Potential novel pharmacological therapies for myocardial remodelling

Left ventricular (LV) remodelling remains an important treatment target in patients after myocardial infarction (MI) and chronic heart failure (CHF). Accumulating evidence has supported the concept that beneficial effects of current pharmacological treatment strategies to improve the prognosis in these patients, such as angiotensin-converting enzyme (ACE) inhibition, angiotensin type 1 receptor blocker therapy, and beta-blocker therapy, are related, at least in part, to their effects on LV remodelling and dysfunction. However, despite modern reperfusion therapy after MI and optimized treatment of patients with CHF, LV remodelling is observed in a substantial proportion of patients and is associated with an adverse clinical outcome. These observations call for novel therapeutic strategies to prevent or even reverse cardiac remodelling. Recent insights from experimental studies have provided new targets for interventions to prevent or reverse LV remodelling, i.e. reduced endothelial nitric oxide (NO) synthase-derived NO availability, activation of cardiac and leukocyte-dependent oxidant stress pathways, inflammatory pathway activation, matrix-metalloproteinase activation, or stem cell transfer and delivery of novel paracrine factors. An important challenge in translating these observations from preclinical studies into clinical treatment strategies relates to the fact that clinical studies are designed on top of established pharmacological therapy, whereas most experimental studies have tested novel interventions without concomitant drug regimens such as ACE inhibitors or beta-blockers. Therefore, animal studies may overestimate the effect of potential novel treatment strategies on LV remodelling and dysfunction, since established pharmacological therapies may act, in part, via identical or similar signalling pathways. Nevertheless, preclinical studies provide essential information for identifying potential novel targets, and their potential drawbacks, and are required for developing novel clinical treatment strategies to prevent or reverse LV remodelling and dysfunctio

CHMP2B mutants linked to frontotemporal dementia impair maturation of dendritic spines.: CHMP2B and dendritic spines

International audienceThe highly conserved ESCRT-III complex is responsible for deformation and cleavage of membranes during endosomal trafficking and other cellular activities. In humans, dominant mutations in the ESCRT-III subunit CHMP2B cause frontotemporal dementia (FTD). The decade-long process leading to this cortical degeneration is not well understood. One possibility is that, akin to other neurodegenerative diseases, the pathogenic protein affects the integrity of dendritic spines and synapses before any neuronal death. Using confocal microscopy and 3D reconstruction, we examined whether expressing the FTD-linked mutants CHMP2B(intron5) and CHMP2B(Delta10) in cultured hippocampal neurons modified the number or structure of spines. Both mutants induced a significant decrease in the proportion of large spines with mushroom morphology, without overt degeneration. Furthermore, CHMP2B(Delta10) induced a drop in frequency and amplitude of spontaneous excitatory postsynaptic currents, suggesting that the more potent synapses were lost. These effects seemed unrelated to changes in autophagy. Depletion of endogenous CHMP2B by RNAi resulted in morphological changes similar to those induced by mutant CHMP2B, consistent with dominant-negative activity of pathogenic mutants. Thus, CHMP2B is required for spine growth. Taken together, these results demonstrate that a mutant ESCRT-III subunit linked to a human neurodegenerative disease can disrupt the normal pattern of spine development

Illustration of an extended risk analysis applied for an offshore fish farm

Escaped farmed salmon and infestation of salmon lice represent the two biggest threats to the long-term survivorship of wild salmon populations. These two issues, together with other environmental-related issues, have made it necessary for the Norwegian Government to impose stricter regulations on salmon production at sea. So far, the regulations have limited the growth expansion within some of the designated production areas and have further forced companies to move farms to more exposed locations. As one of many measures, the Norwegian Government has established a temporary license scheme, allowing the issuance of licenses for innovative solutions to combat these issues. The licensing scheme has led to the development of so-called offshore farms. These farms are designed to withstand the harsh environmental conditions at the open sea and are being perceived as a favorable solution to combat the issue of salmon lice, as well as solving the limitations in the availability of production areas near the coast. Considering that these farms are expected to increase in dimension, with larger containment of salmons, the risk of fish escape can become potentially high. While offshore farms are designed to withstand the harsh environmental conditions at the open sea, uncertainties will always be present when new technology is being introduced. An extended risk analysis was made to better account for the uncertainties of potential failures leading to fish escape incidences, using the upcoming offshore "Havfarm 1" for illustration. The risk analysis has been illustrated specifically for the farm's net pen system, where risk descriptions have been made on account of experts' belief of risk and the knowledge to which these beliefs are based. As the risk analysis, to a greater extent, considers the uncertainty dimension of risk, it is more in line with how risk has been conceptualized and measured in recent years.M-A

