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Zimmer, Claudia ; Riesch, Rüdiger ; Jourdan, Jonas ; Bierbach, David ; Arias-Rodriguez, Lenin ; Plath, Martin
Divergent selection between ecologically dissimilar habitats promotes local adaptation, which can lead to reproductive isolation (RI). Populations in the Poecilia mexicana species complex have independently adapted to toxic hydrogen sulfide and show varying degrees of RI. Here, we examined the variation in the mate choice component of prezygotic RI. Mate choice tests across drainages (with stimulus males from another drainage) suggest that specific features of the males coupled with a general female preference for yellow color patterns explain the observed variation. Analyses of male body coloration identified the intensity of yellow fin coloration as a strong candidate to explain this pattern, and common-garden rearing suggested heritable population differences. Male sexual ornamentation apparently evolved differently across sulfide-adapted populations, for example because of differences in natural counterselection via predation. The ubiquitous preference for yellow color ornaments in poeciliid females likely undermines the emergence of strong RI, as female discrimination in favor of own males becomes weaker when yellow fin coloration in the respective sulfide ecotype increases. Our study illustrates the complexity of the (partly non-parallel) pathways to divergence among replicated ecological gradients. We suggest that future work should identify the genomic loci involved in the pattern reported here, making use of the increasing genomic and transcriptomic datasets available for our study system.
Tiotropium as an add-on treatment option for severe uncontrolled asthma in preschool patients
(2021)
Zielen, Stefan ; Reichert, Gianna ; Donath, Helena ; Trischler, Jordis ; Schulze, Johannes B. ; Eickmeier, Olaf ; Eckrich, Jonas Martin ; Blümchen, Katharina
Background: Toddlers with asthma suffer disproportionally more than school-aged children from exacerbations with emergency visits and hospital admissions despite inhaled corticosteroid (ICS) treatment. A recent trial for children ≤ 5 years showed tolerability of tiotropium and potential to reduce asthma-related events.
Methods: We conducted a retrospective analysis of electronic outpatient records (2017‒2019) of children < 6 years treated with ICS plus long-acting β2-agonists (LABAs) plus tiotropium as an add-on for uncontrolled severe asthma. The primary endpoint was a comparison of systemic corticosteroid (SCS) prescriptions 6 months before and after ICS/LABA/tiotropium start. Secondary endpoints included physician visits, hospitalisations and antibiotic prescriptions. We compared outcomes with children without asthma matched for age, sex, season and screening date.
Results: Compared with a mean 2.42 (95% CI: 1.75, 3.36) SCS courses per patient within 6 months prior to ICS/LABA/tiotropium, 0.74 (95% CI: 0.25, 1.08) SCS courses per patient were prescribed within 6 months after starting ICS/LABA/tiotropium (P< 0.001). Physician visits dropped from 9.23 (95% CI: 7.15, 12.72) to 5.76 (95% CI: 3.10, 7.70) per patient (P< 0.01). Nineteen hospitalisations were recorded 6 months before ICS/LABA/tiotropium compared with one hospitalisation after (P< 0.01). A mean 1.79 antibiotic courses (95% CI: 1.22, 2.23) per patient were prescribed before ICS/LABA/tiotropium compared with 0.74 (95% CI: 0.22, 1.00) after ICS/LABA/tiotropium (P< 0.001). Hospitalisation rates for patients at observation end were not statistically different from healthy controls before/after matching.
Interpretation: Our retrospective study showed that adding tiotropium to ICS/LABA is a new treatment option for patients with severe preschool asthma; however, larger confirmatory studies are needed.
Söderholm, Jonas ; Waldenström, Jesper ; Askarieh, Galia ; Pilli, Massimo ; Bochud, Pierre-Yves ; Negro, Francesco ; Pawlotsky, Jean-Michel ; Zeuzem, Stefan ; Ferrari, Carlo ; Norkrans, Gunnar ; Wejstål, Rune ; Westin, Johan ; Neumann, Avidan U. ; Haagmans, Bart L. ; Lindh, Magnus ; Missale, Gabriele ; Hellstrand, Kristoffer ; Lagging, Martin
Background: Interferon and ribavirin therapy for chronic hepatitis C virus (HCV) infection yields sustained virological response (SVR) rates of 50–80%. Several factors such as non-1 genotype, beneficial IL28B genetic variants, low baseline IP-10, and the functionality of HCV-specific T cells predict SVR. With the pending introduction of new therapies for HCV entailing very rapid clearance of plasma HCV RNA, the importance of baseline biomarkers likely will increase in order to tailor therapy. CD26 (DPPIV) truncates the chemokine IP-10 into a shorter antagonistic form, and this truncation of IP-10 has been suggested to influence treatment outcome in patients with chronic HCV infection patients. In addition, previous reports have shown CD26 to be a co-stimulator for T cells. The aim of the present study was to assess the utility of CD26 as a biomarker for treatment outcome in chronic hepatitis C and to define its association with HCV-specific T cells.
