TY - JOUR A1 - Hetzer, Benjamin A1 - Orth-Höller, Dorothea A1 - Würzner, Reinhard A1 - Kreidl, Peter A1 - Lackner, Michaela A1 - Müller, Thomas A1 - Knabl, Ludwig A1 - Geisler-Moroder, Daniel Rudolf A1 - Mellmann, Alexander A1 - Sesli, Özcan A1 - Holzknecht, Jeanett A1 - Noce, Damia A1 - Akarathum, Noppadon A1 - Chotinaruemol, Somporn A1 - Prelog, Martina A1 - Oberdorfer, Peninnah T1 - “Enhanced acquisition of antibiotic-resistant intestinal E. coli during the first year of life assessed in a prospective cohort study” JF - Antimicrobial Resistance & Infection Control N2 - Background Increasing bacterial resistance to antibiotics is a serious problem worldwide. We sought to record the acquisition of antibiotic-resistant Escherichia coli (E. coli) in healthy infants in Northern Thailand and investigated potential determinants. Methods Stool samples from 142 infants after birth, at ages 2wk, 2mo, 4 to 6mo, and 1y, and parent stool samples were screened for E. coli resistance to tetracycline, ampicillin, co-trimoxazole, and cefazoline by culture, and isolates were further investigated for multiresistance by disc diffusion method. Pulsed-field gel electrophoresis was performed to identify persistent and transmitted strains. Genetic comparison of resistant and transmitted strains was done by multilocus sequence typing (MLST) and strains were further investigated for extra- and intra-intestinal virulence factors by multiplex PCR. Results Forty-seven (33%) neonatal meconium samples contained resistant E. coli. Prevalence increased continuously: After 1y, resistance proportion (tetracycline 80%, ampicillin 72%, co-trimoxazole 66%, cefazoline 35%) almost matched those in parents. In 8 infants (6%), identical E. coli strains were found in at least 3 sampling time points (suggesting persistence). Transmission of resistant E. coli from parents to child was observed in only 8 families. MLST showed high diversity. We could not identify any virulence genes or factors associated with persistence, or transmission of resistant E. coli. Full-term, vaginal birth and birth in rural hospital were identified as risk factors for early childhood colonization with resistant E. coli. Conclusion One third of healthy Thai neonates harboured antibiotic-resistant E. coli in meconium. The proportion of resistant E. coli increased during the first year of life almost reaching the value in adults. We hypothesize that enhancement of infection control measures and cautious use of antibiotics may help to control further increase of resistance. KW - Escherichia coli KW - antibiotic resistance KW - multiresistance KW - transmission KW - persistence KW - children KW - neonates Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320284 VL - 8 ER - TY - JOUR A1 - Mammadova-Bach, Elmina A1 - Braun, Attila T1 - Zinc homeostasis in platelet-related diseases JF - International Journal of Molecular Sciences N2 - Zn\(^{2+}\) deficiency in the human population is frequent in underdeveloped countries. Worldwide, approximatively 2 billion people consume Zn\(^{2+}\)-deficient diets, accounting for 1–4% of deaths each year, mainly in infants with a compromised immune system. Depending on the severity of Zn\(^{2+}\) deficiency, clinical symptoms are associated with impaired wound healing, alopecia, diarrhea, poor growth, dysfunction of the immune and nervous system with congenital abnormalities and bleeding disorders. Poor nutritional Zn\(^{2+}\) status in patients with metastatic squamous cell carcinoma or with advanced non-Hodgkin lymphoma, was accompanied by cutaneous bleeding and platelet dysfunction. Forcing Zn\(^{2+}\) uptake in the gut using different nutritional supplementation of Zn\(^{2+}\) could ameliorate many of these pathological symptoms in humans. Feeding adult rodents with a low Zn\(^{2+}\) diet caused poor platelet aggregation and increased bleeding tendency, thereby attracting great scientific interest in investigating the role of Zn\(^{2+}\) in hemostasis. Storage protein metallothionein maintains or releases Zn\(^{2+}\) in the cytoplasm, and the dynamic change of this cytoplasmic Zn\(^{2+}\) pool is regulated by the redox status of the cell. An increase of labile Zn\(^{2+}\) pool can be toxic for the cells, and therefore cytoplasmic Zn\(^{2+}\) levels are tightly regulated by several Zn\(^{2+}\) transporters located on the cell surface and also on the intracellular membrane of Zn\(^{2+}\) storage organelles, such as secretory vesicles, endoplasmic reticulum or Golgi apparatus. Although Zn\(^{2+}\) is a critical cofactor for more than 2000 transcription factors and 300 enzymes, regulating cell differentiation, proliferation, and basic metabolic functions of the cells, the molecular mechanisms of Zn\(^{2+}\) transport and the physiological role of Zn\(^{2+}\) store in megakaryocyte and platelet function remain elusive. In this review, we summarize the contribution of extracellular or intracellular Zn\(^{2+}\) to megakaryocyte and platelet function and discuss the consequences of dysregulated Zn\(^{2+}\) homeostasis in platelet-related diseases by focusing on thrombosis, ischemic stroke and storage pool diseases. KW - Zinc KW - platelets KW - hemostasis KW - thrombosis KW - ischemic stroke KW - storage-pool diseases Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285554 SN - 1422-0067 VL - 20 IS - 21 ER - TY - JOUR A1 - Zetzl, Teresa A1 - Schuler, Michael A1 - Renner, Agnes A1 - Jentschke, Elisabeth A1 - van Oorschot, Birgitt T1 - Yoga intervention and reminder e-mails for reducing cancer-related fatigue - a study protocol of a randomized controlled trial JF - BMC Psychology N2 - Background Almost 90% of cancer patients suffer from symptoms of fatigue during treatment. Supporting treatments are increasingly used to alleviate the burden of fatigue. This study examines the short-term and long-term effects of yoga on fatigue and the effect of weekly reminder e-mails on exercise frequency and fatigue symptoms. Methods The aim of the first part of the study will evaluate the effectiveness of yoga for cancer patients with mixed diagnoses reporting fatigue. We will randomly allocate 128 patients to an intervention group (N = 64) receiving yoga and a wait-list control group (N = 64) receiving yoga 9 weeks later. The yoga therapy will be performed in weekly sessions of 60 min each for 8 weeks. The primary outcome will be self-reported fatigue symptoms. In the second part of the study, the effectiveness of reminder e-mails with regard to the exercise frequency and self-reported fatigue symptoms will be evaluated. A randomized allocated group of the participants (“email”) receives weekly reminder e-mails, the other group does not. Data will be assessed using questionnaires the beginning and after yoga therapy as well as after 6  months. Discussion Support of patients suffering from fatigue is an important goal in cancer patients care. If yoga therapy will reduce fatigue, this type of therapy may be introduced into routine practice. If the reminder e-mails prove to be helpful, new offers for patients may also develop from this. KW - Cancer KW - Fatigue KW - Yoga KW - Reminder e-mails KW - Supportive therapy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202268 VL - 7 ER - TY - JOUR A1 - Mansour, Ahmed M. A1 - Steiger, Christoph A1 - Nagel, Christoph A1 - Schatzschneider, Ulrich T1 - Wavelength‐dependent control of the CO release kinetics of manganese(I) tricarbonyl PhotoCORMs with benzimidazole coligands JF - European Journal of Inorganic Chemistry N2 - A series of photoactivatable CO‐releasing molecules (PhotoCORMs) was prepared from manganese pentacarbonyl bromide and 1H‐benzimidazol‐2‐ylmethyl‐(N‐phenyl)amine ligands (L) bearing different electron‐donating and electron‐withdrawing groups R = H, 4‐CH\(_3\), 4‐OCH\(_3\), 4‐Cl, 4‐NO\(_2\), 2‐, 3‐, and 4‐COOCH\(_3\) on the phenyl substituent to give octahedral manganese(I) complexes of the general formula [MnBr(CO)\(_3\)(L)]. Aerated DMSO solutions of the compounds are stable in the dark for 16 h with no CO release. However, the compounds rapidly release CO upon illumination at 412–525 nm, depending on the substitution pattern. Its influence on the photophysical and photochemical properties was systematically explored using UV/Vis spectroscopy and CO release measurements with a commercial gas sensor system. In the nitro‐substituted compound, the electronically excited state switched from benzimidazole‐ to phenyl‐centered, leading to a markedly different photochemical behavior of this visible‐light activated PhotoCORM. KW - CO‐releasing molecules (CORMs) KW - Manganese Carbonyl ligands KW - Benzimidazole KW - TDDFT Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218362 VL - 2019 IS - 42 ER - TY - JOUR A1 - Kehrberger, Sandra A1 - Holzschuh, Andrea T1 - Warmer temperatures advance flowering in a spring plant more strongly than emergence of two solitary spring bee species JF - PLoS ONE N2 - Climate warming has the potential to disrupt plant-pollinator interactions or to increase competition of co-flowering plants for pollinators, due to species-specific phenological responses to temperature. However, studies focusing on the effect of temperature on solitary bee emergence and the flowering onset of their food plants under natural conditions are still rare. We studied the effect of temperature on the phenology of the two spring bees Osmia cornuta and Osmia bicornis, by placing bee cocoons on eleven grasslands differing in mean site temperature. On seven grasslands, we additionally studied the effect of temperature on the phenology of the red-list plant Pulsatilla vulgaris, which was the first flowering plant, and of co-flowering plants with later flowering. With a warming of 0.1°C, the abundance-weighted mean emergence of O. cornuta males advanced by 0.4 days. Females of both species did not shift their emergence. Warmer temperatures advanced the abundance-weighted mean flowering of P. vulgaris by 1.3 days per 0.1°C increase, but did not shift flowering onset of co-flowering plants. Competition for pollinators between P. vulgaris and co-flowering plants does not increase within the studied temperature range. We demonstrate that temperature advances plant flowering more strongly than bee emergence suggesting an increased risk of pollinator limitation for the first flowers of P. vulgaris. KW - Flowering plants KW - Bees KW - Proteus vulgaris KW - Evolutionary emergence KW - Plants KW - Species delimitation KW - Flowers KW - Insect flight Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201165 VL - 14 IS - 6 ER - TY - JOUR A1 - Jaślan, Dawid A1 - Dreyer, Ingo A1 - Lu, Jinping A1 - O'Malley, Ronan A1 - Dindas, Julian A1 - Marten, Irene A1 - Hedrich, Rainer T1 - Voltage-dependent gating of SV channel TPC1 confers vacuole excitability JF - Nature Communications N2 - In contrast to the plasma membrane, the vacuole membrane has not yet been associated with electrical excitation of plants. Here, we show that mesophyll vacuoles from Arabidopsis sense and control the membrane potential essentially via the K\(^+\)-permeable TPC1 and TPK channels. Electrical stimuli elicit transient depolarization of the vacuole membrane that can last for seconds. Electrical excitability is suppressed by increased vacuolar Ca\(^{2+}\) levels. In comparison to wild type, vacuoles from the fou2 mutant, harboring TPC1 channels insensitive to luminal Ca\(^{2+}\), can be excited fully by even weak electrical stimuli. The TPC1-loss-of-function mutant tpc1-2 does not respond to electrical stimulation at all, and the loss of TPK1/TPK3-mediated K\(^{+}\) transport affects the duration of TPC1-dependent membrane depolarization. In combination with mathematical modeling, these results show that the vacuolar K\(^+\)-conducting TPC1 and TPK1/TPK3 channels act in concert to provide for Ca\(^{2+}\)- and voltage-induced electrical excitability to the central organelle of plant cells. KW - Biophysics KW - Plant signalling Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202029 VL - 10 ER - TY - JOUR A1 - Rubo, Marius A1 - Gamer, Matthias T1 - Visuo-tactile congruency influences the body schema during full body ownership illusion JF - Consciousness and Cognition N2 - Previous research showed that full body ownership illusions in virtual reality (VR) can be robustly induced by providing congruent visual stimulation, and that congruent tactile experiences provide a dispensable extension to an already established phenomenon. Here we show that visuo-tactile congruency indeed does not add to already high measures for body ownership on explicit measures, but does modulate movement behavior when walking in the laboratory. Specifically, participants who took ownership over a more corpulent virtual body with intact visuo-tactile congruency increased safety distances towards the laboratory's walls compared to participants who experienced the same illusion with deteriorated visuo-tactile congruency. This effect is in line with the body schema more readily adapting to a more corpulent body after receiving congruent tactile information. We conclude that the action-oriented, unconscious body schema relies more heavily on tactile information compared to more explicit aspects of body ownership. KW - Full body ownership illusion KW - Visuo-tactile congruency KW - Body schema KW - Movement behavior Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227095 VL - 73 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Wakabayashi, Hiroshi A1 - Chen, Xinyu A1 - Hayakawa, Nobuyuki A1 - Lapa, Constantin A1 - Rowe, Steven P. A1 - Javadi, Mehrbod S. A1 - Robinson, Simon A1 - Higuchi, Takahiro T1 - Ventricular distribution pattern of the novel sympathetic nerve PET radiotracer \(^{18}\)F-LMI1195 in Rabbit Hearts JF - Scientific Reports N2 - 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. KW - Cardiovascular diseases KW - Heart failure Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202707 VL - 9 ER - TY - JOUR A1 - Suchotzki, Kristina A1 - Kakavand, Aileen A1 - Gamer, Matthias T1 - Validity of the reaction time concealed information test in a prison sample JF - Frontiers in Psychiatry N2 - 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. KW - concealed information test KW - deception KW - lying KW - reaction times KW - inmates KW - forensic sample Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177714 VL - 9 IS - 745 ER - TY - JOUR A1 - Mayr, Stefan A1 - Kuenzer, Claudia A1 - Gessner, Ursula A1 - Klein, Igor A1 - Rutzinger, Martin T1 - Validation of earth observation time-series: a review for large-area and temporally dense land surface products JF - Remote Sensing N2 - 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. KW - accuracy KW - error estimation KW - global KW - intercomparison KW - remote sensing KW - uncertainty Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193202 SN - 2072-4292 VL - 11 IS - 22 ER - TY - JOUR A1 - Cecil, Alexander A1 - Gentschev, Ivaylo A1 - Adelfinger, Marion A1 - Dandekar, Thomas A1 - Szalay, Aladar A. T1 - Vaccinia virus injected human tumors: oncolytic virus efficiency predicted by antigen profiling analysis fitted boolean models JF - Bioengineered N2 - 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. KW - boolean modeling KW - oncolytic virus KW - human xenografted mouse models KW - cancer therapy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200507 VL - 10 IS - 1 ER - TY - JOUR A1 - Grafen, Anika A1 - Schumacher, Fabian A1 - Chithelen, Janice A1 - Kleuser, Burkhard A1 - Beyersdorf, Niklas A1 - Schneider-Schaulies, Jürgen T1 - Use of acid ceramidase and sphingosine kinase inhibitors as antiviral compounds against measles virus infection of lymphocytes in vitro JF - Frontiers in Cell and Developmental Biology N2 - 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. KW - measles virus KW - sphingolipids KW - acid ceramidase KW - acid ceramidase inhibitor ceranib-2 KW - sphingosine kinase KW - sphingosine kinase inhibitor SKI-II Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196099 SN - 2296-634X VL - 7 IS - 218 ER - TY - JOUR A1 - Silwedel, Christine A1 - Speer, Christian P. A1 - Haarmann, Axel A1 - Fehrholz, Markus A1 - Claus, Heike A1 - Schlegel, Nicolas A1 - Glaser, Kirsten T1 - Ureaplasma species modulate cytokine and chemokine responses in human brain microvascular endothelial cells JF - International Journal of Molecular Science N2 - 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. KW - Ureaplasma urealyticum KW - Ureaplasma parvum KW - neuroinflammation KW - meningitis KW - blood–brain barrier KW - HBMEC Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201848 SN - 1422-0067 VL - 20 IS - 14 ER - TY - JOUR A1 - Walther, Grit A1 - Wagner, Lysett A1 - Kurzai, Oliver T1 - Updates on the taxonomy of Mucorales with an emphasis on clinically important taxa JF - Journal of Fungi N2 - 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. KW - Mucorales KW - taxonomy KW - pathogens KW - identification KW - ecology KW - Circinella KW - Lichtheimia KW - Mucor KW - Rhizomucor KW - Rhizopus Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193081 SN - 2309-608X VL - 5 IS - 4 ER - TY - JOUR A1 - Albrecht, Franziska A1 - Mueller, Karsten A1 - Ballarini, Tommaso A1 - Lampe, Leonie A1 - Diehl-Schmid, Janine A1 - Fassbender, Klaus A1 - Fliessbach, Klaus A1 - Jahn, Holger A1 - Jech, Robert A1 - Kassubek, Jan A1 - Kornhuber, Johannes A1 - Landwehrmeyer, Bernhard A1 - Lauer, Martin A1 - Ludolph, Albert C. A1 - Lyros, Epameinondas A1 - Prudlo, Johannes A1 - Schneider, Anja A1 - Synofzik, Matthis A1 - Wiltfang, Jens A1 - Danek, Adrian A1 - Otto, Markus A1 - Schroeter, Matthias L. T1 - Unraveling corticobasal syndrome and alien limb syndrome with structural brain imaging JF - Cortex N2 - 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/). KW - Alien limb syndrome KW - Anarchic limb syndrome KW - Corticobasal syndrome KW - Diagnosis prediction KW - Support vector machine Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221040 VL - 117 ER - TY - JOUR A1 - Figueiredo, Ludmilla A1 - Krauss, Jochen A1 - Steffan-Dewenter, Ingolf A1 - Cabral, Juliano Sarmento T1 - Understanding extinction debts: spatio-temporal scales, mechanisms and a roadmap for future research JF - Ecography N2 - Extinction debt refers to delayed species extinctions expected as a consequence of ecosystem perturbation. Quantifying such extinctions and investigating long‐term consequences of perturbations has proven challenging, because perturbations are not isolated and occur across various spatial and temporal scales, from local habitat losses to global warming. Additionally, the relative importance of eco‐evolutionary processes varies across scales, because levels of ecological organization, i.e. individuals, (meta)populations and (meta)communities, respond hierarchically to perturbations. To summarize our current knowledge of the scales and mechanisms influencing extinction debts, we reviewed recent empirical, theoretical and methodological studies