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Research on collective resilience processes still lacks a detailed understanding of psychological mechanisms at work when groups cope with adverse conditions, i.e., long-term processes, and how such mechanisms affect physical and mental well-being. As collective resilience will play a crucial part in facing looming climate change-related events such as floods, it is important to investigate these processes further. To this end, this study takes a novel holistic approach by combining resilience research, social psychology, and an archeological perspective to investigate the role of social identity as a collective resilience factor in the past and present. We hypothesize that social identification buffers against the negative effects of environmental threats in participants, which increases somatic symptoms related to stress, in a North Sea region historically prone to floods. A cross-sectional study (N = 182) was conducted to analyze the moderating effects of social identification on the relations between perceived threat of North Sea floods and both well-being and life satisfaction. The results support our hypothesis that social identification attenuates the relationship between threat perception and well-being, such that the relation is weaker for more strongly identified individuals. Contrary to our expectations, we did not find this buffering effect to be present for life satisfaction. Future resilience studies should further explore social identity as a resilience factor and how it operates in reducing environmental stress put on individuals and groups. Further, to help communities living in flood-prone areas better cope with future environmental stress, we recommend implementing interventions strengthening their social identities and hence collective resilience.
ϒ production and nuclear modification at forward rapidity in Pb–Pb collisions at √sNN = 5.02TeV
(2021)
The production of ϒ mesons in Pb–Pb collisions at a centre-of-mass energy per nucleon pair √sNN = 5.02 TeV is measured with the muon spectrometer of the ALICE detector at the LHC. The yields as well as the nuclear modification factors are determined in the forward rapidity region 2.5 < y < 4.0, as a function of rapidity, transverse momentum and collision centrality. The results show that the production of the ϒ(1S) meson is suppressed by a factor of about three with respect to the production in proton–proton collisions. For the first time, a significant signal for the ϒ(2S) meson is observed at forward rapidity, indicating a suppression stronger by about a factor 2–3 with respect to the ground state. The measurements are compared with transport, hydrodynamic, comover and statistical hadronisation model calculations.
ϒ production and nuclear modification at forward rapidity in Pb–Pb collisions at √sNN = 5.02 TeV
(2021)
The production of Υ mesons in Pb-Pb collisions at a centre-of-mass energy per nucleon pair sNN−−−√ = 5 TeV is measured with the muon spectrometer of the ALICE detector at the LHC. The yields as well as the nuclear modification factors are determined in the forward rapidity region 2.5<y<4.0, as a function of rapidity, transverse momentum and collision centrality. The results show that the production of the Υ(1S) meson is suppressed by a factor of about three with respect to the production in proton-proton collisions. For the first time, a significant signal for the Υ(2S) meson is observed at forward rapidity, indicating a suppression stronger by about a factor 2-3 with respect to the ground state. The measurements are compared with transport, hydrodynamic, comover and statistical hadronisation model calculations.
The first measurements of the scattering parameters of ΛK pairs in all three charge combinations (ΛK+, ΛK−, and ΛK0S) are presented. The results are achieved through a femtoscopic analysis of ΛK correlations in Pb-Pb collisions at sNN−−−√ = 2.76 TeV recorded by ALICE at the LHC. The femtoscopic correlations result from strong final-state interactions, and are fit with a parametrization allowing for both the characterization of the pair emission source and the measurement of the scattering parameters for the particle pairs. Extensive studies with the THERMINATOR 2 event generator provide a good description of the non-femtoscopic background, which results mainly from collective effects, with unprecedented precision. Furthermore, together with HIJING simulations, this model is used to account for contributions from residual correlations induced by feed-down from particle decays. The extracted scattering parameters indicate that the strong force is repulsive in the ΛK+ interaction and attractive in the ΛK− interaction. The data hint that the and ΛK0S interaction is attractive, however the uncertainty of the result does not permit such a decisive conclusion. The results suggest an effect arising either from different quark-antiquark interactions between the pairs (ss¯ in ΛK+ and uu¯¯¯ in ΛK−) or from different net strangeness for each system (S = 0 for ΛK+, and S = −2 for ΛK−). Finally, the ΛK systems exhibit source radii larger than expected from extrapolation from identical particle femtoscopic studies. This effect is interpreted as resulting from the separation in space-time of the single-particle Λ and K source distributions.
