Untersuchungen zur Induktion der epithelialen Abwehr durch Pseudomonas aeruginosa

Pseudomonas aeruginosa-Infektionen führen in epithelialen Zellen zu einer Aktivierung des Immunsystems. Die Expression des antimikrobiellen Peptids humanes beta-Defensin-2 und des Zytokins Interleukin-8 in kultivierten Keratinozyten kann durch Stimulation mit Pseudomonas aeruginosa-Kulturüberständen induziert werden. In dieser Arbeit wurde Flagellin, das monomere Filamentprotein des Flagellums, mit Hilfe massenspektrometrischer Untersuchungen und Western-Blot-Analysen als induzierender Faktor identifiziert. Eine Freisetzung des Flagellins von der äußeren bakteriellen Membran erfolgte durch oberflächenmodulierende Eigenschaften des durch Pseudomonas aeruginosa produzierten „Biosurfactant“ Rhamnolipid. Immunhistochemische Untersuchungen an Hautpräparaten deuten ferner darauf hin, dass Rhamnolipide zusätzlich den Transport des Flagellins durch die physikalische Barriere der Haut vermitteln können

Effect of Solar Radiation on Current-Carrying Capacity of PVC-insulated Power Cables – the Numerical Point of View

Power cables are usually buried in the soil, which results in their relatively high current-carrying capacity. However, there are cases in which the starting/final section of a cable line runs along a pole of an overhead power line. Power cables can be directly exposed to solar radiation then, and this negatively influences their current-carrying capacity as well as estimated life of the cables’ insulation. An analysis of thermal phenomena in PVC-insulated low-voltage power cables, exposed to solar radiation, is conducted in the paper. Current-carrying capacity of an example cable system, for various placements of the cables, is evaluated. The analysis has shown that solar radiation may significantly reduce current-carrying capacity of PVC-insulated cables. A possible method of protection of cables against solar radiation, and its effectiveness, is presented. To investigate the mentioned thermal phenomena, a Computational Fluid Dynamics (CFD) has been used

Entwicklung neuer Strategien zur Überwindung transporter-basierter Pharmakoresistenz bei Epilepsien

