Atrial fibrillation (AF) is the most common clinical tachyarrhythmia associated with significant morbidity and mortality and is expected to affect approximately 30 million North Americans and Europeans by 2050. AF is a persistent disease, caused by progressive, often age-related, derailment of proteostasis resulting in structural remodeling of the atrial cardiomyocytes. It has been widely acknowledged that the progressive nature of the disease hampers the effective functional conversion to sinus rhythm in patients and explains the limited effect of current drug therapies. Therefore, research is directed at preventing new-onset AF by limiting the development of substrates underlying AF promotion. Upstream therapy refers to the use of drugs that modify the atrial substrate- or target-specific mechanisms of AF, with the ultimate aim to prevent the occurrence (primary prevention) and recurrence of the arrhythmia following (spontaneous) conversion and to prevent the progression of AF (secondary prevention). Recently, we observed that heat shock protein (HSP)-inducing drugs, such as geranylgeranylacetone, prevent derailment of proteostasis and remodeling of cardiomyocytes and thereby attenuate the AF substrate in cellular, Drosophila melanogaster, and animal experimental models. Also, correlative data from human studies were consistent with a protective role of HSPs in preventing the progression from paroxysmal AF to permanent AF and in the recurrence of AF. In this review, we discuss novel HSP-inducing compounds as emerging therapeutics for the primary and secondary prevention of AF. © 2012 Elsevier Inc.
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According to the "membrane sensor" hypothesis, the membrane's physical properties and microdomain organization play an initiating role in the heat shock response. Clinical conditions such as cancer, diabetes and neurodegenerative diseases are all coupled with specific changes in the physical state and lipid composition of cellular membranes and characterized by altered heat shock protein levels in cells suggesting that these "membrane defects" can cause suboptimal hsp-gene expression. Such observations provide a new rationale for the introduction of novel, heat shock protein modulating drug candidates. Intercalating compounds can be used to alter membrane properties and by doing so normalize dysregulated expression of heat shock proteins, resulting in a beneficial therapeutic effect for reversing the pathological impact of disease. The membrane (and lipid) interacting hydroximic acid (HA) derivatives discussed in this review physiologically restore the heat shock protein stress response, creating a new class of "membrane-lipid therapy" pharmaceuticals. The diseases that HA derivatives potentially target are diverse and include, among others, insulin resistance and diabetes, neuropathy, atrial fibrillation, and amyotrophic lateral sclerosis. At a molecular level HA derivatives are broad spectrum, multi-target compounds as they fluidize yet stabilize membranes and remodel their lipid rafts while otherwise acting as PARP inhibitors. The HA derivatives have the potential to ameliorate disparate conditions, whether of acute or chronic nature. Many of these diseases presently are either untreatable or inadequately treated with currently available pharmaceuticals. Ultimately, the HA derivatives promise to play a major role in future pharmacotherapy.
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Background: The heat shock protein (HSP) inducer, geranylgeranylacetone (GGA), was previously found to protect against atrial fibrillation (AF) remodeling in experimental model systems. Clinical application of GGA in AF is limited, due to low systemic concentrations owing to the hydrophobic character of GGA.Objectives: To identify novel HSP-inducing compounds, with improved physicochemical properties, that prevent contractile dysfunction in experimental model systems for AF.
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In this study we tested 39 Lactococcus lactis strains isolated from diverse habitats for their robustness under heat and oxidative stress, demonstrating high diversity in survival (up to 4 log units). Strains with an L. lactis subsp. lactis phenotype generally displayed more-robust phenotypes than strains with an L. lactis subsp. cremoris phenotype, whereas the habitat from which the strains had been isolated did not appear to influence stress survival. Comparison of the stress survival phenotypes with already available comparative genomic data sets revealed that the absence or presence of specific genes, including genes encoding a GntR family transcriptional regulator, a manganese ABC transporter permease, a cellobiose phosphotransferase system (PTS) component, the FtsY protein, and hypothetical proteins, was associated with heat or oxidative stress survival. Finally, 14 selected strains also displayed diversity in survival after spray drying, ranging from 20% survival for the most robust strains, which appears acceptable for industrial application, to 0.1% survival for the least-tolerant strains. The high and low levels of survival upon spray drying correlated clearly with the combined robustness under heat and oxidative stress. These results demonstrate the relevance of screening culture collections for robustness under heat and oxidative stress on top of the typical screening for acidifying and flavor-forming properties. © 2014, American Society for Microbiology.