Methods: Baseline plasma from 153 genotype 1 and 58 genotype 2/3 infected patients enrolled in an international multicenter phase III trial (DITTO-HCV) and 36 genotype 1 infected patients participating in a Swedish trial (TTG1) were evaluated regarding baseline soluble CD26 (sCD26) and the functionality of HCV-specific CD8+ T cells.
Results: Genotype 1 infected patients achieving SVR in the DITTO (P = 0.002) and the TTG1 (P = 0.02) studies had lower pretreatment sCD26 concentrations compared with non-SVR patients. Sixty-five percent of patients with sCD26 concentrations below 600 ng/mL achieved SVR compared with 39% of the patients with sCD26 exceeding 600 ng/mL (P = 0.01). Patients with sCD26 concentrations below 600 ng/mL had significantly higher frequencies of HCV-specific CD8+ T cells (P = 0.02).
Conclusions: Low baseline systemic concentrations of sCD26 predict favorable treatment outcome in chronic HCV infection and may be associated with higher blood counts of HCV-specific CD8+ T cells.
Sylvester, Francisco ; Weichert, Fabian G. ; Lozano, Verónica L. ; Groh, Ksenia J. ; Bálint, Miklós ; Baumann, Lisa ; Bässler, Claus ; Brack, Werner ; Brandl, Barbara ; Curtius, Joachim ; Dierkes, Paul ; Döll, Petra ; Ebersberger, Ingo ; Fragkostefanakis, Sotirios ; Helfrich, Eric J. N. ; Hickler, Thomas ; Johann, Sarah ; Jourdan, Jonas ; Klimpel, Sven ; Kminek, Helge ; Liquin, Florencia ; Möllendorf, Darrel ; Mueller, Thomas ; Oehlmann, Jörg ; Ottermanns, Richard ; Pauls, Steffen U. ; Piepenbring, Meike ; Pfefferle, Jakob ; Schenk, Gerrit Jasper ; Scheepens, Johannes Fredericus ; Scheringer, Martin ; Schiwy, Sabrina ; Schlottmann, Antje ; Schneider, Flurina ; Schulte, Lisa Maria ; Schulze-Sylvester, Maria ; Stelzer, Ernst H. K. ; Strobl, Frederic ; Sundermann, Andrea ; Tockner, Klement ; Tröger, Tobias ; Vilcinskas, Andreas ; Völker, Carolin ; Winkelmann, Ricarda ; Hollert, Henner
Stöver, Timo ; Dazert, Stefan ; Plontke, Stefan K.-R. ; Kramer, S. ; Ambrosch, Petra ; Ahrens, Christoph ; Betz, Christian Stefan ; Beutner, Dirk ; Bohr, Christopher ; Bruchhage, Karl-Ludwig ; Canis, Martin ; Dietz, Andreas ; Guntinas-Lichius, Orlando ; Hagen, Rudolf ; Hosemann, Werner ; Iro, Heinrich ; Klußmann, Jens Peter ; Knopf, Andreas ; Lang, Stephan ; Leinung, Martin ; Lenarz, Thomas ; Löwenheim, Hubert Martin ; Matthias, Christian ; Mlynski, Robert Arndt ; Olze, Heidi ; Park, Jonas Jae-Hyun ; Plinkert, Peter K. ; Radeloff, Andreas Daniel ; Rotter, Nicole ; Rudack, Claudia ; Bozzato, Alessandro ; Schipper, Jörg H. ; Schrader, Martin ; Schuler, Patrick ; Strieth, Sebastian ; Stuck, Boris ; Volkenstein, Stefan ; Westhofen, Martin ; Wolf, Gregor ; Wollenberg, Barbara ; Zahnert, Thomas ; Zenk, Johannes ; Hoffmann, Thomas K.
