasileiros que na tentativa de dar sentido ao processo deslocamento e de manter ligações transnacionais com o Brasil levam suas crenças, práticas, identidades religiosas para o estrangeiro, missionários e outros "entrepreneurs" religiosos, o turismo espiritual de estrangeiros que vão ao Brasil em busca de cura ou desenvolvimento espiritual, e as indústrias culturais, a mídia e a Internet que disseminam globalmente imagens do Brasil como uma terra exótica onde o sagrado faz parte intrínseca de sua cultura e natureza

Cardiac Hypertrophy Changes Compartmentation of cAMP in Non-Raft Membrane Microdomains

3′,5′-Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger which plays critical roles in cardiac function and disease. In adult mouse ventricular myocytes (AMVMs), several distinct functionally relevant microdomains with tightly compartmentalized cAMP signaling have been described. At least two types of microdomains reside in AMVM plasma membrane which are associated with caveolin-rich raft and non-raft sarcolemma, each with distinct cAMP dynamics and their differential regulation by receptors and cAMP degrading enzymes phosphodiesterases (PDEs). However, it is still unclear how cardiac disease such as hypertrophy leading to heart failure affects cAMP signals specifically in the non-raft membrane microdomains. To answer this question, we generated a novel transgenic mouse line expressing a highly sensitive Förster resonance energy transfer (FRET)-based biosensor E1-CAAX targeted to non-lipid raft membrane microdomains of AMVMs and subjected these mice to pressure overload induced cardiac hypertrophy. We could detect specific changes in PDE3-dependent compartmentation of β-adrenergic receptor induced cAMP in non-raft membrane microdomains which were clearly different from those occurring in caveolin-rich sarcolemma. This indicates differential regulation and distinct responses of these membrane microdomains to cardiac remodeling

A Transgenic Mouse Model of Eccentric Left Ventricular Hypertrophy With Preserved Ejection Fraction Exhibits Alterations in the Autophagy-Lysosomal Pathway

The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP) are the main proteolytic systems involved in cellular homeostasis. Since cardiomyocytes, as terminally differentiated cells, lack the ability to share damaged proteins with their daughter cells, they are especially reliant on these protein degradation systems for their proper function. Alterations of the UPS and ALP have been reported in a wide range of cardiac diseases, including cardiomyopathies. In this study, we determined whether the UPS and ALP are altered in a mouse model of eccentric left ventricular (LV) hypertrophy expressing both cyclin T1 and Gαq under the control of the cardiac-specific α-myosin heavy chain promoter (double transgenic; DTG). Compared to wild-type (WT) littermates, DTG mice showed higher end-diastolic (ED) LV wall thicknesses and diameter with preserved ejection fraction (EF). The cardiomyopathic phenotype was further confirmed by an upregulation of the fetal gene program and genes associated with fibrosis as well as a downregulation of genes involved in Ca2+ handling. Likewise, higher NT-proBNP levels were detected in DTG mice. Investigation of the UPS showed elevated steady-state levels of (poly)ubiquitinated proteins without alterations of all proteasomal activities in DTG mice. Evaluation of ALP key marker revealed a mixed pattern with higher protein levels of microtubule-associated protein 1 light chain 3 beta (LC3)-I and lysosomal-associated membrane protein-2, lower protein levels of beclin-1 and FYVE and coiled-coil domain-containing protein 1 (FYCO1) and unchanged protein levels of p62/SQSTM1 in DTG mice when compared to WT. At transcriptional level, a > 1.2-fold expression was observed for Erbb2, Hdac6, Lamp2, Nrg1, and Sqstm1, while a < 0.8-fold expression was revealed for Fyco1 in DTG mice. The results related to the ALP suggested overall a repression of the ALP during the initiation process, but an induction of the ALP at the level of autophagosome-lysosome fusion and the delivery of ubiquitinated cargo to the ALP for degradation

I-1-deficiency negatively impacts survival in a cardiomyopathy mouse model

Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, diastolic dysfunction and increased interstitial fibrosis. Current treatment is based on beta-adrenoceptor (AR) and calcium channel blockers. Since mice deficient of protein phosphatase-1 inhibitor-1 (I-1), an amplifier in beta-AR signalling, were protected from pathological adrenergic stimulation in vivo, we hypothesized that I-1 ablation could result in an improved outcome in a HCM mouse model. We crossed mice deficient of I-1 with homozygous myosin-binding protein C knock-out (Mybpc3 KO) mice exhibiting cardiac dilatation and reduced survival. Unexpectedly, survival time was shorter in double I-1/Mybpc3 KO than in single Mybpc3 KO mice. Longitudinal echocardiographic assessment revealed lower fractional area change, and higher diastolic left ventricular inner dimensions and end-diastolic volumes in Mybpc3 KO than in WT mice. In comparison to Mybpc3 KO, double I-1/Mybpc3 KO presented higher left ventricular end-diastolic volumes, inner dimensions and ventricular surface areas with increasing differences over time. Phosphorylation levels of PKA-downstream targets and mRNA levels of hypertrophic markers did not differ between I-1/Mybpc3 KO and single Mybpc3 KO mice, except a trend towards higher beta-myosin heavy chain levels in double I-1/Mybpc3 KO. The data indicate that interference with beta-AR signalling has no long-term benefit in this severe MYBPC3-related cardiomyopathy mouse model