The first measurements of the scattering parameters of ΛK pairs in all three charge combinations (ΛK+, ΛK−, and ΛK0S) are presented. The results are achieved through a femtoscopic analysis of ΛK correlations in Pb-Pb collisions at sNN−−−√ = 2.76 TeV recorded by ALICE at the LHC. The femtoscopic correlations result from strong final-state interactions, and are fit with a parametrization allowing for both the characterization of the pair emission source and the measurement of the scattering parameters for the particle pairs. Extensive studies with the THERMINATOR 2 event generator provide a good description of the non-femtoscopic background, which results mainly from collective effects, with unprecedented precision. Furthermore, together with HIJING simulations, this model is used to account for contributions from residual correlations induced by feed-down from particle decays. The extracted scattering parameters indicate that the strong force is repulsive in the ΛK+ interaction and attractive in the ΛK− interaction. The data hint that the and ΛK0S interaction is attractive, however the uncertainty of the result does not permit such a decisive conclusion. The results suggest an effect arising either from different quark-antiquark interactions between the pairs (ss¯ in ΛK+ and uu¯¯¯ in ΛK−) or from different net strangeness for each system (S = 0 for ΛK+, and S = −2 for ΛK−). Finally, the ΛK systems exhibit source radii larger than expected from extrapolation from identical particle femtoscopic studies. This effect is interpreted as resulting from the separation in space-time of the single-particle Λ and K source distributions.
The production cross section of prompt Λ+c charmed baryons was measured with the ALICE detector at the LHC at midrapidity in proton-proton (pp) and proton-lead (p-Pb) collisions at a centre-of-mass energy per nucleon pair of sNN−−−√=5.02 TeV. The Λ+c and Λ¯¯¯¯−c baryons were reconstructed in the hadronic decay channels Λ+c→pK−π+ and Λ+c→pK0S and respective charge conjugates. The measured differential cross sections as a function of transverse momentum (pT) and the pT-integrated Λ+c production cross section in pp and in p-Pb collisions are presented. The Λ+c nuclear modification factor (RpPb), calculated from the cross sections in pp and in p-Pb collisions, is presented and compared with the RpPb of D mesons. The Λ+c/D0 ratio is also presented and compared with the light-flavour baryon-to-meson ratios p/π and Λ/K0S, and measurements from other LHC experiments. The results are compared to predictions from model calculations and Monte Carlo event generators.
The production cross section of prompt Λ+c charm baryons was measured with the ALICE detector at the LHC at midrapidity in proton-proton (pp) and proton-lead (p-Pb) collisions at a centre-of-mass energy per nucleon pair of sNN−−−√=5.02 TeV. The Λ+c and Λ¯¯¯¯−c baryons were reconstructed in the hadronic decay channels Λ+c→pK−π+ and Λ+c→pK0S and respective charge conjugates. The measured differential cross sections as a function of transverse momentum (pT) and the pT-integrated Λ+c production cross section in pp and in p-Pb collisions are presented. The Λ+c nuclear modification factor (RpPb), calculated from the cross sections in pp and in p-Pb collisions, is presented and compared with the RpPb of D mesons. The Λ+c/D0 ratio is also presented and compared with the light-flavour baryon-to-meson ratios p/π and Λ/K0S, and measurements from other LHC experiments. The results are compared to predictions from model calculations and Monte Carlo event generators.
The production cross section of prompt Λ+c charm baryons was measured with the ALICE detector at the LHC at midrapidity in proton-proton (pp) and proton-lead (p-Pb) collisions at a centre-of-mass energy per nucleon pair of sNN−−−√=5.02 TeV. The Λ+c and Λ¯¯¯¯−c baryons were reconstructed in the hadronic decay channels Λ+c→pK−π+ and Λ+c→pK0S and respective charge conjugates. The measured differential cross sections as a function of transverse momentum (pT) and the pT-integrated Λ+c production cross section in pp and in p-Pb collisions are presented. The Λ+c nuclear modification factor (RpPb), calculated from the cross sections in pp and in p-Pb collisions, is presented and compared with the RpPb of D mesons. The Λ+c/D0 ratio is also presented and compared with the light-flavour baryon-to-meson ratios p/π and Λ/K0S, and measurements from other LHC experiments. The results are compared to predictions from model calculations and Monte Carlo event generators.
