Amiodarone disrupts cholesterol biosynthesis pathway and causes accumulation of circulating desmosterol by inhibiting 24-dehydrocholesterol reductase

Background We have earlier reported that amiodarone, a potent and commonly used antiarrhythmic drug increases serum desmosterol, the last precursor of cholesterol, in 20 cardiac patients by an unknown mechanism. Objective Here, we extended our study to a large number of cardiac patients of heterogeneous diagnoses, evaluated the effects of combining amiodarone and statins (inhibitors of cholesterol synthesis at the rate-limiting step of hydroxy-methyl-glutaryl CoA reductase) on desmosterol levels and investigated the mechanism(s) by which amiodarone interferes with the metabolism of desmosterol using in vitro studies. Methods and Results We report in a clinical case-control setting of 236 cardiac patients (126 with and 110 without amiodarone treatment) that amiodarone medication is accompanied by a robust increase in serum desmosterol levels independently of gender, age, body mass index, cardiac and other diseases, and the use of statins. Lipid analyses in patient samples taken before and after initiation of amiodarone therapy showed a systematic increase of desmosterol upon drug administration, strongly arguing for a direct causal link between amiodarone and desmosterol accumulation. Mechanistically, we found that amiodarone resulted in desmosterol accumulation in cultured human cells and that the compound directly inhibited the 24-dehydrocholesterol reductase (DHCR24) enzyme activity. Conclusion These novel findings demonstrate that amiodarone blocks the cholesterol synthesis pathway by inhibiting DHCR24, causing a robust accumulation of cellular desmosterol in cells and in the sera of amiodarone-treated patients. It is conceivable that the antiarrhythmic potential and side effects of amiodarone may in part result from inhibition of the cholesterol synthesis pathway.Peer reviewe

De novo assembly of genomes from long sequence reads reveals uncharted territories of Propionibacterium freudenreichii

Background: Propionibacterium freudenreichii is an industrially important bacterium granted the Generally Recognized as Safe (the GRAS) status, due to its long safe use in food bioprocesses. Despite the recognized role in the food industry and in the production of vitamin B12, as well as its documented health-promoting potential, P. freudenreichii remained poorly characterised at the genomic level. At present, only three complete genome sequences are available for the species. Results: We used the PacBio RS II sequencing platform to generate complete genomes of 20 P. freudenreichii strains and compared them in detail. Comparative analyses revealed both sequence conservation and genome organisational diversity among the strains. Assembly from long reads resulted in the discovery of additional circular elements: two putative conjugative plasmids and three active, lysogenic bacteriophages. It also permitted characterisation of the CRISPR-Cas systems. The use of the PacBio sequencing platform allowed identification of DNA modifications, which in turn allowed characterisation of the restriction-modification systems together with their recognition motifs. The observed genomic differences suggested strain variation in surface piliation and specific mucus binding, which were validated by experimental studies. The phenotypic characterisation displayed large diversity between the strains in ability to utilise a range of carbohydrates, to grow at unfavourable conditions and to form a biofilm. Conclusion: The complete genome sequencing allowed detailed characterisation of the industrially important species, P. freudenreichii by facilitating the discovery of previously unknown features. The results presented here lay a solid foundation for future genetic and functional genomic investigations of this actinobacterial species.Peer reviewe

Proceedings of the 10th International

ABSTRACT Intensive Programs (IP) have been organized by four European partner universities. The main idea is to gather approximately 40 students and 15 teachers together for three weeks to conceive, design, implement, and operate embedded system prototypes. Self-evaluation is an integrated part of the IP. The results of the evaluations are used to improve the concept, content, and practical arrangements for the next IP. The same partner network has organized similar intensive projects with different topics, but using the same internal evaluation method. We can recognize issues which make the IP successful and are common to the intensive project concept, independent of the topic. Based on the evaluation material, we will make some recommendations that can help organize similar intensive projects in the future

Microfluidic analysis techniques for safety assessment of pharmaceutical nano- and microsystems

