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Institut
- Theodor-Boveri-Institut für Biowissenschaften (88)
- Graduate School of Life Sciences (51)
- Physikalisches Institut (38)
- Institut für Psychologie (28)
- Institut für Anorganische Chemie (27)
- Institut für Organische Chemie (27)
- Medizinische Klinik und Poliklinik II (24)
- Neurologische Klinik und Poliklinik (24)
- Institut für Geographie und Geologie (20)
- Abteilung für Funktionswerkstoffe der Medizin und der Zahnheilkunde (18)
Schriftenreihe
Sonstige beteiligte Institutionen
- Johns Hopkins School of Medicine (2)
- VolkswagenStiftung (2)
- Bio-Imaging Center Würzburg (1)
- CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - the development agency of the Brazilian Federal Government (1)
- Center for Nanosystems Chemistry (CNC), Universität Würzburg (1)
- DAAD - Deutscher Akademischer Austauschdienst (1)
- Department of Hematology and Oncology, Sana Hospital Hof, Hof, Germany (1)
- Department of Laboratory Medicine and Medicine Huddinge, Karolinska Institutet and University Hospital, Stockholm, Sweden (1)
- Department of Medicine A, University Hospital of Münster, Münster, Germany (1)
- Ernst Strüngmann Institute for Neuroscience in Cooperation with Max Planck Society (ESI) (1)
ResearcherID
- B-4606-2017 (1)
Werner, Rudolf A. ; Wakabayashi, Hiroshi ; Chen, Xinyu ; Hayakawa, Nobuyuki ; Lapa, Constantin ; Rowe, Steven P. ; Javadi, Mehrbod S. ; Robinson, Simon ; Higuchi, Takahiro
We aimed to determine a detailed regional ventricular distribution pattern of the novel cardiac nerve PET radiotracer \(^{18}\)F-LMI1195 in healthy rabbits. Ex-vivo high resolution autoradiographic imaging was conducted to identify accurate ventricular distribution of \(^{18}\)F-LMI1195. In healthy rabbits, \(^{18}\)F-LMI1195 was administered followed by the reference perfusion marker \(^{201}\)Tl for a dual-radiotracer analysis. After 20 min of \(^{18}\)F-LMI1195 distribution time, the rabbits were euthanized, the hearts were extracted, frozen, and cut into 20-μm short axis slices. Subsequently, the short axis sections were exposed to a phosphor imaging plate to determine \(^{18}\)F-LMI1195 distribution (exposure for 3 h). After complete \(^{18}\)F decay, sections were re-exposed to determine 201Tl distribution (exposure for 7 days). For quantitative analysis, segmental regions of Interest (ROIs) were divided into four left ventricular (LV) and a right ventricular (RV) segment on mid-ventricular short axis sections. Subendocardial, mid-portion, and subepicardial ROIs were placed on the LV lateral wall. \(^{18}\)F-LMI1195 distribution was almost homogeneous throughout the LV wall without any significant differences in all four LV ROIs (anterior, posterior, septal and lateral wall, 99 ± 2, 94 ± 5, 94 ± 4 and 97 ± 3%LV, respectively, n.s.). Subepicardial \(^{201}\)Tl uptake was significantly lower compared to the subendocardial portion (subendocardial, mid-portion, and subepicardial activity: 90 ± 3, 96 ± 2 and *80 ± 5%LV, respectively, *p < 0.01 vs. mid-portion). This was in contradistinction to the transmural wall profile of \(^{18}\)F-LMI1195 (90 ± 4, 96 ± 5 and 84 ± 4%LV, n.s.). A slight but significant discrepant transmural radiotracer distribution pattern of \(^{201}\)Tl in comparison to \(^{18}\)F-LMI1195 may be a reflection of physiological sympathetic innervation and perfusion in rabbit hearts.
