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Bast, Nico ; Mason, Luke ; Freitag, Christine M. ; Smith, Tim ; Portugal, Ana Maria ; Poustka, Luise ; Banaschewski, Tobias ; Johnson, Mark
Background: Visual exploration in autism spectrum disorder (ASD) is characterized by attenuated social attention. The underlying oculomotor function during visual exploration is understudied, whereas oculomotor function during restricted viewing suggested saccade dysmetria in ASD by altered pontocerebellar motor modulation. Methods: Oculomotor function was recorded using remote eye tracking in 142 ASD participants and 142 matched neurotypical controls during free viewing of naturalistic videos with and without human content. The sample was heterogenous concerning age (6–30 years), cognitive ability (60–140 IQ), and male/female ratio (3:1). Oculomotor function was defined as saccade, fixation, and pupil-dilation features that were compared between groups in linear mixed models. Oculomotor function was investigated as ASD classifier and features were correlated with clinical measures. Results: We observed decreased saccade duration (∆M = −0.50, CI [−0.21, −0.78]) and amplitude (∆M = −0.42, CI [−0.12, −0.72]), which was independent of human video content. We observed null findings concerning fixation and pupil-dilation features (POWER = .81). Oculomotor function is a valid ASD classifier comparable to social attention concerning discriminative power. Within ASD, saccade features correlated with measures of restricted and repetitive behavior. Conclusions: We conclude saccade dysmetria as ASD oculomotor phenotype relevant to visual exploration. Decreased saccade amplitude and duration indicate spatially clustered fixations that attenuate visual exploration and emphasize endogenous over exogenous attention. We propose altered pontocerebellar motor modulation as underlying mechanism that contributes to atypical (oculo-)motor coordination and attention function in ASD.
Acinetobacter baumannii is outstanding for its ability to cope with low water activities and therefore its adaptation mechanism to osmotic stress. Here we report on the identification and characterization of five different secondary active compatible solute transporters, belonging to the betaine-choline-carnitine transporter (BCCT) family. Our studies revealed two choline-specific and three glycine betaine-specific BCCTs. Activity of the BCCTs was differentially dependent to the osmolality: one choline and one betaine transporter were osmostress-independent. Addition of choline to resting cells of Acinetobacter grown in the presence of the co-substrate choline or with phosphatidylcholine as sole carbon source led to ATP synthesis in the wild type but not in the BCCT quadruple mutant. This indicates that the BCCTs are essential to transport the energy substrate choline. The role of the different BCCTs in osmostress resistance and in metabolic adaptation of A. baumannii to the human host is discussed.
Westner, Katrin Julia ; Birch, Thomas ; Kemmers, Fleur ; Klein, Sabine ; Höfer, Heidi E. ; Seitz, Hans-Michael
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.
Vutukuri, Rajkumar ; Koch, Alexander ; Trautmann, Sandra ; Schreiber, Yannick ; Thomas, Dominique Jeanette ; Mayser, Franziska ; Meyer zu Heringdorf, Dagmar ; Pfeilschifter, Josef ; Pfeilschifter, Waltraud ; Brunkhorst, Robert
Sphingosine 1-phosphate (S1P) signaling influences numerous cell biological mechanisms such as differentiation, proliferation, survival, migration, and angiogenesis. Intriguingly, our current knowledge is based solely on the role of S1P with an 18-carbon long-chain base length, S1P d18:1. Depending on the composition of the first and rate-limiting enzyme of the sphingolipid de novo metabolism, the serine palmitoyltransferase, other chain lengths have been described in vivo. While cells are also able to produce S1P d20:1, its abundance and function remains elusive so far. Our experiments are highlighting the role of S1P d20:1 in the mouse central nervous system (CNS) and human glioblastoma. We show here that S1P d20:1 and its precursors are detectable in both healthy mouse CNS-tissue and human glioblastoma. On the functional level, we focused our work on one particular, well-characterized pathway, the induction of cyclooxygenase (COX)-2 expression via the S1P receptor 2 (S1P2). Intriguingly, S1P d20:1 only fairly induces COX-2 expression and can block the S1P d18:1-induced COX-2 expression mediated via S1P2 activation in the human glioblastoma cell line LN229. This data indicates that S1P d20:1 might act as an endogenous modulator of S1P signaling via a partial agonism at the S1P2 receptor. While our findings might stimulate further research on the relevance of long-chain base lengths in sphingolipid signaling, the metabolism of S1P d20:1 has to be considered as an integral part of S1P signaling pathways in vivo.
