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Atg8-family proteins - structural features and molecular interactions in autophagy and beyond
(2020)
Autophagy is a common name for a number of catabolic processes, which keep the cellular homeostasis by removing damaged and dysfunctional intracellular components. Impairment or misbalance of autophagy can lead to various diseases, such as neurodegeneration, infection diseases, and cancer. A central axis of autophagy is formed along the interactions of autophagy modifiers (Atg8-family proteins) with a variety of their cellular counter partners. Besides autophagy, Atg8-proteins participate in many other pathways, among which membrane trafficking and neuronal signaling are the most known. Despite the fact that autophagy modifiers are well-studied, as the small globular proteins show similarity to ubiquitin on a structural level, the mechanism of their interactions are still not completely understood. A thorough analysis and classification of all known mechanisms of Atg8-protein interactions could shed light on their functioning and connect the pathways involving Atg8-proteins. In this review, we present our views of the key features of the Atg8-proteins and describe the basic principles of their recognition and binding by interaction partners. We discuss affinity and selectivity of their interactions as well as provide perspectives for discovery of new Atg8-interacting proteins and therapeutic approaches to tackle major human diseases.
We present the results of geochemical analysis of silver coinage issued by Rome and dated between the fourth and second century BCE, which are complemented by data of coinage issued by Carthage, the Brettii, and the Greek colony of Emporion. Each of these minting authorities represents one of the major parties involved in the struggle for hegemony in the fourth to second centuries BCE Western Mediterranean region. This study retraces how the metal supply shifts in response to the transforming power relations and how this change is related to Rome's rise to the virtually uncontested ruler of the region.
Objective: Phenotypic (Sensititre Myco, pDST) and genotypic drug susceptibility testing (GenoType NTM DR, gDST) in M. avium complex (MAC) have become available as standardized assays, but comparable data is needed. This study aimed to investigate the phenotypic and genotypic drug susceptibility patterns in MAC clinical isolates.
Methods: Overall, 98 isolates from 85 patients were included. pDST and gDST were performed on all isolates and results compared regarding specificity and sensitivity using pDST as a reference method. The impact of drug instability on pDST results was studied using a biological assay over 14 days. In addition, the evolution of antimicrobial resistance was investigated in sequential isolates of 13 patients.
Results: Macrolide resistance was rare, 1.2% (95% CI 0.7–7.3) of isolates in the base cohort. No aminoglycoside resistances were found, but 14.1% of the studied isolates (95% CI 7.8–23.8) showed intermediate susceptibility. The GenoType NTM DR identified two out of four macrolide-resistant isolates. Antibiotic stability was demonstrated to be poor in rifampicin, rifabutin, and doxycycylin.
Conclusions: pDST results in NTM for unstable antibiotics must be interpreted with care. A combination of pDST and gDST will be useful for the guidance of antimicrobial therapy in MAC-disease.
Echovirus-30 (E-30) is a non-polio enterovirus responsible for meningitis outbreaks in children worldwide. To gain access to the central nervous system (CNS), E-30 first has to cross the blood-brain barrier (BBB) or the blood-cerebrospinal fluid barrier (BCSFB). E-30 may use lipid rafts of the host cells to interact with and to invade the BCSFB. To study enteroviral infection of the BCSFB, an established in vitro model based on human immortalized brain choroid plexus papilloma (HIBCPP) cells has been used. Here, we investigated the impact of E-30 infection on the protein content of the lipid rafts at the BCSFB in vitro. Mass spectrometry analysis following E-30 infection versus uninfected conditions revealed differential abundancy in proteins implicated in cellular adhesion, cytoskeleton remodeling, and endocytosis/vesicle budding. Further, we evaluated the blocking of endocytosis via clathrin/dynamin blocking and its consequences for E-30 induced barrier disruption. Interestingly, blocking of endocytosis had no impact on the capacity of E-30 to induce loss of barrier properties in HIBCPP cells. Altogether, these data highlight the impact of E-30 on HIBCPP cells microdomain as an important factor for host cell alteration.
Interspecies hydrogen transfer in anoxic ecosystems is essential for the complete microbial breakdown of organic matter to methane. Acetogenic bacteria are key players in anaerobic food webs and have been considered as prime candidates for hydrogen cycling. We have tested this hypothesis by mutational analysis of the hydrogenase in the model acetogen Acetobacterium woodii. Hydrogenase-deletion mutants no longer grew on H2 + CO2 or organic substrates such as fructose, lactate, or ethanol. Heterotrophic growth could be restored by addition of molecular hydrogen to the culture, indicating that hydrogen is an intermediate in heterotrophic growth. Indeed, hydrogen production from fructose was detected in a stirred-tank reactor. The mutant grew well on organic substrates plus caffeate, an alternative electron acceptor that does not require molecular hydrogen but NADH as reductant. These data are consistent with the notion that molecular hydrogen is produced from organic substrates and then used as reductant for CO2 reduction. Surprisingly, hydrogen cycling in A. woodii is different from the known modes of interspecies or intraspecies hydrogen cycling. Our data are consistent with a novel type of hydrogen cycling that connects an oxidative and reductive metabolic module in one bacterial cell, "intracellular syntrophy."
Background: Capture and storage of the energy carrier hydrogen as well as of the greenhouse gas carbon dioxide are two major problems that mankind faces currently. Chemical catalysts have been developed, but only recently a group of anaerobic bacteria that convert hydrogen and carbon dioxide to acetate, formate, or biofuels such as ethanol has come into focus, the acetogenic bacteria. These biocatalysts produce the liquid organic hydrogen carrier formic acid from H2 + CO2 or even carbon monoxide with highest rates ever reported. The autotrophic, hydrogen-oxidizing, and CO2-reducing acetogens have in common a specialized metabolism to catalyze CO2 reduction, the Wood–Ljungdahl pathway (WLP). The WLP does not yield net ATP, but is hooked up to a membrane-bound respiratory chain that enables ATP synthesis coupled to CO2 fixation. The nature of the respiratory enzyme has been an enigma since the discovery of these bacteria and has been unraveled in this study.
Results: We have produced a His-tagged variant of the ferredoxin:NAD oxidoreductase (Rnf complex) from the model acetogen Acetobacterium woodii, solubilized the enzyme from the cytoplasmic membrane, and purified it by Ni2+–NTA affinity chromatography. The enzyme was incorporated into artificial liposomes and catalyzed Na+ transport coupled to ferredoxin-dependent NAD reduction. Our results using the purified enzyme do not only verify that the Rnf complex from A. woodii is Na+-dependent, they also demonstrate for the first time that this membrane-embedded molecular engine creates a Na+ gradient across the membrane of A. woodii which can be used for ATP synthesis.
Discussion: We present a protocol for homologous production and purification for an Rnf complex. The enzyme catalyzed electron-transfer driven Na+ export and, thus, our studies provided the long-awaited biochemical proof that the Rnf complex is a respiratory enzyme.
Hintergrund. Die Achtung der individuellen Autonomie ist eines von vier medizinethischen Prinzipien, das im Kontext von Medizin und Forschung insbesondere in Bezug auf die informierte Einwilligung einer Person thematisiert wird. Menschen mit Demenz können aufgrund innerer oder äußerer Faktoren in ihrer Einwilligungsfähigkeit beeinträchtigt sein, was zu einer Einschränkung ihres Rechts auf Selbstbestimmung führen kann. Im diesbezüglichen Spannungsfeld zwischen Fürsorge und Autonomie soll Entscheidungsassistenz zur Ermöglichung selbstbestimmter Entscheidungen beitragen.