Detecting whether a suspect possesses incriminating (e.g., crime-related) information can provide valuable decision aids in court. To this means, the Concealed Information Test (CIT) has been developed and is currently applied on a regular basis in Japan. But whereas research has revealed a high validity of the CIT in student and normal populations, research investigating its validity in forensic samples in scarce. This applies even more to the reaction time-based CIT (RT-CIT), where no such research is available so far. The current study tested the application of the RT-CIT for an imaginary mock crime scenario both in a sample of prisoners (n = 27) and a matched control group (n = 25). Results revealed a high validity of the RT-CIT for discriminating between crime-related and crime-unrelated information, visible in medium to very high effect sizes for error rates and reaction times. Interestingly, in accordance with theories that criminal offenders may have worse response inhibition capacities and that response inhibition plays a crucial role in the RT-CIT, CIT-effects in the error rates were even elevated in the prisoners compared to the control group. No support for this hypothesis could, however, be found in reaction time CIT-effects. Also, performance in a standard Stroop task, that was conducted to measure executive functioning, did not differ between both groups and no correlation was found between Stroop task performance and performance in the RT-CIT. Despite frequently raised concerns that the RT-CIT may not be applicable in non-student and forensic populations, our results thereby do suggest that such a use may be possible and that effects seem to be quite large. Future research should build up on these findings by increasing the realism of the crime and interrogation situation and by further investigating the replicability and the theoretical substantiation of increased effects in non-student and forensic samples.
Large-area remote sensing time-series offer unique features for the extensive investigation of our environment. Since various error sources in the acquisition chain of datasets exist, only properly validated results can be of value for research and downstream decision processes. This review presents an overview of validation approaches concerning temporally dense time-series of land surface geo-information products that cover the continental to global scale. Categorization according to utilized validation data revealed that product intercomparisons and comparison to reference data are the conventional validation methods. The reviewed studies are mainly based on optical sensors and orientated towards global coverage, with vegetation-related variables as the focus. Trends indicate an increase in remote sensing-based studies that feature long-term datasets of land surface variables. The hereby corresponding validation efforts show only minor methodological diversification in the past two decades. To sustain comprehensive and standardized validation efforts, the provision of spatiotemporally dense validation data in order to estimate actual differences between measurement and the true state has to be maintained. The promotion of novel approaches can, on the other hand, prove beneficial for various downstream applications, although typically only theoretical uncertainties are provided.
Virotherapy on the basis of oncolytic vaccinia virus (VACV) strains is a promising approach for cancer therapy. Recently, we showed that the oncolytic vaccinia virus GLV-1h68 has a therapeutic potential in treating human prostate and hepatocellular carcinomas in xenografted mice. In this study, we describe the use of dynamic boolean modeling for tumor growth prediction of vaccinia virus-injected human tumors. Antigen profiling data of vaccinia virus GLV-1h68-injected human xenografted mice were obtained, analyzed and used to calculate differences in the tumor growth signaling network by tumor type and gender. Our model combines networks for apoptosis, MAPK, p53, WNT, Hedgehog, the T-killer cell mediated cell death, Interferon and Interleukin signaling networks. The in silico findings conform very well with in vivo findings of tumor growth. Similar to a previously published analysis of vaccinia virus-injected canine tumors, we were able to confirm the suitability of our boolean modeling for prediction of human tumor growth after virus infection in the current study as well. In summary, these findings indicate that our boolean models could be a useful tool for testing of the efficacy of VACV-mediated cancer therapy already before its use in human patients.
Almost all life forms on earth have adapted to the most impactful and most predictable recurring change in environmental condition, the cycle of day and night, caused by the axial rotation of the planet. As a result many animals have evolved intricate endogenous clocks, which adapt and synchronize the organisms’ physiology, metabolism and behaviour to the daily change in environmental conditions. The scientific field researching these endogenous clocks is called chronobiology and has steadily grown in size, scope and relevance since the works of the earliest pioneers in the 1960s.