Epilepsien zählen zu den häufigsten neurologischen Erkrankungen bei Hund, Katze und Mensch. Sie sind mit einer fortschreitenden Schädigung des zentralen Nervensystems und mit erheblichen Einschränkungen im täglichen Leben verbunden. Trotz Entwicklung zahlreicher neuer Antiepileptika über die letzten Jahrzehnte spricht etwa ein Drittel der Veterinär- und Humanpatienten nicht auf eine Pharmakotherapie an. Diese Pharmakoresistenz von Epilepsien stellt ein schwerwiegendes und bisher ungelöstes Problem für die betroffenen Patienten dar und macht neue Therapiestrategien dringend erforderlich. Eine Ursache der Pharmakoresistenz bei Epilepsien stellt die Überexpression von Multidrug-Transportern in den Endothelzellen der Blut-Hirn-Schranke dar. Die physiologische Funktion dieser Efflux-Transporter besteht darin, den Eintritt von Xenobiotika in das Gewebe bestimmter Körperregionen zu verhindern. Eine Überexpression bei pharmakoresistenten Patienten führt zu einem vermehrten Efflux-Transport von Antiepileptika in die Blutbahn, so dass trotz therapeutischer Plasma-Konzentrationen keine ausreichenden Wirkstoffspiegel im Bereich des epileptischen Fokus erreicht werden können. Auf der Basis der Multidrug-Transporter-Hypothese wurden im Rahmen dieser Dissertation zwei mögliche neue Behandlungsstrategien zur Überwindung der Pharmakoresistenz von Epilepsien im Tiermodell untersucht. In den letzten Jahrzehnten wurde ein direkter intra- oder extraneuronaler Transport von Substanzen nach intranasaler (i.n.) Applikation aus der Nasenhöhle in das Gehirn wiederholt beschrieben. Diese Möglichkeit zur Umgehung der Blut-Hirn-Schranke und der dort lokalisierten Efflux-Transporter wurde im Rahmen dieser Arbeit mittels Untersuchungen zur Gehirngängigkeit von Antiepileptika nach i.n.-Applikation im Rattenmodell näher überprüft. Mikrodialyse-Untersuchungen zur Bestimmung der Extrazellulär-Konzentration von Phenobarbital, Lamotrigin und Carbamazepin im Bereich des frontalen Cortex ergaben keine Hinweise auf einen effektiveren Substanztransport nach i.n.-Applikation im Vergleich zur intravenösen (i.v.) Applikationsform. Die Bestimmung der Phenobarbital-Konzentration im Gesamtgehirngewebe nach i.n.- und i.v.-Verabreichung resultierte ebenfalls in gleichwertigen Konzentrationen. Die Untersuchung einzelner Gehirnregionen 10 min nach i.n. Applikation ergab für den Bulbus olfactorius eine signifikant höhere Gehirn-Plasma-Ratio im Vergleich zur i.v.-Applikation. Im Amygdala-Kindling-Modell der Temporallappen-Epilepsie konnte eine dosisabhängige antikonvulsive Wirkung nach i.n.-Applikation von Phenobarbital beobachtet werden, die in vergleichbarem Maße auch nach i.v.-Applikation zu beobachten war. Insgesamt geben die Untersuchungsergebnisse keinen Hinweis darauf, dass ein direkter Transport von Antiepileptika aus der Nasenhöhle in das Gehirn in therapeutisch relevantem Ausmaß stattfindet und eine Umgehung der Blut-Hirn-Schranke auf diese Weise möglich ist. Eine besondere Eignung der i.n.-Applikation zur Therapie pharmakoresistenter Patienten erscheint daher unwahrscheinlich, kann jedoch endgültig erst durch Untersuchungen in einem Tiermodell für pharmakoresistente Epilepsie beurteilt werden. Die nach i.n.-Applikation von Phenobarbital erreichten Plasma-Konzentrationen in Kombination mit der gezeigten antikonvulsiven Wirksamkeit lassen diesen Applikationsweg jedoch zur nicht invasiven Behandlung eines Status epilepticus oder von Anfalls-Clustern Erfolg versprechend erscheinen. Dem Multidrug-Transporter P-Glycoprotein (P-gp) wird in Zusammenhang mit transporter-basierter Pharmakoresistenz bei Epilepsie besondere Bedeutung beigemessen. Durch pharmakologische Inhibition der P-gp-Funktion gelang im Tiermodell bereits die Überwindung von Pharmakoresistenz. Die Anwendung von Hemmstoffen bringt jedoch den Nachteil einer P-gp-Inhibition in allen Körperregionen mit sich. Eine auf die Blut-Hirn-Schranke begrenzte Reduktion der P-gp-Expression wäre durch den Mechanismus der RNA-Interferenz zu erreichen. Für in vivo-Untersuchungen an Ratten wurde gegen P-gp-mRNA gerichtete „small interfering RNA“ (siRNA) zum Schutz vor endogenen Nukleasen in Liposomen eingeschlossen. Zudem wurde für ein Targeting das Peptid ApoE4 an die Oberfläche der Liposomen gebunden, welches eine Endozytose an Endothelzellen der Blut-Hirn-Schranke vermittelt. Das Ziel einer P-gp-Reduktion auf Protein-Ebene nach i.v.-Applikation derart geschützter und zielgesteuerter siRNA konnte jedoch nicht erreicht werden. Die Quantifizierung der P-gp-Expression in den Endothelzellen der Blut-Hirn-Schranke anhand immunhistochemisch gefärbter Gehirnschnitte ergab 24 h nach Applikation keine Verminderung der P-gp-Expression. Die Ursachen für die ausgebliebene P-gp-Reduktion sind in weiterführenden Untersuchungen zu klären

Erratum to: What can ecosystems learn? Expanding evolutionary ecology with learning theory.

BACKGROUND: The structure and organisation of ecological interactions within an ecosystem is modified by the evolution and coevolution of the individual species it contains. Understanding how historical conditions have shaped this architecture is vital for understanding system responses to change at scales from the microbial upwards. However, in the absence of a group selection process, the collective behaviours and ecosystem functions exhibited by the whole community cannot be organised or adapted in a Darwinian sense. A long-standing open question thus persists: Are there alternative organising principles that enable us to understand and predict how the coevolution of the component species creates and maintains complex collective behaviours exhibited by the ecosystem as a whole? RESULTS: Here we answer this question by incorporating principles from connectionist learning, a previously unrelated discipline already using well-developed theories on how emergent behaviours arise in simple networks. Specifically, we show conditions where natural selection on ecological interactions is functionally equivalent to a simple type of connectionist learning, 'unsupervised learning', well-known in neural-network models of cognitive systems to produce many non-trivial collective behaviours. Accordingly, we find that a community can self-organise in a well-defined and non-trivial sense without selection at the community level; its organisation can be conditioned by past experience in the same sense as connectionist learning models habituate to stimuli. This conditioning drives the community to form a distributed ecological memory of multiple past states, causing the community to: a) converge to these states from any random initial composition; b) accurately restore historical compositions from small fragments; c) recover a state composition following disturbance; and d) to correctly classify ambiguous initial compositions according to their similarity to learned compositions. We examine how the formation of alternative stable states alters the community's response to changing environmental forcing, and we identify conditions under which the ecosystem exhibits hysteresis with potential for catastrophic regime shifts. CONCLUSIONS: This work highlights the potential of connectionist theory to expand our understanding of evo-eco dynamics and collective ecological behaviours. Within this framework we find that, despite not being a Darwinian unit, ecological communities can behave like connectionist learning systems, creating internal conditions that habituate to past environmental conditions and actively recalling those conditions. REVIEWERS: This article was reviewed by Prof. Ricard V Solé, Universitat Pompeu Fabra, Barcelona and Prof. Rob Knight, University of Colorado, Boulder

What can ecosystems learn? Expanding evolutionary ecology with learning theory.