addressing either the spatio–temporal scales of extinction debts or the eco‐evolutionary mechanisms delaying extinctions. Extinction debts were detected across a range of ecosystems and taxonomic groups, with estimates ranging from 9 to 90% of current species richness. The duration over which debts have been sustained varies from 5 to 570 yr, and projections of the total period required to settle a debt can extend to 1000 yr. Reported causes of delayed extinctions are 1) life‐history traits that prolong individual survival, and 2) population and metapopulation dynamics that maintain populations under deteriorated conditions. Other potential factors that may extend survival time such as microevolutionary dynamics, or delayed extinctions of interaction partners, have rarely been analyzed. Therefore, we propose a roadmap for future research with three key avenues: 1) the microevolutionary dynamics of extinction processes, 2) the disjunctive loss of interacting species and 3) the impact of multiple regimes of perturbation on the payment of debts. For their ability to integrate processes occurring at different levels of ecological organization, we highlight mechanistic simulation models as tools to address these knowledge gaps and to deepen our understanding of extinction dynamics. KW - Anthropocene KW - biotic interaction KW - extinction dynamics KW - mechanistic modelling KW - time lag KW - transient dynamics Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204859 VL - 42 IS - 12 ER - TY - JOUR A1 - González, María Magdalena A1 - Dorner, Daniela A1 - Bretz, Thomas A1 - García-González, José Andrés T1 - Unbiased long-term monitoring at TeV energies JF - Galaxies N2 - For the understanding of the variable, transient and non-thermal universe, unbiased long-term monitoring is crucial. To constrain the emission mechanisms at the highest energies, it is important to characterize the very high energy emission and its correlation with observations at other wavelengths. At very high energies, only a limited number of instruments is available. This article reviews the current status of monitoring of the extra-galactic sky at TeV energies. KW - monitoring KW - very high energies (VHE) KW - TeV energies Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197389 SN - 2075-4434 VL - 7 IS - 2 ER - TY - JOUR A1 - Lekszas, Caroline A1 - Nanda, Indrajit A1 - Vona, Barbara A1 - Böck, Julia A1 - Ashrafzadeh, Farah A1 - Donyadideh, Nahid A1 - Ebrahimzadeh, Farnoosh A1 - Ahangari, Najmeh A1 - Maroofian, Reza A1 - Karimiani, Ehsan Ghayoor A1 - Haaf, Thomas T1 - Unbalanced segregation of a paternal t(9;11)(p24.3;p15.4) translocation causing familial Beckwith-Wiedemann syndrome: a case report JF - BMC Medical Genomics N2 - Background The vast majority of cases with Beckwith-Wiedemann syndrome (BWS) are caused by a molecular defect in the imprinted chromosome region 11p15.5. The underlying mechanisms include epimutations, uniparental disomy, copy number variations, and structural rearrangements. In addition, maternal loss-of-function mutations in CDKN1C are found. Despite growing knowledge on BWS pathogenesis, up to 20% of patients with BWS phenotype remain without molecular diagnosis. Case presentation Herein, we report an Iranian family with two females affected with BWS in different generations. Bisulfite pyrosequencing revealed hypermethylation of the H19/IGF2: intergenic differentially methylated region (IG DMR), also known as imprinting center 1 (IC1) and hypomethylation of the KCNQ1OT1: transcriptional start site (TSS) DMR (IC2). Array CGH demonstrated an 8 Mb duplication on chromosome 11p15.5p15.4 (205,827-8,150,933) and a 1 Mb deletion on chromosome 9p24.3 (209,020-1,288,114). Chromosome painting revealed that this duplication-deficiency in both patients is due to unbalanced segregation of a paternal reciprocal t(9;11)(p24.3;p15.4) translocation. Conclusions This is the first report of a paternally inherited unbalanced translocation between the chromosome 9 and 11 short arms underlying familial BWS. Copy number variations involving the 11p15.5 region are detected by the consensus diagnostic algorithm. However, in complex cases which do not only affect the BWS region itself, characterization of submicroscopic chromosome rearrangements can assist to estimate the recurrence risk and possible phenotypic outcomes. KW - Familial Beckwith-Wiedemann syndrome KW - copy number variation KW - duplication-deficiency KW - genomic imprinting KW - submicroscopic chromosome rearrangement KW - reciprocal translocation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200422 VL - 12 ER - TY - JOUR A1 - Lübtow, Michael M. A1 - Marciniak, Henning A1 - Schmiedel, Alexander A1 - Roos, Markus A1 - Lambert, Christoph A1 - Luxenhofer, Robert T1 - Ultra-high to ultra-low drug loaded micelles: Probing host-guest interactions by fluorescence spectroscopy JF - Chemistry - A European Journal N2 - Polymer micelles are an attractive means to solubilize water insoluble compounds such as drugs. Drug loading, formulations stability and control over drug release are crucial factors for drug‐loaded polymer micelles. The interactions between the polymeric host and the guest molecules are considered critical to control these factors but typically barely understood. Here, we compare two isomeric polymer micelles, one of which enables ultra‐high curcumin loading exceeding 50 wt.%, while the other allows a drug loading of only 25 wt.%. In the low capacity micelles, steady‐state fluorescence revealed a very unusual feature of curcumin fluorescence, a high energy emission at 510 nm. Time‐resolved fluorescence upconversion showed that the fluorescence life time of the corresponding species is too short in the high‐capacity micelles, preventing an observable emission in steady‐state. Therefore, contrary to common perception, stronger interactions between host and guest can be detrimental to the drug loading in polymer micelles. KW - curcumin KW - drug delivery KW - fluorenscence KW - poly(2-oxazine) KW - pol(2-oxazoline) KW - Polymer-drug interaction KW - upconversion Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206128 VL - 25 IS - 54 ER - TY - JOUR A1 - Dörk, Thilo A1 - Peterlongo, Peter A1 - Mannermaa, Arto A1 - Bolla, Manjeet K. A1 - Wang, Qin A1 - Dennis, Joe A1 - Ahearn, Thomas A1 - Andrulis, Irene L. A1 - Anton-Culver, Hoda A1 - Arndt, Volker A1 - Aronson, Kristan J. A1 - Augustinsson, Annelie A1 - Beane Freeman, Laura E. A1 - Beckmann, Matthias W. A1 - Beeghly-Fadiel, Alicia A1 - Behrens, Sabine A1 - Bermisheva, Marina A1 - Blomqvist, Carl A1 - Bogdanova, Natalia V. A1 - Bojesen, Stig E. A1 - Brauch, Hiltrud A1 - Brenner, Hermann A1 - Burwinkel, Barbara A1 - Canzian, Federico A1 - Chan, Tsun L. A1 - Chang-Claude, Jenny A1 - Chanock, Stephen J. A1 - Choi, Ji-Yeob A1 - Christiansen, Hans A1 - Clarke, Christine L. A1 - Couch, Fergus J. A1 - Czene, Kamila A1 - Daly, Mary B. A1 - dos-Santos-Silva, Isabel A1 - Dwek, Miriam A1 - Eccles, Diana M. A1 - Ekici, Arif B. A1 - Eriksson, Mikael A1 - Evans, D. Gareth A1 - Fasching, Peter A. A1 - Figueroa, Jonine A1 - Flyger, Henrik A1 - Fritschi, Lin A1 - Gabrielson, Marike A1 - Gago-Dominguez, Manuela A1 - Gao, Chi A1 - Gapstur, Susan M. A1 - García-Closas, Montserrat A1 - García-Sáenz, José A. A1 - Gaudet, Mia M. A1 - Giles, Graham G. A1 - Goldberg, Mark S. A1 - Goldgar, David E. A1 - Guenél, Pascal A1 - Haeberle, Lothar A1 - Haimann, Christopher A. A1 - Håkansson, Niclas A1 - Hall, Per A1 - Hamann, Ute A1 - Hartman, Mikael A1 - Hauke, Jan A1 - Hein, Alexander A1 - Hillemanns, Peter A1 - Hogervorst, Frans B. L. A1 - Hooning, Maartje J. A1 - Hopper, John L. A1 - Howell, Tony A1 - Huo, Dezheng A1 - Ito, Hidemi A1 - Iwasaki, Motoki A1 - Jakubowska, Anna A1 - Janni, Wolfgang A1 - John, Esther M. A1 - Jung, Audrey A1 - Kaaks, Rudolf A1 - Kang, Daehee A1 - Kapoor, Pooja Middha A1 - Khusnutdinova, Elza A1 - Kim, Sung-Won A1 - Kitahara, Cari M. A1 - Koutros, Stella A1 - Kraft, Peter A1 - Kristensen, Vessela N. A1 - Kwong, Ava A1 - Lambrechts, Diether A1 - Le Marchand, Loic A1 - Li, Jingmei A1 - Lindström, Sara A1 - Linet, Martha A1 - Lo, Wing-Yee A1 - Long, Jirong A1 - Lophatananon, Artitaya A1 - Lubiński, Jan A1 - Manoochehri, Mehdi A1 - Manoukian, Siranoush A1 - Margolin, Sara A1 - Martinez, Elena A1 - Matsuo, Keitaro A1 - Mavroudis, Dimitris A1 - Meindl, Alfons A1 - Menon, Usha A1 - Milne, Roger L. A1 - Mohd Taib, Nur Aishah A1 - Muir, Kenneth A1 - Mulligan, Anna Marie A1 - Neuhausen, Susan L. A1 - Nevanlinna, Heli A1 - Neven, Patrick A1 - Newman, William G. A1 - Offit, Kenneth A1 - Olopade, Olufunmilayo I. A1 - Olshan, Andrew F. A1 - Olson, Janet E. A1 - Olsson, Håkan A1 - Park, Sue K. A1 - Park-Simon, Tjoung-Won A1 - Peto, Julian A1 - Plaseska-Karanfilska, Dijana A1 - Pohl-Rescigno, Esther A1 - Presneau, Nadege A1 - Rack, Brigitte A1 - Radice, Paolo A1 - Rashid, Muhammad U. A1 - Rennert, Gad A1 - Rennert, Hedy S. A1 - Romero, Atocha A1 - Ruebner, Matthias A1 - Saloustros, Emmanouil A1 - Schmidt, Marjanka K. A1 - Schmutzler, Rita K. A1 - Schneider, Michael O. A1 - Schoemaker, Minouk J. A1 - Scott, Christopher A1 - Shen, Chen-Yang A1 - Shu, Xiao-Ou A1 - Simard, Jaques A1 - Slager, Susan A1 - Smichkoska, Snezhana A1 - Southey, Melissa C. A1 - Spinelli, John J. A1 - Stone, Jennifer A1 - Surowy, Harald A1 - Swerdlow, Anthony J. A1 - Tamimi, Rulla M. A1 - Tapper, William J. A1 - Teo, Soo H. A1 - Terry, Mary Beth A1 - Toland, Amanda E. A1 - Tollenaar, Rob A. E. M. A1 - Torres, Diana A1 - Torres-Mejía, Gabriela A1 - Troester, Melissa A. A1 - Truong, Thérèse A1 - Tsugane, Shoichiro A1 - Untch, Michael A1 - Vachon, Celine M. A1 - van den Ouweland, Ans M. W. A1 - van Veen, Elke M. A1 - Vijai, Joseph A1 - Wendt, Camilla A1 - Wolk, Alicja A1 - Yu, Jyh-Cherng A1 - Zheng, Wei A1 - Ziogas, Argyrios A1 - Ziv, Elad A1 - Dunnig, Alison A1 - Pharaoh, Paul D. P. A1 - Schindler, Detlev A1 - Devilee, Peter A1 - Easton, Douglas F. T1 - Two truncating variants in FANCC and breast cancer risk JF - Scientific Reports N2 - Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants. KW - oncology KW - risk factors Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222838 VL - 9 ER - TY - JOUR A1 - Goos, Carina A1 - Dejung, Mario A1 - Wehman, Ann M. A1 - M-Natus, Elisabeth A1 - Schmidt, Johannes A1 - Sunter, Jack A1 - Engstler, Markus A1 - Butter, Falk A1 - Kramer, Susanne T1 - Trypanosomes can initiate nuclear export co-transcriptionally JF - Nucleic Acids Research N2 - The nuclear envelope serves as important messenger RNA (mRNA) surveillance system. In yeast and human, several control systems act in parallel to prevent nuclear export of unprocessed mRNAs. Trypanosomes lack homologues to most of the involved proteins and their nuclear mRNA metabolism is non-conventional exemplified by polycistronic transcription and mRNA processing by trans-splicing. We here visualized nuclear export in trypanosomes by intra- and intermolecular multi-colour single molecule FISH. We found that, in striking contrast to other eukaryotes, the initiation of nuclear export requires neither the completion of transcription nor splicing. Nevertheless, we show that unspliced mRNAs are mostly prevented from reaching the nucleus-distant cytoplasm and instead accumulate at the nuclear periphery in cytoplasmic nuclear periphery granules (NPGs). Further characterization of NPGs by electron microscopy and proteomics revealed that the granules are located at the cytoplasmic site of the nuclear pores and contain most cytoplasmic RNA-binding proteins but none of the major translation initiation factors, consistent with a function in preventing faulty mRNAs from reaching translation. Our data indicate that trypanosomes regulate the completion of nuclear export, rather than the initiation. Nuclear export control remains poorly understood, in any organism, and the described way of control may not be restricted to trypanosomes. KW - molecular biology KW - nuclear export KW - trypanosomes KW - mRNA KW - nuclear envelope Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177709 VL - 47 IS - 1 ER - TY - JOUR A1 - Bothe, Friederike A1 - Deubel, Anne-Kathrin A1 - Hesse, Eliane A1 - Lotz, Benedict A1 - Groll, Jürgen A1 - Werner, Carsten A1 - Richter, Wiltrud A1 - Hagmann, Sebastien T1 - Treatment of focal cartilage defects in minipigs with zonal chondrocyte/mesenchymal progenitor cell constructs JF - International Journal of Molecular Sciences N2 - Despite advances in cartilage repair strategies, treatment of focal chondral lesions remains an important challenge to prevent osteoarthritis. Articular cartilage is organized into several layers and lack of zonal organization of current grafts is held responsible for insufficient biomechanical and biochemical quality of repair-tissue. The aim was to develop a zonal approach for cartilage regeneration to determine whether the outcome can be improved compared to a non-zonal strategy. Hydrogel-filled polycaprolactone (PCL)-constructs with a chondrocyte-seeded upper-layer deemed to induce hyaline cartilage and a mesenchymal stromal cell (MSC)-containing bottom-layer deemed to induce calcified cartilage were compared to chondrocyte-based non-zonal grafts in a minipig model. Grafts showed comparable hardness at implantation and did not cause visible signs of inflammation. After 6 months, X-ray microtomography (µCT)-analysis revealed significant bone-loss in both treatment groups compared to empty controls. PCL-enforcement and some hydrogel-remnants were retained in all defects, but most implants were pressed into the subchondral bone. Despite important heterogeneities, both treatments reached a significantly lower modified O’Driscoll-score compared to empty controls. Thus, PCL may have induced bone-erosion during joint loading and misplacement of grafts in vivo precluding adequate permanent orientation of zones compared to surrounding native cartilage. KW - cartilage repair KW - osteochondral defect KW - tissue engineering KW - starPEG hydrogel KW - chondrocyte KW - MSC KW - zonal construct KW - minipig Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285118 SN - 1422-0067 VL - 20 IS - 3 ER - TY - JOUR A1 - Hollmann, Claudia A1 - Wiese, Teresa A1 - Dennstädt, Fabio A1 - Fink, Julian A1 - Schneider-Schaulies, Jürgen A1 - Beyersdorf, Niklas T1 - Translational approaches targeting ceramide generation from sphingomyelin in T cells to modulate immunity in humans JF - Frontiers in Immunology N2 - In T cells, as in all other cells of the body, sphingolipids form important structural components of membranes. Due to metabolic modifications, sphingolipids additionally play an active part in the signaling of cell surface receptors of T cells like the T cell receptor or the co-stimulatory molecule CD28. Moreover, the sphingolipid composition of their membranes crucially affects the integrity and function of subcellular compartments such as the lysosome. Previously, studying sphingolipid metabolism has been severely hampered by the limited number of analytical methods/model systems available. Besides well-established high resolution mass spectrometry new tools are now available like novel minimally modified sphingolipid subspecies for click chemistry as well as recently generated mouse mutants with deficiencies/overexpression of sphingolipid-modifying enzymes. Making use of these tools we and others discovered that the sphingolipid sphingomyelin is metabolized to ceramide to different degrees in distinct T cell subpopulations of mice and humans. This knowledge has already been translated into novel immunomodulatory approaches in mice and will in the future hopefully also be applicable to humans. In this paper we are, thus, summarizing the most recent findings on the impact of sphingolipid metabolism on T cell activation, differentiation, and effector functions. Moreover, we are discussing the therapeutic concepts arising from these insights and drugs or drug candidates which are already in clinical use or could be developed for clinical use in patients with diseases as distant as major depression and chronic viral infection. KW - sphingolipids KW - CD4+ T cells KW - regulatory T cells (Treg) KW - CD8+ T cells KW - anti-depressant drug Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198806 SN - 1664-3224 VL - 10 IS - 2363 ER - TY - JOUR A1 - Lechermeier, Carina G. A1 - Zimmer, Frederic A1 - Lüffe, Teresa M. A1 - Lesch, Klaus-Peter A1 - Romanos, Marcel A1 - Lillesaar, Christina A1 - Drepper, Carsten T1 - Transcript analysis of zebrafish GLUT3 genes, slc2a3a and slc2a3b, define overlapping as well as distinct expression domains in the zebrafish (Danio rerio) central nervous system JF - Frontiers in Molecular Neuroscience N2 - The transport of glucose across the cell plasma membrane is vital to most mammalian cells. The glucose transporter (GLUT; also called SLC2A) family of transmembrane solute carriers is responsible for this function in vivo. GLUT proteins encompass 14 different isoforms in humans with different cell type-specific expression patterns and activities. Central to glucose utilization and delivery in the brain is the neuronally expressed GLUT3. Recent research has shown an involvement of GLUT3 genetic variation or altered expression in several different brain disorders, including Huntington’s and Alzheimer’s diseases. Furthermore, GLUT3 was identified as a potential risk gene for multiple psychiatric disorders. To study the role of GLUT3 in brain function and disease a more detailed knowledge of its expression in model organisms is needed. Zebrafish (Danio rerio) has in recent years gained popularity as a model organism for brain research and is now well-established for modeling psychiatric disorders. Here, we have analyzed the sequence of GLUT3 orthologs and identified two paralogous genes in the zebrafish, slc2a3a and slc2a3b. Interestingly, the Glut3b protein sequence contains a unique stretch of amino acids, which may be important for functional regulation. The slc2a3a transcript is detectable in the central nervous system including distinct cellular populations in telencephalon, diencephalon, mesencephalon and rhombencephalon at embryonic and larval stages. Conversely, the slc2a3b transcript shows a rather diffuse expression pattern at different embryonic stages and brain regions. Expression of slc2a3a is maintained in the adult brain and is found in the telencephalon, diencephalon, mesencephalon, cerebellum and medulla oblongata. The slc2a3b transcripts are present in overlapping as well as distinct regions compared to slc2a3a. Double in situ hybridizations were used to demonstrate that slc2a3a is expressed by some GABAergic neurons at embryonic stages. This detailed description of zebrafish slc2a3a and slc2a3b expression at developmental and adult stages paves the way for further investigations of normal GLUT3 function and its role in brain disorders. KW - glucose transporter KW - nervous system KW - brain disorders KW - psychiatric disorders KW - brain development KW - GABA KW - GAD1 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201797 VL - 12 IS - 199 ER - TY - JOUR A1 - Kreckel, Jennifer A1 - Anany, Mohammed A. A1 - Siegmund, Daniela A1 - Wajant, Harald T1 - TRAF2 controls death receptor-induced caspase-8 processing and facilitates proinflammatory signaling JF - Frontiers in Immunology N2 - Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) knockout (KO) cells were generated to investigate the role of TRAF2 in signaling by TNFR1 and the CD95-type death receptors (DRs) TRAILR1/2 and CD95. To prevent negative selection effects arising from the increased cell death sensitivity of TRAF2-deficient cells, cell lines were used for the generation of the TRAF2 KO variants that were protected from DR-induced apoptosis downstream of caspase-8 activation. As already described in the literature, TRAF2 KO cells displayed enhanced constitutive alternative NFκB signaling and reduced TNFR1-induced activation of the classical NFκB pathway. There was furthermore a significant but only partial reduction in CD95-type DR-induced upregulation of the proinflammatory NFκB-regulated cytokine interleukin-8 (IL8), which could be reversed by reexpression of TRAF2. In contrast, expression of the TRAF2-related TRAF1 protein failed to functionally restore TRAF2 deficiency. TRAF2 deficiency resulted furthermore in enhanced procaspase-8 processing by DRs, but this surprisingly came along with a reduction in net caspase-8 activity. In sum, our data argue for (i) a non-obligate promoting function of TRAF2 in proinflammatory DR signaling and (ii) a yet unrecognized stabilizing effect of TRAF2 on caspase-8 activity. KW - caspase-8 KW - death receptors KW - CD95 KW - TNFR1 KW - TRAF1 KW - TRAF2 KW - TRAILR1 KW - TRAILR2 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201822 VL - 10 IS - 2024 ER - TY - JOUR A1 - Lenczyk, Carsten A1 - Roy, Dipak Kumar A1 - Oberdorf, Kai A1 - Nitsch, Jörn A1 - Dewhurst, Rian D. A1 - Radacki, Krzysztof A1 - Halet, Jean-François A1 - Marder, Todd B. A1 - Bickelhaupt, Matthias A1 - Braunschweig, Holger T1 - Toward Transition‐Metal‐Templated Construction of Arylated B\(_{4}\) Chains by Dihydroborane Dehydrocoupling JF - Chemistry - A European Journal N2 - The reactivity of a diruthenium tetrahydride complex towards three selected dihydroboranes was investigated. The use of [DurBH\(_{2}\)] (Dur=2,3,5,6‐Me\(_{4}\)C\(_{6}\)H) and [(Me\(_{3}\)Si)\(_{2}\)NBH\(_{2}\)] led to the formation of bridging borylene complexes of the form [(Cp\(^{*}\)RuH)\(_{2}\)BR] (Cp\(^{*}\)=C\(_{5}\)Me\(_{5}\); 1 a: R=Dur; 1 b: R=N(SiMe\(_{3}\))\(_{2}\)) through oxidative addition of the B−H bonds with concomitant hydrogen liberation. Employing the more electron‐deficient dihydroborane [3,5‐(CF\(_{3}\))\(_{2}\)‐C\(_{6}\)H\(_{3}\)BH\(_{2}\)] led to the formation of an anionic complex bearing a tetraarylated chain of four boron atoms, namely Li(THF)\(_{4}\)[(Cp\(^{*}\)Ru)\(_{2}\)B\(_{4}\)H\(_{5}\)(3,5‐(CF\(_{3}\))\(_{2}\)C\(_{6}\)H\(_{3}\))\(_{4}\)] (4), through an unusual, incomplete threefold dehydrocoupling process. A comparative theoretical investigation of the bonding in a simplified model of 4 and the analogous complex nido‐[1,2(Cp\(^{*}\)Ru)\(_{2}\)(μ‐H)B\(_{4}\)H\(_{9}\)] (I) indicates that there appear to be no classical σ‐bonds between the boron atoms in complex I, whereas in the case of 4 the B\(_{4}\) chain better resembles a network of three B−B σ bonds, the central bond being significantly weaker than the other two. KW - transition metal KW - B−H activation KW - boron KW - dehydrocoupling KW - ruthenium Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214324 VL - 25 IS - 72 ER - TY - JOUR A1 - Rödel, Michaela A1 - Teßmar, Jörg A1 - Groll, Jürgen A1 - Gbureck, Uwe T1 - Tough and Elastic alpha-Tricalcium Phosphate Cement Composites with Degradable PEG-Based Cross-Linker JF - Materials N2 - Dual setting cements composed of an in situ forming hydrogel and a reactive mineral phase combine high compressive strength of the cement with sufficient ductility and bending strength of the polymeric network. Previous studies were focused on the modification with non-degradable hydrogels based on 2-hydroxyethyl methacrylate (HEMA). Here, we describe the synthesis of suitable triblock degradable poly(ethylene glycol)-poly(lactide) (PEG-PLLA) cross-linker to improve the resorption capacity of such composites. A study with four different formulations was established. As reference, pure hydroxyapatite (HA) cements and composites with 40 wt% HEMA in the liquid cement phase were produced. Furthermore, HEMA was modified with 10 wt% of PEG-PLLA cross-linker or a test series containing only 25% cross-linker was chosen for composites with a fully degradable polymeric phase. Hence, we developed suitable systems with increased elasticity and 5-6 times higher toughn ess values in comparison to pure inorganic cement matrix. Furthermore, conversion rate from alpha-tricalcium phosphate (alpha-TCP) to HA was still about 90% for all composite formulations, whereas crystal size decreased. Based on this material development and advancement for a dual setting system, we managed to overcome the drawback of brittleness for pure calcium phosphate cements. KW - dual setting system KW - bending strength KW - calcium phosphate cement KW - composite material KW - HEMA KW - hydroxyapatite KW - free radical polymerization Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226437 VL - 12 IS - 53 ER - TY - JOUR A1 - Harjus, Linda T1 - Top down Initiated Medial Linguistic Politics : A Normative Inquiry into the Application of Andalusian Varieties Conducted by the Radio Channel Canal Fiesta Radio JF - promptus - Würzburger Beiträge zur Romanistik N2 - This contribution deals with the phonetic heterogeneity of spoken Spanish in Andalusia in the sector of public auditory media, specifically in the program ¡Anda Levanta! of Canal Fiesta Radio. First, we take into consideration Article 10 of the Statute of the Autonomy of Andalusia, which enhances the protection, promotion, study, and prestige of the Andalusian modalities and its respective variety (cf. Parlamento de Andalucía 2007: 13). Second, we refer to the Libro de Estilo, a mandatory guide for presenters of public audiovisual media in Andalusia since 2014. The results of the qualitative analysis indicate divergences between the presenters and their audience with regard to their use of phonetic characteristics typical of the Andalusian varieties: where the presenters tend to avoid the salient aspects of the varieties, the audience employs a range of phonetic characteristics typical for Andalusian varieties, including some of the characteristics that are considered less prestigious. KW - Andalusian varieties KW - linguistic politics KW - European Spanish KW - sociophonetics KW - language in media Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221836 SN - 2364-6705 VL - 5 ER - TY - JOUR A1 - Wajant, Harald A1 - Siegmund, Daniela T1 - TNFR1 and TNFR2 in the control of the life and death balance of macrophages JF - Frontiers in Cell and Developmental Biology N2 - Macrophages stand in the first line of defense against a variety of pathogens but are also involved in the maintenance of tissue homeostasis. To fulfill their functions macrophages sense a broad range of pathogen- and damage-associated molecular patterns (PAMPs/DAMPs) by plasma membrane and intracellular pattern recognition receptors (PRRs). Intriguingly, the overwhelming majority of PPRs trigger the production of the pleiotropic cytokine tumor necrosis factor-alpha (TNF). TNF affects almost any type of cell including macrophages themselves. TNF promotes the inflammatory activity of macrophages but also controls macrophage survival and death. TNF exerts its activities by stimulation of two different types of receptors, TNF receptor-1 (TNFR1) and TNFR2, which are both expressed by macrophages. The two TNF receptor types trigger distinct and common signaling pathways that can work in an interconnected manner. Based on a brief general description of major TNF receptor-associated signaling pathways, we focus in this review on research of recent years that revealed insights into the molecular mechanisms how the TNFR1-TNFR2 signaling network controls the life and death balance of macrophages. In particular, we discuss how the TNFR1-TNFR2 signaling network is integrated into PRR signaling. KW - apoptosis KW - necroptosis KW - TNF KW - TNFR1 KW - TNFR2 KW - ripk1 KW - ripk3 KW - caspase-8 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201551 VL - 7 IS - 91 ER - TY - JOUR A1 - Petritsch, Berhard A1 - Kosmala, Aleksander A1 - Weng, Andreas Max A1 - Bley, Thorsten Alexander T1 - Tin-filtered 100kV ultra-low-dose CT of the paranasal sinus: initial clinical results JF - PLoS ONE N2 - Objectives To investigate the feasibility, diagnostic image quality and radiation dose of 3\(^{rd}\) generation dual-source computed tomography (CT) using a tin-filtered 100 kV protocol in patients with suspected acute inflammatory sinus disease. Methods We retrospectively evaluated 109 consecutive patients who underwent CT (Siemens SOMATOM Force, Erlangen, Germany) of the paranasal sinus with a new tin-filtered scanprotocol (Sn100 kV; tube current 35 mAs) using iterative reconstruction. Two readers independently assessed subjective image quality using a five-point Likert scale (1 = excellent, 5 = non-diagnostic). Inter-observer agreement was calculated and expressed as percentage of agreement. Noise was determined for calculation of signal-to-noise-ratio (SNR). Effective radiation dose (ED) was calculated from the dose-length-product (DLP). Results All examinations showed diagnostic image quality regarding evaluation of inflammatory sinus disease. On average, subjective general image quality was rated moderate (= 3) with a percentage of agreement between the observers of 81%. The mean image noise was 14.3 HU. The calculated median SNR was 6.0 for intraorbital fat, and 3.6 for the vitreous body, respectively. The median DLP was 2.1 mGy*cm, resulting in a median ED of 0.012 mSv. Conclusions Taking the study limitations into account, ultra-low-dose tin-filtered CT of the paranasal sinus at a tube voltage of 100 kV utilizing an iterative reconstruction algorithm provides for reliable exclusion of suspected acute inflammatory sinus disease in 100% of the cases. KW - Computed axial tomography KW - Inflammatory diseases KW - Radiation exposure KW - Diagnostic medicine KW - Fats KW - Mastoid process KW - X-ray radiography KW - Soft tissues Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204127 VL - 14 IS - 5 ER - TY - JOUR A1 - Schleier, Domenik A1 - Reusch, Engelbert A1 - Lummel, Lisa A1 - Hemberger, Patrick A1 - Fischer, Ingo T1 - Threshold photoelectron spectroscopy of IO and IOH JF - ChemPhysChem N2 - Iodine oxides appear as reactive intermediates in atmospheric chemistry. Here, we investigate IO and HOI by mass‐selective threshold photoelectron spectroscopy (ms‐TPES), using synchrotron radiation. IO and HOI are generated by photolyzing iodine in the presence of ozone. For both molecules, accurate ionization energies are determined, 9.71±0.02 eV for IO and 9.79±0.02 eV for HOI. The strong spin‐spin interaction in the 3Σ− ground state of IO+ leads to an energy splitting into the Ω=0 and Ω=±1 sublevels. Upon ionization, the I−O bond shortens significantly in both molecules; thus, a vibrational progression, assigned to the I−O stretch, is apparent in both spectra. KW - ionization potential KW - radicals KW - reactive intermediates KW - photolysis KW - synchrotron radiatoren Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204751 VL - 20 IS - 19 ER - TY - JOUR A1 - Hartmann, Sylvia A1 - Plütschow, Annette A1 - Mottok, Anja A1 - Bernd, Heinz‐Wolfram A1 - Feller, Alfred C. A1 - Ott, German A1 - Cogliatti, Sergio A1 - Fend, Falko A1 - Quintanilla‐Martinez, Leticia A1 - Stein, Harald A1 - Klapper, Wolfram A1 - Möller, Peter A1 - Rosenwald, Andreas A1 - Engert, Andreas A1 - Hansmann, Martin‐Leo A1 - Eichenauer, Dennis A. T1 - The time to relapse correlates with the histopathological growth pattern in nodular lymphocyte predominant Hodgkin lymphoma JF - American Journal of Hematology N2 - Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can present with different histopathological growth patterns. The impact of these histopathological growth patterns on relapse characteristics is unknown. We therefore analyzed paired biopsies obtained at initial diagnosis and relapse from 33 NLPHL patients who had received first‐line treatment within German Hodgkin Study Group (GHSG) trial protocols, and from a second cohort of 41 relapsed NLPHL patients who had been treated outside GHSG studies. Among the 33 GHSG patients, 21 patients presented with a typical growth pattern at initial diagnosis, whereas 12 patients had a variant histology. The histopathological growth patterns at initial diagnosis and at relapse were consistent in 67% of cases. A variant histology at initial diagnosis was associated with a shorter median time to lymphoma recurrence (2.8 vs 5.2 years; P = .0219). A similar tendency towards a shorter median time to lymphoma recurrence was observed for patients presenting with a variant histology at relapse, irrespective of the growth pattern at initial diagnosis. Results obtained from the 41 NLPHL patients who had been treated outside GHSG studies were comparable (median time to lymphoma recurrence for variant histology vs typical growth pattern at initial diagnosis: 1.5 vs 7.0 years). In conclusion, the histopathological growth pattern remains consistent at relapse in the majority of NLPHL cases, and has major impact on the time of relapse. KW - Hodgkin lymphoma KW - relapse KW - growth patterns Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212594 VL - 94 IS - 11 SP - 1208 EP - 1213 ER - TY - JOUR A1 - Scheurer, Mario Joachim Johannes A1 - Brands, Roman Camillus A1 - El-Mesery, Mohamed A1 - Hartmann, Stefan A1 - Müller-Richter, Urs Dietmar Achim A1 - Kübler, Alexander Christian A1 - Seher, Axel T1 - The selection of NFκB inhibitors to block inflammation and induce sensitisation to FasL-induced apoptosis in HNSCC cell lines is critical for their use as a prospective cancer therapy JF - International Journal of Molecular Science N2 - Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors — Cortisol, MLN4924, QNZ and TPCA1 — on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low μM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted. KW - HNSCC KW - NFκB KW - inhibitor KW - TPCA1 KW - apoptosis KW - inflammation KW - TNFα KW - FasL Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201524 SN - 1422-0067 VL - 20 IS - 6 ER - TY - JOUR A1 - Moremi, Nyambura A1 - Claus, Heike A1 - Vogel, Ulrich A1 - Mshana, Stephen E. T1 - The role of patients and healthcare workers Staphylococcus aureus nasal colonization in occurrence of surgical site infection among patients admitted in two centers in Tanzania JF - Antimicrobial Resistance & Infection Control N2 - Background Colonization with Staphylococcus aureus has been identified as a risk for subsequent occurrence of infection. This study investigated the relationship between S. aureus colonization of patients and healthcare workers (HCWs), and subsequent surgical site infections (SSI). Methods Between December 2014 and September 2015, a total of 930 patients and 143 HCWs were enrolled from the Bugando Medical Centre and Sekou Toure hospital in Mwanza, Tanzania. On admission and discharge nasal swabs, with an additional of wound swab for those who developed SSI were collected from patients whereas HCWs were swabbed once. Identification and antimicrobial susceptibility testing were done by VITEK-MS and VITEK-2, respectively. Detection of Panton Valentine leukocidin (PVL) and mecA genes was done by PCR. S. aureus isolates were further characterized by spa typing and Multi-Locus Sequence Typing (MLST). Results Among 930 patients screened for S. aureus on admission, 129 (13.9%) were positive of which 5.4% (7/129) were methicillin-resistant S. aureus (MRSA). Amongst 363 patients rescreened on discharge, 301 patients had been tested negative on admission of whom 29 (9.6%) turned positive after their hospital stay. Three (10.3%) of the 29 acquired S. aureus were MRSA. Inducible Clindamycin resistance occurred more often among acquired S. aureus isolates than among isolates from admission [34.5% (10/29) vs. 17.1% (22/129), P = 0.018]. S. aureus contributed to 21.1% (n = 12) of the 57 cases of investigated SSIs among 536 patients followed. Seven out of eight S. aureus carriage/infection pairs had the same spa and sequence types. The previously reported dominant PVL-positive ST88 MRSA strain with spa type t690 was detected in patients and HCW. Conclusion A significant proportion of patients acquired S. aureus during hospitalization. The finding of more than 90% of S. aureus SSI to be of endogenous source underscores the need of improving infection prevention and control measures including screening and decolonization of high risk patients. KW - S. aureus KW - colonization KW - surgical site infection KW - Tanzania Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224185 VL - 8 ER - TY - JOUR A1 - Pfister, Roland A1 - Frings, Christian A1 - Moeller, Birte T1 - The Role of Congruency for Distractor-Response Binding: A Caveat JF - Advances in Cognitive Psychologe N2 - Responding in the presence of stimuli leads to an integration of stimulus features and response features into event fles, which can later be retrieved to assist action control. This integration mechanism is not limited to target stimuli, but can also include distractors (distractor-response binding). A recurring research question is which factors determine whether or not distractors are integrated. One suggested candidate factor is target-distractor congruency: Distractor-response binding effects were reported to be stronger for congruent than for incongruent target-distractor pairs. Here, we discuss a general problem with including the factor of congruency in typical analyses used to study distractor-based binding effects. Integrating this factor leads to a confound that may explain any differences between distractor-response binding effects of congruent and incongruent distractors with a simple congruency effect. Simulation data confrmed this argument. We propose to interpret previous data cautiously and discuss potential avenues to circumvent this problem in the future. KW - action control KW - distractor-response binding KW - congruency sequences KW - sequence analysis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200265 VL - 15 IS - 2 ER - TY - JOUR A1 - Meyer, Till Jasper A1 - Scherzad, Agmal A1 - Moratin, Helena A1 - Gehrke, Thomas Eckert A1 - Killisperger, Julian A1 - Hagen, Rudolf A1 - Wohlleben, Gisela A1 - Polat, Bülent A1 - Dembski, Sofia A1 - Kleinsasser, Norbert A1 - Hackenberg, Stephan T1 - The radiosensitizing effect of zinc oxide nanoparticles in sub-cytotoxic