Passive listening to preferred motor tempo modulates corticospinal excitability

Rhythms are an essential characteristic of our lives and auditory-motor coupling affects a variety of behaviors. Previous research has shown that neural regions associated with motor system processing are coupled to perceptual rhythmic processing, such that the perception of rhythmic stimuli can entrain motor responses. However, the degree to which individual preference modulates the motor system is unknown. Recent work has shown that passively listening to metrically strong rhythms increases corticospinal excitability, as indicated by transcranial magnetic stimulation (TMS). Furthermore, neuroimaging evidence suggests that premotor activity increases while listening to tempos occurring within a preferred tempo category. Preferred tempo (PT) refers to the rate of a hypothetical endogenous oscillator that may be indicated by spontaneous motor tempo (SMT) and preferred perceptual tempo (PPT) measurements. The present study investigated whether listening to a rhythm at an individual's PT preferentially modulates motor excitability. SMT was obtained in human participants through a tapping task, in which subjects were asked to tap a response key at their most comfortable rate. Subjects listened to tone sequences at 11 log-spaced tempos and rated their preference for each (PPT). SMT and PPT measurements were correlated, indicating that preferred and produced tempos occurred at a similar rate. Crucially, single-pulse TMS delivered to left M1 during PPT judgments revealed that corticospinal excitability, measured by motor-evoked potentials, was modulated by tempos traveling closer to individual PT. However, the specific nature of this modulation differed across individuals, with some exhibiting an increase in excitability around PT and others exhibiting a decrease. These findings suggest that auditory-motor coupling induced by rhythms is preferentially modulated by rhythms occurring at a preferred rate, and that individual differences can alter the nature of this coupling

Entwicklung und in-vitro-Testung von Arzneistoffträgersystemen für antivirale und antitumorale Arzneistoffe

