Cyclotide–membrane interactions: Defining factors of membrane binding, depletion and disruption

AbstractThe cyclotide family of plant-derived peptides is defined by a cyclic backbone and three disulfide bonds locked into a cyclic cystine knot. They display a diverse range of biological activities, many of which have been linked to an ability to target biological membranes. In the current work, we show that membrane binding and disrupting properties of prototypic cyclotides are dependent on lipid composition, using neutral (zwitterionic) membranes with or without cholesterol and/or anionic lipids. Cycloviolacin O2 (cyO2) caused potent membrane disruption, and showed selectivity towards anionic membranes, whereas kalata B1 and kalata B2 cyclotides were significantly less lytic towards all tested model membranes. To investigate the role of the charged amino acids of cyO2 in the membrane selectivity, these were neutralized using chemical modifications. In contrast to previous studies on the cytotoxic and antimicrobial effects of these derivatives, the Glu6 methyl ester of cyO2 was more potent than the native peptide. However, using membranes of Escherichia coli lipids gave the opposite result: the activity of the native peptide increased 50-fold. By using a combination of ellipsometry and LC-MS, we demonstrated that this unusual membrane specificity is due to native cyO2 extracting preferentially phosphatidylethanolamine-lipids from the membrane, i.e., PE-C16:0/cyC17:0 and PE-C16:0/C18:1

Implementation of the EU environmental law in the context of cross-border damage to marine environment: case study of the Baltic Sea

The purpose of the thesis is to analyse the applicability and implementation of the European Union (EU) environmental law to cross-border damage to the marine environment, also assessing their applicability to the Baltic Sea as well as progress on implementation, and additionally to review the relationship between the EU law and HELCOM – intergovernmental body responsible for carrying out the obligations under the Helsinki Convention on the Protection of the Marine Environment of the Baltic Sea

Opti-Owecs: Final Report Vol. 0: Executive Summary

It was the particular mission of the project 'Structural and Economic Optimisation of Bottom-Mounted Offshore Wind Energy Converters' (Opti-OWECS) to extend the state-of-the-art, to determine required methods and to demonstrate practical solutions which will significantly reduce the electricity cost. This will facilitate the exploitation of true offshore sites on a commercial base in a medium time scale of 5 to 10 years from now. In several fields, e.g. support structure design, installation of the offshore wind energy converters, operation and maintenance, dynamics of the entire offshore wind energy converter, structural reliability considerations, etc., the study demonstrated new propositions which will contribute significantly to a mature offshore wind energy technology. This was achieved due to a smooth cooperation of leading industrial engineers and researchers from the wind energy field, offshore technology and power management. Moreover, an innovative design methodology devoted particularly to offshore wind energy conversion systems (OWECS) was developed and successfully demonstrated. The so-called 'integrated OWECS design approach' considers the components of an offshore wind farm as parts of an entire system. Therefore interactions between sub-systems are considered in a complete and practical form as possible so that the design solution is governed by overall criteria such as: levelised production costs, adaptation to the actual site conditions, dynamics of the entire system, installation effort as well as OWECS availability. Furthermore, a novel OWECS cost model was developed which led among other work of the project to the identification of the main cost drivers, i.e. annual mean wind speed, distance from shore, operation and maintenance aspects including wind turbine reliability and availability. A link between these results and a database of the offshore wind energy potential in Europe, developed by the previous Joule project JOUR 0072, facilitated the first estimate of energy cost consistent over entire regions of Northern Europe. The European Commission has supported the project in the scope of the framework of the Non Nuclear Energy Programme JOULE Ill (Research and Technical Development) under grant JOR3-CT95-0087

Amblyopia and quality of life: a systematic review

Background/Aims Amblyopia is a common condition which can affect up to 5% of the general population. The health-related quality of life (HRQoL) implications of amblyopia and/or its treatment have been explored in the literature. Methods A systematic literature search was undertaken (16th-30th January 2007) to identify the HRQoL implications of amblyopia and/or its treatment. Results A total of 25 papers were included in the literature review. The HRQoL implications of amblyopia related specifically to amblyopia treatment, rather than the condition itself. These included the impact upon family life; social interactions; difficulties undertaking daily activities; and feelings and behaviour. The identified studies adopted a number of methodologies. The study populations included; children with the condition; parents of children with amblyopia; and adults who had undertaken amblyopia treatment as a child. Some studies developed their own measures of HRQoL, and others determined HRQoL through proxy measures. Conclusions The reported findings of the HRQoL implications are of importance when considering the management of cases of amblyopia. Further research is required to assess the immediate and long-term effects of amblyopia and/or its treatment upon HRQoL using a more standardised approach

Natural products in modern life science

With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure–activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific questions in Nature can be of value to increase the attraction for young students in modern life science

Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis

Peer reviewedPublisher PD

Evaluation of emergency department performance:A systematic review on recommended performance and quality-in-care measures

BACKGROUND: Evaluation of emergency department (ED) performance remains a difficult task due to the lack of consensus on performance measures that reflects high quality, efficiency, and sustainability. AIM: To describe, map, and critically evaluate which performance measures that the published literature regard as being most relevant in assessing overall ED performance. METHODS: Following the PRISMA guidelines, a systematic literature review of review articles reporting accentuated ED performance measures was conducted in the databases of PubMed, Cochrane Library, and Web of Science. Study eligibility criteria includes: 1) the main purpose was to discuss, analyse, or promote performance measures best reflecting ED performance, 2) the article was a review article, and 3) the article reported macro-level performance measures, thus reflecting an overall departmental performance level. RESULTS: A number of articles addresses this study’s objective (n = 14 of 46 unique hits). Time intervals and patient-related measures were dominant in the identified performance measures in review articles from US, UK, Sweden and Canada. Length of stay (LOS), time between patient arrival to initial clinical assessment, and time between patient arrivals to admission were highlighted by the majority of articles. Concurrently, “patients left without being seen” (LWBS), unplanned re-attendance within a maximum of 72 hours, mortality/morbidity, and number of unintended incidents were the most highlighted performance measures that related directly to the patient. Performance measures related to employees were only stated in two of the 14 included articles. CONCLUSIONS: A total of 55 ED performance measures were identified. ED time intervals were the most recommended performance measures followed by patient centeredness and safety performance measures. ED employee related performance measures were rarely mentioned in the investigated literature. The study’s results allow for advancement towards improved performance measurement and standardised assessment across EDs

AMP Is a True Physiological Regulator of AMP-Activated Protein Kinase by Both Allosteric Activation and Enhancing Net Phosphorylation

SummaryWhile allosteric activation of AMPK is triggered only by AMP, binding of both ADP and AMP has been reported to promote phosphorylation and inhibit dephosphorylation at Thr172. Because cellular concentrations of ADP and ATP are higher than AMP, it has been proposed that ADP is the physiological signal that promotes phosphorylation and that allosteric activation is not significant in vivo. However, we report that: AMP is 10-fold more potent than ADP in inhibiting Thr172 dephosphorylation; only AMP enhances LKB1-induced Thr172 phosphorylation; and AMP can cause >10-fold allosteric activation even at concentrations 1–2 orders of magnitude lower than ATP. We also provide evidence that allosteric activation by AMP can cause increased phosphorylation of acetyl-CoA carboxylase in intact cells under conditions in which there is no change in Thr172 phosphorylation. Thus, AMP is a true physiological regulator of AMPK, and allosteric regulation is an important component of the overall activation mechanism