Hintergrund: Ab Frühjahr 2020 kam es zur weltweiten Verbreitung von SARS-CoV‑2 mit der heute als erste Welle der Pandemie bezeichneten Phase ab März 2020. Diese resultierte an vielen Kliniken in Umstrukturierungen und Ressourcenverschiebungen. Ziel unserer Arbeit war die Erfassung der Auswirkungen der Pandemie auf die universitäre Hals-Nasen-Ohren(HNO)-Heilkunde für die Forschung, Lehre und Weiterbildung. Material und Methoden: Die Direktorinnen und Direktoren der 39 Universitäts-HNO-Kliniken in Deutschland wurden mithilfe einer strukturierten Online-Befragung zu den Auswirkungen der Pandemie im Zeitraum von März bis April 2020 auf die Forschung, Lehre und die Weiterbildung befragt. Ergebnisse: Alle 39 Direktorinnen und Direktoren beteiligten sich an der Umfrage. Hiervon gaben 74,4 % (29/39) an, dass es zu einer Verschlechterung ihrer Forschungstätigkeit infolge der Pandemie gekommen sei. Von 61,5 % (24/39) wurde berichtet, dass pandemiebezogene Forschungsaspekte aufgegriffen wurden. Von allen Kliniken wurde eine Einschränkung der Präsenzlehre berichtet und 97,5 % (38/39) führten neue digitale Lehrformate ein. Im Beobachtungszeitraum sahen 74,4 % der Klinikdirektoren die Weiterbildung der Assistenten nicht gefährdet. Schlussfolgerung: Die Ergebnisse geben einen Einblick in die heterogenen Auswirkungen der Pandemie. Die kurzfristige Bearbeitung pandemiebezogener Forschungsthemen und die Einführung innovativer digitaler Konzepte für die studentische Lehre belegt eindrücklich das große innovative Potenzial und die schnelle Reaktionsfähigkeit der HNO-Universitätskliniken, um auch während der Pandemie ihre Aufgaben in der Forschung, Lehre und Weiterbildung bestmöglich zu erfüllen.
Steinert, Hannah ; Sochor, Florian ; Wacker, Anna ; Buck, Janina ; Helmling, Christina ; Hiller, Fabian ; Keyhani, Sara ; Noeske, Jonas ; Grimm, Steffen ; Rudolph, Martin M. ; Keller, Heiko ; Mooney, Rachel Anne ; Dick, Rolf van ; Süß, Beatrix ; Fürtig, Boris ; Wöhnert, Jens ; Schwalbe, Harald
In bacteria, the regulation of gene expression by cis-acting transcriptional riboswitches located in the 5'-untranslated regions of messenger RNA requires the temporal synchronization of RNA synthesis and ligand binding-dependent conformational refolding. Ligand binding to the aptamer domain of the riboswitch induces premature termination of the mRNA synthesis of ligand-associated genes due to the coupled formation of 3'-structural elements acting as terminators. To date, there has been no high resolution structural description of the concerted process of synthesis and ligand-induced restructuring of the regulatory RNA element. Here, we show that for the guanine-sensing xpt-pbuX riboswitch from Bacillus subtilis, the conformation of the full-length transcripts is static: it exclusively populates the functional off-state but cannot switch to the on-state, regardless of the presence or absence of ligand. We show that only the combined matching of transcription rates and ligand binding enables transcription intermediates to undergo ligand-dependent conformational refolding.