Die vorliegende Arbeit gliederte sich in 3 Teilbereiche. Der erste Teilbereich beschäftigte sich mit der antiviralen in vitro Wirkung von EDDS (Ethylendiamindinbernsteinsäure), sowie mit der Wirkung von EDDS, DTPA (Diethylentriaminpentaessigsäure) und DFO (Desferrioxamin) im Tiermodell. EDDS zeigte in vitro eine vielversprechende Wirkung gegenüber verschiedenen HCMV­ Stämmen. Hierunter befanden sich GCV­ und HPMPC­resistente Stämme. Dies ist von großer Bedeutung für die Entwicklung neuer Wirkstoffe, da die Therapie von HCMV­bedingten Erkrankungen mit hohen Nebenwirkungen verbunden ist und zudem durch vermehrtes Auftreten von Resistenzen gegenüber den etablierten Therapeutika GCV, HPMPC und Foscarnet erschwert wird. Die in­vitro­Daten legen einen ähnlichen antiviralen Wirkmechanismus des EDDS verglichen mit DTPA nahe. Diese Ähnlichkeit wird durch die enge strukturelle Verwandschaft der Stoffe noch unterstrichen. Im Mausmodell zeigte jedoch keiner der 3 untersuchten Chelatoren eine erfolgversprechende protektive Wirkung gegenüber MCMV­Infektionen. Damit wurden vorangegangene Untersuchungen im Rattenmodell bestätigt. Trotz vielversprechender anderslautender Ergebnisse, die auf eine in­vivo­Wirkung von DFO gegenüber CMV­Infektionen hinwiesen, scheint damit der Einsatz der Chelatoren aufgrund ihrer sehr kurzen Halbwertszeit im Körper stark limitiert. Der zweite Teil der Dissertation befaßt sich mit der Entwicklung und Untersuchung von peptidischen Wirkstoffträgersystemen für DTPA. Hierbei ließen sich reproduzierbar lösliche HSA­DTPA­ und GelB­DTPA­Konjugate, sowie HSA­DTPA­ und GelB­DTPA­NP herstellen. Die antivirale und die antitumorale Wirkung dieser Konjugate wurde in vitro untersucht. Da für die antitumorale Wirkung von DTPA bisher keine Daten vorlagen, wurde zunächst die Cytotoxizität in einer NB­Zellinie und in 3 Brustkrebs­Zellinien bestimmt. Als Vergleich dienten HFF. Es zeigte sich, daß DTPA in unterschiedlichen Konzentrationen gegenüber den untersuchten Zellinien cytotoxisch war, eine Tumorspezifität konnte jedoch nicht festgestellt werden. Die Cytotoxizität und die antivirale Wirkung des DTPA wurden in vitro durch Bindung an die unterschiedlichen peptidischen Trägersysteme deutlich erhöht. Dies führte jedoch nicht zu einer Erhöhung der therapeutischen Breite, da HFF in gleichem Maße stärker geschädigt wurden. Trotzdem bieten die Trägersystem­ Zubereitungen im Hinblick auf eine in­vivo­Anwendung einige Vorteile. Es könnten geringere Mengen DTPA eingesetzt werden, was eine verringerte Ausschwemmung von Metallionen zur Folge hätte. Neben einer verlängerten Zirkulationszeit im Organismus könnte die veränderte Körperverteilung zu Verbesserungen führen. Im Falle der antitumoralen Anwendung wäre dies eine Anreicherung im Tumor aufgrund des EPR­Effektes. Für die antivirale Anwendung wären die Anreicherung in entzündeten Geweben, sowie die Anreicherung in Monozyten und Makrophagen von großem Interesse, da diesen Zellen ein entscheidender Anteil an dem durch CMV verursachten Multiorganbefall zugerechnet wird. Trotzdem bedarf der in­vivo­Einsatz einer eingehenden Evaluierung und erscheint aufgrund der geringen therapeutische Breite insbesondere im Hinblick auf die Therapie von Tumoren stark eingeschränkt. Bezüglich des cytotoxischen Mechanismus weist die Wirkung der DTPA­Konjugate darauf hin, daß DTPA den Zellzyklus und die Virusreplikation durch Wechselwirkung mit der Zellmembran und dadurch Veränderung der Signaltransduktion beeinflußt. Da eine geringere DTPA­Menge größere Effekte verursacht, erscheint es unwahrscheinlich, daß die Komplexierung von Metallionen für die Wirkungen verantwortlich war. Im dritten Teil dieser Dissertation wurde eine PLA­NP­Trägersystem für das antitumoral wirksame Enzym BS­RNase entwickelt. BS­RNase zeigte in vitro und bei intratumoraler Applikation sehr vielversprechende, selektive antitumorale Effekte gegenüber proliferierenden und ruhenden Tumorzellen. Die systemische Applikation war jedoch nicht erfolgreich. Dieses Scheitern wurde auf hohe Antigenität, kurze Halbwertszeit der Substanz im Körper und auf eine ungenügende Körperverteilung zurückgeführt. NP sind geeignet die Zirkulation im Körper zu verlängern und reichern sich in Tumoren aufgrund des EPR­Effektes an. PLA­NP wurden ausgewählt, da sie BS­RNase in ausreichendem Maß binden und da PLA ein bioabbaubares und bioverträgliches Material ist. In vitro unterschied sich die nanopartikuläre Zubereitung bei der Wirkung gegenüber normalen, Lymphom­ und Leukämiezellen nicht. Beide BS­RNase­Zubereitungen induzierten Apoptose in parentalen und chemoresistenten Krebszellen. Normale Zellen wurden nicht in ihrer Viabilität beeinträchtigt. Die aspermatogenen und antiembryonalen Wirkungen von BS­RNase­Zubereitungen weisen auf ihre antitumoralen Eigenschaften hin. In diesen beiden Testsystemen übertraf die nanopartikuläre Zubereitung die Wirkung der BS­RNase­Lösung. In­vivo­Versuche müssen nun den tatsächlichen Stellenwert der BS­RNase­PLA­NP zeigen

Chemoresistance acquisition induces a global shift of expression of aniogenesis-associated genes and increased pro-angogenic activity in neuroblastoma cells