Λ+c production and baryon-to-meson ratios in pp and p–Pb collisions at √sNN = 5.02 TeV at the LHC
(2021)
The prompt production of the charm baryon Λ+c and the Λ+c/D0 production ratios were measured at midrapidity with the ALICE detector in pp and p-Pb collisions at sNN−−−√=5.02TeV. These new measurements show a clear decrease of the Λ+c/D0 ratio with increasing transverse momentum (pT) in both collision systems in the range 2<pT<12 GeV/c, exhibiting similarities with the light-flavour baryon-to-meson ratios p/π and Λ/K0S. At low pT, predictions that include additional colour-reconnection mechanisms beyond the leading-colour approximation; assume the existence of additional higher-mass charm-baryon states; or include hadronisation via coalescence can describe the data, while predictions driven by charm-quark fragmentation processes measured in e+e− and e−p collisions significantly underestimate the data. The results presented in this letter provide significant evidence that the established assumption of universality (colliding-system independence) of parton-to-hadron fragmentation is not sufficient to describe charm-baryon production in hadronic collisions at LHC energies.
Λ+c production and baryon-to-meson ratios in pp and p–Pb collisions at √sNN = 5.02 TeV at the LHC
(2021)
The prompt production of the charm baryon Λ+c and the Λ+c/D0 production ratios were measured at midrapidity with the ALICE detector in pp and p-Pb collisions at sNN−−−√=5.02TeV. These new measurements show a clear decrease of the Λ+c/D0 ratio with increasing transverse momentum (pT) in both collision systems in the range 2<pT<12 GeV/c, exhibiting similarities with the light-flavour baryon-to-meson ratios p/π and Λ/K0S. At low pT, predictions that include additional colour-reconnection mechanisms beyond the leading-colour approximation; assume the existence of additional higher-mass charm-baryon states; or include hadronisation via coalescence can describe the data, while predictions driven by charm-quark fragmentation processes measured in e+e− and e−p collisions significantly underestimate the data. The results presented in this letter provide significant evidence that the established assumption of universality (colliding-system independence) of parton-to-hadron fragmentation is not sufficient to describe charm-baryon production in hadronic collisions at LHC energies.
Λ+c production and baryon-to-meson ratios in pp and p–Pb collisions at √sNN = 5.02 TeV at the LHC
(2021)
The prompt production of the charm baryon Λ+c and the Λ+c/D0 production ratios were measured at midrapidity with the ALICE detector in pp and p-Pb collisions at sNN−−−√=5.02TeV. These new measurements show a clear decrease of the Λ+c/D0 ratio with increasing transverse momentum (pT) in both collision systems in the range 2<pT<12 GeV/c, exhibiting similarities with the light-flavour baryon-to-meson ratios p/π and Λ/K0S. At low pT, predictions that include additional colour-reconnection mechanisms beyond the leading-colour approximation; assume the existence of additional higher-mass charm-baryon states; or include hadronisation via coalescence can describe the data, while predictions driven by charm-quark fragmentation processes measured in e+e− and e−p collisions significantly underestimate the data. The results presented in this letter provide significant evidence that the established assumption of universality (colliding-system independence) of parton-to-hadron fragmentation is not sufficient to describe charm-baryon production in hadronic collisions at LHC energies.