The number one model organism for the research of circadian clocks is the fruit fly, Drosophila melanogaster, whose clock serves as the entry point to understanding the basic inner workings of such an intricately constructed endogenous timekeeping system. In this thesis it was attempted to combine the research on the circadian clock with the techniques of optogenetics, a fairly new scientific field, launched by the discovery of Channelrhodopsin 2 just over 15 years ago. Channelrhodopsin 2 is a light-gated ion channel found in the green alga Chlamydomonas reinhardtii. In optogenetics, researches use these light-gated ion channels like Channelrhodopsin 2 by heterologously expressing them in cells and tissues of other organisms, which can then be stimulated by the application of light. This is most useful when studying neurons, as these channels provide an almost non-invasive tool to depolarize the neuronal plasma membranes at will. The goal of this thesis was to develop an optogenetic tool, which would be able to influence and phase shift the circadian clock of Drosophila melanogaster upon illumination. A phase shift is the adaptive response of the circadian clock to an outside stimulus that signals a change in the environmental light cycle. An optogenetic tool, able to influence and phase shift the circadian clock predictably and reliably, would open up many new ways and methods of researching the neuronal network of the clock and which neurons communicate to what extent, ultimately synchronizing the network.
The first optogenetic tool to be tested in the circadian clock of Drosophila melanogaster was ChR2-XXL, a channelrhodopsin variant with dramatically increased expression levels and photocurrents combined with a prolonged open state. The specific expression of ChR2-XXL and of later constructs was facilitated by deploying the three different clock-specific GAL4-driver lines, clk856-gal4, pdf-gal4 and mai179-gal4. Although ChR2-XXL was shown to be highly effective at depolarizing neurons, these stimulations proved to be unable to significantly phase shift the circadian clock of Drosophila. The second series of experiments was conducted with the conceptually novel optogenetic tools Olf-bPAC and SthK-bPAC, which respectively combine a cyclic nucleotide-gated ion channel (Olf and SthK) with the light-activated adenylyl-cyclase bPAC. These tools proved to be quite useful when expressed in the motor neurons of instar-3 larvae of Drosophila, paralyzing the larvae upon illumination, as well as affecting body length. This way, these new tools could be precisely characterized, spawning a successfully published research paper, centered around their electrophysiological characterization and their applicability in model organisms like Drosophila. In the circadian clock however, these tools caused substantial damage, producing severe arrhythmicity and anomalies in neuronal development. Using a temperature-sensitive GAL80-line to delay the expression until after the flies had eclosed, yielded no positive results either. The last series of experiments saw the use of another new series of optogenetic tools, modelled after the Olf-bPAC, with bPAC swapped out for CyclOp, a membrane-bound guanylyl-cyclase, coupled with less potent versions of the Olf. This final attempt however also ended up being unsuccessful. While these tools could efficiently depolarize neuronal membranes upon illumination, they were ultimately unable to stimulate the circadian clock in way that would cause it to phase shift.
Taken together, these mostly negative results indicate that an optogenetic manipulation of the circadian clock of Drosophila melanogaster is an extremely challenging subject. As light already constitutes the most impactful environmental factor on the circadian clock, the combination of chronobiology with optogenetics demands the parameters of the conducted experiments to be tuned with an extremely high degree of precision, if one hopes to receive positive results from these types of experiments at all.
Grafen, Anika ; Schumacher, Fabian ; Chithelen, Janice ; Kleuser, Burkhard ; Beyersdorf, Niklas ; Schneider-Schaulies, Jürgen
As structural membrane components and signaling effector molecules sphingolipids influence a plethora of host cell functions, and by doing so also the replication of viruses. Investigating the effects of various inhibitors of sphingolipid metabolism in primary human peripheral blood lymphocytes (PBL) and the human B cell line BJAB we found that not only the sphingosine kinase (SphK) inhibitor SKI-II, but also the acid ceramidase inhibitor ceranib-2 efficiently inhibited measles virus (MV) replication. Virus uptake into the target cells was not grossly altered by the two inhibitors, while titers of newly synthesized MV were reduced by approximately 1 log (90%) in PBL and 70–80% in BJAB cells. Lipidomic analyses revealed that in PBL SKI-II led to increased ceramide levels, whereas in BJAB cells ceranib-2 increased ceramides. SKI-II treatment decreased sphingosine-1-phosphate (S1P) levels in PBL and BJAB cells. Furthermore, we found that MV infection of lymphocytes induced a transient (0.5–6 h) increase in S1P, which was prevented by SKI-II. Investigating the effect of the inhibitors on the metabolic (mTORC1) activity we found that ceranib-2 reduced the phosphorylation of p70 S6K in PBL, and that both inhibitors, ceranib-2 and SKI-II, reduced the phosphorylation of p70 S6K in BJAB cells. As mTORC1 activity is required for efficient MV replication, this effect of the inhibitors is one possible antiviral mechanism. In addition, reduced intracellular S1P levels affect a number of signaling pathways and functions including Hsp90 activity, which was reported to be required for MV replication. Accordingly, we found that pharmacological inhibition of Hsp90 with the inhibitor 17-AAG strongly impaired MV replication in primary PBL. Thus, our data suggest that treatment of lymphocytes with both, acid ceramidase and SphK inhibitors, impair MV replication by affecting a number of cellular activities including mTORC1 and Hsp90, which alter the metabolic state of the cells causing a hostile environment for the virus.