Zielrichtung der Arbeit. Ziel der vorliegenden Dissertation ist die Definition, Implementierung und Evaluation von Entscheidungsassistenzmaßnahmen für Menschen mit Demenz, um deren Autonomie in Entscheidungsprozessen zu unterstützen. Drei Teilprojekte umfassen die Ermittlung des internationalen Forschungsstands zu Entscheidungsassistenz bei Demenz, die Definition und Pilotierung von Unterstützungstools in der Praxis und die Analyse des individuellen Erlebens der vereinfachten Aufklärungsgespräche durch Menschen mit Demenz.
Methode. Im ersten Teilprojekt wurde eine am PRISMA-Standard orientierte systematische Literaturrecherche in Medline und PsycINFO durchgeführt. Die extrahierten relevanten Informationen wurden inhaltlich systematisiert. Aufbauend auf diesen Ergebnissen wurden im zweiten Teilprojekt konkrete Unterstützungstools definiert und in reale Aufklärungsgespräche (Lumbalpunktion) implementiert. Die Tools wurden in der Pilotierung in der Praxis sowie in einem iterativen Diskussionsprozess mit Experten weiterentwickelt. Im dritten Teilprojekt wurde das individuelle Erleben der Teilnehmer der vereinfachten Aufklärungsgespräche mittels problemzentrierter Interviews untersucht und die Daten einer qualitativen Inhaltsanalyse unterzogen.
Ergebnisse. Die Datenbankrecherche ergab initial 2348 Treffer. Nach Screenings der Titel, Abstracts und Volltexte konnten 11 Artikel eingeschlossen werden. Vier der eingeschlossenen Studien sind Interventionsstudien, die übrigen sieben qualitative Interviewstudien. Die identifizierten Unterstützungsmaßnahmen wurden zunächst den beiden Kategorien Interventionen und Strategien und anschließend unter Zuhilfenahme des Konzepts des Contextual Consents fünf komplexitätssteigernden Dimensionen einer Entscheidungssituation zugeordnet (individuelle, soziale, medizinische, informationelle und Folgendimension). Darauf aufbauend wurden im zweiten Teilprojekt acht Entscheidungsassistenzmaßnahmen abgeleitet: (1) Gesprächsstruktur, (2) Elaborierte klare Sprache, (3) Ambiente / Raumgestaltung, (4) Stichwortlisten, (5) Prioritätenkarten, (6) Visualisierung, (7) Vereinfachte schriftliche Einverständniserklärung sowie (8) Personenzentrierte Haltung des Entscheidungsassistenten (1-7: Tools, 8: Grundeinstellung). Die Tools zielen überwiegend auf eine Komplexitätsreduktion in der informationellen Dimension unter Berücksichtigung der fähigkeitsbezogenen und der bedürfnisbezogenen individuellen Dimension ab. Durch Anpassungen der Informationsdarbietung oder der kommunikativen Interaktion im Gespräch dienen sie mehrheitlich der Förderung des (Informations-) Verständnisses. Die Analyse der qualitativen Daten im dritten Teilprojekt zeigt, dass die Erfahrung der vereinfachten Aufklärungsgespräche durch drei übergreifende Themen gekennzeichnet ist. Die Kategorie Formalität versus Informationsgewinn illustriert die individuelle Bedeutung des Aufklärungsgesprächs für die Teilnehmer und deren Bewertung des Prozesses der informierten Einwilligung. Die Kategorie Wahrnehmung der Unterstützung skizziert die Bewertungen der angewandten Unterstützungstools durch die Teilnehmer. Die Kategorie Der Wahrheit ins Auge sehen müssen stellt dar, dass die erlebte Situation des vereinfachten Aufklärungsgesprächs wesentlich durch die Verdachtsdiagnose Demenz bestimmt ist, die im Rahmen aller Aufklärungsgespräche besprochen wurde.
Fazit. Bislang gibt es wenig empirische Forschung zu Entscheidungsassistenz für Menschen mit Demenz und Unterstützungsmaßnahmen werden überwiegend unsystematisch entwickelt und angewendet. Die Wirksamkeit einzelner Unterstützungsmaßnahmen kann aufgrund fehlender Interventionsstudien selten beurteilt werden. Unterstützungsmaßnahmen zielen überwiegend auf eine Komplexitätsreduktion in der Informationsdarbietung und im kommunikativen Interaktionsprozess ab, wobei sie kognitive Beeinträchtigungen und Interaktions-/ Entscheidungsbedürfnisse von Menschen mit Demenz berücksichtigen. Die definierten Tools können als erste konkret handhabbare Werkzeuge verstanden werden, die das strukturierte Leisten von Entscheidungsassistenz für Menschen mit Demenz erleichtern sollen. Sie sind übertragbar auf verschiedene Entscheidungssituationen. Eine Bewertung der Wirksamkeit der definierten Tools sollte in weiteren Entscheidungssituationen und mit größeren Stichproben weiteruntersucht werden. Die Ergebnisse der Evaluation liefern jedoch erste Hinweise darauf, dass einige Teilnehmer sich von einzelnen Tools unterstützt gefühlt haben und die anvisierte Komplexitätsreduktion in der informationellen Dimension in einigen Fällen erfolgreich war. Eine wesentliche Komplexitätssteigerung in der untersuchten Entscheidungssituation entstand durch die negative Emotionen auslösende Vermittlung einer potentiellen Demenzdiagnose (Folgendimension). Dieses Ergebnis impliziert, dass die definierte „verständnisfördernde Toolbox“ um Unterstützungsmaßnahmen zur emotionalen Entlastung von Menschen mit Demenz erweitert werden muss, da davon ausgegangen werden kann, dass vielfältige Entscheidungssituationen für Menschen mit Demenz emotional hoch belastend sind.
Background: Balloon pulmonary angioplasty is an evolving, interventional treatment option for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary hypertension at rest as well as exercise capacity is considered to be relevant outcome parameters. The aim of the present study was to determine whether measurement of pulmonary hemodynamics during exercise before and six months after balloon pulmonary angioplasty have an added value.
Methods: From March 2014 to July 2018, 172 consecutive patients underwent balloon pulmonary angioplasty. Of these, 64 consecutive patients with inoperable CTEPH underwent a comprehensive diagnostic workup that included right heart catheterization at rest and during exercise before balloon pulmonary angioplasty treatments and six months after the last intervention.
Results: Improvements in pulmonary hemodynamics at rest and during exercise, in quality of life, and in exercise capacity were observed six months after balloon pulmonary angioplasty: WHO functional class improved in 78% of patients. The mean pulmonary arterial pressure (mPAP) at rest was reduced from 41 ± 9 to 31 ± 9 mmHg (p < 0.0001). The mPAP/cardiac output slope decreased after balloon pulmonary angioplasty (11.2 ± 25.6 WU to 7.7 ± 4.1 WU; p < 0.0001), and correlated with N-terminal fragment of pro-brain natriuretic peptide (p = 0.035) and 6-minute walking distance (p = 0.01).
Conclusions: Exercise right heart catheterization provides valuable information on the changes of pulmonary hemodynamics after balloon pulmonary angioplasty in inoperable CTEPH patients that are not obtainable by measuring resting hemodynamics.