Hintergrund: Das Kindesalter wurde bei der Entwicklung von wirksamen Präventions- und Interventionsprogrammen bei Computerspiel- und Internetabhängigkeit bisher kaum berücksichtigt. PROTECTdissonanz wurde daher als 1-stündiges dissonanzbasiertes universelles Primärpräventionsprogramm für die Klassenstufe 5 konzipiert. Die vorliegende Pilotstudie überprüft die unmittelbaren Effekte der Dissonanzinduktion auf die Einstellung zum Gaming. Methodik: In einem einarmigen A+B-Design mit drei Messzeitpunkten (T0, T1, T2) wurde die Einstellung zum Gaming anhand des Gaming Attitude Test (GAT) erfasst. In die Baselinesequenz (Sequenz A, T0 bis T1, Teilstichprobe) wurden N = 83 Schüler_innen eingeschlossen (Alter: M = 10.27; SD = 0.48) und in die Interventionssequenz (Sequenz B, T1 bis T2, Gesamtstichprobe) N = 200 Schüler_innen (Alter: M = 10.24; SD = 0.47). Akzeptanz und Zufriedenheit wurden nach der Intervention erfasst. Ergebnisse: Hierarchisch lineare Wachstumsmodelle zeigten eine signifikante Reduktion der GAT-Symptome durch die Intervention, sowohl im Gesamtwert des GAT als auch auf der Subskala „Bagatellisierung negativer Konsequenzen“. Im natürlichen Verlauf (Baselinesequenz A) zeigten sich keine Veränderungen. Die Schüler_innen bewerteten PROTECTdissonanz zudem mit einer hohen Zufriedenheit. Schlussfolgerungen: Eine kurze, gezielte übung zur Dissonanzinduktion zeigt unmittelbare Effekte auf ein Einstellungsmaß zum Gaming. Zur Weiterverfolgung dieses vielversprechenden Ansatzes sollte in künftigen Studien untersucht werden, ob sich eine verringerte Bagatellisierung negativer Konsequenzen von Gaming im Sinne der kognitiven Dissonanztheorie auch tatsächlich in einer Verhaltensänderung widerspiegelt.
»Denken braucht Zeit«
(2021)
Denis Thouard, Inhaber der Alfred Grosser-Gastprofessur im Wintersemester 2021/22, spricht im Interview über die heutige Rolle der Geistes- und Sozialwissenschaften, über seine Beschäftigung mit Kant und Schleiermacher und über die Aktualität von Georg Simmel.
Zurück zur Präsenz
(2021)
Prof. Christiane Thompson, Vizepräsidentin für Studium, Lehre und wissenschaftliche Weiterbildung an der Goethe-Universität, über einen sehr besonderen Semesterstart. 75 bis 85 Prozent der Lehrveranstaltungen werden wieder in Präsenz angeboten. Thompson bittet um Geduld und gegenseitige Rücksichtnahme.
Vor rund 60 Jahren ist das Buch Mensch und Raum von Otto Friedrich Bollnow erstmals erschienen. Der folgende Beitrag geht der Frage nach, inwieweit die Überlegungen des Philosophen (unter bestimmten Aspekten) noch heute aktuell sind. Bollnows Raum-Verständnis weicht in seiner phänomenologischen Orientierung geradezu grundlegend vom heute vorherrschenden sozialwissenschaftlichen Raumdenken ab. Umso mehr regt Bollnow dazu an, die Lehren des wissenschaftlichen Mainstream kritisch gegen den Strich zu lesen. Ins Zentrum der Suche nach heute möglicherweise bedeutsamen Themen und Methoden des Denkens rückt das Wohnen. Wie denkt Bollnow das Wohnen, und was sagt uns dies in einer Zeit, in der die Menschen ganz anders wohnen als in den 1950er Jahren? Brücken zu methodologisch benachbarten Theorien und Philosophen werden ebenso geschlagen (z. B. Heidegger, Dürckheim, Müller-Freienfels) wie zu anderen thematisch relevanten Arbeiten von Bollnow.
This research project investigated how motor activity, such as cycling, influences the acquisition of foreign language vocabulary under two distinct conditions of auditory-motor-synchronisation. In a mixed subject design, 48 participants had to learn 40 Polish-German vocabulary pairs by auditory presentation over headphones in two different conditions, in which they performed motor activity cycling on a bicycle ergometer: in experiment 1, vocabulary was presented in a fixed rhythm while in experiment 2, participants self-initiated the presentation of vocabulary through pedalling. After having listened to the word pairs, they had to perform online vocabulary tests, one directly after the learning session and a second one 24 hours later from home. Additionally, the individual pitch perception preference (i.e. fundamental vs. spectral pitch perception) of the participants was determined.
The results showed that fundamental listeners forgot significantly more vocabulary than spectral listeners during the fixed than during the self-initiated condition. There was no difference within the groups for the self-initiated condition. The analysis of the motor data revealed a significantly more accurate synchronisation for fundamental listeners during the fixed condition. Therefore, this study provides first evidence for the benefit of self-initiated auditory-motor synchronisation in the process of learning a foreign language in adults. It also reveals that pitch preference has an effect on auditory-motor synchronisation.