dosing is associated with oxidative stress in vitro JF - Materials N2 - Radioresistance is an important cause of head and neck cancer therapy failure. Zinc oxide nanoparticles (ZnO-NP) mediate tumor-selective toxic effects. The aim of this study was to evaluate the potential for radiosensitization of ZnO-NP. The dose-dependent cytotoxicity of ZnO-NP\(_{20 nm}\) and ZnO-NP\(_{100 nm}\) was investigated in FaDu and primary fibroblasts (FB) by an MTT assay. The clonogenic survival assay was used to evaluate the effects of ZnO-NP alone and in combination with irradiation on FB and FaDu. A formamidopyrimidine-DNA glycosylase (FPG)-modified single-cell microgel electrophoresis (comet) assay was applied to detect oxidative DNA damage in FB as a function of ZnO-NP and irradiation exposure. A significantly increased cytotoxicity after FaDu exposure to ZnO-NP\(_{20 nm}\) or ZnO-NP\(_{100 nm}\) was observed in a concentration of 10 µg/mL or 1 µg/mL respectively in 30 µg/mL of ZnO-NP\(_{20 nm}\) or 20 µg/mL of ZnO-NP\(_{100 nm}\) in FB. The addition of 1, 5, or 10 µg/mL ZnO-NP\(_{20 nm}\) or ZnO-NP\(_{100 nm}\) significantly reduced the clonogenic survival of FaDu after irradiation. The sub-cytotoxic dosage of ZnO-NP\(_{100 nm}\) increased the oxidative DNA damage compared to the irradiated control. This effect was not significant for ZnO-NP\(_{20 nm}\). ZnO-NP showed radiosensitizing properties in the sub-cytotoxic dosage. At least for the ZnO-NP\(_{100 nm}\), an increased level of oxidative stress is a possible mechanism of the radiosensitizing effect. KW - zinc oxide nanoparticles KW - irradiation KW - oxidative DNA damage KW - head and neck squamous cell carcinoma Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193897 SN - 1996-1944 VL - 12 IS - 24 ER - TY - JOUR A1 - Rueckl, Kilian A1 - Runer, Armin A1 - Bechler, Ulrich A1 - Faschingbauer, Martin A1 - Boelch, Sebastian Philipp A1 - Keyes Sculco, Peter A1 - Boettner, Friedrich T1 - The posterior-anterior-flexed view is essential for the evaluation of valgus osteoarthritis. A prospective study on 134 valgus knees JF - BMC Muscoskeletal Disorders N2 - Background Radiographic imaging is an important tool to assess osteoarthritis (OA). Lateral compartment osteoarthritis (valgus OA) usually starts with cartilage degeneration along the posterior aspect of the lateral femoral condyle. There is evidence that the posterior-anterior (PA)-flexed view is more sensitive when diagnosing early stages of valgus OA compared to the anterior-posterior (AP) view. The current paper analyzes the value of the PA-flexed view for patients scheduled for total knee arthroplasty (TKA). Methods Radiographs of 134 valgus knees were assessed prior to TKA. The minimal joint space width (minJSW) was measured on AP and PA-flexed views. The extent of mechanical deformity was measured on hip to ankle standing films. Results 49 (36.6%) AP views showed Kellgren and Lawrence (K/L)-grade 4 osteoarthritis in the lateral compartment, 82 (63.4%) showed grade 3 or less. The PA-flexed view resulted in an increased K/L-grading to grade 4 for 53 knees (62.4%) that were considered grade 3 or less on standard AP-radiographs. There was a significant differences between lateral minJSW on AP and PA-flexed view for patients with up to 10 degrees of mechanical valgus deformity (p < 0.001), as well as 11 to 15 degrees of mechanical deformity (p = 0.021). Only knees with severe deformity of more than 15 degrees did not show a difference in minJSW between PA-flexed view and AP view (p = 0.345). Conclusions The PA-flexed view is superior to the standard AP view in quantifying the extent of valgus OA in patients with zero to fifteen degrees of valgus deformity. It is recommended for the initial assessment of patients with valgus osteoarthritis and better documents the extent of osteoarthritis prior to TKA. KW - Valgus osteoarthritis KW - Knee KW - PA-flexed view KW - View KW - Radiographs Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200536 VL - 20 ER - TY - JOUR A1 - Schartl, Manfred A1 - Kneitz, Susanne A1 - Volkoff, Helene A1 - Adolfi, Mateus A1 - Schmidt, Cornelia A1 - Fischer, Petra A1 - Minx, Patrick A1 - Tomlinson, Chad A1 - Meyer, Axel A1 - Warren, Wesley C. T1 - The piranha genome provides molecular insight associated to its unique feeding behavior JF - Genome Biology and Evolution N2 - The piranha enjoys notoriety due to its infamous predatory behavior but much is still not understood about its evolutionary origins and the underlying molecular mechanisms for its unusual feeding biology. We sequenced and assembled the red-bellied piranha (Pygocentrus nattereri) genome to aid future phenotypic and genetic investigations. The assembled draft genome is similar to other related fishes in repeat composition and gene count. Our evaluation of genes under positive selection suggests candidates for adaptations of piranhas’ feeding behavior in neural functions, behavior, and regulation of energy metabolism. In the fasted brain, we find genes differentially expressed that are involved in lipid metabolism and appetite regulation as well as genes that may control the aggression/boldness behavior of hungry piranhas. Our first analysis of the piranha genome offers new insight and resources for the study of piranha biology and for feeding motivation and starvation in other organisms. KW - whole-genome sequencing KW - genome annotation KW - comparative genomics KW - RNA-seq transcriptome KW - energy homeostasis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202218 VL - 11 IS - 8 ER - TY - JOUR A1 - Staiger, Simona A1 - Seufert, Pascal A1 - Arand, Katja A1 - Burghardt, Markus A1 - Popp, Christian A1 - Riederer, Markus T1 - The permeation barrier of plant cuticles: uptake of active ingredients is limited by very long-chain aliphatic rather than cyclic wax compounds JF - Pest Management Science N2 - BACKGROUND: The barrier to diffusion of organic solutes across the plant cuticle is composed of waxes consisting of very long-chain aliphatic (VLCA) and, to varying degrees, cyclic compounds like pentacyclic triterpenoids. The roles of both fractions in controlling cuticular penetration by organic solutes, e.g. the active ingredients (AI) of pesticides, are unknown to date. We studied thepermeabilityof isolated leaf cuticularmembranes from Garcinia xanthochymus andPrunus laurocerasus for lipophilic azoxystrobin and theobromine as model compounds for hydrophilic AIs. RESULTS: The wax of P. laurocerasus consists of VLCA (12%) and cyclic compounds (88%), whereas VLCAs make up 97% of the wax of G. xanthochymus.We showthat treating isolated cuticles with methanol almost quantitatively releases the cyclic fraction while leaving the VLCA fraction essentially intact. All VLCAs were subsequently removed using chloroform. In both species, the permeance of the two model compounds did not change significantly after methanol treatment, whereas chloroform extraction had a large effect on organic solute permeability. CONCLUSION: The VLCA wax fractionmakes up the permeability barrier for organic solutes, whereas cyclic compounds even in high amounts have a negligible role. This is of significance when optimizing the foliar uptake of pesticides. KW - cuticular permeability KW - active ingredients KW - very long-chain aliphatic compounds KW - cyclic compounds KW - pesicicles Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204778 VL - 75 IS - 12 ER - TY - JOUR A1 - Kitzenmaier, Alexandra A1 - Schaefer, Natascha A1 - Kasaragod, Vikram Babu A1 - Polster, Tilman A1 - Hantschmann, Ralph A1 - Schindelin, Hermann A1 - Villmann, Carmen T1 - The P429L loss of function mutation of the human glycine transporter 2 associated with hyperekplexia JF - European Journal of Neuroscience N2 - Glycine transporter 2 (GlyT2) mutations across the entire sequence have been shown to represent the presynaptic component of the neurological disease hyperekplexia. Dominant, recessive and compound heterozygous mutations have been identified, most of them leading to impaired glycine uptake. Here, we identified a novel loss of function mutation of the GlyT2 resulting from an amino acid exchange of proline 429 to leucine in a family with both parents being heterozygous carriers. A homozygous child suffered from severe neuromotor deficits. We characterised the GlyT2P429L variant at the molecular, cellular and protein level. Functionality was determined by glycine uptake assays. Homology modelling revealed that the mutation localises to α‐helix 5, presumably disrupting the integrity of this α‐helix. GlyT2P429L shows protein trafficking through various intracellular compartments to the cellular surface. However, the protein expression at the whole cell level was significantly reduced. Although present at the cellular surface, GlyT2P429L demonstrated a loss of protein function. Coexpression of the mutant with the wild‐type protein, reflecting the situation in the parents, did not affect transporter function, thus explaining their non‐symptomatic phenotype. Nevertheless, when the mutant was expressed in excess compared with the wild‐type protein, glycine uptake was significantly reduced. Thus, these data demonstrate that the proline residue at position 429 is structurally important for the correct formation of α‐helix 5. The failure in functionality of the mutated GlyT2 is most probably due to structural changes localised in close proximity to the sodium‐binding site of the transporter. KW - glycine transporter 2 KW - glyvine uptake KW - loss of function KW - presynaptic hyperekplexia KW - protein transport KW - structural disruption Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206158 VL - 50 IS - 12 ER - TY - JOUR A1 - Hoche, Joscha A1 - Schulz, Alexander A1 - Dietrich, Lysanne Monika A1 - Humeniuk, Alexander A1 - Stolte, Matthias A1 - Schmidt, David A1 - Brixner, Tobias A1 - Würthner, Frank A1 - Mitric, Roland T1 - The origin of the solvent dependence of fluorescence quantum yields in dipolar merocyanine dyes JF - Chemical Science N2 - Fluorophores with high quantum yields are desired for a variety of applications. Optimization of promising chromophores requires an understanding of the non-radiative decay channels that compete with the emission of photons. We synthesized a new derivative of the famous laser dye 4-dicyanomethylen-2-methyl-6-p-dimethylaminostyryl-4H-pyran (DCM),i.e., merocyanine 4-(dicyanomethylene)-2-tert-butyl-6-[3-(3-butyl-benzothiazol-2-ylidene)1-propenyl]-4H-pyran (DCBT). We measured fluorescence lifetimes and quantum yields in a variety of solvents and found a trend opposite to the energy gap law.This motivated a theoretical investigation into the possible non-radiative decay channels. We propose that a barrier to a conical intersection exists that is very sensitive to the solvent polarity. The conical intersection is characterized by a twisted geometry which allows a subsequent photoisomerization. Transient absorption measurements confirmed the formation of a photoisomer in unpolar solvents, while the measurements of fluorescence quantum yields at low temperature demonstrated the existence of an activation energy barrier. KW - solvent-dependent fluorescence yield Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198707 UR - https://doi.org/10.1039/C9SC05012D VL - 10 ER - TY - JOUR A1 - Robinson, Thomas M. A1 - Hutmacher, Dietmar W. A1 - Dalton, Paul D. T1 - The next frontier in melt electrospinning: taming the jet JF - Advanced Functional Materials N2 - There is a specialized niche for the electrohydrodynamic jetting of melts, from biomedical products to filtration and soft matter applications. The next frontier includes optics, microfluidics, flexible electronic devices, and soft network composites in biomaterial science and soft robotics. The recent emphasis on reproducibly direct‐writing continual molten jets has enabled a spectrum of contemporary microscale 3D objects to be fabricated. One strong suit of melt processing is the capacity for the jet to solidify rapidly into a fiber, thus fixing a particular structure into position. The ability to direct‐write complex and multiscaled architectures and structures has greatly contributed to a large number of recent studies, explicitly, toward fiber–hydrogel composites and fugitive inks, and has expanded into several biomedical applications such as cartilage, skin, periosteum, and cardiovascular tissue engineering. Following the footsteps of a publication that summarized melt electrowriting literature up to 2015, the most recent literature from then until now is reviewed to provide a continuous and comprehensive timeline that demonstrates the latest advances as well as new perspectives for this emerging technology. KW - 3D printing KW - additive manufacturing KW - eletrhydrodynamic KW - melt electrospinning writing Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204819 VL - 29 ER - TY - JOUR A1 - Sbiera, Silviu A1 - Kunz, Meik A1 - Weigand, Isabel A1 - Deutschbein, Timo A1 - Dandekar, Thomas A1 - Fassnacht, Martin T1 - The new genetic landscape of Cushing’s disease: deubiquitinases in the spotlight JF - Cancers N2 - Cushing’s disease (CD) is a rare condition caused by adrenocorticotropic hormone (ACTH)-producing adenomas of the pituitary, which lead to hypercortisolism that is associated with high morbidity and mortality. Treatment options in case of persistent or recurrent disease are limited, but new insights into the pathogenesis of CD are raising hope for new therapeutic avenues. Here, we have performed a meta-analysis of the available sequencing data in CD to create a comprehensive picture of CD’s genetics. Our analyses clearly indicate that somatic mutations in the deubiquitinases are the key drivers in CD, namely USP8 (36.5%) and USP48 (13.3%). While in USP48 only Met415 is affected by mutations, in USP8 there are 26 different mutations described. However, these different mutations are clustering in the same hotspot region (affecting in 94.5% of cases Ser718 and Pro720). In contrast, pathogenic variants classically associated with tumorigenesis in genes like TP53 and BRAF are also present in CD but with low incidence (12.5% and 7%). Importantly, several of these mutations might have therapeutic potential as there are drugs already investigated in preclinical and clinical setting for other diseases. Furthermore, network and pathway analyses of all somatic mutations in CD suggest a rather unified picture hinting towards converging oncogenic pathways. KW - Cushing’s disease KW - pathogenesis KW - somatic mutations KW - deubiquitinases Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193194 SN - 2072-6694 VL - 11 IS - 11 ER - TY - JOUR A1 - El-Mesery, Mohamed A1 - Rosenthal, Tina A1 - Rauert-Wunderlich, Hilka A1 - Schreder, Martin A1 - Stühmer, Thorsten A1 - Leich, Ellen A1 - Schlosser, Andreas A1 - Ehrenschwender, Martin A1 - Wajant, Harald A1 - Siegmund, Daniela T1 - The NEDD8-activating enzyme inhibitor MLN4924 sensitizes a TNFR1+ subgroup of multiple myeloma cells for TNF-induced cell death JF - Cell Death & Disease N2 - The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase βTrCP. MLN4924 therefore inhibits also the βTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.g., RPMI-8226, MM.1S, KMS-12BM) and about half of the primary myeloma samples tested are sensitized to TNF-induced cell death by MLN4924. This correlated with MLN4924-mediated inhibition of TNF-induced activation of the classical NFκB pathway and reduced the efficacy of TNF-induced TNFR1 signaling complex formation. Interestingly, binding studies revealed a straightforward correlation between cell surface TNFR1 expression in multiple myeloma cell lines and their sensitivity for MLN4924/TNF-induced cell death. The cell surface expression levels of TNFR1 in the investigated MM cell lines largely correlated with TNFR1 mRNA expression. This suggests that the variable levels of cell surface expression of TNFR1 in myeloma cell lines are decisive for TNF/MLN4924 sensitivity. Indeed, introduction of TNFR1 into TNFR1-negative TNF/MLN4924-resistant KMS-11BM cells, was sufficient to sensitize this cell line for TNF/MLN4924-induced cell death. Thus, MLN4924 might be especially effective in myeloma patients with TNFR1+ myeloma cells and a TNFhigh tumor microenvironment. KW - cancer therapy KW - tumour-necrosis factors Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226666 VL - 10 ER - TY - JOUR A1 - Lange, Benjamin P. A1 - Andrian-Werburg, Maximilian T. P. von A1 - Adler, Dorothea C. A1 - Zaretsky, Eugen T1 - The name is the game: nicknames as predictors of personality and mating strategy in online dating JF - Frontiers in Communication N2 - Objective: We investigated the communicative function of online dating nicknames. Our aim was to assess if it is possible to correctly guess personality traits of a user simply by reading his/her nickname. Method: We had 69 nickname users (average age: 33.59 years, 36 female) complete questionnaires assessing their personality (Big 5 + narcissism) and mating strategy (short- vs. long-term). We then checked (using a total of 638 participants, average age: 26.83 years, 355 female), whether personality and mating strategy of the nickname users could be assessed correctly based only on the nickname. We also captured the motivation to contact the user behind a nickname and looked at linguistic features of the nicknames. Results: We found that personality and mating strategy could be inferred from a nickname. Furthermore, going by trends, women were better at intersexual personality judgments, whereas men were better in intrasexual judgements. We also found several correlates of the motivation to contact the person behind the nickname. Among other factors, long nicknames seemed to deter people from contacting the nickname user. Conclusions: Findings display that humans are capable of making accurate personality judgements in computer-mediated communication by means of even small cues like nicknames. KW - computer-mediated communication KW - linguistic cues KW - nicknames KW - online dating KW - personality judgments KW - hyperpersonal communication Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201659 VL - 4 IS - 3 ER - TY - JOUR A1 - Pattschull, Grit A1 - Walz, Susanne A1 - Gründl, Marco A1 - Schwab, Melissa A1 - Rühl, Eva A1 - Baluapuri, Apoorva A1 - Cindric-Vranesic, Anita A1 - Kneitz, Susanne A1 - Wolf, Elmar A1 - Ade, Carsten P. A1 - Rosenwald, Andreas A1 - von Eyss, Björn A1 - Gaubatz, Stefan T1 - The Myb-MuvB complex is required for YAP-dependent transcription of mitotic genes JF - Cell Reports N2 - YAP and TAZ, downstream effectors of the Hippo pathway, are important regulators of proliferation. Here, we show that the ability of YAP to activate mitotic gene expression is dependent on the Myb-MuvB (MMB) complex, a master regulator of genes expressed in the G2/M phase of the cell cycle. By carrying out genome-wide expression and binding analyses, we found that YAP promotes binding of the MMB subunit B-MYB to