In Ergänzung zu einem vorangegangenen Projekt (Schönwiese et al., 2005) ist in der vorliegenden Studie eine weitere extremwertstatistische Untersuchung durchgeführt worden. Dazu wurden auf der Basis von täglichen Klimadaten aus Hessen und Umgebung (49°N bis 52°N, 7°O bis 11°O), und zwar der Temperatur von 53 Stationen und des Niederschlages von 84 Stationen, Schwellen extremer Werte definiert, um die Anzahl der Über- bzw. Unterschreitungen dieser Schwellen auf signifikante Trends hin zu untersuchen. Bei der Temperatur findet sich dabei eine systematische Zunahme von Hitzetagen (Maximumtemperatur über 30 °C) im August, wohingegen im Juli fast keine, und im Juni nur vereinzelt signifikante Zunahmen von Hitzetagen gefunden wurden. Hierbei zeigt sich, wie auch bei anderen Temperatur-Schwellen eine Abnahme der Signifikanz mit zunehmender Schwellenhöhe, was durch selteneres Auftreten besonders extremer Ereignisse verursacht wird. Im Winter und Frühjahr hat entsprechend die Anzahl der Frost- bzw. Eistage (Minimum- bzw. Maximumtemperatur unter 0 °C) signifikant abgenommen. Besonders ausgeprägt ist dies für die Frosttage im Frühling der Fall. Beim Niederschlag hat im Sommer, wiederum vor allem im August, die Anzahl von Trockentagen zugenommen. Extrem hohe Niederschlagssummen sind dagegen in dieser Jahreszeit seltener geworden, in den anderen Jahreszeiten jedoch häufiger. Vor allem der März zeichnet sich durch verbreitet hochsignifikante Zunahmen von Tagen mit Starkniederschlägen aus. Die Erhaltungsneigung von besonders warmen bzw. kalten Witterungen hat sich in den meisten Monaten nicht signifikant verändert. Es ist jedoch eine Neigung zu kürzeren relativ einheitlichen Witterungsabschnitten im Februar und März, sowie zu längeren im Oktober und November zu beobachten. Diese Ergebnisse sind jedoch vermutlich nicht sehr robust, da sich bei einer Verkürzung des Zeitfensters der Autokorrelationsfunktion die Signifikanzen teilweise (vor allem im April) deutlich verändern. Bei den Trends der Zahl der Trockenperioden erkennt man im Sommer einen positiven Trend; sie nehmen somit zu. Dies gilt sowohl für die 7-tägigen als auch für die 11-tägigen Trockenperioden. Die übrigen Jahreszeiten zeigen bei den 7-tägigen Trockenperioden nur schwache oder negative Trends. Bei den 11-tägigen Trockenperioden gilt dies nur für das Frühjahr und den Herbst, im Winter sind die Trends im Norden überwiegend positiv, im Süden negativ. Betrachtet man die Länge der längsten Trockenperioden, so nimmt diese im Sommer zu, im Frühjahr und im Gesamtjahr jedoch ab. Im Herbst ist das Bild uneinheitlich; dies kann aber auch daran liegen, dass lange sommerliche Trockenperioden in den Herbst hineinreichen und dann dort gezählt werden. Ein weiterer Aspekt ist die Analyse der Anzahl und Länge bestimmter Witterungsabschnitte (Clusteranalyse), die durch relativ hohe oder tiefe Temperatur bzw. relativ wenig bzw. viel Niederschlag definiert sind. So können beispielsweise Tage mit weniger als 1 mm Niederschlag als Trockencluster bezeichnet werden. Dabei erkennt man im Sommer einen Trend zu mehr Trockenclustern,in Übereinstimmung mit den oben genannten Ergebnissen, in den übrigen Jahreszeiten und im Gesamtjahr jedoch einen Trend zu weniger Trockenclustern. Innerhalb des Sommers ist dieser Trend im August am stärksten, in den übrigen Jahreszeiten im März, Oktober und Dezember. Bei den Clustern von Feuchteereignissen, das heißt Tagen mit relativ viel Niederschlag, ist das Bild umgekehrt. Im Sommer nimmt deren Zahl ab, ansonsten nimmt sie zu. Die stärksten Trends sind dabei wiederum im August (Abnahme) bzw. im März, Oktober und Dezember (jeweils Zunahme) zu erkennen. Alle diese Trends werden im der Regel umso schwächer, je höher die Schranke der Niederschlagsmenge gewählt wird. Bei den Temperaturdaten sind die Trends von Frost- und Eistagen nur im November überwiegend positiv, in allen Wintermonaten (Dezember, Januar und Februar) jedoch fast ausschließlich negativ. Darin spiegelt sich somit der Trend zu höheren Temperaturen wider. Bei den Wärmeclustern ändern sich die Trends mit der Höhe der Schranke. Bei der Schranke von 25°C zeigen der Juli, insbesondere aber der August positive Trends. Bei der 30°C-Schranke bleibt der Augusttrend positiv, der Julitrend wird dagegen negativ. Bei der Schranke von 35°C werden die Augusttrends dann deutlich geringer, während die Julitrends, wenn auch schwächer ausgeprägt, negativ bleiben. Die Trends im Juni sind dagegen insgesamt schwach. Betrachtet man die Signifikanz der Trends, so sind insbesondere die Trends bei hohen Schranken weniger signifikant. Dies gilt für die hohen Niederschlagschranken (20mm, 30mm, 95%-Perzentil, 99%-Perzentil) ebenso wie für die hohen Temperaturschranken (30°C, 35°C). Weiterhin ist die Signifikanz dann niedrig, wenn die Zahl der Cluster im betrachteten Zeitraum klein ist. In Monaten und Jahreszeiten, in denen nur wenige Cluster auftreten, ist der Trend der Zahl der Cluster meist nicht signifikant. Insgesamt zeigen beim Niederschlag die untere Schranke von 1mm sowie die oberen Schranken von 10mm und 90% die signifikantesten Trends. Bei den Temperaturdaten ist das bei den Frosttagen generell, bei den Eistagen im Januar und Februar sowie bei den sommerlichen Clustern mit einer Tagesmaximumtemperatur von über 25°C der Fall (mit zum Teil über 95% bzw. 99% Signifikanz).