BACKGROUND: Chemoresistance acquisition may influence cancer cell biology. Here, bioinformatics analysis of gene expression data was used to identify chemoresistance-associated changes in neuroblastoma biology. RESULTS: Bioinformatics analysis of gene expression data revealed that expression of angiogenesis-associated genes significantly differs between chemosensitive and chemoresistant neuroblastoma cells. A subsequent systematic analysis of a panel of 14 chemosensitive and chemoresistant neuroblastoma cell lines in vitro and in animal experiments indicated a consistent shift to a more pro-angiogenic phenotype in chemoresistant neuroblastoma cells. The molecular mechanims underlying increased pro-angiogenic activity of neuroblastoma cells are individual and differ between the investigated chemoresistant cell lines. Treatment of animals carrying doxorubicin-resistant neuroblastoma xenografts with doxorubicin, a cytotoxic drug known to exert anti-angiogenic activity, resulted in decreased tumour vessel formation and growth indicating chemoresistance-associated enhanced pro-angiogenic activity to be relevant for tumour progression and to represent a potential therapeutic target. CONCLUSION: A bioinformatics approach allowed to identify a relevant chemoresistance-associated shift in neuroblastoma cell biology. The chemoresistance-associated enhanced pro-angiogenic activity observed in neuroblastoma cells is relevant for tumour progression and represents a potential therapeutic target

Artificial Intelligence in Energy Demand Response: A Taxonomy of Input Data Requirements

The ongoing energy transition increases the share of renewable energy sources. To combat inherent intermittency of RES, increasing system flexibility forms a major opportunity. One way to provide flexibility is demand response (DR). Research already reflects several approaches of artificial intelligence (AI) for DR. However, these approaches often lack considerations concerning their applicability, i.e., necessary input data. To help putting these algorithms into practice, the objective of this paper is to analyze, how input data requirements of AI approaches in the field of DR can be systematized from a practice-oriented information systems perspective. Therefore, we develop a taxonomy consisting of eight dimensions encompassing 30 characteristics. Our taxonomy contributes to research by illustrating how future AI approaches in the field of DR should represent their input data requirements. For practitioners, our developed taxonomy adds value as a structuring tool, e.g., to verify applicability with respect to input data requirements

Methane turnover and temperature response of methane-oxidizing bacteria in permafrost-affected soils of northeast Siberia

The abundance, activity, and temperature response of aerobic methane-oxidizing bacteria were studied in permafrost-affected tundra soils of northeast Siberia. The soils were characterized by both a high accumulation of organic matter at the surface and high methane concentrations in the water-saturated soils. The methane oxidation rates of up to 835 nmol CH4 h−1 g−1 in the surface soils were similar to the highest values reported so far for natural wetland soils worldwide. The temperature response of methane oxidation was measured during short incubations and revealed maximum rates between 22 °C and 28 °C. The active methanotrophic community was characterized by its phospholipid fatty acid (PLFA) concentrations and with stable isotope probing (SIP). Concentrations of 16:1ω8 and 18:1ω8 PLFAs, specific to methanotrophic bacteria, correlated significantly with the potential methane oxidation rates. In all soils, distinct 16:1 PLFAs were dominant, indicating a predominance of type I methanotrophs. However, long-term incubation of soil samples at 0 °C and 22 °C demonstrated a shift in the composition of the active community with rising temperatures. At 0 °C, only the concentrations of 16:1 PLFAs increased and those of 18:1 PLFAs decreased, whereas the opposite was true at 22 °C. Similarly, SIP with 13CH4 showed a temperature-dependent pattern. When the soils were incubated at 0 °C, most of the incorporated label (83%) was found in 16:1 PLFAs and only 2% in 18:1 PLFAs. In soils incubated at 22 °C, almost equal amounts of 13C label were incorporated into 16:1 PLFAs and 18:1 PLFAs (33% and 36%, respectively). We concluded that the highly active methane-oxidizing community in cold permafrost-affected soils was dominated by type I methanotrophs under in situ conditions. However, rising temperatures, as predicted for the future, seem to increase the importance of type II methanotrophs, which may affect methane cycling in northern wetlands

Is the Bombali virus pathogenic in humans?