Das Geschichtswerk des Florus findet in der modernen althistorischen Forschung nur wenig Anerkennung. Dies geschieht nicht ohne Grund, entspringen doch manche Berichte allzu deutlich der Phantasie des Historiographen und basieren auf einer auf Effekte abzielenden Darstellungskunst. Ein Beispiel hierfür liefert seine Schilderung des Ablaufs der clades Variana, die – beim Wort genommen – kein Vertrauen verdient und daher zumeist in der aktuellen Diskussion über die Vorgänge in Germanien übergangen wird. Dagegen ist Florus anerkanntermaßen ein wichtiger Repräsentant für die Geschichtsschreibung des 2. und 3. Jahrhunderts n. Chr. Der Beitrag zielt nicht darauf ab, das viel diskutierte Problem der ‚Varusschlacht‘ und ihre Lokalisierung erneut zu traktieren, vielmehr sollen neben dem Geschichtsbild des Autors und seiner Auffassung über die den geschichtlichen Prozess beeinflussenden Kräfte die Zeitbezüge verdeutlicht werden, die hinter dem Berichteten als solchem erkennbar sind. Damit gewährt das Werk interessante Einblicke in Erwartungen, Vorstellungen und Mentalitäten der Zeitgenossen des Autors, was jenseits positivistischer Vermittlung von Fakten auch für den Historiker von Bedeutung ist.
Im Frühjahr 23 n. Chr. sah sich Kaiser Tiberius veranlasst, dem Senat Bericht zu erstatten über die Lage im Heer und die Schwierigkeiten der Gewinnung von Rekruten. Tacitus nimmt dies seinerseits zum Anlass, mit Bezug auf die seinerzeitige Situation über die Verteilung der wichtigsten Truppenverbände an den verschiedenen Reichsgrenzen zu informieren. Der Zeitpunkt des kaiserlichen Rapports an den Senat war offenbar nicht zufällig gewählt, das Jahr 23 wird später von Tacitus als Wendepunkt im persönlichen Verhalten und in der Politik des Tiberius angesehen. Bei der Übersicht über die Truppen und deren Stärke fällt hinsichtlich der Rheinfront der betonte Hinweis auf, dass diese nicht nur zum Schutz gegen Germanien, sondern auch gegen Gallien dienen sollten. In diesem Beitrag soll zunächst das historische Umfeld erörtert werden, in welches maßgeblich Anlass und Zeitpunkt der Mitteilung des Kaisers an den Senats und die Übersicht über die Heeresstärke eingeordnet werden können (I.). In einem zweiten Punkt wird auf einige grundlegende Aspekte der Grenzpolitik des Tiberius nach Abberufung des Germanicus von der Rheinfront eingegangen werden (II.). Schließlich soll auf die besondere Situation der Truppen am Rhein und ihren Bezug zum inneren, vornehmlich östlichen Gallien hingewiesen werden (III.).
Das Working Paper bietet die zusammenfassende Stellungnahme von Prof. Volker Wieland zum Ankaufprogramm der Europäischen Zentralbank für Anleihen des öffentlichen Sektors (Public Sector Purchase Programme, PSPP) am Bundesverfassungsgericht am 30.07.2019. Dabei liegt der Schwerpunkt auf der Frage der Einordnung des PSPP als monetäre, geldpolitische Maßnahme und der Verhältnismäßigkeit des Programms und seiner Umsetzung. Ebenfalls wird kurz auf die weiteren Fragen zur Umsetzung, insbesondere Ankündigung, Begrenzung und Abstand zum Primärmarkt für Staatsanleihen eingegangen.
Wie lassen sich die Chancen und Gefahren menschlicher Wirkmacht erkennen und einschätzen? Wie umgehen mit den Auswirkungen des menschlichen Handelns? Dazu forscht Darrel Moellendorf, der an der Goethe-Universität politische Philosophie lehrt. Ein Gespräch über Klimawandel, Moral, Gerechtigkeit und das Anthropozän.
Entorhinal-retrosplenial circuits for allocentric-egocentric transformation of boundary coding
(2020)
Spatial navigation requires landmark coding from two perspectives, relying on viewpoint-invariant and self-referenced representations. The brain encodes information within each reference frame but their interactions and functional dependency remains unclear. Here we investigate the relationship between neurons in the rat's retrosplenial cortex (RSC) and entorhinal cortex (MEC) that increase firing near boundaries of space. Border cells in RSC specifically encode walls, but not objects, and are sensitive to the animal’s direction to nearby borders. These egocentric representations are generated independent of visual or whisker sensation but are affected by inputs from MEC that contains allocentric spatial cells. Pharmaco- and optogenetic inhibition of MEC led to a disruption of border coding in RSC, but not vice versa, indicating allocentric-to-egocentric transformation. Finally, RSC border cells fire prospective to the animal’s next motion, unlike those in MEC, revealing the MEC-RSC pathway as an extended border coding circuit that implements coordinate transformation to guide navigation behavior.
Aerobic and resistance exercise acutely increase cognitive performance (CP). High-intensity functional training (HIFT) combines the characteristics of both regimes but its effect on CP is unclear. Thirty-five healthy individuals (26.7 ± 3.6 years, 18 females) were randomly allocated to three groups. The first (HIFT) performed a functional whole-body workout at maximal effort and in circuit format, while a second walked at 60% of the heart rate reserve (WALK). The third group remained physically inactive reading a book (CON). Before and after the 15-min intervention period, CP was assessed with the Stroop Test, Trail Making Test and Digit Span Test. Repeated-measures ANOVAs and post-hoc 95% confidence intervals (95% CI) were used to detect time/group differences. A significant group*time interaction was found for the backwards condition of the Digit Span Test (p = 0.04) and according to the 95% CI, HIFT was superior to WALK and CON. Analysis of the sum score of the Digit Span Test and the incongruent condition of the Stroop Test, furthermore, revealed main effects for time (p < 0.05) with HIFT being the only intervention improving CP. No differences were found for the Trail Making Test (p > 0.05). In conclusion, HIFT represents an appropriate method to acutely improve working memory, potentially being superior to moderate aerobic-type exercise.
Experiments in cadavers have demonstrated significant mechanical interactions between constituents of myofascial chains. However, evidence for such force transmission effects is scarce under in vivo conditions. The purpose of this trial was to examine the impact of ankle motion on soft tissue displacement of the dorsal thigh. Eleven healthy active individuals (26.8 ± 4.3 years, six males), in prone position and with the knee extended, underwent passive calf stretches (ankle dorsal extension) imposed by an isokinetic dynamometer. High-resolution ultrasound was used to simultaneously capture the displacement of the semimembranosus muscle, which was quantified by means of cross-correlation analysis. Inactivity of the leg muscles was controlled using surface electromyography (EMG). One participant had to be excluded due to major EMG activity during the experiment. According to a one-sample t test testing the difference to the neutral zero position, ankle dorsal extension induced substantial caudal muscle displacements (5.76 ± 2.67 mm, p < 0.0001). Correlation analysis (Spearman), furthermore, revealed a strong association between maximal dorsal extension and semimembranosus motion (rho = 0.76, p = 0.02). In conclusion, the present trial provides initial in vivo evidence for a mechanical force transmission between serially connected skeletal muscles. This means that local alterations of the mechanical tissue properties may modify flexibility in neighboring (superior or inferior) joints.
Failed jump landings represent a key mechanism of musculoskeletal trauma. It has been speculated that cognitive dual-task loading during the flight phase may moderate the injury risk. This study aimed to explore whether increased visual distraction can compromise landing biomechanics. Twenty-one healthy, physically active participants (15 females, 25.8 ± 0.4 years) completed a series of 30 counter-movement jumps (CMJ) onto a capacitive pressure platform. In addition to safely landing on one leg, they were required to memorize either one, two or three jersey numbers shown during the flight phase (randomly selected and equally balanced over all jumps). Outcomes included the number of recall errors as well as landing errors and three variables of landing kinetics (time to stabilization/TTS, peak ground reaction force/pGRF, length of the centre of pressure trace/COPT). Differences between the conditions were calculated using the Friedman test and the post hoc Bonferroni-Holm corrected Wilcoxon test. Regardless of the condition, landing errors remained unchanged (p = .46). In contrast, increased visual distraction resulted in a higher number of recall errors (chi² = 13.3, p = .001). Higher cognitive loading, furthermore, appeared to negatively impact mediolateral COPT (p < .05). Time to stabilization (p = .84) and pGRF (p = .78) were unaffected. A simple visual distraction in a controlled experimental setting is sufficient to adversely affect landing stability and task-related short-term memory during CMJ. The ability to precisely perceive the environment during movement under time constraints may, hence, represent a new injury risk factor and should be investigated in a prospective trial.