Repair of Mybpc3 mRNA by 5′-trans-splicing in a Mouse Model of Hypertrophic Cardiomyopathy

International audienceRNA trans-splicing has been explored as a therapeutic option for a variety of genetic diseases, but not for cardiac genetic disease. Hypertrophic cardiomyopathy (HCM) is an autosomal-dominant disease, characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction. MYBPC3, encoding cardiac myosin-binding protein C (cMyBP-C) is frequently mutated. We evaluated the 5′-trans-splicing strategy in a mouse model of HCM carrying a Mybpc3 mutation. 5′-trans-splicing was induced between two independently transcribed molecules, the mutant endogenous Mypbc3 pre-mRNA and an engineered pre-trans-splicing molecule (PTM) carrying a FLAG-tagged wild-type (WT) Mybpc3 cDNA sequence. PTMs were packaged into adeno-associated virus (AAV) for transduction of cultured cardiac myocytes and the heart in vivo. Full-length repaired Mybpc3 mRNA represented up to 66% of total Mybpc3 transcripts in cardiac myocytes and 0.14% in the heart. Repaired cMyBP-C protein was detected by immunoprecipitation in cells and in vivo and exhibited correct incorporation into the sarcomere in cardiac myocytes. This study provides (i) the first evidence of successful 5′-trans-splicing in vivo and (ii) proof-of-concept of mRNA repair in the most prevalent cardiac genetic disease. Since current therapeutic options for HCM only alleviate symptoms, these findings open new horizons for causal therapy of the severe forms of the disease

Cardiac repair in guinea pigs with human engineered heart tissue from induced pluripotent stem cells

Myocardial injury results in a loss of contractile tissue mass that, in the absence of efficient regeneration, is essentially irreversible. Transplantation of human pluripotent stem cell–derived cardiomyocytes has beneficial but variable effects. We created human engineered heart tissue (hEHT) strips from human induced pluripotent stem cell (hiPSC)–derived cardiomyocytes and hiPSC-derived endothelial cells. The hEHTs were transplanted onto large defects (22% of the left ventricular wall, 35% decline in left ventricular function) of guinea pig hearts 7 days after cryoinjury, and the results were compared with those obtained with human endothelial cell patches (hEETs) or cell-free patches. Twenty-eight days after transplantation, the hearts repaired with hEHT strips exhibited, within the scar, human heart muscle grafts, which had remuscularized 12% of the infarct area. These grafts showed cardiomyocyte proliferation, vascularization, and evidence for electrical coupling to the intact heart tissue in a subset of engrafted hearts. hEHT strips improved left ventricular function by 31% compared to that before implantation, whereas the hEET or cell-free patches had no effect. Together, our study demonstrates that three-dimensional human heart muscle constructs can repair the injured heart

Ranolazine antagonizes catecholamine-induced dysfunction in isolated cardiomyocytes, but lacks long-term therapeutic effectsin vivoin a mouse model of hypertrophic cardiomyopathy

Aims Hypertrophic cardiomyopathy (HCM) is often accompanied by increased myofilament Ca2+ sensitivity and diastolic dysfunction. Recent findings indicate increased late Na+ current density in human HCM cardiomyocytes. Since ranolazine has the potential to decrease myofilament Ca2+ sensitivity and late Na+ current, we investigated its effects in an Mybpc3-targeted knock-in (KI) mouse model of HCM. Methods and results Unloaded sarcomere shortening and Ca2+ transients were measured in KI and wild-type (WT) cardiomyocytes. Measurements were performed at baseline (1 Hz) and under increased workload (30 nM isoprenaline (ISO), 5 Hz) in the absence or presence of 10 mu M ranolazine. KI myocytes showed shorter diastolic sarcomere length at baseline, stronger inotropic response to ISO, and drastic drop of diastolic sarcomere length under increased workload. Ranolazine attenuated ISO responses in WT and KI cells and prevented workload-induced diastolic failure in KI. Late Na+ current density was diminished and insensitive to ranolazine in KI cardiomyocytes. Ca2+ sensitivity of skinned KI trabeculae was slightly decreased by ranolazine. Phosphorylation analysis of cAMP-dependent protein kinase A-target proteins and ISO concentration-response measurements on muscle strips indicated antagonism at beta-adrenoceptors with 10 mu M ranolazine shifting the ISO response by 0.6 log units. Six-month treatment with ranolazine (plasma level > 20 mu M) demonstrated a beta-blocking effect, but did not reverse cardiac hypertrophy or dysfunction in KI mice. Conclusion Ranolazine improved tolerance to high workload in mouse HCM cardiomyocytes, not by blocking late Na+ current, but by antagonizing beta-adrenergic stimulation and slightly desensitizing myofilaments to Ca2+. This effect did not translate in therapeutic efficacy in vivo

Spiritual War: Revival, Child Prophesies, and a Battle Over Sorcery in Vanuatu

Sorcery and Christianity have been in an intimate and seemingly opposing relationship on the small Ahamb Island in Vanuatu for more than a century. While sorcery is seen as the most potent threat to the good life as it brings suffering and death, Christianity appears as the main tool to address this and other problems of cosmological and social character. During a turbulent time on the island in 2014, a Christian charismatic revival, largely led by children, became the subject of hope for change on Ahamb. A main event within the revival was a dramatic spiritual war that confronted the island community with the plain and unvarnished realities of good and evil, of God and sorcery, while revealing secrets that literally became a question of life and death