BACKGROUND: The structure and organisation of ecological interactions within an ecosystem is modified by the evolution and coevolution of the individual species it contains. Understanding how historical conditions have shaped this architecture is vital for understanding system responses to change at scales from the microbial upwards. However, in the absence of a group selection process, the collective behaviours and ecosystem functions exhibited by the whole community cannot be organised or adapted in a Darwinian sense. A long-standing open question thus persists: Are there alternative organising principles that enable us to understand and predict how the coevolution of the component species creates and maintains complex collective behaviours exhibited by the ecosystem as a whole? RESULTS: Here we answer this question by incorporating principles from connectionist learning, a previously unrelated discipline already using well-developed theories on how emergent behaviours arise in simple networks. Specifically, we show conditions where natural selection on ecological interactions is functionally equivalent to a simple type of connectionist learning, 'unsupervised learning', well-known in neural-network models of cognitive systems to produce many non-trivial collective behaviours. Accordingly, we find that a community can self-organise in a well-defined and non-trivial sense without selection at the community level; its organisation can be conditioned by past experience in the same sense as connectionist learning models habituate to stimuli. This conditioning drives the community to form a distributed ecological memory of multiple past states, causing the community to: a) converge to these states from any random initial composition; b) accurately restore historical compositions from small fragments; c) recover a state composition following disturbance; and d) to correctly classify ambiguous initial compositions according to their similarity to learned compositions. We examine how the formation of alternative stable states alters the community's response to changing environmental forcing, and we identify conditions under which the ecosystem exhibits hysteresis with potential for catastrophic regime shifts. CONCLUSIONS: This work highlights the potential of connectionist theory to expand our understanding of evo-eco dynamics and collective ecological behaviours. Within this framework we find that, despite not being a Darwinian unit, ecological communities can behave like connectionist learning systems, creating internal conditions that habituate to past environmental conditions and actively recalling those conditions. REVIEWERS: This article was reviewed by Prof. Ricard V Solé, Universitat Pompeu Fabra, Barcelona and Prof. Rob Knight, University of Colorado, Boulder

Helyi termék, mint a periférikus térségek identitásképző és településmarketing eszköze = Local products as a tool of identity building and settlement marketing for peripheral areas

A közösségi összetartás, a helyhez való kötődés meggyengülésének számos negatív hatása van egy település sorsára, vagyis egy település életében stratégiai jelentősége van az identitás és imázs tudatos építésének. Tanulmányunk célja, hogy a szakirodalomból kiindulva kérdőíves felmérésen és esettanulmányokon keresztül megvizsgáljuk, hogy a helyi termékek előállítása mint a helyi gazdaságfejlesztés jól ismert eszközei tudatos településmarketinggel kiegészülve hogyan gyakorolnak a gazdasági hasznon túli pozitív hatásokat a települések fejlődésére. Véleményünk szerint a helyi termékek ugyanis kiváló eszköznek bizonyulhatnak mind a belső (lakosság), mind a külső célközönség számára a települési identitás és imázs formálására, kialakítására. A társadalmi-gazdasági szempontból erőforráshiányos térségekben a hagyományokra épülő, közösségi alapon felépített helyi termék előállítás sok esetben az egyetlen eszköze a hiteles identitás és imázs kialakításának. Éppen ezért e tanulmányban arra teszünk kísérletet, hogy a szakirodalomból már jól ismert helyi termékeken alapuló gazdaságfejlesztési modelleket megvizsgálva feltérképezzük az adaptáció lehetséges lépéseit, kihívásait és a továbbfejlődés irányait. = The weakening of community cohesion and attachment to the place has many negative effects on the fate of a settlement, therefore the conscious construction of identity and image is of strategic importance in the life of a settlement. The aim of our study is to examine, starting from the literature, through a questionnaire survey and case studies, how the production of local products, as a well-known tool of local economic development, complemented by conscious settlement marketing, exerts positive effects on the development of settlements beyond the economic benefit. In our opinion, local products can prove to be an excellent tool for both internal (residents) and external target audiences to shape and develop the settlement's identity and image. In regions lacking resources from a socio-economic point of view, local product production based on traditions and built on a community basis is in many cases the only means of creating an authentic identity and image. That is why, in this study, we attempt to map the possible steps, challenges and directions of further development by examining economic development models based on local products that are already well known from the literature