This chapter reviews the evolution of microfabrication methods and materials, applicable to manufacturing of micro total analysis systems (or lab‐on‐a‐chip), from a general perspective. It discusses the possibilities and limitations associated with microfluidic cell culturing, or so called organ‐on‐a‐chip technology, together with selected examples of their exploitation to characterization of pharmaceutical nano‐ and microsystems. Materials selection plays a pivotal role in terms of ensuring the cell adhesion and viability as well as defining the prevailing culture conditions inside the microfluidic channels. The chapter focuses on the hepatic safety assessment of nanoparticles and gives an overview of the development of microfluidic immobilized enzyme reactors that could facilitate examination of the hepatic effects of nanomedicines under physiologically relevant conditions. It also provides an overview of the future prospects regarding system‐level integration possibilities facilitated by microfabrication of miniaturized separation and sample preparation systems as integral parts of microfluidic in vitro models.Non peer reviewe

The impacts of environmental warming on Odonata: a review

Climate change brings with it unprecedented rates of increase in environmental temperature, which will have major consequences for the earth's flora and fauna. The Odonata represent a taxon that has many strong links to this abiotic factor due to its tropical evolutionary history and adaptations to temperate climates. Temperature is known to affect odonate physiology including life-history traits such as developmental rate, phenology and seasonal regulation as well as immune function and the production of pigment for thermoregulation. A range of behaviours are likely to be affected which will, in turn, influence other parts of the aquatic ecosystem, primarily through trophic interactions. Temperature may influence changes in geographical distributions, through a shifting of species' fundamental niches, changes in the distribution of suitable habitat and variation in the dispersal ability of species. Finally, such a rapid change in the environment results in a strong selective pressure towards adaptation to cope and the inevitable loss of some populations and, potentially, species. Where data are lacking for odonates, studies on other invertebrate groups will be considered. Finally, directions for research are suggested, particularly laboratory studies that investigate underlying causes of climate-driven macroecological patterns

Ipomoea batatas (L.) Lam.: a rich source of lipophilic phytochemicals

The lipophilic extracts from the storage root of 13 cultivars of sweet potato (Ipomoea batatas (L.) Lam.) were evaluated by gas chromatography-mass spectrometry with the aim to valorize them and offer information on their nutritional properties and potential health benefits. The amount of lipophilic extractives ranged from 0.87 to 1.32% dry weight. Fatty acids and sterols were the major families of compounds identified. The most abundant saturated and unsaturated fatty acids were hexadecanoic acid (182-428 mg/kg) and octadeca-9,12-dienoic acid (133-554 mg/kg), respectively. β-Sitosterol was the principal phytosterol, representing 55.2-77.6% of this family, followed by campesterol. Long-chain aliphatic alcohols and α-tocopherol were also detected but in smaller amounts. The results suggest that sweet potato should be considered as an important dietary source of lipophilic phytochemicals.info:eu-repo/semantics/publishedVersio

Challenging fear: Chemical alarm signals are not causing morphology changes in crucian carp (Carassius carassius)

Crucian carp develops a deep body in the presence of chemical cues from predators, which makes the fish less vulnerable to gape-limited predators. The active components originate in conspecifics eaten by predators, and are found in the filtrate of homogenised conspecific skin. Chemical alarm signals, causing fright reactions, have been the suspected inducers of such morphological changes. We improved the extraction procedure of alarm signals by collecting the supernatant after centrifugation of skin homogenates. This removes the minute particles that normally make a filtered sample get turbid. Supernatants were subsequently diluted and frozen into ice-cubes. Presence of alarm signals was confirmed by presenting thawed ice-cubes to crucian carp in behaviour tests at start of laboratory growth experiments. Frozen extracts were added further on three times a week. Altogether, we tested potential body-depth-promoting properties of alarm signals twice in the laboratory and once in the field. Each experiment lasted for a minimum of 50 days. Despite growth of crucian carp in all experiments, no morphology changes were obtained. Accordingly, we conclude that the classical alarm signals that are releasing instant fright reactions are not inducing morphological changes in this species. The chemical signals inducing a body-depth increase are suspected to be present in the particles removed during centrifugation (i.e., in the precipitate). Tissue particles may be metabolized by bacteria in the intestine of predators, resulting in water-soluble cues. Such latent chemical signals have been found in other aquatic organisms, but hitherto not reported in fishe