the promoters of mitotic target genes. YAP binds to B-MYB and stimulates B-MYB chromatin association through distal enhancer elements that interact with MMB-regulated promoters through chromatin looping. The cooperation between YAP and B-MYB is critical for YAP-mediated entry into mitosis. Furthermore, the expression of genes coactivated by YAP and B-MYB is associated with poor survival of cancer patients. Our findings provide a molecular mechanism by which YAP and MMB regulate mitotic gene expression and suggest a link between two cancer-relevant signaling pathways. KW - YAP KW - B-MYB KW - Myb-MuvB KW - mitotic genes KW - enhancer KW - transcription Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202039 VL - 27 IS - 12 ER - TY - JOUR A1 - Jakubietz, Rafael G. A1 - Jakubietz, Danni F. A1 - Horch, Raymund E. A1 - Gruenert, Joerg G. A1 - Meffert, Rainer H. A1 - Jakubietz, Michael G. T1 - The microvascular peroneal artery perforator flap as a "lifeboat" for pedicled flaps JF - Plastic and Reconstructive Surgery – Global Open N2 - Background: Pedicled perforator flaps have expanded reconstructive options in extremity reconstruction. Despite preoperative mapping, intraoperative findings may require microvascular tissue transfer when no adequate perforators can be found. The free peroneal artery perforator flap may serve as a reliable back-up plan in small defects. Methods: In 16 patients with small soft tissue defects on the upper and lower extremities, perforator-based propeller flaps were planned. The handheld Doppler device was used to localize potential perforators for a propeller flap in close proximity to the defect. Perforators of the proximal peroneal artery were also marked to allow conversion to microvascular tissue transfer. Results: In 6 cases, no adequate perforators were found intraoperatively. In 4 patients, the peroneal artery perforator flap was harvested and transferred. The pedicle length did not exceed 4 cm. No flap loss occurred. Conclusions: When no adequate perforator capable of nourishing a propeller flap can be found intraoperatively, the free peroneal artery flap is a good option to reconstruct small soft tissue defects in the distal extremities. The short vascular pedicle is less ideal in cases with a large zone of injury requiring a more distant site of anastomosis or when recipient vessels are located in deeper tissue planes. KW - surgery Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202233 VL - 7 IS - 9 ER - TY - JOUR A1 - Westermann, Alexander J. A1 - Venturini, Elisa A1 - Sellin, Mikael E. A1 - Förstner, Konrad U. A1 - Hardt, Wolf-Dietrich A1 - Vogel, Jörg T1 - The major RNA-binding protein ProQ impacts virulence gene expression in Salmonella enterica serovar Typhimurium JF - mBio N2 - FinO domain proteins such as ProQ of the model pathogen Salmonella enterica have emerged as a new class of major RNA-binding proteins in bacteria. ProQ has been shown to target hundreds of transcripts, including mRNAs from many virulence regions, but its role, if any, in bacterial pathogenesis has not been studied. Here, using a Dual RNA-seq approach to profile ProQ-dependent gene expression changes as Salmonella infects human cells, we reveal dysregulation of bacterial motility, chemotaxis, and virulence genes which is accompanied by altered MAPK (mitogen-activated protein kinase) signaling in the host. Comparison with the other major RNA chaperone in Salmonella, Hfq, reinforces the notion that these two global RNA-binding proteins work in parallel to ensure full virulence. Of newly discovered infection-associated ProQ-bound small noncoding RNAs (sRNAs), we show that the 3′UTR-derived sRNA STnc540 is capable of repressing an infection-induced magnesium transporter mRNA in a ProQ-dependent manner. Together, this comprehensive study uncovers the relevance of ProQ for Salmonella pathogenesis and highlights the importance of RNA-binding proteins in regulating bacterial virulence programs. IMPORTANCE The protein ProQ has recently been discovered as the centerpiece of a previously overlooked “third domain” of small RNA-mediated control of gene expression in bacteria. As in vitro work continues to reveal molecular mechanisms, it is also important to understand how ProQ affects the life cycle of bacterial pathogens as these pathogens infect eukaryotic cells. Here, we have determined how ProQ shapes Salmonella virulence and how the activities of this RNA-binding protein compare with those of Hfq, another central protein in RNA-based gene regulation in this and other bacteria. To this end, we apply global transcriptomics of pathogen and host cells during infection. In doing so, we reveal ProQ-dependent transcript changes in key virulence and host immune pathways. Moreover, we differentiate the roles of ProQ from those of Hfq during infection, for both coding and noncoding transcripts, and provide an important resource for those interested in ProQ-dependent small RNAs in enteric bacteria. KW - Hfq KW - noncoding RNA KW - ProQ KW - RNA-seq KW - bacterial pathogen KW - posttranscriptional control Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177722 VL - 10 IS - 1 ER - TY - JOUR A1 - Mayer, Alexander E. A1 - Löffler, Mona C. A1 - Loza Valdés, Angel E. A1 - Schmitz, Werner A1 - El-Merahbi, Rabih A1 - Trujillo-Viera, Jonathan A1 - Erk, Manuela A1 - Zhang, Thianzhou A1 - Braun, Ursula A1 - Heikenwalder, Mathias A1 - Leitges, Michael A1 - Schulze, Almut A1 - Sumara, Grzegorz T1 - The kinase PKD3 provides negative feedback on cholesterol and triglyceride synthesis by suppressing insulin signaling JF - Science Signaling N2 - Hepatic activation of protein kinase C (PKC) isoforms by diacylglycerol (DAG) promotes insulin resistance and contributes to the development of type 2 diabetes (T2D). The closely related protein kinase D (PKD) isoforms act as effectors for DAG and PKC. Here, we showed that PKD3 was the predominant PKD isoform expressed in hepatocytes and was activated by lipid overload. PKD3 suppressed the activity of downstream insulin effectors including the kinase AKT and mechanistic target of rapamycin complex 1 and 2 (mTORC1 and mTORC2). Hepatic deletion of PKD3 in mice improved insulin-induced glucose tolerance. However, increased insulin signaling in the absence of PKD3 promoted lipogenesis mediated by SREBP (sterol regulatory element-binding protein) and consequently increased triglyceride and cholesterol content in the livers of PKD3-deficient mice fed a high-fat diet. Conversely, hepatic-specific overexpression of a constitutively active PKD3 mutant suppressed insulin-induced signaling and caused insulin resistance. Our results indicate that PKD3 provides feedback on hepatic lipid production and suppresses insulin signaling. Therefore, manipulation of PKD3 activity could be used to decrease hepatic lipid content or improve hepatic insulin sensitivity. KW - Protein kinase D3 (PKD3) KW - cholesterol KW - diacylglycerol (DAG) KW - liver KW - metabolism Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250025 ET - accepted manuscript ER - TY - JOUR A1 - Schmalzl, J. A1 - Plumhoff, P. A1 - Gilbert, F. A1 - Gohlke, F. A1 - Konrads, C. A1 - Brunner, U. A1 - Jakob, F. A1 - Ebert, R. A1 - Steinert, AF T1 - The inflamed biceps tendon as a pain generator in the shoulder: A histological and biomolecular analysis JF - Journal of Orthopaedic Surgery N2 - Introduction: The long head of the biceps (LHB) is often resected in shoulder surgery. However, its contribution to inflammatory processes in the shoulder remains unclear. In the present study, inflamed and noninflamed human LHBs were comparatively characterized for features of inflammation. Materials and methods: Twenty-two resected LHB tendons were classified into inflamed (n = 11) and noninflamed (n = 11) samples. For histological examination, samples were stained with hematoxylin eosin, Azan, van Gieson, and Masson Goldner trichrome. Neuronal tissue was immunohistochemically visualized. In addition, specific inflammatory marker gene expression of primary LHB-derived cell cultures were analyzed. Results: Features of tendinopathy, such as collagen disorganization, infiltration by inflammatory cells, neovascularization, and extensive neuronal innervation were found in the tendinitis group. Compared to noninflamed samples, inflamed LHBs showed a significantly increased inflammatory marker gene expression Conclusion: Structural and biomolecular differences of both groups suggest that the LHB tendon acts as an important pain generator in the shoulder joint. These findings can, on the one hand, contribute to the understanding of the biomolecular genesis of LHB tendinitis and, on the other hand, provide possibilities for new therapeutic approaches. KW - biceps tendinitis KW - biomolecular processes KW - inflammatory gene KW - interleukin KW - long head of biceps tendon KW - pain generator KW - shoulder pain Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228611 VL - 27 IS - 1 ER - TY - JOUR A1 - Rasche, Leo A1 - Kortüm, K. Martin A1 - Raab, Marc S. A1 - Weinhold, Niels T1 - The impact of tumor heterogeneity on diagnostics and novel therapeutic strategies in multiple myeloma JF - International Journal of Molecular Sciences N2 - Myeloma is characterized by extensive inter-patient genomic heterogeneity due to multiple different initiating events. A recent multi-region sequencing study demonstrated spatial differences, with progression events, such as TP53 mutations, frequently being restricted to focal lesions. In this review article, we describe the clinical impact of these two types of tumor heterogeneity. Target mutations are often dominant at one site but absent at other sites, which poses a significant challenge to personalized therapy in myeloma. The same holds true for high-risk subclones, which can be locally restricted, and as such not detectable at the iliac crest, which is the usual sampling site. Imaging can improve current risk classifiers and monitoring of residual disease, but does not allow for deciphering the molecular characteristics of tumor clones. In the era of novel immunotherapies, the clinical impact of heterogeneity certainly needs to be re-defined. Yet, preliminary observations indicate an ongoing impact of spatial heterogeneity on the efficacy of monoclonal antibodies. In conclusion, we recommend combining molecular tests with imaging to improve risk prediction and monitoring of residual disease. Overcoming intra-tumor heterogeneity is the prerequisite for curing myeloma. Novel immunotherapies are promising but research addressing their impact on the spatial clonal architecture is highly warranted. KW - multiple myeloma KW - spatial heterogeneity KW - risk stratification KW - minimal residual disease KW - targeted therapy KW - clinical imaging KW - immunotherapy KW - daratumumab Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285402 SN - 1422-0067 VL - 20 IS - 5 ER - TY - JOUR A1 - Klement, Rainer J. A1 - Abbasi-Senger, N. A1 - Adebahr, S. A1 - Alheid, H. A1 - Allgaeuer, M. A1 - Becker, G. A1 - Blanck, O. A1 - Boda-Heggemann, J. A1 - Brunner, T. A1 - Duma, M. A1 - Eble, M. J. A1 - Ernst, I. A1 - Gerum, S. A1 - Habermehl, D. A1 - Hass, P. A1 - Henkenberens, C. A1 - Hildebrandt, G. A1 - Imhoff, D. A1 - Kahl, H. A1 - Klass, N. D. A1 - Krempien, R. A1 - Lewitzki, V. A1 - Lohaus, F. A1 - Ostheimer, C. A1 - Papachristofilou, A. A1 - Petersen, C. A1 - Rieber, J. A1 - Schneider, T. A1 - Schrade, E. A1 - Semrau, R. A1 - Wachter, S. A1 - Wittig, A. A1 - Guckenberger, M. A1 - Andratschke, N. T1 - The impact of local control on overall survival after stereotactic body radiotherapy for liver and lung metastases from colorectal cancer: a combined analysis of 388 patients with 500 metastases JF - BMC Cancer N2 - Background The aim of this analysis was to model the effect of local control (LC) on overall survival (OS) in patients treated with stereotactic body radiotherapy (SBRT) for liver or lung metastases from colorectal cancer. Methods The analysis is based on pooled data from two retrospective SBRT databases for pulmonary and hepatic metastases from 27 centers from Germany and Switzerland. Only patients with metastases from colorectal cancer were considered to avoid histology as a confounding factor. An illness-death model was employed to model the relationship between LC and OS. Results Three hundred eighty-eight patients with 500 metastatic lesions (lung n = 209, liver n = 291) were included and analyzed. Median follow-up time for local recurrence assessment was 12.1 months. Ninety-nine patients with 112 lesions experienced local failure. Seventy-one of these patients died after local failure. Median survival time was 27.9 months in all patients and 25.4 months versus 30.6 months in patients with and without local failure after SBRT. The baseline risk of death after local failure exceeds the baseline risk of death without local failure at 10 months indicating better survival with LC. Conclusion In CRC patients with lung or liver metastases, our findings suggest improved long-term OS by achieving metastatic disease control using SBRT in patients with a projected OS estimate of > 12 months. KW - colorectal cancer KW - illness-death model KW - liver metastases KW - lung metastases KW - tumor control probability KW - stereotactic body radiation therapy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325877 VL - 19 ER - TY - JOUR A1 - Näschen, Kristian A1 - Diekkrüger, Bernd A1 - Evers, Mariele A1 - Höllermann, Britta A1 - Steinbach, Stefanie A1 - Thonfeld, Frank T1 - The impact of land use/land cover change (LULCC) on water resources in a tropical catchment in Tanzania under different climate change scenarios JF - Sustainability N2 - Many parts of sub-Saharan Africa (SSA) are prone to land use and land cover change (LULCC). In many cases, natural systems are converted into agricultural land to feed the growing population. However, despite climate change being a major focus nowadays, the impacts of these conversions on water resources, which are essential for agricultural production, is still often neglected, jeopardizing the sustainability of the socio-ecological system. This study investigates historic land use/land cover (LULC) patterns as well as potential future LULCC and its effect on water quantities in a complex tropical catchment in Tanzania. It then compares the results using two climate change scenarios. The Land Change Modeler (LCM) is used to analyze and to project LULC patterns until 2030 and the Soil and Water Assessment Tool (SWAT) is utilized to simulate the water balance under various LULC conditions. Results show decreasing low flows by 6–8% for the LULC scenarios, whereas high flows increase by up to 84% for the combined LULC and climate change scenarios. The effect of climate change is stronger compared to the effect of LULCC, but also contains higher uncertainties. The effects of LULCC are more distinct, although crop specific effects show diverging effects on water balance components. This study develops a methodology for quantifying the impact of land use and climate change and therefore contributes to the sustainable management of the investigated catchment, as it shows the impact of environmental change on hydrological extremes (low flow and floods) and determines hot spots, which are critical for environmental development. KW - SWAT model KW - Land Change Modeler KW - Scenario analysis KW - Extreme flows KW - Tanzania KW - Kilombero Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193825 SN - 2071-1050 VL - 11 IS - 24 ER - TY - JOUR A1 - Radchuk, Volodymyr A1 - Rajiv, Sharma A1 - Potokina, Elena A1 - Radchuk, Ruslana A1 - Weier, Diana A1 - Munz, Eberhard A1 - Schreiber, Miriam A1 - Mascher, Martin A1 - Stein, Nils A1 - Wicker, Thomas A1 - Kilian, Benjamin A1 - Borisjuk, Ljudmilla T1 - The highly divergent \(Jekyll\) genes, required for sexual reproduction, are lineage specific for the related grass tribes Triticeae and Bromeae JF - Plant Journal N2 - Phylogenetically related groups of species contain lineage-specific genes that exhibit no sequence similarity to any genes outside the lineage. We describe here that the Jekyll gene, required for sexual reproduction, exists in two much diverged allelic variants, Jek1 and Jek3. Despite low similarity, the Jek1 and Jek3 proteins share identical signal peptides, conserved cysteine positions and direct repeats. The Jek1/Jek3 sequences are located at the same chromosomal locus and inherited in a monogenic Mendelian fashion. Jek3 has a similar expression as Jek1 and complements the Jek1 function in Jek1-deficient plants. Jek1 and Jek3 allelic variants were almost equally distributed in a collection of 485 wild and domesticated barley accessions. All domesticated barleys harboring the Jek1 allele belong to single haplotype J1-H1 indicating a genetic bottleneck during domestication. Domesticated barleys harboring the Jek3 allele consisted of three haplotypes. Jekyll-like sequences were found only in species of the closely related tribes Bromeae and Triticeae but not in other Poaceae. Non-invasive magnetic resonance imaging revealed intrinsic grain structure in Triticeae and Bromeae, associated with the Jekyll function. The emergence of Jekyll suggests its role in the separation of the Bromeae and Triticeae lineages within the Poaceae and identifies the Jekyll genes as lineage-specific. KW - gene alleles KW - lineage-specific genes KW - Triticeae KW - Hordeum vulgare KW - Triticum aestivum KW - gene family evolution KW - plant reproduction Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224769 VL - 98 IS - 6 ER - TY - JOUR A1 - Du, Kang A1 - Wuertz, Sven A1 - Adolfi, Mateus A1 - Kneitz, Susanne A1 - Stöck, Matthias A1 - Oliveira, Marcos A1 - Nóbrega, Rafael A1 - Ormanns, Jenny A1 - Kloas, Werner A1 - Feron, Romain A1 - Klopp, Christophe A1 - Parrinello, Hugues A1 - Journot, Laurent A1 - He, Shunping A1 - Postlethwait, John A1 - Meyer, Axel A1 - Guiguen, Yann A1 - Schartl, Manfred T1 - The genome of the arapaima (Arapaima gigas) provides insights into gigantism, fast growth and chromosomal sex determination system JF - Scientific Reports N2 - We have sequenced the genome of the largest freshwater fish species of the world, the arapaima. Analysis of gene family dynamics and signatures of positive selection identified genes involved in the specific adaptations and unique features of this iconic species, in particular it’s large size and fast growth. Genome sequences from both sexes combined with RAD-tag analyses from other males and females led to the isolation of male-specific scaffolds and supports an XY sex determination system in arapaima. Whole transcriptome sequencing showed that the product of the gland-like secretory organ on the head surface of males and females may not only provide nutritional fluid for sex-unbiased parental care, but that the organ itself has a more specific function in males, which engage more in parental care. KW - Genome KW - Genomics Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201333 