Silwedel, Christine ; Speer, Christian P. ; Haarmann, Axel ; Fehrholz, Markus ; Claus, Heike ; Schlegel, Nicolas ; Glaser, Kirsten
Ureaplasma species are common colonizers of the adult genitourinary tract and often considered as low-virulence commensals. Intraamniotic Ureaplasma infections, however, facilitate chorioamnionitis and preterm birth, and cases of Ureaplasma-induced neonatal sepsis, pneumonia, and meningitis raise a growing awareness of their clinical relevance. In vitro studies are scarce but demonstrate distinct Ureaplasma-driven impacts on immune mechanisms. The current study addressed cytokine and chemokine responses upon exposure of native or lipopolysaccharide (LPS) co-stimulated human brain microvascular endothelial cells (HBMEC) to Ureaplasma urealyticum or U. parvum, using qRT-PCR, RNA sequencing, multi-analyte immunoassay, and flow cytometry. Ureaplasma exposure in native HBMEC reduced monocyte chemoattractant protein (MCP)-3 mRNA expression (p < 0.01, vs. broth). In co-stimulated HBMEC, Ureaplasma spp. attenuated LPS-evoked mRNA responses for C-X-C chemokine ligand 5, MCP-1, and MCP-3 (p < 0.05, vs. LPS) and mitigated LPS-driven interleukin (IL)-1α protein secretion, as well as IL-8 mRNA and protein responses (p < 0.05). Furthermore, Ureaplasma isolates increased C-X-C chemokine receptor 4 mRNA levels in native and LPS co-stimulated HBMEC (p < 0.05). The presented results may imply immunomodulatory capacities of Ureaplasma spp. which may ultimately promote chronic colonization and long-term neuroinflammation.
Fungi of the order Mucorales colonize all kinds of wet, organic materials and represent a permanent part of the human environment. They are economically important as fermenting agents of soybean products and producers of enzymes, but also as plant parasites and spoilage organisms. Several taxa cause life-threatening infections, predominantly in patients with impaired immunity. The order Mucorales has now been assigned to the phylum Mucoromycota and is comprised of 261 species in 55 genera. Of these accepted species, 38 have been reported to cause infections in humans, as a clinical entity known as mucormycosis. Due to molecular phylogenetic studies, the taxonomy of the order has changed widely during the last years. Characteristics such as homothallism, the shape of the suspensors, or the formation of sporangiola are shown to be not taxonomically relevant. Several genera including Absidia, Backusella, Circinella, Mucor, and Rhizomucor have been amended and their revisions are summarized in this review. Medically important species that have been affected by recent changes include Lichtheimia corymbifera, Mucor circinelloides, and Rhizopus microsporus. The species concept of Rhizopus arrhizus (syn. R. oryzae) is still a matter of debate. Currently, species identification of the Mucorales is best performed by sequencing of the internal transcribed spacer (ITS) region. Ecologically, the Mucorales represent a diverse group but for the majority of taxa, the ecological role and the geographic distribution remain unknown. Understanding the biology of these opportunistic fungal pathogens is a prerequisite for the prevention of infections, and, consequently, studies on the ecology of the Mucorales are urgently needed.