Molecular analysis of the ribosome recycling factor ABCE1 bound to the 30S post-splitting complex
(2020)
Nürenberg-Goloub, Elina ; Kratzat, Hanna ; Heinemann, Holger ; Heuer, André ; Kötter, Peter ; Berninghausen, Otto ; Becker, Thomas ; Tampé, Robert ; Beckmann, Roland
Ribosome recycling by the twin-ATPase ABCE1 is a key regulatory process in mRNA translation and surveillance and in ribosome-associated protein quality control in Eukarya and Archaea. Here, we captured the archaeal 30S ribosome post-splitting complex at 2.8 Å resolution by cryo-electron microscopy. The structure reveals the dynamic behavior of structural motifs unique to ABCE1, which ultimately leads to ribosome splitting. More specifically, we provide molecular details on how conformational rearrangements of the iron–sulfur cluster domain and hinge regions of ABCE1 are linked to closure of its nucleotide-binding sites. The combination of mutational and functional analyses uncovers an intricate allosteric network between the ribosome, regulatory domains of ABCE1, and its two structurally and functionally asymmetric ATP-binding sites. Based on these data, we propose a refined model of how signals from the ribosome are integrated into the ATPase cycle of ABCE1 to orchestrate ribosome recycling.
The mammalian target of rapamycin and the integrated stress response are central cellular hubs regulating translation upon stress. The precise proteins and pathway specificity of translation targets of these pathways remained largely unclear. We recently described a new method for quantitative translation proteomics and found that both pathways control translation of the same sets of proteins.
Gökbuget, Nicola ; Zugmaier, Gerhard ; Dombret, Hervé ; Stein, Anthony ; Bonifacio, Massimiliano ; Graux, Carlos ; Faul, Christoph ; Brüggemann, Monika ; Taylor, Kate ; Mergen, Noemi ; Reichle, Albrecht ; Horst, Heinz August ; Havelange, Violaine ; Topp, Max S. ; Bargou, Ralf C.
Minimal residual disease (MRD) is the strongest predictor of relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In BLAST study (NCT01207388), adults with BCP-ALL in remission with MRD after chemotherapy received blinatumomab, a CD19 BiTE® immuno-oncotherapy, 15 µg/m2/day for up to four 6-week cycles (4 weeks continuous infusion, 2 weeks off). Survival was evaluated for 110 patients, including 74 who received HSCT in continuous complete remission. With a median follow-up of 59·8 months, median survival (months) was 36·5 (95% CI: 22.0–not reached [NR]). Median survival was NR (29.5–NR) for complete MRD responders (n = 84) and 14.4 (3.8–32.3) for MRD non-responders (n = 23; p = 0.002); after blinatumomab and HSCT, median survival was NR (25.7–NR) (n = 61) and 16.5 (1.1–NR) (n = 10; p = 0.065), respectively. This final analysis suggests complete MRD response during blinatumomab treatment is curative. Post-hoc analysis of study data suggests while post blinatumomab HSCT may be beneficial in appropriate patients, long-term survival without HSCT is also possible.
Introduction: Dravet syndrome (DS), a prototypic developmental and genetic epileptic encephalopathy (DEE), is characterized by an early onset of treatment-refractory seizures, together with impairments in motor control, behavior, and cognition. Even with multiple conventional anti-epileptic drugs, seizures remain poorly controlled, and there has been a considerable unmet need for effective and tolerable treatments. Areas covered: This targeted literature review aims to highlight recent changes to the therapeutic landscape for DS by summarizing the most up-to-date, evidence-based research, including pivotal data from the clinical development of stiripentol, cannabidiol, and fenfluramine, which are important milestones for DS treatment, together with the latest findings of other pharmacotherapies in development. In phase III, double-blind, placebo-controlled randomized controlled trials stiripentol, cannabidiol, and fenfluramine have shown clinically relevant reductions in convulsive seizure frequency, and are generally well tolerated. Stiripentol was associated with responder rates (greater than 50% reduction in convulsive seizure frequency) of 67%-71%, when added to valproic acid and clobazam; cannabidiol was associated with responder rates of 43%-49% (48%-63% in conjunction with clobazam), and fenfluramine of 54%-68% across studies. Therapies in development include soticlestat, ataluren, verapamil, and clemizole, with strategies to treat the underlying cause of DS, including gene therapy and antisense oligonucleotides beginning to emerge from preclinical studies. Expert opinion: Despite the challenges of drug development in rare diseases, this is an exciting time for the treatment of DS, with the promise of new efficacious and well-tolerated therapies, which may pave the way for treatment advances in other DEEs.