Perceptual-cognitive function and unplanned athletic movement task performance: a systematic review
(2020)
The performance of choice-reaction tasks during athletic movement has been demonstrated to evoke unfavorable biomechanics in the lower limb. However, the mechanism of this observation is unknown. We conducted a systematic review examining the association between (1) the biomechanical and functional safety of unplanned sports-related movements (e.g., jumps/runs with a spontaneously indicated landing leg/cutting direction) and (2) markers of perceptual–cognitive function (PCF). A literature search in three databases (PubMed, ScienceDirect and Google Scholar) identified five relevant articles. The study quality, rated by means of a modified Downs and Black checklist, was moderate to high (average: 13/16 points). Four of five papers, in at least one parameter, found either an association of PCF with task safety or significantly reduced task safety in low vs. high PCF performers. However, as (a) the outcomes, populations and statistical methods of the included trials were highly heterogeneous and (b) only two out of five studies had an adequate control condition (pre-planned movement task), the evidence was classified as conflicting. In summary, PCF may represent a factor affecting injury risk and performance during unplanned sports-related movements, but future research strengthening the evidence for this association is warranted.
High-intensity functional training (HIFT) has become a popular method in the sports and fitness sector. In contrast to unimodal approaches such as strength or endurance training, it has been hypothesized to induce concurrent adaptations in multiple markers of motor function. However, to date, the effectiveness of HIFT in this regard has not been studied. The present systematic review quantified the chronic effects of HIFT on motor function in healthy individuals. A multilevel meta-analysis with a robust random effects meta-regession model was used to pool the standardized mean differences (SMD) between (a) HIFT and (b) no-exercise (NEX) as well as conventional endurance, resistance and balance training for outcomes of muscle strength, endurance capacity and balance. The influence of possible effect modifiers such as program duration, session duration, age or sex was examined in a moderator analysis. Seventeen papers with moderate to high methodological quality (PEDro scale) were identified. Compared to NEX, HIFT had small to moderate positive effects on endurance capacity (SMD: 0.42, 95% CI 0.07–0.78, p = 0.03) and strength (0.60, 95% CI 0.02–1.18, p = 0.04) but no effect on balance (SMD: − 0.10, 95% CI − 1.13 to 0.92, p = 0.42). Regarding endurance, HIFT showed similar effectiveness as moderate-intensity endurance training (SMD: − 0.11, 95% CI − 1.17 to 0.95, p = 0.75) and high-intensity interval endurance training (SMD: − 0.15, 95% CI − 1.4 to 1.1, p = 0.66). No comparisons of HIFT vs. classical resistance or balance training were found. Moderator analyses revealed no influence of most effect modifiers. However, regarding endurance, females seemed to respond more strongly to HIFT in the comparison to NEX (p < .05). HIFT appears to represent an appropriate method to induce chronic improvements in motor function. While being superior to NEX and non-inferior to endurance training, current evidence does not allow a comparison against resistance and balance training. The impact of possible effect moderators should be further elucidated in future research.
Confinement measures during the COVID-19 pandemic have caused substantial reductions in global physical activity (PA) levels. In view of the manifold health benefits of PA, the development of interventions counteracting this trend is paramount. Our survey with 15,261 participants (38 ± 15 years, 58.5% females) examined preferences towards digital home exercise programs in 14 countries affected by COVID-19. More than two-thirds of the sample (68.4%, n = 10,433) indicated being interested in home exercise, and most participants were willing to work out at least three times per week (89.3%, n = 9328). Binary logistic regression revealed that female sex, working part-time, younger age, and being registered in a gym were associated with willingness to exercise. Flexibility (71.1%, n = 7377), resistance (68.6%, n = 7116), and endurance training (62.4%, n = 6478) were the most preferred types of exercise. Our results may guide health providers in developing individually tailored PA interventions during the current and future pandemics.
Introduction: The worldwide spread of the novel coronavirus (SARS-CoV2) has prompted numerous countries to restrict public life. Related measures, such as limits on social gatherings, business closures, or lockdowns, are expected to considerably reduce the individual opportunities to move outside the home. As physical activity (PA) and sport participation significantly contribute to health, this study has two objectives. The objectives of this study are to assess changes in PA and well-being since the coronavirus outbreak in affected countries. Additionally, we will evaluate the impact of digital home-based exercise programs on PA as well as physical and mental health outcomes.
Method: A multinational network trial will be conducted with three planned phases (A, B, and C). Part A consists of administering a structured survey. It investigates changes in PA levels and health during the coronavirus outbreak and measures the preferences of the participants regarding online training programs. Part B is a two-armed randomized-controlled trial. Participants assigned to the intervention group (IG) will complete a digital 4-week home exercise training (live streaming via internet) guided by the survey results on content and time of program. The control group (CG) will not receive the program. Part C is 4-week access of both CG and IG to a digital archive of pre-recorded workouts from Part B. Similar to Part A, questionnaires will be used in both Part B and C to estimate the effects of exercise on measures of mental and physical health.
Results and Discussion: The ASAP project will provide valuable insights into the importance of PA during a global pandemic. Our initial survey is the first to determine how governmental confinement measures impact bodily and mental well-being. Based on the results, the intervention studies will be unique to address health problems potentially arising from losses in PA. If proven effective, the newly developed telehealth programs could become a significant and easy-to-distribute factor in combating PA decreases. Results of the study may hence guide policy makers on methods to maintain PA and health when being forced to restrict public life.
Study Register: DRKS00021273.
Competition anxiety has been demonstrated to decrease sports performance while increasing burnout risk. To date, its degree in CrossFit (CF) is unknown. The present study, therefore, examines competition fear and relevant coping skills as well as potential correlates of both in individuals participating in CF events. A total of n = 79 athletes answered a battery of three questionnaires (competition fear index, athletic coping skills inventory, mindfulness attention awareness scale). Substantial levels of anxiety, particularly regarding the somatic dimension of the competition fear index, were reported. The most pronounced coping skill was freedom of worry. While age or level of competition showed no/very small associations with survey data, sex was correlated to the psychological characteristics: women reported higher competition fears and lower coping skill levels (p > 0.05). Competition fears are highly prevalent in CF athletes and the preventive value of population-specific interventions, particularly in females, should be investigated in future trials.
Functional circuit training (FCT) has been demonstrated to acutely enhance cognitive performance (CP). However, the moderators of this observation are unknown. This study aimed to elucidate the role of exercise intensity. According to an a priori sample size calculation, n = 24 healthy participants (26 ± 3 years, 13 females), in randomized order, performed a single 15-min bout of FCT with low (20–39% of the heart rate reserve/HRR), moderate (40–59% HRR) or high intensity (maximal effort). Immediately pre- and post-workout, CP was measured by use of the Digit Span test, Stroop test and Trail Making test. Non-parametric data analyses did not reveal significant differences between conditions (p > 0.05) although parameter-free 95% confidence intervals showed pre-post improvements in some outcomes at moderate and high intensity only. The effort level does not seem to be a major effect modifier regarding short-term increases in CP following HCT in young active adults.