VL - 9 ER - TY - JOUR A1 - Wegener, Sonja A1 - Sauer, Otto A. T1 - The effective point of measurement for depth-dose measurements in small MV photon beams with different detectors JF - Medical Physics N2 - Purpose: The effective point of measurement (EPOM) of cylindrical ionization chambers differs from their geometric center. The exact shift depends on chamber construction details, above all the chamber size, and to some degree on the field-size and beam quality. It generally decreases as the chamber dimensions get smaller. In this work, effective points of measurement in small photon fields of a range of cylindrical chambers of different sizes are investigated, including small chambers that have not been studied previously. Methods: In this investigation, effective points of measurement for different ionization chambers (Farmer type, scanning chambers, micro-ionization chambers) and solid state detectors were determined by measuring depth-ionization curves in a 6 MV beam in field sizes between 2 9 2 cm2 and 10 9 10 cm2 and comparing those curves with curves measured with plane-parallel chambers. Results: It was possible to average the results to one shift per detector, as the results were sufficiently independent of the studied field sizes. For cylindrical ion chambers, shifts of the EPOM were determined to be between 0.49 and 0.30 times the inner chamber radius from the reference point. Conclusions: We experimentally confirmed the previously reported decrease of the EPOM shift with decreasing detector size. Highly accurate data for a large range of detectors, including new very small ones, were determined. Thus, small chambers noticeably differ from the 0.5-times to 0.6-times the inner chamber radius recommendations in current dosimetry protocols. The detector-individual EPOMs need to be considered for measurements of depth-dose curves. KW - depth dose curves KW - effective point of measurement KW - ionization chambers KW - micro-chambers Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206148 VL - 46 IS - 11 ER - TY - JOUR A1 - Reinermann, Sophie A1 - Gessner, Ursula A1 - Asam, Sarah A1 - Kuenzer, Claudia A1 - Dech, Stefan T1 - The Effect of Droughts on Vegetation Condition in Germany: An Analysis Based on Two Decades of Satellite Earth Observation Time Series and Crop Yield Statistics JF - Remote Sensing N2 - Central Europe experienced several droughts in the recent past, such as in the year 2018, which was characterized by extremely low rainfall rates and high temperatures, resulting in substantial agricultural yield losses. Time series of satellite earth observation data enable the characterization of past drought events over large temporal and spatial scales. Within this study, Moderate Resolution Spectroradiometer (MODIS) Enhanced Vegetation Index (EVI) (MOD13Q1) 250 m time series were investigated for the vegetation periods of 2000 to 2018. The spatial and temporal development of vegetation in 2018 was compared to other dry and hot years in Europe, like the drought year 2003. Temporal and spatial inter- and intra-annual patterns of EVI anomalies were analyzed for all of Germany and for its cropland, forest, and grassland areas individually. While vegetation development in spring 2018 was above average, the summer months of 2018 showed negative anomalies in a similar magnitude as in 2003, which was particularly apparent within grassland and cropland areas in Germany. In contrast, the year 2003 showed negative anomalies during the entire growing season. The spatial pattern of vegetation status in 2018 showed high regional variation, with north-eastern Germany mainly affected in June, north-western parts in July, and western Germany in August. The temporal pattern of satellite-derived EVI deviances within the study period 2000-2018 were in good agreement with crop yield statistics for Germany. The study shows that the EVI deviation of the summer months of 2018 were among the most extreme in the study period compared to other years. The spatial pattern and temporal development of vegetation condition between the drought years differ. KW - drought KW - time series KW - heat wave KW - agriculture KW - climate extremes KW - climate change KW - crop statistics KW - MODIS KW - Germany Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225165 VL - 11 IS - 15 ER - TY - JOUR A1 - Griesbeck, Stefanie A1 - Michail, Evripidis A1 - Rauch, Florian A1 - Ogasawara, Hiroaki A1 - Wang, Chenguang A1 - Sato, Yoshikatsu A1 - Edkins, Robert M. A1 - Zhang, Zuolun A1 - Taki, Masayasu A1 - Lambert, Christoph A1 - Yamaguchi, Shigehiro A1 - Marder, Todd B. T1 - The Effect of Branching on the One‐ and Two‐Photon Absorption, Cell Viability, and Localization of Cationic Triarylborane Chromophores with Dipolar versus Octupolar Charge Distributions for Cellular Imaging JF - Chemistry – A European Journal N2 - Two different chromophores, namely a dipolar and an octupolar system, were prepared and their linear and nonlinear optical properties as well as their bioimaging capabilities were compared. Both contain triphenylamine as the donor and a triarylborane as the acceptor, the latter modified with cationic trimethylammonio groups to provide solubility in aqueous media. The octupolar system exhibits a much higher two‐photon brightness, and also better cell viability and enhanced selectivity for lysosomes compared with the dipolar chromophore. Furthermore, both dyes were applied in two‐photon excited fluorescence (TPEF) live‐cell imaging. KW - boranes KW - cell imaging KW - fluorescence KW - lysosome KW - two-photon excited fluorescence Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212887 VL - 25 IS - 57 SP - 13164 EP - 13175 ER - TY - JOUR A1 - Griesbeck, Stefanie A1 - Michail, Evripidis A1 - Rauch, Florian A1 - Ogasawara, Hiroaki A1 - Wang, Chenguang A1 - Sato, Yoshikatsu A1 - Edkins, Robert M. A1 - Zhang, Zuolun A1 - Taki, Masayasu A1 - Lambert, Christoph A1 - Yamaguchi, Shigehiro A1 - Marder, Todd B. T1 - The Effect of Branching on One- and Two-Photon Absorption, Cell Viability and Localization of Cationic Triarylborane Chromophores with Dipolar versus Octupolar Charge Distributions for Cellular Imaging JF - Chemistry - A European Journal N2 - Two different chromophores, namely a dipolar and an octupolar system, were prepared and their linear and nonlinear optical properties as well as their bioimaging capabilities were compared. Both contain triphenylamine as the donor and a triarylborane as the acceptor, the latter modified with cationic trimethylammonio groups to provide solubility in aqueous media. The octupolar system exhibits a much higher two‐photon brightness, and also better cell viability and enhanced selectivity for lysosomes compared with the dipolar chromophore. Furthermore, both dyes were applied in two‐photon excited fluorescence (TPEF) live‐cell imaging. KW - boranes KW - cell imaging KW - fluerescence KW - lysosome KW - two-photon excited fluorescence Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204829 VL - 25 IS - 57 ER - TY - JOUR A1 - Zonneveld, Ben J. M. T1 - The DNA weights per nucleus (genome size) of more than 2350 species of the Flora of The Netherlands, of which 1370 are new to science, including the pattern of their DNA peaks JF - Forum Geobotanicum N2 - Besides external characteristics and reading a piece of DNA (barcode), the DNA weight per nucleus (genome size) via flow cytometry is a key value to detect species and hybrids and determine ploidy. In addition, the DNA weight appears to be related to various properties, such as the size of the cell and the nucleus, the duration of mitosis and meiosis and the generation time. Sometimes it is even possible to distinguish between groups or sections, which can lead to new classification of the genera. The variation in DNA weight is also useful to analyze biodiversity, genome evolution and relationships between related taxa. Moreover, it is important to know how large a genome is before one determines the base sequence of the DNA of a plant. Flow cytometry is also important for understanding fundamental processes in plants such as growth and development and recognizing chimeras. In the literature, DNA weight measurements are usually limited to one genus and often only locally (Siljak et al. 2010; Bai et al. 2012). In this study, however, it was decided to investigate all vascular plants from one country. This can also contribute to the protection of rare plants. This study is the first flora in the world whose weight of DNA per nucleus and peak patterns has been determined. More than 6400 plants, representing more than 2350 (sub)species (more than 90%) have been collected, thanks to the help of almost 100 volunteers of Floristisch Onderzoek Nederland (Floron). Multiple specimens of many species have therefore been measured, preferably from different populations, in some cases more than fifty. For 1370 species, these values were not previously published. Moreover, a good number of the remaining 45% are new for The Netherlands. In principle, each species has a fixed weight of DNA per nucleus. It has also been found that, especially between the genera, there are strong differences in the number of peaks that determine the DNA weight, from one to five peaks. This indicates that in a plant or organ there are sometimes nuclei with multiples of its standard DNA weight (multiple ploidy levels). It is impossible to show graphs of more than 2350 species. Therefore, we have chosen to show the peak pattern in a new way in a short formula. Within most genera there are clear differences in the DNA weights per nucleus between the species, in some other genera the DNA weight is hardly variable. Based on about twenty genera that were previously measured completely in most cases (‘t Hart et al. 2003: Veldkamp and Zonneveld 2011; Soes et al. 2012; Dirkse et al. 2014, 2015; Verloove et al. 2017; Zonneveld [et al.] 2000−2018), it can be noted that even if all species of a genus have the same number of chromosomes, there can still be a difference of up to three times in the weight of the DNA. Therefore, a twice larger DNA weight does not have to indicate four sets of chromosomes. Finally, this research has also found clues to examine further the current taxonomy of a number of species or genera. KW - DNA weight KW - Pflanzen KW - genome KW - flora KW - Netherlands Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189724 UR - http://www.forum-geobotanicum.net/articles/vol_8-2018/zonneveld_flora-of-the-netherlands/zonneveld_flora-of-the-netherlands.pdf SN - 1867-9315 VL - 8 ER - TY - JOUR A1 - Tarau, Ioana-Sandra A1 - Berlin, Andreas A1 - Curcio, Christine A. A1 - Ach, Thomas T1 - The cytoskeleton of the retinal pigment epithelium: from normal aging to age-related macular degeneration JF - International Journal of Molecular Science N2 - The retinal pigment epithelium (RPE) is a unique epithelium, with major roles which are essential in the visual cycle and homeostasis of the outer retina. The RPE is a monolayer of polygonal and pigmented cells strategically placed between the neuroretina and Bruch membrane, adjacent to the fenestrated capillaries of the choriocapillaris. It shows strong apical (towards photoreceptors) to basal/basolateral (towards Bruch membrane) polarization. Multiple functions are bound to a complex structure of highly organized and polarized intracellular components: the cytoskeleton. A strong connection between the intracellular cytoskeleton and extracellular matrix is indispensable to maintaining the function of the RPE and thus, the photoreceptors. Impairments of these intracellular structures and the regular architecture they maintain often result in a disrupted cytoskeleton, which can be found in many retinal diseases, including age-related macular degeneration (AMD). This review article will give an overview of current knowledge on the molecules and proteins involved in cytoskeleton formation in cells, including RPE and how the cytoskeleton is affected under stress conditions — especially in AMD. KW - retinal pigment epithelium KW - cytoskeleton KW - aging KW - age-related macular degeneration KW - actin KW - microfilament KW - microtubules KW - stress fiber Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201781 SN - 1422-0067 VL - 20 IS - 14 ER - TY - JOUR A1 - Albert, A. A1 - André, M. A1 - Anghinolfi, M. A1 - Anton, G. A1 - Ardid, M. A1 - Aubert, J.-J. A1 - Aublin, J. A1 - Avgitas, T. A1 - Baret, B. A1 - Barrios-Martít, J. A1 - Basa, S. A1 - Belhorma, B. A1 - Bertin, V. A1 - Biagi, S. A1 - Bormuth, R. A1 - Boumaaza, J A1 - Bourret, S. A1 - Bouwhuis, M. C. A1 - Brânzas, H. A1 - Bruijn, R. A1 - Brunner, J. A1 - Busto, J. A1 - Capone, A. A1 - Caramete, L. A1 - Carr, J. A1 - Celli, S. A1 - Chabab, M. A1 - Cherkaoui El Moursli, R. A1 - Chiarusi, T. A1 - Circella, M. A1 - Coelho, J. A. B. A1 - Coleiro, A. A1 - Colomer, M A1 - Coniglione, R. A1 - Costantini, H. A1 - Coyle, P. A1 - Creusot, A. A1 - Díaz, A. F. A1 - Deschamps, A. A1 - Distefano, C. A1 - Di Palma, I. A1 - Domi, A. A1 - Donzaud, C. A1 - Dornic, D. A1 - Drouhin, D. A1 - Eberl, T. A1 - El Bojaddaini, I. A1 - El Khayati, N. A1 - Elsässer, D. A1 - Enzenhöfer, A. A1 - Ettahiri, A. A1 - Fassi, F. A1 - Felis, I. A1 - Fermani, P. A1 - Ferrara, G. A1 - Fusco, L. A. A1 - Gay, P. A1 - Glotin, H. A1 - Grégoire, T. A1 - Gracia Ruiz, R. A1 - Graf, K. A1 - Hallmann, S. A1 - van Haren, H. A1 - Heijboer, A. J. A1 - Hello, Y. A1 - Hernández-Rey, J. J. A1 - Hößl, J. A1 - Hofestädt, J. A1 - Illuminati, G. A1 - de Jong, M. A1 - Jongen, M. A1 - Kadler, M. A1 - Kalekin, O. A1 - Katz, U. A1 - Khan-Chowdhury, N. R. A1 - Kouchner, A. A1 - Kreter, M. A1 - Kreykenbohm, I. A1 - Kulikovskiy, V. A1 - Lachaud, C. A1 - Lahmann, R. A1 - Lefèvre, D. A1 - Leonora, E. A1 - Levi, G. A1 - Lotze, M. A1 - Loucatos, S. A1 - Marcelin, M. A1 - Margiotta, A. A1 - Marinelli, A. A1 - Martínez-Mora, J. A. A1 - Mele, R. A1 - Melis, K. A1 - Migliozzi, P. A1 - Moussa, A. A1 - Navas, S. A1 - Nezri, E. A1 - Nuñez, A. A1 - Organokov, M. A1 - Pavalas, G. E. A1 - Pellegrino, C. A1 - Piattelli, P. A1 - Popa, V. A1 - Pradier, T. A1 - Quinn, L. A1 - Racca, C. A1 - Randazzo, N. A1 - Riccobene, G. A1 - Sánchez-Losa, A. A1 - Saldaña, M. A1 - Salvadori, I. A1 - Samtleben, D. F. E. A1 - Sanguineti, M. A1 - Sapienza, P. A1 - Schüssler, F. A1 - Spurio, M. A1 - Stolarczyk, Th. A1 - Taiuti, M. A1 - Tayalati, Y. A1 - Trovato, A. A1 - Vallage, B. A1 - Van Elewyck, V. A1 - Versari, F. A1 - Vivolo, D. A1 - Wilms, J. A1 - Zaborov, D. A1 - Zornoza, J. D. A1 - Zúñiga, J. T1 - The cosmic ray shadow of the Moon observed with the ANTARES neutrino telescope JF - European Physical Journal C N2 - One of the main objectives of the ANTARES telescope is the search for point- like neutrino sources. Both the pointing accuracy and the angular resolution of the detector are important in this context and a reliableway to evaluate this performance is needed. In order to measure the pointing accuracy of the detector, one possibility is to study the shadow of the Moon, i. e. the deficit of the atmospheric muon flux from the direction of the Moon induced by the absorption of cosmic rays. Analysing the data taken between 2007 and 2016, theMoon shadow is observed with 3.5s statistical significance. The detector angular resolution for downwardgoing muons is 0.73. +/- 0.14.. The resulting pointing performance is consistent with the expectations. An independent check of the telescope pointing accuracy is realised with the data collected by a shower array detector onboard of a ship temporarily moving around the ANTARES location. KW - Atmospheric muons Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227802 VL - 78 ER - TY - JOUR A1 - Beer, Katharina A1 - Schenk, Mariela A1 - Helfrich-Förster, Charlotte A1 - Holzschuh, Andrea T1 - The circadian clock uses different environmental time cues to synchronize emergence and locomotion of the solitary bee Osmia bicornis JF - Scientific Reports N2 - Life on earth adapted to the daily reoccurring changes in environment by evolving an endogenous circadian clock. Although the circadian clock has a crucial impact on survival and behavior of solitary bees, many aspects of solitary bee clock mechanisms remain unknown. Our study is the first to show that the circadian clock governs emergence in Osmia bicornis, a bee species which overwinters as adult inside its cocoon. Therefore, its eclosion from the pupal case is separated by an interjacent diapause from its emergence in spring. We show that this bee species synchronizes its emergence to the morning. The daily rhythms of emergence are triggered by temperature cycles but not by light cycles. In contrast to this, the bee’s daily rhythms in locomotion are synchronized by light cycles. Thus, we show that the circadian clock of O. bicornis is set by either temperature or light, depending on what activity is timed. Light is a valuable cue for setting the circadian clock when bees have left the nest. However, for pre-emerged bees, temperature is the most important cue, which may represent an evolutionary adaptation of the circadian system to the cavity-nesting life style of O. bicornis. KW - Behavioural ecology KW - Evolutionary developmental biology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202721 VL - 9 ER - TY - JOUR A1 - Horn, Melanie A1 - Mitesser, Oliver A1 - Hovestadt, Thomas A1 - Yoshii, Taishi A1 - Rieger, Dirk A1 - Helfrich-Förster, Charlotte T1 - The circadian clock improves fitness in the fruit fly, Drosophila melanogaster JF - Frontiers in Physiology N2 - It is assumed that a properly timed circadian clock enhances fitness, but only few studies have truly demonstrated this in animals. We raised each of the three classical Drosophila period mutants for >50 generations in the laboratory in competition with wildtype flies. The populations were either kept under a conventional 24-h day or under cycles that matched the mutant’s natural cycle, i.e., a 19-h day in the case of pers mutants and a 29-h day for perl mutants. The arrhythmic per0 mutants were grown together with wildtype flies under constant light that renders wildtype flies similar arrhythmic as the mutants. In addition, the mutants had to compete with wildtype flies for two summers in two consecutive years under outdoor conditions. We found that wildtype flies quickly outcompeted the mutant flies under the 24-h laboratory day and under outdoor conditions, but perl mutants persisted and even outnumbered the wildtype flies under the 29-h day in the laboratory. In contrast, pers and per0 mutants did not win against wildtype flies under the 19-h day and constant light, respectively. Our results demonstrate that wildtype flies have a clear fitness advantage in terms of fertility and offspring survival over the period mutants and – as revealed for perl mutants – this advantage appears maximal when the endogenous period resonates with the period of the environment. However, the experiments indicate that perl and pers persist at low