Im vorliegenden Report wurde anhand von Daten aus dem IAB-Betriebspanel ein Schlaglicht auf die Innovationskraft hess- ischer Betriebe geworfen. Nur wenige Betriebe sind, in der Regel in Kooperation mit anderen Betrieben und Hochschulen, explizit mit Forschung und Entwicklung beschäftigt. Dennoch investiert ein großer Teil, nämlich ein Drittel der hessischen Betriebe, in die Weiterentwicklung und Verbesserung von Pro- dukten und Dienstleistungen. Acht Prozent der Betriebe haben darüber hinaus den Produktionsprozess verbessert. Diese Anteile haben sich in den letzten Jahren kaum verändert. 17 Prozent der Betriebe haben ihr Angebotsspektrum zuletzt erweitert, und immerhin fünf Prozent entwickeln gänzlich neue Produkte oder Dienstleistungen.Wie gezeigt wurde, konnten im Geschäftsjahr 2018 jedoch nicht sämtliche geplanten Innova-tionen umgesetzt werden. Jeder zwanzigste Betrieb gab an, dass dies nicht möglich war. Hauptgrund ist der Mangel an Fach-kräften. Daneben spielt aber auch die wirtschaftliche Situation der Betriebe eine Rolle: Gemäß der Ergebnisse des IAB-Betriebspanels befinden sich unter den Betrieben, die Produkte, Dienstleistungen oder betriebsinterne Prozesse weiterentwickelt haben, deutlich mehr mit einem positiven Jahresergebnis als solche mit einem negativen Jahresergebnis.
Der Einsatz von Robotern nimmt in den hessischen Betrieben zu. Zwar ist er, außer im Verarbeitenden Gewerbe, derzeit noch wenig verbreitet; die Zahl der Neuanschaffungen ist jedoch in den vergangenen Jahren – gerade auch in kleineren Betrieben – stark gestiegen. Die Corona-Krise könnte diese Entwicklung begünstigen, wenn es aufgrund der Unsicherheiten, die mit globalen Lieferketten verbunden sind, zu einer Verlagerung von Produktionsschritten nach Deutschland kommen sollte. Dies könnte mit einem stärkeren Einsatz von Robotern einhergehen, so die Expertin für Internationale Wirtschaftsbeziehungen Prof. Dr. Dalia Marin im Interview mit der Frankfurter Allgemeinen Zeitung (FAZ vom 01.03.2020). Andererseits könnten den Betrieben die Mittel für größere Investitionen aufgrund des Einbruchs der Wirtschaft fehlen. Auffällig ist, dass die Großbetriebe bei allen Auswertungen im vorliegenden Report als innovationskräftiger erscheinen als die kleinen und mittleren Betriebe. Sie investieren häufiger in Forschung und Ent- wicklung sowie in Produkt-, Dienstleistungs- und Verf- ahrensverbesserungen. Dabei ist jedoch auch anzumerken, dass jeweils ein Drittel der Kleinstbetriebe, der kleinen und mittleren Betriebe an der Verbesserung und Weiterentwicklung ihrer Produkte und Dienstleistungen arbeitet. Es kann hier also nicht von einem klaren Trend, dass die Innovativität mit steigender Betriebsgröße zunimmt, gesprochen werden. Der Innovationsforscher Everett Rogers vermutet, dass die Betriebsgröße eine „Stellvertretervariable“ ist, die leicht zu messen ist, die aber verdeckt, dass vielmehr Faktoren wie eine positive Einstellung von Führungskräften gegenüber Veränder- ungen, eine wenig zentralistische Betriebsstruktur und eine Betriebskultur mit kurzen, auch hierarchieübergreifenden Kommunikationswegen einen entscheidenden Einfluss auf die Innovativität eines Betriebs haben (Rogers 2003: 409ff.). Solche Voraussetzungen lassen sich in Betrieben aller Größenklassen finden. Die Ausstattung der Betriebe mit Hochgeschwindigkeits-Internet als eine technische Voraussetzung für Innovationen ist grundsätzlich als gut anzusehen, allerdings hat die Zufriedenheit damit abgenommen.