Albrecht, Franziska ; Mueller, Karsten ; Ballarini, Tommaso ; Lampe, Leonie ; Diehl-Schmid, Janine ; Fassbender, Klaus ; Fliessbach, Klaus ; Jahn, Holger ; Jech, Robert ; Kassubek, Jan ; Kornhuber, Johannes ; Landwehrmeyer, Bernhard ; Lauer, Martin ; Ludolph, Albert C. ; Lyros, Epameinondas ; Prudlo, Johannes ; Schneider, Anja ; Synofzik, Matthis ; Wiltfang, Jens ; Danek, Adrian ; Otto, Markus ; Schroeter, Matthias L.
Alien limb phenomenon is a rare syndrome associated with a feeling of non-belonging and disowning toward one's limb. In contrast, anarchic limb phenomenon leads to involuntary but goal-directed movements. Alien/anarchic limb phenomena are frequent in corticobasal syndrome (CBS), an atypical parkinsonian syndrome characterized by rigidity, akinesia, dystonia, cortical sensory deficit, and apraxia. The structure function relationship of alien/anarchic limb was investigated in multi centric structural magnetic resonance imaging (MRI) data. Whole-group and single subject comparisons were made in 25 CBS and eight CBS-alien/anarchic limb patients versus controls. Support vector machine was used to see if CBS with and without alien/anarchic limb could be distinguished by structural MRI patterns. Whole-group comparison of CBS versus controls revealed asymmetric frontotemporal atrophy. CBS with alien/anarchic limb syndrome versus controls showed frontoparietal atrophy including the supplementary motor area contralateral to the side of the affected limb. Exploratory analysis identified frontotemporal regions encompassing the pre-/and postcentral gyrus as compromised in CBS with alien limb syndrome. Classification of CBS patients yielded accuracies of 79%. CBS-alien/anarchic limb syndrome was differentiated from CBS patients with an accuracy of 81%. Predictive differences were found in the cingulate gyrus spreading to frontomedian cortex, postcentral gyrus, and temporoparietoocipital regions. We present the first MRI-based group analysis on CBS-alien/anarchic limb. Results pave the way for individual clinical syndrome prediction and allow understanding the underlying neurocognitive architecture. (C) 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Forward Collision Alarms (FCA) intend to signal hazardous traffic situations and the need for an immediate corrective driver response. However, data of naturalistic driving studies revealed that approximately the half of all alarms activated by conventional FCA systems represented unnecessary alarms. In these situations, the alarm activation was correct according to the implemented algorithm, whereas the alarms led to no or only minimal driver responses. Psychological research can make an important contribution to understand drivers’ needs when interacting with driver assistance systems.
The overarching objective of this thesis was to gain a systematic understanding of psychological factors and processes that influence drivers’ perceived need for assistance in potential collision situations. To elucidate under which conditions drivers perceive alarms as unnecessary, a theoretical framework of drivers’ subjective alarm evaluation was developed. A further goal was to investigate the impact of unnecessary alarms on drivers’ responses and acceptance. Four driving simulator studies were carried out to examine the outlined research questions.
In line with the hypotheses derived from the theoretical framework, the results suggest that drivers’ perceived need for assistance is determined by their retrospective subjective hazard perception. While predictions of conventional FCA systems are exclusively based on physical measurements resulting in a time to collision, human drivers additionally consider their own manoeuvre intentions and those attributed to other road users to anticipate the further course of a potentially critical situation. When drivers anticipate a dissolving outcome of a potential conflict, they perceive the situation as less hazardous than the system. Based on this discrepancy, the system would activate an alarm, while drivers’ perceived need for assistance is low. To sum up, the described factors and processes cause drivers to perceive certain alarms as unnecessary. Although drivers accept unnecessary alarms less than useful alarms, unnecessary alarms do not reduce their overall system acceptance. While unnecessary alarms cause moderate driver responses in the short term, the intensity of responses decrease with multiple exposures to unnecessary alarms. However, overall, effects of unnecessary alarms on drivers’ alarm responses and acceptance seem to be rather uncritical.
This thesis provides insights into human factors that explain when FCAs are perceived as unnecessary. These factors might contribute to design FCA systems tailored to drivers’ needs.