frequencies in the population even under the 24-h day. This may be a consequence of a certain mating preference of wildtype and heterozygous females for mutant males and time differences in activity patterns between wildtype and mutants. KW - competition KW - mutants KW - resonance theory KW - mating preference KW - fertility Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195738 SN - 1664-042X VL - 10 IS - 1374 ER - TY - JOUR A1 - Aktas, Bertal H. A1 - Upcin, Berin A1 - Henke, Erik A1 - Padmasekar, Manju A1 - Qin, Xuebin A1 - Ergün, Süleyman T1 - The Best for the Most Important: Maintaining a Pristine Proteome in Stem and Progenitor Cells JF - Stem Cells International N2 - Pluripotent stem cells give rise to reproductively enabled offsprings by generating progressively lineage-restricted multipotent stem cells that would differentiate into lineage-committed stem and progenitor cells. These lineage-committed stem and progenitor cells give rise to all adult tissues and organs. Adult stem and progenitor cells are generated as part of the developmental program and play critical roles in tissue and organ maintenance and/or regeneration. The ability of pluripotent stem cells to self-renew, maintain pluripotency, and differentiate into a multicellular organism is highly dependent on sensing and integrating extracellular and extraorganismal cues. Proteins perform and integrate almost all cellular functions including signal transduction, regulation of gene expression, metabolism, and cell division and death. Therefore, maintenance of an appropriate mix of correctly folded proteins, a pristine proteome, is essential for proper stem cell function. The stem cells' proteome must be pristine because unfolded, misfolded, or otherwise damaged proteins would interfere with unlimited self-renewal, maintenance of pluripotency, differentiation into downstream lineages, and consequently with the development of properly functioning tissue and organs. Understanding how various stem cells generate and maintain a pristine proteome is therefore essential for exploiting their potential in regenerative medicine and possibly for the discovery of novel approaches for maintaining, propagating, and differentiating pluripotent, multipotent, and adult stem cells as well as induced pluripotent stem cells. In this review, we will summarize cellular networks used by various stem cells for generation and maintenance of a pristine proteome. We will also explore the coordination of these networks with one another and their integration with the gene regulatory and signaling networks. KW - Endoplasmic-Reticulum Stress KW - Heme-regulated inhibitor KW - Human Muse Cells KW - Transcription factor NRF1 KW - ER-Stress KW - Hematopoietic Stem KW - Quality-control KW - Messenger-RNAs KW - Neural Differentiation KW - Translation Initiation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227769 ER - TY - JOUR A1 - Wen, Xinbo A1 - Nowak-Król, Agnieszka A1 - Nagler, Oliver A1 - Kraus, Felix A1 - Zhu, Na A1 - Zheng, Nan A1 - Müller, Matthias A1 - Schmidt, David A1 - Xie, Zengqi A1 - Würthner, Frank T1 - Tetrahydroxy-perylene bisimide embedded in zinc oxide thin film as electron transporting layer for high performance non-fullerene organic solar cells JF - Angewandte Chemie International Edition N2 - By introduction of four hydroxy (HO) groups into the two perylene bisimide (PBI) bay areas, new HO‐PBI ligands were obtained which upon deprotonation can complex ZnII ions and photosensitize semiconductive zinc oxide thin films. Such coordination is beneficial for dispersing PBI photosensitizer molecules evenly into metal oxide films to fabricate organic–inorganic hybrid interlayers for organic solar cells. Supported by the photoconductive effect of the ZnO:HO‐PBI hybrid interlayers, improved electron collection and transportation is achieved in fullerene and non‐fullerene polymer solar cell devices, leading to remarkable power conversion efficiencies of up to 15.95 % for a non‐fullerene based organic solar cell. KW - hydroxylation KW - metal complexenes KW - perylene bisimide KW - photoconductive interlayer KW - solar cells Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204723 VL - 58 IS - 37 ER - TY - JOUR A1 - Schmalzl, Jonas A1 - Plumhoff, Piet A1 - Gilbert, Fabian A1 - Gohlke, Frank A1 - Konrads, Christian A1 - Brunner, Ulrich A1 - Jakob, Franz A1 - Ebert, Regina A1 - Steinert, Andre F. T1 - Tendon-derived stem cells from the long head of the biceps tendon JF - Bone & Joint Research N2 - Objectives The long head of the biceps (LHB) is often resected in shoulder surgery and could therefore serve as a cell source for tissue engineering approaches in the shoulder. However, whether it represents a suitable cell source for regenerative approaches, both in the inflamed and non-inflamed states, remains unclear. In the present study, inflamed and native human LHBs were comparatively characterized for features of regeneration. Methods In total, 22 resected LHB tendons were classified into inflamed samples (n = 11) and non-inflamed samples (n = 11). Proliferation potential and specific marker gene expression of primary LHB-derived cell cultures were analyzed. Multipotentiality, including osteogenic, adipogenic, chondrogenic, and tenogenic differentiation potential of both groups were compared under respective lineage-specific culture conditions. Results Inflammation does not seem to affect the proliferation rate of the isolated tendon-derived stem cells (TDSCs) and the tenogenic marker gene expression. Cells from both groups showed an equivalent osteogenic, adipogenic, chondrogenic and tenogenic differentiation potential in histology and real-time polymerase chain reaction (RT-PCR) analysis. Conclusion These results suggest that the LHB tendon might be a suitable cell source for regenerative approaches, both in inflamed and non-inflamed states. The LHB with and without tendinitis has been characterized as a novel source of TDSCs, which might facilitate treatment of degeneration and induction of regeneration in shoulder surgery. KW - biceps tendon KW - tendon-derived stem cell KW - mesenchymal stem cell KW - tissue engineering KW - shoulder Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200370 VL - 8 IS - 9 ER - TY - JOUR A1 - Odorfer, Thorsten M. A1 - Wind, Teresa A1 - Zeller, Daniel T1 - Temporal discrimination thresholds and proprioceptive performance: impact of age and nerve conduction JF - Frontiers in Neuroscience N2 - Background Increasing attention is payed to the contribution of somatosensory processing in motor control. In particular, temporal somatosensory discrimination has been found to be altered differentially in common movement disorders. To date, there have only been speculations as to how impaired temporal discrimination and clinical motor signs may relate to each other. Prior to disentangling this relationship, potential confounders of temporal discrimination, in particular age and peripheral nerve conduction, should be assessed, and a quantifiable measure of proprioceptive performance should be established. ObjectiveTo assess the influence of age and polyneuropathy (PNP) on somatosensory temporal discrimination threshold (STDT), temporal discrimination movement threshold (TDMT), and behavioral measures of proprioception of upper and lower limbs. Methods STDT and TDMT were assessed in 79 subjects (54 healthy, 25 with PNP; age 30–79 years). STDT was tested with surface electrodes over the thenar or dorsal foot region. TDMT was probed with needle electrodes in flexor carpi radialis (FCR) and tibialis anterior (TA) muscle. Goniometer-based devices were used to assess limb proprioception during (i) active pointing to LED markers, (ii) active movements in response to variable visual cues, and (iii) estimation of limb position following passive movements. Pointing (or estimation) error was taken as a measure of proprioceptive performance. Results In healthy subjects, higher age was associated with higher STDT and TDMT at upper and lower extremities, while age did not correlate with proprioceptive performance. Patients with PNP showed higher STDT and TDMT values and decreased proprioceptive performance in active pointing tasks compared to matched healthy subjects. As an additional finding, there was a significant correlation between performance in active pointing tasks and temporal discrimination thresholds. Conclusion Given their notable impact on measures of temporal discrimination, age and peripheral nerve conduction need to be accounted for if STDT and TDMT are applied in patients with movement disorders. As a side observation, the correlation between measures of proprioception and temporal discrimination may prompt further studies on the presumptive link between these two domains. KW - pointing task KW - position estimation KW - aging KW - kinesthesia KW - somatosensory temporal discrimination KW - TDMT KW - temporal discrimination threshold Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195648 SN - 1662-453X VL - 13 IS - 1241 ER - TY - JOUR A1 - Wajant, Harald A1 - Beilhack, Andreas T1 - Targeting regulatory T cells by addressing tumor necrosis factor and its receptors in allogeneic hematopoietic cell transplantation and cancer JF - Frontiers in Immunology N2 - An intricate network of molecular and cellular actors orchestrates the delicate balance between effector immune responses and immune tolerance. The pleiotropic cytokine tumor necrosis factor-alpha (TNF) proves as a pivotal protagonist promoting but also suppressing immune responses. These opposite actions are accomplished through specialist cell types responding to TNF via TNF receptors TNFR1 and TNFR2. Recent findings highlight the importance of TNFR2 as a key regulator of activated natural FoxP3+ regulatory T cells (Tregs) in inflammatory conditions, such as acute graft-vs.-host disease (GvHD) and the tumor microenvironment. Here we review recent advances in our understanding of TNFR2 signaling in T cells and discuss how these can reconcile seemingly conflicting observations when manipulating TNF and TNFRs. As TNFR2 emerges as a new and attractive target we furthermore pinpoint strategies and potential pitfalls for therapeutic targeting of TNFR2 for cancer treatment and immune tolerance after allogeneic hematopoietic cell transplantation. KW - GVHD KW - graft vs. host disease KW - cancer KW - Tregs (regulatory T cells) KW - TNFR family costimulatory receptors KW - TNFR2 agonists KW - TNFR2 antagonism Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201578 VL - 10 IS - 2040 ER - TY - JOUR A1 - Schuhmann, Michael K. A1 - Kraft, Peter A1 - Bieber, Michael A1 - Kollikowski, Alexander M. A1 - Schulze, Harald A1 - Nieswandt, Bernhard A1 - Pham, Mirko A1 - Stegner, David A1 - Stoll, Guido T1 - Targeting platelet GPVI plus rt-PA administration but not α2β1-mediated collagen binding protects against ischemic brain damage in mice JF - International Journal of Molecular Science N2 - Platelet collagen interactions at sites of vascular injuries predominantly involve glycoprotein VI (GPVI) and the integrin α2β1. Both proteins are primarily expressed on platelets and megakaryocytes whereas GPVI expression is also shown on endothelial and integrin α2β1 expression on epithelial cells. We recently showed that depletion of GPVI improves stroke outcome without increasing the risk of cerebral hemorrhage. Genetic variants associated with higher platelet surface integrin α2 (ITGA2) receptor levels have frequently been found to correlate with an increased risk of ischemic stroke in patients. However until now, no preclinical stroke study has addressed whether platelet integrin α2β1 contributes to the pathophysiology of ischemia/reperfusion (I/R) injury. Focal cerebral ischemia was induced in C57BL/6 and Itga2\(^{−/−}\) mice by a 60 min transient middle cerebral artery occlusion (tMCAO). Additionally, wild-type animals were pretreated with anti-GPVI antibody (JAQ1) or Fab fragments of a function blocking antibody against integrin α2β1 (LEN/B). In anti-GPVI treated animals, intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment was applied immediately prior to reperfusion. Stroke outcome, including infarct size and neurological scoring was determined on day 1 after tMCAO. We demonstrate that targeting the integrin α2β1 (pharmacologic; genetic) did neither reduce stroke size nor improve functional outcome on day 1 after tMCAO. In contrast, depletion of platelet GPVI prior to stroke was safe and effective, even when combined with rt-PA treatment. Our results underscore that GPVI, but not ITGA2, is a promising and safe target in the setting of ischemic stroke. KW - ischemic stroke KW - integrin α2 KW - glycoprotein VI KW - recombinant tissue-type plasminogen activator KW - intracranial bleeding KW - transient middle cerebral artery occlusion Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201700 SN - 1422-0067 VL - 20 IS - 8 ER - TY - JOUR A1 - Khayenko, Vladimir A1 - Maric, Hans Michael T1 - Targeting GABA\(_A\)R-associated proteins: new modulators, labels and concepts JF - Frontiers in Molecular Neuroscience N2 - γ-aminobutyric acid type A receptors (GABA\(_A\)Rs) are the major mediators of synaptic inhibition in the brain. Aberrant GABA\(_A\)R activity or regulation is observed in various neurodevelopmental disorders, neurodegenerative diseases and mental illnesses, including epilepsy, Alzheimer’s and schizophrenia. Benzodiazepines, anesthetics and other pharmaceutics targeting these receptors find broad clinical use, but their inherent lack of receptor subtype specificity causes unavoidable side effects, raising a need for new or adjuvant medications. In this review article, we introduce a new strategy to modulate GABAeric signaling: targeting the intracellular protein interactors of GABA\(_A\)Rs. Of special interest are scaffolding, anchoring and supporting proteins that display high GABA\(_A\)R subtype specificity. Recent efforts to target gephyrin, the major intracellular integrator of GABAergic signaling, confirm that GABA\(_A\)R-associated proteins can be successfully targeted through diverse molecules, including recombinant proteins, intrabodies, peptide-based probes and small molecules. Small-molecule artemisinins and peptides derived from endogenous interactors, that specifically target the universal receptor binding site of gephyrin, acutely affect synaptic GABA\(_A\)R numbers and clustering, modifying neuronal transmission. Interference with GABA\(_A\)R trafficking provides another way to modulate inhibitory signaling. Peptides blocking the binding site of GABA\(_A\)R to AP2 increase the surface concentration of GABA\(_A\)R clusters and enhance GABAergic signaling. Engineering of gephyrin binding peptides delivered superior means to interrogate neuronal structure and function. Fluorescent peptides, designed from gephyrin binders, enable live neuronal staining and visualization of gephyrin in the post synaptic sites with submicron resolution. We anticipate that in the future, novel fluorescent probes, with improved size and binding efficiency, may find wide application in super resolution microscopy studies, enlightening the nanoscale architecture of the inhibitory synapse. Broader studies on GABA\(_A\)R accessory proteins and the identification of the exact molecular binding interfaces and affinities will advance the development of novel GABA\(_A\)R modulators and following in vivo studies will reveal their clinical potential as adjuvant or stand-alone drugs. KW - GABAA receptors KW - gephyrin KW - collybistin KW - protein-protein interaction (PPI) KW - super resolution microscopy KW - fluorescent probes KW - dimeric peptide KW - peptide inhibitor design Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201876 VL - 12 IS - 162 ER - TY - JOUR A1 - Otto, C. A1 - Schmidt, S. A1 - Kastner, C. A1 - Denk, S. A1 - Kettler, J. A1 - Müller, N. A1 - Germer, C.T. A1 - Wolf, E. A1 - Gallant, P. A1 - Wiegering, A. T1 - Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells JF - Neoplasia N2 - The transcriptional regulator BRD4 has been shown to be important for the expression of several oncogenes including MYC. Inhibiting of BRD4 has broad antiproliferative activity in different cancer cell types. The small molecule JQ1 blocks the interaction of BRD4 with acetylated histones leading to transcriptional modulation. Depleting BRD4 via engineered bifunctional small molecules named PROTACs (proteolysis targeting chimeras) represents the next-generation approach to JQ1-mediated BRD4 inhibition. PROTACs trigger BRD4 for proteasomale degradation by recruiting E3 ligases. The aim of this study was therefore to validate the importance of BRD4 as a relevant target in colorectal cancer (CRC) cells and to compare the efficacy of BRD4 inhibition with BRD4 degradation on downregulating MYC expression. JQ1 induced a downregulation of both MYC mRNA and MYC protein associated with an antiproliferative phenotype in CRC cells. dBET1 and MZ1 induced degradation of BRD4 followed by a reduction in MYC expression and CRC cell proliferation. In SW480 cells, where dBET1 failed, we found significantly lower levels of the E3 ligase cereblon, which is essential for dBET1-induced BRD4 degradation. To gain mechanistic insight into the unresponsiveness to dBET1, we generated dBET1-resistant LS174t cells and found a strong downregulation of cereblon protein. These findings suggest that inhibition of BRD4 by JQ1 and degradation of BRD4 by dBET1 and MZ1 are powerful tools for reducing MYC expression and CRC cell proliferation. In addition, downregulation of cereblon may be an important mechanism for developing dBET1 resistance, which can be evaded by incubating dBET1-resistant cells with JQ1 or MZ1. KW - Cancer Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202451 VL - 21 IS - 11 ER - TY - JOUR A1 - Kühnisch, Jirko A1 - Herbst, Christopher A1 - Al‐Wakeel‐Marquard, Nadya A1 - Dartsch, Josephine A1 - Holtgrewe, Manuel A1 - Baban, Anwar A1 - Mearini, Giulia A1 - Hardt, Juliane A1 - Kolokotronis, Konstantinos A1 - Gerull, Brenda A1 - Carrier, Lucie A1 - Beule, Dieter A1 - Schubert, Stephan A1 - Messroghli, Daniel A1 - Degener, Franziska A1 - Berger, Felix A1 - Klaassen, Sabine T1 - Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3 JF - Clinical Genetics N2 - The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel‐based next‐generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation—not only in adult—but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP. KW - cardiomyopathy KW - genetics KW - pediatrics KW - sarcomere KW - TNNI3 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213958 VL - 96 IS - 6 SP - 549 EP - 559 ER - TY - JOUR A1 - Heidenreich, Julius F. A1 - Weng, Andreas M. A1 - Donhauser, Julian A1 - Greiser, Andreas A1 - Chow, Kelvin A1 - Nordbeck, Peter A1 - Bley, Thorsten A. A1 - Köstler, Herbert T1 - T1- and ECV-mapping in clinical routine at 3 T: differences between MOLLI, ShMOLLI and SASHA JF - BMC Medical Imaging