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Global society is confronted with various challenges: climate change should be mitigated, and society should adapt to the impacts of climate change, resources will become scarcer and hence resources should be used more efficiently and recovered after use, the growing world population and its growing wealth create unprecedented emissions of pollutants, threatening public health, wildlife and biodiversity. This paper provides an overview of the challenges and risks for sewage systems, next to some opportunities and chances that these developments pose. Some of the challenges are emerging from climate change and resource scarcity, others come from the challenges emerging from stricter regulation of emissions. It also presents risks and threats from within the system, next to external influences which may affect the surroundings of the sewage systems. It finally reflects on barriers to respond to these challenges. http://dx.doi.org/10.13044/j.sdewes.d6.0231 LinkedIn: https://www.linkedin.com/in/sabineeijlander/ https://www.linkedin.com/in/karel-mulder-163aa96/
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Implementation of reliable methodologies allowing Reduction, Refinement, and Replacement (3Rs) of animal testing is a process that takes several decades and is still not complete. Reliable methods are essential for regulatory hazard assessment of chemicals where differences in test protocol can influence the test outcomes and thus affect the confidence in the predictive value of the organisms used as an alternative for mammals. Although test guidelines are common for mammalian studies, they are scarce for non-vertebrate organisms that would allow for the 3Rs of animal testing. Here, we present a set of 30 reporting criteria as the basis for such a guideline for Developmental and Reproductive Toxicology (DART) testing in the nematode Caenorhabditis elegans. Small organisms like C. elegans are upcoming in new approach methodologies for hazard assessment; thus, reliable and robust test protocols are urgently needed. A literature assessment of the fulfilment of the reporting criteria demonstrates that although studies describe methodological details, essential information such as compound purity and lot/batch number or type of container is often not reported. The formulated set of reporting criteria for C. elegans testing can be used by (i) researchers to describe essential experimental details (ii) data scientists that aggregate information to assess data quality and include data in aggregated databases (iii) regulators to assess study data for inclusion in regulatory hazard assessment of chemicals.
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This year, OPTIMAX was warmly welcomed by University College Dublin. For the sixth time students and teachers from Europe, South Africa, South America and Canada have come together enthusiastically to do research in the Radiography domain. As in previous years, there were several research groups consisting of PhD-, MSc- and BSc students and tutors from the OPTIMAX partner Universities or on invitation by partner Universities. OPTIMAX 2018 was partly funded by the partner Universities and partly by the participants.
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Urban tourism increasingly focuses on the role of hospitality in cities, evolving from a means to strengthen tourism as a ‘product’, towards a focus on tourism as an opportunity for revitalization and transformation of destinations. In this context, cities are considered dynamic communities in which ‘hosts’ (entrepreneurs, residents, municipalities) and ‘guests’ (visitors, tourists) co-habitate and co-create multisensorial experiences. This shift in focus comes hand in hand with increasing awareness of competitiveness and sustainability of destinations, expressed by a harmonious relationship between city residents and visitors and a balanced usage of the city as a shared resource. This is of great importance, given the intense usage of urban spaces – the city center of Amsterdam being an illustrative example – and the multiple purposes that these spaces represent for different stakeholders. This paper presents the outcome of a review study into city hospitality experience indicators. We integrate these indicators as a basis for the development of a new scale for measuring the effectiveness of hospitality interventions in relation to outcome variables such as satisfaction and net promotor score (NPS). We thereby provide an important means for scholars and practitioners to develop sustainable tourism actions inclusive of local community interests, in support of efforts toward more balanced city experiences among all stakeholders.
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