Resistance exercise has been demonstrated to improve brain function. However, the optimal workout characteristics are a matter of debate. This randomized, controlled trial aimed to elucidate differences between free-weight (REfree) and machine-based (REmach) training with regard to their ability to acutely enhance cognitive performance (CP). A total of n = 46 healthy individuals (27 ± 4 years, 26 men) performed a 45-min bout of REfree (military press, barbell squat, bench press) or REmach (shoulder press, leg press, chest press). Pre- and post-intervention, CP was examined using the Stroop test, Trail Making Test and Digit Span test. Mann–Whitney U tests did not reveal between-group differences for performance in the Digit Span test, Trail Making test and the color and word conditions of the Stroop test (p > 0.05). However, REfree was superior to REmach in the Stroop color-word condition (+6.3%, p = 0.02, R = 0.35). Additionally, REfree elicited pre-post changes in all parameters except for the Digit Span test and the word condition of the Stroop test while REmach only improved cognitive performance in part A of the Trail Making test. Using free weights seems to be the more effective RE method to acutely improve cognitive function (i.e., inhibitory control). The mechanisms of this finding merit further investigation.
The deep fascia enveloping the skeletal muscle has been shown to contribute to the mechanics of the locomotor system. However, less is known about the role of the superficial fascia (SF). This study aimed to describe the potential interaction between the Hamstring muscles and the SF. Local movement of the dorsal thigh's soft tissue was imposed making use of myofascial force transmission effects across the knee joint: In eleven healthy individuals (26.8 ± 4.3 years, six males), an isokinetic dynamometer moved the ankle into maximal passive dorsal extension (knee extended). Due to the morphological continuity between the gastrocnemius and the Hamstrings, stretching the calf led to soft tissue displacements in the dorsal thigh. Ultrasound recordings were made to dynamically visualize (a) the semimembranosus muscle and (b) the superficial fascia. Differences in and associations between horizontal movement amplitudes of the two structures, quantified via cross‐correlation analyses, were calculated by means of the Mann–Whitney U test and Kendal's tau test, respectively. Mean horizontal movement was significantly higher in the muscle (5.70 mm) than in the SF (0.72 mm, p < 0.001, r = 0.82). However, a strong correlation between the tissue displacements in both locations was detected (p < 0.001, r = 0.91). Direct mechanical relationship may exist between the SF and the skeletal muscle. Deep pathologies or altered muscle stiffness could thus have long‐term consequences for rather superficial structures and vice versa.
The ecological validity of neuropsychological testing (NT) has been questioned in the sports environment. A frequent criticism is that NT, mostly consisting of pen and paper or digital assessments, lacks relevant bodily movement. This study aimed to identify the determinants of a newly developed testing battery integrating both cognitive and motor demands. Twenty active individuals (25 ± 3 years, 11 males) completed the new motor-cognitive testing battery (MC), traditional NT (Stroop test, Trail Making test, Digit Span test) and isolated assessments of motor function (MF; Y-balance test, 20m-sprint, counter-movement jump). Kendal’s tau and partial Spearman correlations were used to detect associations between MC and NT/MF. Except for two items (Reactive Agility A and counter-movement jump; Run-Decide and sprint time; r = 0.37, p < 0.05), MC was not related to MF. Similarly, MC and NT were mostly unrelated, even when controlling for the two significant motor covariates (p > 0.05). The only MC item with (weak to moderate) associations to NT was the Memory Span test (Digit Span backwards and composite; r = 0.43–0.54, p < 0.05). In sum, motor-cognitive function appears to be largely independent from its two assumed components NT and MF and may represent a new parameter in performance diagnostics.
Diese Arbeit nimmt Weiße Freiwillige aus Deutschland in den Blick, die einen Freiwilligendienst im Ausland geleistet haben und in rassistischen Machtverhältnissen eine privilegierte, das heißt Weiße Position einnehmen. Dabei dienen die Critical Whiteness Studies als fruchtbare Grundlage, um die Auseinandersetzung mit Rassismus aus Weißer privilegierter Perspektive zu untersuchen. Die Arbeit geht daher der Frage nach: Inwiefern die Erfahrungen im Freiwilligendienst und die begleitenden rassismuskritischen Seminare Weiße Nord-Nord und Nord-Süd Freiwillige dazu anregen, ihre Privilegien zu reflektieren und sich kritisch im rassistischen Machtsystem zu positionieren. Die Analyse der Interviews mit Weißen Freiwilligen zeigt, dass die Interviewten zum einen unterschiedliche Konfrontationserfahrungen mit Whiteness gemacht haben und zum anderen ihre daraus resultierenden Reflexionsprozesse und Umgangsweisen sehr divers ausfallen. Unterschiede zeigen sich jedoch nicht nur zwischen den Nord-Nord und Nord-Süd Freiwilligen, sondern auch situationsabhängig anhand der jeweiligen Erfahrungen der einzelnen Weißen Freiwilligen. Aus diesen Untersuchungen lässt sich ableiten, dass es auch für rassismus- und machtkritische Begleitseminare weiterhin eine zu bewältigende Herausforderung bleibt, die Relevanz der persönlichen Auseinandersetzung mit Whiteness und somit mit eigenen Privilegien und Verstrickungen in Rassismus – unabhängig vom Zielland des Freiwilligendienstes – zu vermitteln.
Carl von Clausewitz’ Denken über den Krieg steht paradigmatisch für ein instrumentelles Verständnis von Gewalt in der Politik. Gewalt ist für Clausewitz ein Mittel, das im Krieg verwendet wird, um politische Zwecke zu erreichen. Seit dem Ende des Ost-West-Konflikts ist jedoch die Ansicht weit verbreitet, dass Clausewitz’ Überlegungen keine Gültigkeit mehr besitzen. Gegenwärtige Formen des Krieges seien zwar gewaltsam, aber nicht mehr politisch, weil sie nicht allein von Staaten oder aus einer eng verstandenen Staatsräson heraus geführt werden. Der Einwand missversteht jedoch Clausewitz’ Begriff der Politik. Dieser soll im vorliegenden Aufsatz systematisch rekonstruiert werden. Dem zu entwickelnden Interpretationsvorschlag zufolge bezeichnet „Politik“ in Clausewitz’ theoretischem System zunächst einmal nur ganz allgemein eine Interaktion von zwei oder mehr Akteuren, die jeweils ihren Willen realisieren wollen, deren Willen sich jedoch nicht vollständig vereinen lassen. Krieg ist für Clausewitz dann solche Politik, die mit gewaltsamen Mitteln betrieben wird. Vor diesem Hintergrund wird argumentiert, dass Clausewitz’ Theorie des Krieges einen fruchtbaren Analyserahmen bietet, mit dem sich die Transformationen der politischen Gewalt von den Kabinettskriegen des 18. Jahrhunderts bis zu den „neuen Kriegen“ unserer Zeit nachvollziehen lassen.
Nuclear receptor related 1 (Nurr1) is an orphan ligand-activated transcription factor and considered as neuroprotective transcriptional regulator with great potential as therapeutic target for neurodegenerative diseases. However, the collection of available Nurr1 modulators and mechanistic understanding of Nurr1 are limited. Here, we report the discovery of several structurally diverse non-steroidal anti-inflammatory drugs as inverse Nurr1 agonists demonstrating that Nurr1 activity can be regulated bidirectionally. As chemical tools, these ligands enable unraveling the co-regulatory network of Nurr1 and the mode of action distinguishing agonists from inverse agonists. In addition to its ability to dimerize, we observe an ability of Nurr1 to recruit several canonical nuclear receptor co-regulators in a ligand-dependent fashion. Distinct dimerization states and co-regulator interaction patterns arise as discriminating factors of Nurr1 agonists and inverse agonists. Our results contribute a valuable collection of Nurr1 modulators and relevant mechanistic insights for future Nurr1 target validation and drug discovery.