Womöglich ist die gestiegene Unzufriedenheit ein An zeichen für höhere Ansprüche. Im Zuge der Corona-Krise dürfte die Bedeutung von Hochgeschwindigkeits-Internet zugenommen haben; viele Beschäftigte arbeiten zuhause und greifen von dort bspw. auf Betriebsserver zu. Insbesondere im Wirtschaftszweig Handel und Reparatur ist ein recht hoher Anteil der Betriebe unzu- frieden mit der verfügbaren Bandbreite, also in einem Bereich, in dem der Druck zur Online-Vermarktung gerade durch die Corona-Krise wächst. Insgesamt zeigen die Auswertungen jedoch, dass die Innovationskraft der hessischen Betriebe als stabil zu bewerten ist. Im Vergleich zu den Ergebnissen aus dem Befragungsjahr 2017 ergeben sich keine klaren Hinweise einer zunehmenden oder abnehmenden Innovativität. Auffällig ist die ausgeprägte Kooperationsbereitschaft hessischer Betriebe mit Hochschulen und außerhochschulischen Forschungseinrichtungen, die zur Zukunftsfähigkeit der Betriebe beiträgt. Andererseits erweist sich der Fachkräftemangel bereits heute in einigen Betrieben als Innovationsbremse, und personelle Engpässe dürften in den kommenden Jahren an Bedeutung gewinnen. Aktivitäten zur Sicherung des Fachkräftebedarfs sind auch deshalb zu intensivieren, weil damit die Innovationsfähigkeit der hessischen Wirtschaft gestärkt wird
Im vorliegenden Report wurde anhand von Daten aus dem IAB-Betriebspanel ein Schlaglicht auf die Aktivitäten hessischer Betriebe zur Fachkräftebindung geworfen. Beispielhafte Anreize für die Beschäftigten, im Betrieb zu verbleiben, stellen das Angebot betrieblich geförderter Weiterbildungen, die Übernahme von Auszubildenden und die Beteiligung an Gewinn, Erfolg und Kapital eines Betriebs dar. Die Auswertungen zeigen, dass in Hessen gut die Hälfte aller Betriebe über Weiterbildungs- angebote Anreize zur Fachkräftebindung setzt. Allerdings liegt dieser Anteil noch etwas unter dem Anteil der Betriebe in Westdeutschland. Größere Betriebe sind praktisch alle in der Weiterbildung aktiv, jedoch profitiert davon ein geringerer Teil der Belegschaften als in kleineren Betrieben. Insbe- sondere Dienstleistungsbetriebe scheinen Weiterbildung syste-matisch zur Fachkräftebindung zu nutzen. In den allermeisten Betrieben gilt die Weiterbildungszeit als Arbeitszeit, und die Betriebe übernehmen die Weiterbildungskosten vollständig. Beides ist wichtig, damit Weiterbildung für die Beschäftigten attraktiv ist und tatsächlich als Anreiz zur Bindung an den Betrieb wirksam werden kann. Was die Weiterbildungsformate angeht, setzen die hessischen Betriebe nach wie vor insbe- sondere auf externe Kurse, Lehrgänge und Seminare. Weniger verbreitet scheinen arbeitsintegrierte Weiterbildungen zu sein. Insbesondere das selbstgesteuerte Lernen mit Medien wird erst bei gut einem Viertel der hessischen Betriebe genutzt. Allerdings nimmt der Anteil der Betriebe, die diese Formate einsetzen, zu. Es wird interessant sein, im Laufe dieses Jahres und darüber hinaus zu verfolgen, ob und wie sich die Arbeitserfahrungen während der Corona-Krise auf eine Ausweitung des selbstgesteuerten digitalen Lernens auswirken. Die Übernahme von Auszubildenden ist das wichtigste Instrument zur Fachkräftebindung, welches über alle Betriebsgrößen hinweg einen hohen Verbreitungsgrad in den hessischen Betrieben hat. Besonders stark scheint es in Kleinst- und Großbetrieben zum Einsatz zu kommen. Die zunehmend größere Bedeutung von Über- nahmeangeboten zur Fachkräftebindung zeigt sich auch in steigenden Übernahme- quoten. Dagegen setzen nur wenige Betriebe Gewinn-, Erfolgs- und Kapitalbeteiligung der Beschäftigten als gezielte Anreiz- systeme zur Mitarbeiter- bindung ein. Am ehesten unterbreiten Großbetriebe ihren Beschäftigten entsprechende Angebote. Der Report zeigt am Beispiel von drei Formen betrieblicher An- reize, dass bereits viele der hessischen Betriebe entsprechende Impulse setzen. Je nach Betriebsgröße und Branchenzugehörigkeit unterscheidet sich die Intensität der jeweiligen betrieblichen Aktivitäten. Interessant ist aber, dass es nicht nur Großbetriebe sind, die gezielt Anreize zur Fachkräftebindung setzen, sondern auch mittelgroße und selbst Kleinstbetriebe.