Sommer-Trembo, Carolin ; Bierbach, David ; Arias-Rodriguez, Lenin ; Verel, Yesim ; Jourdan, Jonas ; Zimmer, Claudia ; Riesch, Rüdiger ; Streit, Bruno ; Plath, Martin
Background: One aspect of premating isolation between diverging, locally-adapted population pairs is female mate choice for resident over alien male phenotypes. Mating preferences often show considerable individual variation, and whether or not certain individuals are more likely to contribute to population interbreeding remains to be studied. In the Poecilia mexicana-species complex different ecotypes have adapted to hydrogen sulfide (H2S)-toxic springs, and females from adjacent non-sulfidic habitats prefer resident over sulfide-adapted males. We asked if consistent individual differences in behavioral tendencies (animal personality) predict the strength and direction of the mate choice component of premating isolation in this system.
Results: We characterized focal females for their personality and found behavioral measures of ‘novel object exploration’, ‘boldness’ and ‘activity in an unknown area’ to be highly repeatable. Furthermore, the interaction term between our measures of exploration and boldness affected focal females’ strength of preference (SOP) for the resident male phenotype in dichotomous association preference tests. High exploration tendencies were coupled with stronger SOPs for resident over alien mating partners in bold, but not shy, females. Shy and/or little explorative females had an increased likelihood of preferring the non-resident phenotype and thus, are more likely to contribute to rare population hybridization. When we offered large vs. small conspecific stimulus males instead, less explorative females showed stronger preferences for large male body size. However, this effect disappeared when the size difference between the stimulus males was small.
Conclusions: Our results suggest that personality affects female mate choice in a very nuanced fashion. Hence, population differences in the distribution of personality types could be facilitating or impeding reproductive isolation between diverging populations depending on the study system and the male trait(s) upon which females base their mating decisions, respectively.
Rudolf, Martin ; Czajka, Christina ; Börstler, Jessica ; Melaun, Christian ; Jöst, Hanna ; Thien, Heidrun von ; Badusche, Marlis ; Becker, Norbert ; Schmidt-Chanasit, Jonas ; Krüger, Andreas ; Tannich, Egbert ; Becker, Stefanie
Mosquitoes and other arthropods may transmit medically important pathogens, in particular viruses such as West Nile virus. The presence of suitable hosts and competent vectors for those zoonotic viruses is essential for an enzootic transmission, which is a prerequisite for epidemics. To establish reliable risk projections, it is an urgent need for an exact identification of mosquito species, which is especially challenging in the case of sibling species, such as Culex. pipiens pipiens biotypes pipiens and molestus. To facilitate detection of different Culex pipiens forms and their hybrids we established a multiplex real-time PCR. Culex pipiens samples were obtained by egg raft collection and rearing until imago stage or adult sampling using CO2 baited traps and gravid traps. In total, we tested more than 16,500 samples collected all over Germany in the years 2011 and 2012. The predominant species in Germany are Culex pipiens pipiens biotype pipiens and Culex. torrentium, but we also detected Culex pipiens pipiens biotype molestus and hybrids of the two pipiens biotypes at sites where both species occur sympatrically. This report of a potentially important bridge vector for West Nile virus might have major impact in the risk projections for West Nile virus in Germany.