In this report, we present the contributions, outcomes, ideas, discussions and conclusions obtained at the PaleoMaps Workshop 2019, that took place at the Institute of Geography of the University of Cologne on 23 and 24 September 2019. The twofold aim of the workshop was: (1) to provide an overview of approaches and methods that are presently used to incorporate paleoenvironmental information in human–environment interaction modeling applications, and building thereon; (2) to devise new approaches and solutions that might be used to enhance the reconstruction of past human–environmental interconnections. This report first outlines the presented papers, and then provides a joint protocol of the often extensive discussions that came up following the presentations or else during the refreshment intervals. It concludes by adressing the open points to be resolved in future research avenues, e.g., implementation of open science practices, new procedures for reviewing of publications, and future concepts for quality assurance of the often complex paleoenvironmental data. This report may serve as an overview of the state of the art in paleoenvironment mapping and modeling. It includes an extensive compilation of the basic literature, as provided by the workshop attendants, which will itself facilitate the necessary future research.
Lack of sensitive diagnostic tests impairs the understanding of the epidemiology of histoplasmosis, a disease whose burden is estimated to be largely underrated. Broad-range PCRs have been applied to identify fungal agents from pathology blocks, but sensitivity is variable. In this study, we compared the results of a specific Histoplasma qPCR (H. qPCR) with the results of a broad-range qPCR (28S qPCR) on formalin-fixed, paraffin-embedded (FFPE) tissue specimens from patients with proven fungal infections (n = 67), histologically suggestive of histoplasmosis (n = 36) and other mycoses (n = 31). The clinical sensitivity for histoplasmosis of the H. qPCR and the 28S qPCR was 94% and 48.5%, respectively. Samples suggestive for other fungal infections were negative with the H. qPCR. The 28S qPCR did not amplify DNA of Histoplasma in FFPE in these samples, but could amplify DNA of Emergomyces (n = 1) and Paracoccidioides (n = 2) in three samples suggestive for histoplasmosis but negative in the H. qPCR. In conclusion, amplification of Histoplasma DNA from FFPE samples is more sensitive with the H. qPCR than with the 28S qPCR. However, the 28S qPCR identified DNA of other fungi in H. qPCR-negative samples presenting like histoplasmosis, suggesting that the combination of both assays may improve the diagnosis.
In murine models, the expression of inducible nitric oxide synthase (iNOS) in myocardial infarction (MI) has been reported to be the result of tissue injury and inflammation. In the present study, mRNA expression of iNOS, hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) was investigated in postmortem human infarction hearts. Since HIF-1α is the inducible subunit of the transcription factor HIF-1, which regulates transcription of iNOS and VEGF, the interrelation between the three genes was observed, to examine the molecular processes during the emergence of MI. iNOS and VEGF mRNAs were found to be significantly upregulated in the affected regions of MI hearts in comparison to healthy controls. Upregulation of HIF-1α was also present but not significant. Correlation analysis of the three genes indicated a stronger and significant correlation between HIF-1α and iNOS mRNAs than between HIF-1α and VEGF. The results of the study revealed differences in the expression patterns of HIF-1 downstream targets. The stronger transcription of iNOS by HIF-1 in the affected regions of MI hearts may represent a pathological process, since no correlation of iNOS and HIF-1α mRNA was found in non-affected areas of MI hearts. Oxidative stress is considered to cause molecular changes in MI, leading to increased iNOS expression. Therefore, it may also represent a forensic marker for detection of early changes in heart tissue.
Transfer RNA fragments replace microRNA regulators of the cholinergic post-stroke immune blockade
(2020)
Stroke is a leading cause of death and disability. Recovery depends on a delicate balance between inflammatory responses and immune suppression, tipping the scale between brain protection and susceptibility to infection. Peripheral cholinergic blockade of immune reactions fine-tunes this immune response, but its molecular regulators are unknown. Here, we report a regulatory shift in small RNA types in patient blood sequenced two days after ischemic stroke, comprising massive decreases of microRNA levels and concomitant increases of transfer RNA fragments (tRFs) targeting cholinergic transcripts. Electrophoresis-based size-selection followed by RT-qPCR validated the top 6 upregulated tRFs in a separate cohort of stroke patients, and independent datasets of small and long RNA sequencing pinpointed immune cell subsets pivotal to these responses, implicating CD14+ monocytes in the cholinergic inflammatory reflex. In-depth small RNA targeting analyses revealed the most-perturbed pathways following stroke and implied a structural dichotomy between microRNA and tRF target sets. Furthermore, lipopolysaccharide stimulation of murine RAW 264.7 cells and human CD14+ monocytes upregulated the top 6 stroke-perturbed tRFs, and overexpression of stroke-inducible tRF-22-WE8SPOX52 using an ssRNA mimic induced downregulation of immune regulator Z-DNA binding protein 1 (Zbp1). In summary, we identified a “changing of the guards” between RNA types that may systemically affect homeostasis in post-stroke immune responses, and pinpointed multiple affected pathways, which opens new venues for establishing therapeutics and biomarkers at the protein- and RNA-level.
Significance Statement Ischemic stroke triggers peripheral immunosuppression, increasing the susceptibility to post-stroke pneumonia that is linked with poor survival. The post-stroke brain initiates intensive communication with the immune system, and acetylcholine contributes to these messages; but the responsible molecules are yet unknown. We discovered a “changing of the guards,” where microRNA levels decreased but small transfer RNA fragments (tRFs) increased in post-stroke blood. This molecular switch may re-balance acetylcholine signaling in CD14+ monocytes by regulating their gene expression and modulating post-stroke immunity. Our observations point out to tRFs as molecular regulators of post-stroke immune responses that may be potential therapeutic targets.
Transfer RNA fragments replace microRNA regulators of the cholinergic poststroke immune blockade
(2020)
Stroke is a leading cause of death and disability. Recovery depends on a delicate balance between inflammatory responses and immune suppression, tipping the scale between brain protection and susceptibility to infection. Peripheral cholinergic blockade of immune reactions fine-tunes this immune response, but its molecular regulators are unknown. Here, we report a regulatory shift in small RNA types in patient blood sequenced 2 d after ischemic stroke, comprising massive decreases of microRNA levels and concomitant increases of transfer RNA fragments (tRFs) targeting cholinergic transcripts. Electrophoresis-based size-selection followed by qRT-PCR validated the top six up-regulated tRFs in a separate cohort of stroke patients, and independent datasets of small and long RNA sequencing pinpointed immune cell subsets pivotal to these responses, implicating CD14+ monocytes in the cholinergic inflammatory reflex. In-depth small RNA targeting analyses revealed the most-perturbed pathways following stroke and implied a structural dichotomy between microRNA and tRF target sets. Furthermore, lipopolysaccharide stimulation of murine RAW 264.7 cells and human CD14+ monocytes up-regulated the top six stroke-perturbed tRFs, and overexpression of stroke-inducible tRF-22-WE8SPOX52 using a single-stranded RNA mimic induced down-regulation of immune regulator Z-DNA binding protein 1. In summary, we identified a “changing of the guards” between small RNA types that may systemically affect homeostasis in poststroke immune responses, and pinpointed multiple affected pathways, which opens new venues for establishing therapeutics and biomarkers at the protein and RNA level.