Flagellin Delivery by Pseudomonas aeruginosa Rhamnolipids Induces the Antimicrobial Protein Psoriasin in Human Skin

The opportunistic pathogen Pseudomonas aeruginosa can cause severe infections in patients suffering from disruption or disorder of the skin barrier as in burns, chronic wounds, and after surgery. On healthy skin P. aeruginosa causes rarely infections. To gain insight into the interaction of the ubiquitous bacterium P. aeruginosa and healthy human skin, the induction of the antimicrobial protein psoriasin by P. aeruginosa grown on an ex vivo skin model was analyzed. We show that presence of the P. aeruginosa derived biosurfactant rhamnolipid was indispensable for flagellin-induced psoriasin expression in human skin, contrary to in vitro conditions. The importance of the bacterial virulence factor flagellin as the major inducing factor of psoriasin expression in skin was demonstrated by use of a flagellin-deficient mutant. Rhamnolipid mediated shuttle across the outer skin barrier was not restricted to flagellin since rhamnolipids enable psoriasin expression by the cytokines IL-17 and IL-22 after topical application on human skin. Rhamnolipid production was detected for several clinical strains and the formation of vesicles was observed under skin physiological conditions. In conclusion we demonstrate herein that rhamnolipids enable the induction of the antimicrobial protein psoriasin by flagellin in human skin without direct contact of bacteria and responding cells. Hereby, human skin might control the microflora to prevent colonization of unwanted microbes in the earliest steps before potential pathogens can develop strategies to subvert the immune response

What can ecosystems learn? Expanding evolutionary ecology with learning theory

Background: The structure and organisation of ecological interactions within an ecosystem is modified by the evolution and coevolution of the individual species it contains. Understanding how historical conditions have shaped this architecture is vital for understanding system responses to change at scales from the microbial upwards. However, in the absence of a group selection process, the collective behaviours and ecosystem functions exhibited by the whole community cannot be organised or adapted in a Darwinian sense. A long-standing open question thus persists: Are there alternative organising principles that enable us to understand and predict how the coevolution of the component species creates and maintains complex collective behaviours exhibited by the ecosystem as a whole?Results: Here we answer this question by incorporating principles from connectionist learning, a previously unrelated discipline already using well-developed theories on how emergent behaviours arise in simple networks. Specifically, we show conditions where natural selection on ecological interactions is functionally equivalent to a simple type of connectionist learning, ‘unsupervised learning’, well-known in neural-network models of cognitive systems to produce many non-trivial collective behaviours. Accordingly, we find that a community can self-organise in a well-defined and non-trivial sense without selection at the community level; its organisation can be conditioned by past experience in the same sense as connectionist learning models habituate to stimuli. This conditioning drives the community to form a distributed ecological memory of multiple past states, causing the community to: a) converge to these states from any random initial composition; b) accurately restore historical compositions from small fragments; c) recover a state composition following disturbance; and d) to correctly classify ambiguous initial compositions according to their similarity to learned compositions. We examine how the formation of alternative stable states alters the community’s response to changing environmental forcing, and we identify conditions under which the ecosystem exhibits hysteresis with potential for catastrophic regime shifts.Conclusions: This work highlights the potential of connectionist theory to expand our understanding of evo-eco dynamics and collective ecological behaviours. Within this framework we find that, despite not being a Darwinian unit, ecological communities can behave like connectionist learning systems, creating internal conditions that habituate to past environmental conditions and actively recalling those conditions.Theoretical ecology, Communityassembly, Network structures, Ecological memory, Associative learning, Regime shifts, Community matrix*Correspondence

Testing Sensitivity of A-Type Residual Current Devices to Earth Fault Currents with Harmonics

In many applications, modern current-using equipment utilizes power electronic converters to control the consumed power and to adjust the motor speed. Such equipment is used both in industrial and domestic installations. A characteristic feature of the converters is producing distorted earth fault currents, which contain a wide spectrum of harmonics, including high-order harmonics. Nowadays, protection against electric shock in low-voltage power systems is commonly performed with the use of residual current devices (RCDs). In the presence of harmonics, the RCDs may have a tripping current significantly different from that provided for the nominal sinusoidal waveform. Thus, in some cases, protection against electric shock may not be effective. The aim of this paper is to present the result of a wide-range laboratory test of the sensitivity of A-type RCDs in the presence of harmonics. This test has shown that the behavior of RCDs in the presence of harmonics can be varied, including the cases in which the RCD does not react to the distorted earth fault current, as well as cases in which the sensitivity of the RCD is increased. The properties of the main elements of RCDs, including the current sensor, for high-frequency current components are discussed as well