Transformative Learning and Faith Development in Graduate Seminary Students

This study sought to understand the transformative learning experiences and faith development of students at a graduate theological seminary. The theories of Jack Mezirow and James Fowler were used in constituting a conceptual framework. The Barnes Fowler-Scale, an instrument designed to place individuals at a particular stage of faith development, was distributed to the whole school population. Several volunteer students from faith stages 2 through 5 were selected to be interviewed. A semi-structured interview protocol was used to learn more about the interviewees’ learning experiences in seminary. The reliability of the Barnes Fowler-Scale was found to be very low with this population (a=.30). It was suggested that the instrument be used as a conversation starter, rather than as a stable indicator of faith development stage, until it had undergone more testing and revision. A pictorial model of the overall student seminary experience was constructed after analyzing the interviews using qualitative research methods. Themes in three major life roles emerged—the Seminary Setting, the Personal Role, and the Professional Roles. Some themes explored in the Seminary Setting included curriculum, Bible, reasons for graduate education, importance of community, and the juggling/balancing act. In the Personal Role, the themes of reason, spiritual practices, why that particular seminary, support of family, personality, reflection, the past, and the future were explored. The themes of academia, prior Christian education, and the best education for a minister were examined in the academic domain under Professional Roles. In the ministerial domain under Professional Roles, the following themes were reviewed: dichotomies, denomination, and women in ministry. Faith development and transformative learning were discussed in each of the three major life roles. Catalysts and supports for transformative learning and faith development were identified and explored in more detail. Recommendations for institutional and instructional practice were offered, and suggestions for further research in both faith development and transformative learning were made

Finite Element Modeling of Piezoelectric Ultrasonic Transducers

The optimization of piezoelectric ultrasonic transducers has tradisionally been done through trial and error, somewhat guided by one-dimentional simulations. This can often be a very time-consuming and expensive process, hence a more extensive simulation method is desired.A series of finite element models of piezoelectric ultrasonic transducer has been made in COMSOL Multiphysics. The initial models were designed to emulate the conditions assumed in a one-dimentional transducer model, and their validity could thus be confirmed by said model. Later models did not emulate these conditions, and a lossless model of a spherical disc with backing and a single matching layer was successfully implemented. Attemps had been made to include mechanical loss in the initial models, but was only partially achieved. All loss was thus excluded from later models. A final model with a piezoelectric layer poled in the radial direction was not successfully designed, as the varying poling direction proved to be difficult to implement

Reverse transcription-polymerase chain reaction screening for FSH receptor mRNA in rat uterine tissue

Luteinizing hormone/chorionic gonadotropin hormone receptors have been localized to extraovarian sites in the mammalian female, including uterus. In the ovary, LH receptor expression is regulated in part by the binding of FSH to its own receptor. The objective of this study was to investigate the possible uterine expression of FSH receptor mRNA in uterine tissue. Rat ovary, uterus, liver, kidney, and hypothalamus were screened for the expression of FSH receptor mRNA by means of a reverse transcription - polymerase chain reaction (RT-PCR) amplification assay. Immature rats were primed with PMSG to stimulate follicular growth and development, followed 52 hours later by an injection of hCG to induce ovulation. Rats were then sacrificed at selected times (i.e. 2, 3, 6, 10, 13 days) following PMSG treatment. Total cellular RNA was isolated from tissues and used as template for reverse transcription using avian myeloblastosis virus (AMV) reverse transcriptase and an oligonucleotide primer complementary to the rat FSH receptor cDNA sequence. The cDNA product of the RT reaction was then used as template for PGR. The primers used in the PGR were designed to specifically amplify a 761 base pair region of the FSH receptor cDNA sequence. Upon electrophoretic separation of the RT-PCR products, the 761 bp product, and thus expression of FSH receptor mRNA, was evident in ovary from each of the time points tested. The 761 bp product was not present, however, in any of the other tissue types, including human endometrium. These results suggest that FSH binding to receptor in the uterus is not involved in regulating the uterine expression of LH/CG receptors. As such, further studies are needed to determine the factors and mechanisms regulating ectopic LH/CQ receptor expression

Conditional transgenic expression of fibroblast growth factor 9 in the adult mouse heart reduces heart failure mortality after myocardial infarction