Transfer RNA fragments replace microRNA regulators of the cholinergic post-stroke immune blockade
(2020)
Stroke is a leading cause of death and disability. Recovery depends on balance between inflammatory response and immune suppression, which can be CNS-protective but may worsen prognosis by increasing patients’ susceptibility to infections. Peripheral cholinergic blockade of immune reactions fine-tunes this immune response, but its molecular regulators are unknown. Therefore, we sought small RNA balancers of the cholinergic anti-inflammatory pathway in peripheral blood from ischemic stroke patients. Using RNA-sequencing and RT-qPCR, we discovered in patients’ blood on day 2 after stroke a “change of guards” reflected in massive decreases in microRNAs (miRs) and increases in transfer RNA fragments (tRFs) targeting cholinergic transcripts. Electrophoresis-based size-selection followed by RT-qPCR validated the top 6 upregulated tRFs in a separate cohort of stroke patients, and independent small RNA-sequencing datasets presented post-stroke enriched tRFs as originating from lymphocytes and monocytes. In these immune compartments, we found CD14+ monocytes to express the highest amounts of cholinergic transcripts. In-depth analysis of CD14+ regulatory circuits revealed minimally overlapping subsets of transcription factors carrying complementary motifs to miRs or tRFs, indicating different roles for the stroke-perturbed members of these small RNA species. Furthermore, LPS-stimulated murine RAW264.7 cells presented dexamethasone-suppressible upregulation of the top 6 tRFs identified in human patients, indicating an evolutionarily conserved and pharmaceutically treatable tRF response to inflammatory cues. Our findings identify tRF/miR subgroups which may co-modulate the homeostatic response to stroke in patients’ blood and open novel venues for establishing RNA-targeted concepts for post-stroke diagnosis and therapeutics.
The genus Giraffa likely evolved around seven million years ago in Indo-Asia and spread over the Arabian-African land bridge into Eastern Africa. The oldest fossil of the African lineage was found in Kenya and dated to 7-5.4 Mya. Beside modern giraffe, four additional African species have likely existed (G. gracilis, G. pygmaea, G. stillei, and G. jumae). Based on their morphological similarities, G. gracilis is often considered to be the closest relative of the modern giraffe. Nevertheless, the phylogeny within the genus Giraffa is largely unresolved.
Modern giraffe (Giraffa sp.) have been neglected by the scientific community for a long time and still very little is known about their biology. Traditionally, present-day giraffe have been considered a single species (G. camelopardalis) which is divided into six to eleven subspecies, with nine subspecies being the most accepted classification. This classification was based on morphological differences and geographic ranges. However, recent genetic analyses found hidden diversity within Giraffa and proposed four genetically distinct giraffe species (G. camelopardalis, G. reticulata, G. tippelskirchi, G. giraffa) with presumably little gene flow among them.
Gene flow on a population level is the exchange of genetic information among populations facilitated by the migration of individuals between populations. Additionally, it is an important criterion to delineate species, because many species concepts, especially the Biological Species Concept, rely on the concept of reproductive isolation. Yet, new genetic methods are identifying an increasing number of species that show signs of introgressive hybridization or gene flow among them. Therefore, strict reproductive isolation cannot always be applied to delineate species, especially in young, probably still diverging, species such as giraffe.
Therefore, giraffe are ideal study organisms to investigate the level of gene flow in recently diverged species with adjacent or potentially overlapping ranges. Furthermore, their recent classification as “Vulnerable” by the IUCN and their unreliable distribution maps require the genetic evaluation of their population structure, distribution and conservation status.
In Publication 1 (Winter et al. (2018a), Ecological Genetics and Genomics, 7–8, 1–5), I studied the distribution and matrilineal population structure of Angolan giraffe (G. giraffa angolensis) using sequences from the cytochrome b gene (1,140 bp) and the mitochondrial control region for individuals from across their known range and beyond, and additionally including individuals from all known giraffe species and subspecies. The reconstruction of a phylogenetic tree and a mitochondrial haplotype network allowed to identify the most easterly known natural population of Angolan giraffe, a population that was previously assigned to their sister-subspecies South African giraffe (G. giraffa giraffa), indicating the limit of classification by morphology and geography. Furthermore, the analyses show that Namibia’s iconic desert-dwelling giraffe population is genetically distinct, even from the nearest population at Etosha National Park, suggesting very limited, if any, natural exchange of matrilines. Yet, no geographic barriers are known for this region that would prevent genetic exchange. Therefore, the two populations are likely on different evolutionary trajectories. Limited individuals with an Etosha haplotype further suggest that translocation of Etosha giraffe into the desert population had only a minor impact on the local population. Two separate haplogroups within Etosha National Park suggest an “out of Etosha” radiation of Angolan giraffe to the East followed by a later back-migration.
In Publication 2 (Winter et al. (2018b), Ecology and Evolution, 8(20), 10156–10165), I investigated the genetic population structure of giraffe across their range (n = 137) with focus on the amount of gene flow among the proposed giraffe species with a 3-fold increased set of nuclear introns (n = 21). Limited gene flow of less than one effective migrant per generation, even between the closely related northern (G. camelopardalis) and reticulated giraffe (G. reticulata) further supports the existence of four giraffe species by a different methodology, gene flow. This is significant because most species concepts build on reproductive isolation. Furthermore, this result is corroborated by four distinct major clades in a phylogenetic tree analysis, and distinct clusters in Principal Component Analysis and STRUCTURE analysis. All these analyses suggest a low level of genetic exchange among the four giraffe species and, therefore, a high degree of reproductive isolation in accordance with the Biological Species Concept (BSC). In Addition, only a single individual in 137 was identified as being potential of natural hybrid origin, which promotes the four-species concept further. ...
Background: The back pain screening tool Risk-Prevention-Index Social (RPI-S) identifies the individual psychosocial risk for low back pain chronification and supports the allocation of patients at risk in additional multidisciplinary treatments. The study objectives were to evaluate (1) the prognostic validity of the RPI-S for a 6-month time frame and (2) the clinical benefit of the RPI-S. Methods: In a multicenter single-blind 3-armed randomized controlled trial, n = 660 persons (age 18-65 years) were randomly assigned to a twelve-week uni- or multidisciplinary exercise intervention or control group. Psychosocial risk was assessed by the RPI-S domain social environment (RPI-SSE) and the outcome pain by the Chronic Pain Grade Questionnaire (baseline M1, 12-weeks M4, 24-weeks M5). Prognostic validity was quantified by the root mean squared error (RMSE) within the control group. The clinical benefit of RPI-SSE was calculated by repeated measures ANOVA in intervention groups. Results: A subsample of n = 274 participants (mean = 38.0 years, SD 13.1) was analyzed, of which 30% were classified at risk in their psychosocial profile. The half-year prognostic validity was good (RMSE for disability of 9.04 at M4 and of 9.73 at M5; RMSE for pain intensity of 12.45 at M4 and of 14.49 at M5). People at risk showed significantly stronger reduction in pain disability and intensity at M4/M5, if participating in a multidisciplinary exercise treatment. Subjects at no risk showed a smaller reduction in pain disability in both interventions and no group differences for pain intensity. Regarding disability due to pain, around 41% of the sample would gain an unfitted treatment without the back pain screening. Conclusion: The RPI-SSE prognostic validity demonstrated good applicability and a clinical benefit confirmed by a clear advantage of an individualized treatment possibility.
Aims: In primary central nervous system tumours, epithelial-to-mesenchymal transition (EMT) gene expression is associated with increased malignancy. However, it has also been shown that EMT factors in gliomas are almost exclusively expressed by glioma vessel-associated pericytes (GA-Peris). In this study, we aimed to identify the mechanism of EMT in GA-Peris and its impact on angiogenic processes.
Methods; In glioma patients, vascular density and the expression of the pericytic markers platelet derived growth factor receptor (PDGFR)-β and smooth muscle actin (αSMA) were examined in relation to the expression of the EMT transcription factor SLUG and were correlated with survival of patients with glioblastoma (GBM). Functional mechanisms of SLUG regulation and the effects on primary human brain vascular pericytes (HBVP) were studied in vitro by measuring proliferation, cell motility and growth characteristics.