Einleitung: Das Arbeiten in einer Notfallsituation ist stark von einer strukturierten Herangehensweise im Patientenmanagement abhängig. Junge Assistenzärzte sind in ihrem Alltag häufig die ersten vor Ort und sollten daher bereits mit Abschluss des Studiums in der Lage sein, häufige Notfallsituationen zu meistern. In den letzten Jahren hat sich die Simulation als hauptsächlich genutzte Methode für die Ausbildung im Fach Notfallmedizin herauskristallisiert, sodass immer mehr Universitäten realitätsnahe Szenarien für die Ausbildung nutzen. Jedoch ist unklar welches Ausmaß an Realitätsnähe in Hinblick auf Kosten/Aufwand-Nutzen-Bilanz sinnvoll ist. Das Ziel der vorliegenden Arbeit ist es, den Effekt von zwei unterschiedlich realitätsnahen Lernumgebungen (Seminarraum vs. realistische Simulationsumgebung) auf die erlernten notfallmedizinischen Kompetenzen zu analysieren. Dazu wurden Krankheitsbilder gewählt, die jedem Arzt in Präklinik, auf Station und im ambulanten Bereich begegnen können und die zügig erkannt und behandelt werden müssen: Asthma, Sepsis und Apoplex.
Material und Methoden: Bei der vorliegenden Arbeit handelt es sich um eine vergleichende Effektivitätsanalyse im crossover-Design. Teilnehmende waren Studierende des 4. Studienjahres der Goethe-Universität Frankfurt am Main, die den 3-TagesNotfallmedizinkurs im Rahmen ihrer curricularen Ausbildung im Querschnittsbereich Notfallmedizin absolvierten. Am ersten Tag durchliefen alle Studierenden ein standardisiertes Skillstraining notfallmedizinischer Basiskompetenzen. An den Folgetagen wurden verschiedene leitsymptombasierte Module vermittelt, die neben der interaktiven Erarbeitung der theoretischen Lerninhalte eine direkte Anwendung in themenspezifischen Szenarien fokussierten. Für die vorliegende Studie wurden die Teilnehmenden in vier Gruppen randomisiert, wobei Gruppen eins und zwei das Training in der Seminarraumumgebung durchliefen, während drei und vier die Szenarien in der realitätsnahen Simulationsumgebung absolvierten. Am dritten Tag fand eine formative Überprüfung der erlernten Fähigkeiten in Form eines OSCEs statt. Bei dieser Überprüfung absolvierten die Gruppen eins und drei in der Seminarraumumgebung und Gruppen zwei und vier im realitätsnahen Umfeld der Simulation das Assessment. Die Datenauswertung erfolgte mit MS Excel und bias.
Ergebnisse und Fazit: Die vorliegende Studie fand zwischen Juli und Oktober 2018 an der Goethe-Universität in Frankfurt am Main statt. 134 Teilnehmer absolvierten die Studie vollständig. Die Ergebnisse zeigen deutliche Unterschiede in der Performance der vier Gruppen, sowohl insgesamt als auch nach Geschlechtern und mit dem van-Elteren-Test. Prozentual betrachtet zeigten die Teilnehmenden der Gruppe 4 (Training und Prüfung im realitätsnahen Umfeld) die höchsten Ergebnisse. Die Realitätsnähe hat einen positiven Einfluss auf die Performance der Studierenden.
Iron deficiency (ID) is a common manifestation of inflammatory bowel disease (IBD), arising primarily due to chronic inflammation and/or blood loss. There is no gold standard for ID diagnosis, which is often complicated by concomitant inflammation. Zinc protoporphyrin (ZnPP) correlates with parameters of iron homeostasis and has been identified as a promising marker for ID, irrespective of inflammation. We investigated the diagnostic performance of ZnPP in ID, iron deficiency anemia, anemia of chronic disease and mixed anemia in a cross-sectional study in 130 patients with IBD. Different parameters were compared by receiver operator characteristic (ROC) analysis as detectors of iron-restricted erythropoiesis (IRE). IRE was detected in 91 patients (70.0%); fifty-nine (64.8%) had absolute ID and 23 (25.4%) functional ID. When inflammation was present, ZnPP was a more reliable sole biomarker of IRE than MCV, transferrin saturation (TSAT) or ferritin (AUC; 0.855 vs. 0.763, 0.834% and 0.772, respectively). The specificity of TSAT was significantly lower than ZnPP when inflammation was present (38% vs. 71%, respectively). We conclude that ZnPP is a reliable biomarker of functional ID in patients with IBD and more dependable than ferritin or TSAT, which are influenced by chronic inflammation. We propose that ZnPP may also have utility in patients with other chronic diseases.