BACKGROUND: Fibroblast growth factor 9 (FGF9) is secreted from bone marrow cells, which have been shown to improve systolic function after myocardial infarction (MI) in a clinical trial. FGF9 promotes cardiac vascularization during embryonic development but is only weakly expressed in the adult heart. METHODS AND RESULTS: We used a tetracycline-responsive binary transgene system based on the α-myosin heavy chain promoter to test whether conditional expression of FGF9 in the adult myocardium supports adaptation after MI. In sham-operated mice, transgenic FGF9 stimulated left ventricular hypertrophy with microvessel expansion and preserved systolic and diastolic function. After coronary artery ligation, transgenic FGF9 enhanced hypertrophy of the noninfarcted left ventricular myocardium with increased microvessel density, reduced interstitial fibrosis, attenuated fetal gene expression, and improved systolic function. Heart failure mortality after MI was markedly reduced by transgenic FGF9, whereas rupture rates were not affected. Adenoviral FGF9 gene transfer after MI similarly promoted left ventricular hypertrophy with improved systolic function and reduced heart failure mortality. Mechanistically, FGF9 stimulated proliferation and network formation of endothelial cells but induced no direct hypertrophic effects in neonatal or adult rat cardiomyocytes in vitro. FGF9-stimulated endothelial cell supernatants, however, induced cardiomyocyte hypertrophy via paracrine release of bone morphogenetic protein 6. In accord with this observation, expression of bone morphogenetic protein 6 and phosphorylation of its downstream targets SMAD1/5 were increased in the myocardium of FGF9 transgenic mice. CONCLUSIONS: Conditional expression of FGF9 promotes myocardial vascularization and hypertrophy with enhanced systolic function and reduced heart failure mortality after MI. These observations suggest a previously unrecognized therapeutic potential for FGF9 after MI

Un-done: The historiographical dialogue between past and present

Art critic for The Nation and professor of at Columbia, Arthur C. Danto led the charge with his essay “The End of Art” in 1984 to declare the end of art. Thirty-eight years later, the awareness of colonial problematics in the elite institutionalism of art history today warrants a reanalysis of art historical ontologies of progress (and their ties to colonialism), which have seemingly disbanded in the discipline’s current rhetoric. Because Danto’s historical framework to end art focuses on progress through artistic means, does it fall short or even negate itself by missing the deconstruction of colonial afterlives still present in art institutionalism? Moreover, does Danto’s end to art ultimately reiterate colonial and imperial dictations over time, and thus undercut a historical futurity for “non-Western” “artists”? In comparing Danto’s theoretical discipline with the work of Titus Kapar, Yuki Kihara, and Jason Garcia (Okuu Pin), I present a hypothetical dialogue between the art historical constructs of time and the present investment in decolonizing art with a critique through appropriation. Kaphar’s work underlines how representation can challenge the game of identity performance for the benefit of institutions, Kihara challenges the pervasive ignorance towards stereotyping Pacific Islanders by resisting and confusing the West-East binary boundaries, while Garcia challenges the hero complex historical figures still have in popular culture even if they are academically deconstructed. Ultimately, they perform a legitimacy to an end of Western hegemony that Danto alludes to

Rescue of Aspergillus nidulans severely debilitating null mutations in ESCRT-0, I, II and III genes by inactivation of a salt-tolerance pathway allows examination of ESCRT gene roles in pH signalling.

The Aspergillus pal pathway hijacks ESCRT proteins into ambient pH signalling complexes. We show that components of ESCRT-0, ESCRT-I, ESCRT-II and ESCRT-III are nearly essential for growth, precluding assessment of null mutants for pH signalling or trafficking. This severely debilitating effect is rescued by loss-of-function mutations in two cation tolerance genes, one of which, sltA, encodes a transcription factor whose inactivation promotes hypervacuolation. Exploiting a conditional expression sltA allele, we demonstrate that deletion of vps27 (ESCRT-0), vps23 (ESCRT-I), vps36 (ESCRT-II), or vps20 or vps32 (both ESCRT-III) leads to numerous small vacuoles, a phenotype also suppressed by SltA downregulation. This situation contrasts with normal vacuoles and vacuole-associated class E compartments seen in Saccharomyces cerevisiae ESCRT null mutants. Exploiting the suppressor phenotype of sltA− mutations, we establish that Vps23, Vps36, Vps20 and Vps32 are essential for pH signalling. Phosphatidylinositol 3-phosphate-recognising protein Vps27 (ESCRT-0) is not, consistent with normal pH signalling in rabB null mutants unable to recruit Vps34 kinase to early endosomes. In contrast to the lack of pH signalling in the absence of Vps20 or Vps32, detectable signalling occurs in the absence of ESCRT-III subunit Vps24. Our data support a model in which certain ESCRT proteins are recruited to the plasma membrane to mediate pH signalling

Structure of cellular ESCRT-III spirals and their relationship to HIV budding

Abstract The ESCRT machinery along with the AAA+ ATPase Vps4 drive membrane scission for trafficking into multivesicular bodies in the endocytic pathway and for the topologically related processes of viral budding and cytokinesis, but how they accomplish this remains unclear. Using deep-etch electron microscopy, we find that endogenous ESCRT-III filaments stabilized by depleting cells of Vps4 create uniform membrane-deforming conical spirals which are assemblies of specific ESCRT-III heteropolymers. To explore functional roles for ESCRT-III filaments, we examine HIV-1 Gag-mediated budding of virus-like particles and find that depleting Vps4 traps ESCRT-III filaments around nascent Gag assemblies. Interpolating between the observed structures suggests a new role for Vps4 in separating ESCRT-III from Gag or other cargo to allow centripetal growth of a neck constricting ESCRT-III spiral. DOI: 10.7554/eLife.02184.00