Results: The number of PDGFR-β- and αSMA-positive pericytes did not change with increased malignancy nor showed an association with the survival of GBM patients. However, SLUG-expressing pericytes displayed considerable morphological changes in GBM-associated vessels, and TGF-β induced SLUG upregulation led to enhanced proliferation, motility and altered growth patterns in HBVP. Downregulation of SLUG or addition of a TGF-β antagonising antibody abolished these effects.
Conclusions: We provide evidence that in GA-Peris, elevated SLUG expression is mediated by TGF-β, a cytokine secreted by most glioma cells, indicating that the latter actively modulate neovascularisation not only by modulating endothelial cells, but also by influencing pericytes. This process might be responsible for the formation of an unstructured tumour vasculature as well as for the breakdown of the blood–brain barrier in GBM.
The two main phytocannabinoids—delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)—have been extensively studied, and it has been shown that THC can induce transient psychosis. At the same time, CBD appears to have no psychotomimetic potential. On the contrary, emerging evidence for CBD's antipsychotic properties suggests that it may attenuate effects induced by THC. Thus, we investigated and compared the effects of THC and CBD administration on emotion, cognition, and attention as well as the impact of CBD pre-treatment on THC effects in healthy volunteers. We performed a placebo-controlled, double-blind, experimental trial (GEI-TCP II; ClinicalTrials.gov identifier: NCT02487381) with 60 healthy volunteers randomly allocated to four parallel intervention groups, receiving either placebo, 800 mg CBD, 20 mg THC, or both cannabinoids. Subjects underwent neuropsychological tests assessing working memory (Letter Number Sequencing test), cognitive processing speed (Digit Symbol Coding task), attention (d2 Test of Attention), and emotional state (adjective mood rating scale [EWL]). Administration of CBD alone did not influence the emotional state, cognitive performance, and attention. At the same time, THC affected two of six emotional categories—more precisely, the performance-related activity and extraversion—, reduced the cognitive processing speed and impaired the performance on the d2 Test of Attention. Interestingly, pre-treatment with CBD did not attenuate the effects induced by THC. These findings show that the acute intake of CBD itself has no effect per se in healthy volunteers and that a single dose of CBD prior to THC administration was insufficient to mitigate the detrimental impact of THC in the given setting. This is in support of a complex interaction between CBD and THC whose effects are not counterbalanced by CBD under all circumstances.
This thesis investigates the acquisition pace and the typical developmental path in eL2 acquisition of selected phenomena of German morphosyntax and semantics and compared them to monolingual acquisition. In addition, the influence of ‘Age of Onset’ and of external factors on eL2 acquisition is examined.
To date, the most studies on eL2 acquisition focused on language production. Based on mostly longitudinal spontaneous speech data of only small number of children, they indicate that eL2 learners acquire sentence structure and subject-verb-agreement faster than monolingual children, whereas the acquisition of case marking causes them more difficulties. Moreover, similar developmental paths to those of monolingual children are claimed. Only several studies examined comprehension abilities in eL2 learners, however overwhelmingly in cross-sectional design. The findings from comprehension studies on telic and atelic verbs, and on wh-questions indicate that eL2 children acquire their target-like interpretation faster than monolingual children. The same acquisition stages towards target-like interpretation like in monolingual acquisition are assumed as well. Taking together, to date, no study exists, that examines comprehension and production abilities in a large group of eL2 learners of German in a longitudinal design.
This thesis extends the previous results by investigating pace of acquisition, impact of factors, and individual developmental paths in a longitudinal design with large groups of participants. Language data of 29 eL2 learners of German (age at T1: 3;7 years, LoE: 10 months) and 45 monolingual German-speaking children (age at T1: 3;7) are examined. The eL2 learners were tested in six test rounds (age at T6: 6;9 years). The monolingual children were tested in five test rounds (are at T5: 5;7). The standardized test LiSe-DaZ (Schulz & Tracy, 2011) was employed to examine children’s language skills.
eL2 learners show a significantly greater rate of change, thus faster acquisition pace, than monolingual children in the following scales: comprehension of telicity, comprehension of wh-questions, production of prepositions, and production of conjunctions. These phenomena are acquired early in monolingual children. No differences regarding acquisition pace between eL2 children and monolingual children are found for comprehension of negation, production of case marking, and production of focus particles. These phenomena are acquired late in monolingual development and involve semantic and pragmatic knowledge. The findings of faster acquisition pace of several phenomena are in line with several studies that reported that eL2 children develop faster than monolingual children.
Independent on whether a phenomenon is acquired early or late, no effects of external factors on eL2 children’s performance are found. These findings indicate that acquisition of core, rule-based phenomena is not sensitive to external factors if the first exposure to L2 takes place around the age of three.
Moreover, eL2 children show the same developmental stages and error types in comprehension of telicity, comprehension of negation, production of matrix and subordinate clauses. This is also independent on how fast they acquire a structure under consideration. Thus, these findings provide a further support for similar developmental paths of eL2 and monolingual children towards target-like comprehension and production.
Vernetzen und gestalten : Gespräch mit Uni-Präsidentin Birgitta Wolff zum Ende ihrer Amtszeit
(2020)
Das neue Jahr beginnt mit einem Wechsel an der Uni-Spitze. Universitätspräsidentin Birgitta Wolff übergibt nach sechs Jahren das Amt an Enrico Schleiff, der von 2012 bis 2018 bereits als Vizepräsident für die Goethe-Universität aktiv war. Im Interview mit dem UniReport spricht Wolff über das besondere »Corona-Jahr« 2020 und die aktuelle Position der Uni.
Recent developments in Hungary and Poland have made democratic backsliding a major issue of concern within the European Union (EU). This article focuses on the secondary agents that facilitate democratic backsliding in Hungary and Poland: the European People’s Party (EPP), which has continually protected the Hungarian Fidesz government from EU sanctions, and the Hungarian ruling party Fidesz, which repeatedly promised to block any EU-level sanctions against Poland in the Council. The article analyses these agents’ behaviour as an instance of transnational complicity and passes a tentative judgment as to which of the two cases is normatively more problematic. The analysis has implications for possible countervailing responses to democratic backsliding within EU member states.
Aim: Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials & methods: We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE – responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results: Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10-5) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion: This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.
Post-exercise hypotension (PEH) is the phenomenon of lowered blood pressure after a single bout of exercise. Only a fraction of people develops PEH but its occurrence correlates well with long-term effects of sports on blood pressure. Therefore, PEH has been suggested as a suitable predictor for the effectivity of exercise as therapy in hypertension. Local vascular bioactive lipids might play a potential role in this context. We performed a cross-over clinical pilot study with 18 healthy volunteers to investigate the occurrence of PEH after a single short-term endurance exercise. Furthermore, we investigated the plasma lipid profile with focus on arachidonic acid (AA)-derived metabolites as potential biomarkers of PEH. A single bout of ergometer cycling induced a significant PEH in healthy volunteers with the expected high inter-individual variability. Targeted lipid spectrum analysis revealed significant upregulation of several lipids in the direct post-exercise phase. Among these changes, only 15- hydroxyeicosatetranoic acid (HETE) correlated significantly with the extent of PEH but in an AA-independent manner, suggesting that 15-HETE might act as specific PEH-marker. Our data indicate that specific lipid modulation might facilitate the identification of patients who will benefit from exercise activity in hypertension therapy. However, larger trials including hypertonic patients are necessary to verify the clinical value of this hypothesis.