Zellen außer Balance : neue Therapieansätze für komplexe Krankheiten – das Clusterprojekt ENABLE
(2021)
Marmor, Stein, Eisen, Müll, Haare, Staub… es gibt kaum ein Material, das Peter Buggenhout in seinen hybriden Arbeiten nicht verarbeitet. Das Kunstmuseum Reutlingen / konkret gibt in seiner umfassenden Überblicksausstellung „Peter Buggenhout: nicht geheuer“ einen Einblick in bisherige Arbeiten des belgischen Bildhauers.
Z-boson production in p–Pb collisions at √sNN = 8.16 TeV and Pb–Pb collisions at √sNN = 5.02 TeV
(2021)
Measurement of Z-boson production in p-Pb collisions at sNN−−−√=8.16 TeV and Pb-Pb collisions at sNN−−−√=5.02 TeV is reported. It is performed in the dimuon decay channel, through the detection of muons with pseudorapidity −4<ημ<−2.5 and transverse momentum pμT>20 GeV/c in the laboratory frame. The invariant yield and nuclear modification factor are measured for opposite-sign dimuons with invariant mass 60<mμμ<120 GeVc2 and rapidity 2.5<yμμcms<4. They are presented as a function of rapidity and, for the Pb-Pb collisions, of centrality as well. The results are compared with theoretical calculations, both with and without nuclear modifications to the Parton Distribution Functions (PDFs). In p-Pb collisions the center-of-mass frame is boosted with respect to the laboratory frame, and the measurements cover the backward (−4.46<yμμcms<−2.96) and forward (2.03<yμμcms<3.53) rapidity regions. For the p-Pb collisions, the results are consistent within experimental and theoretical uncertainties with calculations that include both free-nucleon and nuclear-modified PDFs. For the Pb-Pb collisions, a 3.4σ deviation is seen in the integrated yield between the data and calculations based on the free-nucleon PDFs, while good agreement is found once nuclear modifications are considered.
Human GLUTs represent a family of specialized transporters that facilitate the diffusion of hexoses through membranes along a concentration gradient. The 14 isoforms share high sequence identity but differ in substrate specificity and affinity, and tissue distribution. According to their structure similarity, GLUTs are divided into three classes, with class 1 comprising the most intensively studied isoforms GLUTs1 4. An abnormal function of different GLUT members has been related to the pathogenesis of various diseases, including cancer and diabetes. Hence, GLUTs are the subject of intensive research, and efforts concentrate on identifying GLUT-selective ligands for putative medical purposes and their application in studies aiming to further unravel the metabolic roles of these transporters.
The hexose transporter deficient (hxt0) yeast strain EBY.VW4000 is devoid of all its endogenous hexose transporters and unable to grow on glucose or related hexoses. This strain has proven to be a valuable platform to investigate heterologous transporters due to its easy handling, increased robustness, and versatile applications. However, the functional expression of GLUTs in yeast requires certain modifications. Single point mutations of GLUT1 and GLUT5 led to their functional expression in EBY.VW4000, whereas the native GLUT1 was actively expressed in EBY.S7, a hxt0 strain carrying the fgy1 mutation that putatively reduces the phosphatidylinositol-4-phosphate (PI4P) content in the plasma membrane. GLUT4 was only actively expressed in the hxt0 strain SDY.022, which also contains the fgy1 mutation and in which ERG4 is additionally deleted. Erg4 is one of the late enzymes in the ergosterol pathway, and therefore SDY.022 probably has an altered sterol composition in its membrane.
The goal of this thesis was to actively express GLUT2 and GLUT3 in a hxt0 yeast strain, providing a convenient system for their ligand screening. A PCR-derived amino acid exchange in the sequence of GLUT3 enabled its functional expression in EBY.VW4000 and the unmodified GLUT3 protein was active in EBY.S7. Functional expression of GLUT2 was achieved by rational design. The extracellular loop between the transmembrane regions 1 and 2 is significantly larger in GLUT2 than in other class 1 GLUTs. By truncating this loop by 34 amino acids and exchanging an alanine for a serine, a GLUT3-like loop was implemented. The resulting construct GLUT2∆loopS was functional in EBY.S7. With an additional point mutation in the transmembrane region 11, GLUT2∆loopS_Q455R was also actively expressed in EBY.VW4000. Inhibition studies with the known GLUT inhibitors phloretin and quercetin showed a reduced transporter activity for GLUT2 and GLUT3 in uptake assays and growth tests when inhibitors were present, demonstrating that both systems are amenable for ligand screening experiments.