Motivation: The potential of the Bombali virus, a novel Ebolavirus, to cause disease in humans remains unknown. We have previously identified potential determinants of Ebolavirus pathogenicity in humans by analysing the amino acid positions that are differentially conserved (specificity 15 determining positions; SDPs) between human pathogenic Ebolaviruses and the non-pathogenic Reston virus. Here, we include the many Ebolavirus genome sequences that have since become available into our analysis and investigate the amino acid sequence of the Bombali virus proteins at the SDPs that discriminate between human pathogenic and non-human pathogenic Ebolaviruses. 20 Results: The use of 1408 Ebolavirus genomes (196 in the original analysis) resulted in a set of 166 SDPs (reduced from 180), 146 (88%) of which were retained from the original analysis. This indicates the robustness of our approach and refines the set of SDPs that distinguish human pathogenic Ebolaviruses from Reston virus. At SDPs, Bombali virus shared the majority of amino acids with the human pathogenic Ebolaviruses (63.25%). However, for two SDPs in VP24 (M136L, R139S) 25 that have been proposed to be critical for the lack of Reston virus human pathogenicity because they alter the VP24-karyopherin interaction, the Bombali virus amino acids match those of Reston virus. Thus, Bombali virus may not be pathogenic in humans. Supporting this, no Bombali virusassociated disease outbreaks have been reported, although Bombali virus was isolated from fruit bats cohabitating in close contact with humans, and anti-Ebolavirus antibodies that may indicate 30 contact with Bombali virus have been detected in humans

Risks Posed by Reston, the Forgotten Ebolavirus

Out of the five members of the Ebolavirus family, four cause lifethreatening disease, whereas the fifth, Reston virus (RESTV), is nonpathogenic in humans. The reasons for this discrepancy remain unclear. In this review, we analyze the currently available information to provide a state-of-the-art summary of the factors that determine the human pathogenicity of Ebolaviruses. RESTV causes sporadic infections in cynomolgus monkeys and is found in domestic pigs throughout the Philippines and China. Phylogenetic analyses revealed that RESTV is most closely related to the Sudan virus, which causes a high mortality rate in humans. Amino acid sequence differences between RESTV and the other Ebolaviruses are found in all nine Ebolavirus proteins, though no one residue appears sufficient to confer pathogenicity. Changes in the glycoprotein contribute to differences in Ebolavirus pathogenicity but are not sufficient to confer pathogenicity on their own. Similarly, differences in VP24 and VP35 affect viral immune evasion and are associated with changes in human pathogenicity. A recent in silico analysis systematically determined the functional consequences of sequence variations between RESTV and human-pathogenic Ebolaviruses. Multiple positions in VP24 were differently conserved between RESTV and the other Ebolaviruses and may alter human pathogenicity. In conclusion, the factors that determine the pathogenicity of Ebolaviruses in humans remain insufficiently understood. An improved understanding of these pathogenicity-determining factors is of crucial importance for disease prevention and for the early detection of emergent and potentially human-pathogenic RESTVs

How to trade electricity flexibility using artificial intelligence - An integrated algorithmic framework

In course of the energy transition, the growing share of Renewable Energy Sources (RES) makes electricity generation more decentralized and intermittent. This increases the relevance of exploiting flexibility potentials that help balancing intermittent RES supply and demand and, thus, contribute to overall system resilience. Digital technologies, in the form of automated trading algorithms, may considerably contribute to flexibility exploitation, as they enable faster and more accurate market interactions. In this paper, we develop an integrated algorithmic framework that finds an optimal trading strategy for flexibility on multiple markets. Hence, our work supports the trading of flexibility in a multi-market environment that results in enhanced market integration and harmonization of economically traded and physically delivered electricity, which finally promotes resilience in highly complex electricity systems