The newly established GLUT2 yeast system was then used to screen a library of compounds pre-selected by in silico screening. Thereby, eleven identified GLUT2 inhibitors exhibited strong potencies with IC50 values ranging from 0.61 to 19.3 µM. By employing the other yeast systems, these compounds were tested for their effects on GLUT1, and GLUTs3-5, revealing that nine of the identified ligands were GLUT2-selective. In contrast, one was a pan-class 1 inhibitor (inhibiting GLUTs1-4), and one affected GLUT2 and GLUT5, the two fructose transporting isoforms. These compounds will serve as useful tools for investigations on the role of GLUT2 in metabolic diseases and might even evolve into pharmaceutical agents targeting GLUT2-associated diseases.
Due to the beneficial effect of the putatively changed sterol composition in SDY.022 (by ERG4 deletion) on the functional expression of GLUT4, it was hypothesized that the presence of the human sterol cholesterol, or cholesterol-like sterols, might have a beneficial effect on GLUT expression, too. Thus, it was attempted to generate hxt0 strains that synthesize these sterols by genetic modifications targeting the ergosterol pathway. In the scope of these experiments, several strains with different sterol compositions were generated. Drop tests on glucose medium with the different strains expressing GLUT1 or GLUT4 revealed that the deletion of ERG6 is clearly advantageous for a functional expression of GLUT1 (but not GLUT4). This indicates that the methyl group at the ergosterol side chain (introduced by Erg6 and reduced by Erg4) negatively influences GLUT1 activity. However, this effect on GLUT1 activity was less pronounced than the putative altered PI4P content in EBY.S7.
Additionally, in this thesis, a new tool to measure glucose transport rates of transporters expressed in the hxt0 yeast system was developed to facilitate their kinetic characterization. For this, the pH-sensitive GFP variant pHluorin was employed as a biosensor for the cytosolic pH (pHcyt) by measuring the ratio (R390/470) of emission intensities at 512 nm from two different excitation wavelengths (390 and 470 nm). Sugar-starved cells exhibit a slightly acidic pHcyt because ATP production is depleted, reducing the activity of ATP-dependent proton pumps.
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Xenocoumacin (Xcn) 1 and 2 are the major antibiotics produced by the insect-pathogenic bacterium Xenorhabdus nematophila. Although the antimicrobial activity of Xcns has been explored, research regarding their action on mammalian cells is lacking. We aimed to investigate the action of Xcns in the context of inflammation and angiogenesis. We found that Xcns do not impair the viability of primary endothelial cells (ECs). Particularly Xcn2, but not Xcn1, inhibited the pro-inflammatory activation of ECs: Xcn2 diminished the interaction between ECs and leukocytes by downregulating cell adhesion molecule expression and blocked critical steps of the NF-κB activation pathway including the nuclear translocation of NF-κB p65 as well as the activation of inhibitor of κBα (IκBα) and IκB kinase β (IKKβ). Furthermore, the synthesis of pro-inflammatory mediators and enzymes, nitric oxide (NO) production and prostaglandin E2 (PGE2), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2), was evaluated in leukocytes. The results showed that Xcns reduced viability, NO release, and iNOS expression in activated macrophages. Beyond these anti-inflammatory properties, Xcn2 effectively hindered pro-angiogenic processes in HUVECs, such as proliferation, undirected and chemotactic migration, sprouting, and network formation. Most importantly, we revealed that Xcn2 inhibits de novo protein synthesis in ECs. Consequently, protein levels of receptors that mediate the inflammatory and angiogenic signaling processes and that have a short half-live are reduced by Xcn2 treatment, thus explaining the observed pharmacological activities. Overall, our research highlights that Xcn2 exhibits significant pharmacological in vitro activity regarding inflammation and angiogenesis, which is worth to be further investigated preclinically.