N2 - Background T1 mapping sequences such as MOLLI, ShMOLLI and SASHA make use of different technical approaches, bearing strengths and weaknesses. It is well known that obtained T1 relaxation times differ between the sequence techniques as well as between different hardware. Yet, T1 quantification is a promising tool for myocardial tissue characterization, disregarding the absence of established reference values. The purpose of this study was to evaluate the feasibility of native and post-contrast T1 mapping methods as well as ECV maps and its diagnostic benefits in a clinical environment when scanning patients with various cardiac diseases at 3 T. Methods Native and post-contrast T1 mapping data acquired on a 3 T full-body scanner using the three pulse sequences 5(3)3 MOLLI, ShMOLLI and SASHA in 19 patients with clinical indication for contrast enhanced MRI were compared. We analyzed global and segmental T1 relaxation times as well as respective extracellular volumes and compared the emerged differences between the used pulse sequences. Results T1 times acquired with MOLLI and ShMOLLI exhibited systematic T1 deviation compared to SASHA. Myocardial MOLLI T1 times were 19% lower and ShMOLLI T1 times 25% lower compared to SASHA. Native blood T1 times from MOLLI were 13% lower than SASHA, while post-contrast MOLLI T1-times were only 5% lower. ECV values exhibited comparably biased estimation with MOLLI and ShMOLLI compared to SASHA in good agreement with results reported in literature. Pathology-suspect segments were clearly differentiated from remote myocardium with all three sequences. Conclusion Myocardial T1 mapping yields systematically biased pre- and post-contrast T1 times depending on the applied pulse sequence. Additionally calculating ECV attenuates this bias, making MOLLI, ShMOLLI and SASHA better comparable. Therefore, myocardial T1 mapping is a powerful clinical tool for classification of soft tissue abnormalities in spite of the absence of established reference values. KW - T1 mapping KW - MOLLI KW - ShMOLLI KW - SASHA KW - Extracellular volume KW - 3 T Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201999 VL - 19 ER - TY - JOUR A1 - Rauschenberger, Tabea A1 - Schmitt, Viola A1 - Azeem, Muhammad A1 - Klein-Hessling, Stefan A1 - Murti, Krisna A1 - Grän, Franziska A1 - Goebeler, Matthias A1 - Kerstan, Andreas A1 - Klein, Matthias A1 - Bopp, Tobias A1 - Serfling, Edgar A1 - Muhammad, Khalid T1 - T cells control chemokine secretion by keratinocytes JF - Frontiers in Immunology N2 - The massive infiltration of lymphocytes into the skin is a hallmark of numerous human skin disorders. By co-culturing murine keratinocytes with splenic T cells we demonstrate here that T cells affect and control the synthesis and secretion of chemokines by keratinocytes. While pre-activated CD8\(^+\)T cells induce the synthesis of CXCL9 and CXCL10 in keratinocytes and keep in check the synthesis of CXCL1, CXCL5, and CCL20, keratinocytes dampen the synthesis of CCL3 and CCL4 in pre-activated CD8\(^+\)T cells. One key molecule is IFN-γ that is synthesized by CD8\(^+\)T cells under the control of NFATc1 and NFATc2. CD8\(^+\)T cells deficient for both NFAT factors are unable to induce CXCL9 and CXCL10 expression. In addition, CD8\(^+\)T cells induced numerous type I IFN-inducible “defense genes” in keratinocytes encoding the PD1 and CD40 ligands, TNF-α and caspase-1. The enhanced expression of type I IFN-inducible genes resembles the gene expression pattern at the dermal/epidermal interface in lichen planus, an inflammatory T lymphocyte-driven skin disease, in which we detected the expression of CXCL10 in keratinocytes in close vicinity to the infiltration front of T cells. These data reflect the multifaceted interplay of lymphocytes with keratinocytes at the molecular level. KW - chemokine KW - keratinocytes KW - IFN KW - lichen planus KW - T cells KW - Nfatc1 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195695 SN - 1664-3224 VL - 10 IS - 1917 ER - TY - JOUR A1 - Villalobos, Alvaro S. A1 - Wiese, Jutta A1 - Imhoff, Johannes F. A1 - Dorador, Cristina A1 - Keller, Alexander A1 - Hentschel, Ute T1 - Systematic affiliation and genome analysis of Subtercola vilae DB165T with particular emphasis on cold adaptation of an isolate from a high-altitude cold volcano lake JF - Microorganisms N2 - Among the Microbacteriaceae the species of Subtercola and Agreia form closely associated clusters. Phylogenetic analysis demonstrated three major phylogenetic branches of these species. One of these branches contains the two psychrophilic species Subtercola frigoramans and Subtercola vilae, together with a larger number of isolates from various cold environments. Genomic evidence supports the separation of Agreia and Subtercola species. In order to gain insight into the ability of S. vilae to adapt to life in this extreme environment, we analyzed the genome with a particular focus on properties related to possible adaptation to a cold environment. General properties of the genome are presented, including carbon and energy metabolism, as well as secondary metabolite production. The repertoire of genes in the genome of S. vilae DB165\(^T\) linked to adaptations to the harsh conditions found in Llullaillaco Volcano Lake includes several mechanisms to transcribe proteins under low temperatures, such as a high number of tRNAs and cold shock proteins. In addition, S. vilae DB165\(^T\) is capable of producing a number of proteins to cope with oxidative stress, which is of particular relevance at low temperature environments, in which reactive oxygen species are more abundant. Most important, it obtains capacities to produce cryo-protectants, and to combat against ice crystal formation, it produces ice-binding proteins. Two new ice-binding proteins were identified which are unique to S. vilae DB165\(^T\). These results indicate that S. vilae has the capacity to employ different mechanisms to live under the extreme and cold conditions prevalent in Llullaillaco Volcano Lake. KW - cold adaptation KW - Subtercola vilae KW - genome analysis KW - systematic affiliation KW - Llullaillaco Volcano Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197394 SN - 2076-2607 VL - 7 IS - 4 ER - TY - JOUR A1 - Grebinyk, Anna A1 - Prylutska, Svitlana A1 - Chepurna, Oksana A1 - Grebinyk, Sergii A1 - Prylutskyy, Yuriy A1 - Ritter, Uwe A1 - Ohulchanskyy, Tymish Y. A1 - Matyshevska, Olga A1 - Dandekar, Thomas A1 - Frohme, Marcus T1 - Synergy of chemo- and photodynamic therapies with C\(_{60}\) Fullerene-Doxorubicin nanocomplex JF - Nanomaterials N2 - A nanosized drug complex was explored to improve the efficiency of cancer chemotherapy, complementing it with nanodelivery and photodynamic therapy. For this, nanomolar amounts of a non-covalent nanocomplex of Doxorubicin (Dox) with carbon nanoparticle C\(_{60}\) fullerene (C\(_{60}\)) were applied in 1:1 and 2:1 molar ratio, exploiting C\(_{60}\) both as a drug-carrier and as a photosensitizer. The fluorescence microscopy analysis of human leukemic CCRF-CEM cells, in vitro cancer model, treated with nanocomplexes showed Dox’s nuclear and C\(_{60}\)'s extranuclear localization. It gave an opportunity to realize a double hit strategy against cancer cells based on Dox's antiproliferative activity and C\(_{60}\)'s photoinduced pro-oxidant activity. When cells were treated with 2:1 C\(_{60}\)-Dox and irradiated at 405 nm the high cytotoxicity of photo-irradiated C\(_{60}\)-Dox enabled a nanomolar concentration of Dox and C\(_{60}\) to efficiently kill cancer cells in vitro. The high pro-oxidant and pro-apoptotic efficiency decreased IC\(_{50}\) 16, 9 and 7 × 10\(^3\)-fold, if compared with the action of Dox, non-irradiated nanocomplex, and C\(_{60}\)'s photodynamic effect, correspondingly. Hereafter, a strong synergy of therapy arising from the combination of C\(_{60}\)-mediated Dox delivery and C\(_{60}\) photoexcitation was revealed. Our data indicate that a combination of chemo- and photodynamic therapies with C\(_{60}\)-Dox nanoformulation provides a promising synergetic approach for cancer treatment. KW - photodynamic chemotherapy KW - synergistic effect KW - C\(_{60}\) fullerene KW - Doxorubicin KW - nanocomplex KW - leukemic cells KW - apoptosis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193140 SN - 2079-4991 VL - 9 IS - 11 ER - TY - JOUR A1 - Elhfnawy, Ahmed Mohamed A1 - Volkmann, Jens A1 - Schliesser, Mira A1 - Fluri, Felix T1 - Symptomatic vs. asymptomatic 20–40% internal carotid artery stenosis: Does the plaque size matter? JF - Frontiers in Neurology N2 - Background: Around 9–15% of ischemic strokes are related to internal carotid artery (ICA)-stenosis ≥50%. However, the extent to which ICA-stenosis <50% causes ischemic cerebrovascular events is uncertain. We examined the relation between plaque cross-sectional area and length and the risk of ischemic stroke or TIA among patients with ICA-stenosis of 20–40%. Methods: We retrospectively identified patients admitted to the Department of Neurology, University Hospital of Würzburg, from January 2011 until September 2016 with ischemic stroke or TIA and concomitant ICA-stenosis of 20–40%, either symptomatic or asymptomatic. Plaque length and cross-sectional area were assessed on ultrasound scans. Results: We identified 41 patients with ischemic stroke or TIA and ICA-stenosis of 20–40%; 14 symptomatic and 27 asymptomatic. The plaque cross-sectional area was significantly larger among symptomatic than asymptomatic ICA-stenosis; median values (IQR) were 0.45 (0.21–0.69) cm2 and 0.27 (0.21–0.38) cm2, p = 0.03, respectively. A plaque cross-sectional area ≥0.36 cm2 had a sensitivity of 71% and a specificity of 76% for symptomatic compared with asymptomatic ICA-stenosis. In a sex-adjusted multivariate logistic regression, a plaque cross-sectional area ≥0.36 cm2 and a plaque length ≥1.65 cm were associated with an OR (95% CI) of 5.54 (1.2–25.6), p = 0.028 and 1.78 (0.36–8.73), p = 0.48, respectively, for symptomatic ICA-stenosis. Conclusion: Large plaques might increase the risk of ischemic stroke or TIA among patients with low-grade ICA-stenosis of 20–40%. Sufficiently powered prospective longitudinal cohort studies are needed to definitively test the stroke risk stratification value of carotid plaque length and cross-sectional area in the setting of current optimal medical treatment. KW - ischemic stroke KW - carotid atherosclerosis KW - carotid stenosis KW - plaque cross-sectional area KW - length of stenosis KW - carotid ultrasound Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201262 VL - 10 IS - 960 ER - TY - JOUR A1 - Jansen, Hendrik A1 - Heintel, Timo M. A1 - Jordan, Martin A1 - Meffert, Rainer H. A1 - Frey, Soenke P. T1 - Survived traumatic hemipelvectomy with salvage of the limb in a 14  months old toddler JF - Trauma Case Reports N2 - We report on a 14 months old toddler who sustained a traumatic hemipelvectomy by being crushed between a car and a stone wall. After stabilization in the resuscitation room he was treated operatively by laparotomy, osteosynthesis of the pelvic ring, reconstruction of the both external iliac vessels and the urethra and reposition of the testicles. After 66 days he was discharged into rehabilitation. Implants were removed after eight months. 20 months after the injury, the leg was plegic, initial radiological signs of femoral head necrosis showed up but the infant was able to walk with an orthesis and a walker. Up to our knowledge, this is the youngest patient described in the literature with a survived traumatic hemipelvectomy and salvaged limb. KW - Hemipelvectomy KW - Survival KW - Limb salvage KW - Toddler Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202207 VL - 22 ER - TY - JOUR A1 - Wagner, Johanna A1 - Eiken, Barbara A1 - Haubitz, Imme A1 - Lichthardt, Sven A1 - Matthes, Niels A1 - Löb, Stefan A1 - Klein, Ingo A1 - Germer, Christoph-Thomas A1 - Wiegering, Armin T1 - Suprapubic bladder drainage and epidural catheters following abdominal surgery—a risk for urinary tract infections? JF - PLoS ONE N2 - Background Epidural catheters are state of the art for postoperative analgesic in abdominal surgery. Due to neurolysis it can lead to postoperative urinary tract retention (POUR), which leads to prolonged bladder catheterization, which has an increased risk for urinary tract infections (UTI). Our aim was to identify the current perioperative management of urinary catheters and, second, to identify the optimal time of suprapubic bladder catheter removal in regard to the removal of the epidural catheter. Methods We sent a questionnaire to 102 German hospitals and analyzed the 83 received answers to evaluate the current handling of bladder drainage and epidural catheters. Then, we conducted a retrospective study including 501 patients, who received an epidural and suprapubic catheter after abdominal surgery at the University Hospital Würzburg. We divided the patients into three groups according to the point in time of suprapubic bladder drainage removal in regard to the removal of the epidural catheter and analyzed the onset of a UTI. Results Our survey showed that in almost all hospitals (98.8%), patients received an epidural catheter and a bladder drainage after abdominal surgery. The point in time of urinary catheter removal was equally distributed between before, simultaneously and after the removal of the epidural catheter (respectively: ~28–29%). The retrospective study showed a catheter-associated UTI in 6.7%. Women were affected significantly more often than men (10,7% versus 2,5%, p<0.001). There was a non-significant trend to more UTIs when the suprapubic catheter was removed after the epidural catheter (before: 5.7%, after: 8.4%). Conclusion The point in time of suprapubic bladder drainage removal in relation to the removal of the epidural catheter does not seem to correlate with the rate of UTIs. The current handling in Germany is inhomogeneous, so further studies to standardize treatment are recommended. KW - catheters KW - epidural block KW - bladder KW - urinary tract infections KW - abdominal surgery KW - catheterization KW - surgical and invasive medical procedures KW - rectum Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177731 VL - 14 IS - 1 ER - TY - JOUR A1 - Schlegel, Jan A1 - Peters, Simon A1 - Doose, Sören A1 - Schubert-Unkmeir, Alexandra A1 - Sauer, Markus T1 - Super-resolution microscopy reveals local accumulation of plasma membrane gangliosides at Neisseria meningitidis Invasion Sites JF - Frontiers in Cell and Developmental Biology N2 - Neisseria meningitidis (meningococcus) is a Gram-negative bacterium responsible for epidemic meningitis and sepsis worldwide. A critical step in the development of meningitis is the interaction of bacteria with cells forming the blood-cerebrospinal fluid barrier, which requires tight adhesion of the pathogen to highly specialized brain endothelial cells. Two endothelial receptors, CD147 and the β2-adrenergic receptor, have been found to be sequentially recruited by meningococci involving the interaction with type IV pilus. Despite the identification of cellular key players in bacterial adhesion the detailed mechanism of invasion is still poorly understood. Here, we investigated cellular dynamics and mobility of the type IV pilus receptor CD147 upon treatment with pili enriched fractions and specific antibodies directed against two extracellular Ig-like domains in living human brain microvascular endothelial cells. Modulation of CD147 mobility after ligand binding revealed by single-molecule tracking experiments demonstrates receptor activation and indicates plasma membrane rearrangements. Exploiting the binding of Shiga (STxB) and Cholera toxin B (CTxB) subunits to the two native plasma membrane sphingolipids globotriaosylceramide (Gb3) and raft-associated monosialotetrahexosylganglioside GM1, respectively, we investigated their involvement in bacterial invasion by super-resolution microscopy. Structured illumination microscopy (SIM) and direct stochastic optical reconstruction microscopy (dSTORM) unraveled accumulation and coating of meningococci with GM1 upon cellular uptake. Blocking of CTxB binding sites did not impair bacterial adhesion but dramatically reduced bacterial invasion efficiency. In addition, cell cycle arrest in G1 phase induced by serum starvation led to an overall increase of GM1 molecules in the plasma membrane and consequently also in bacterial invasion efficiency. Our results will help to understand downstream signaling events after initial type IV pilus-host cell interactions and thus have general impact on the development of new therapeutics targeting key molecules involved in infection. KW - Neisseria meningitidis KW - sphingolipids KW - gangliosides and lipid rafts KW - super-resolution microscopy KW - single-molecule tracking Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201639 VL - 7 IS - 194 ER - TY - JOUR A1 - Steinmetzger, Christian A1 - Bessi, Irene A1 - Lenz, Ann-Kathrin A1 - Höbartner, Claudia T1 - Structure-fluorescence activation relationships of a large Stokes shift fluorogenic RNA aptamer JF - Nucleic Acids Research N2 - The Chili RNA aptamer is a 52 nt long fluorogen-activating RNA aptamer (FLAP) that confers fluorescence to structurally diverse derivatives of fluorescent protein chromophores. A key feature of Chili is the formation of highly stable complexes with different ligands, which exhibit bright, highly Stokes-shifted fluorescence emission. In this work, we have analyzed the interactions between the Chili RNA and a family of conditionally fluorescent ligands using a variety of spectroscopic, calorimetric and biochemical techniques to reveal key structure - fluorescence activation relationships (SFARs). The ligands under investigation form two categories with emission maxima of ~540 nm or ~590 nm, respectively, and bind with affinities in the nanomolar to low-micromolar range. Isothermal titration calorimetry was used to elucidate the enthalpic and entropic contributions to binding affinity for a cationic ligand that is unique to the Chili aptamer. In addition to fluorescence activation, ligand binding was also observed by NMR spectroscopy, revealing characteristic signals for the formation of a G-quadruplex only upon ligand binding. These data shed light on the molecular features required and responsible for the large Stokes shift and the strong fluorescence enhancement of red and green emitting RNA-chromophore complexes. KW - Chili RNA Aptamer KW - fluorogen-activating RNA aptamer (FLAP) KW - Stokes-shifted fluorescence emission KW - key structure - fluorescence activation relationships (SFARs) KW - ligand binding Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-192340 ER - TY - JOUR A1 - Kasaragod, Vikram Babu A1 - Schindelin, Hermann T1 - Structure of Heteropentameric GABAA Receptors and Receptor-Anchoring Properties of Gephyrin JF - Frontiers in Molecular Neuroscience N2 - γ-Aminobutyric acid type A receptors (GABAARs) mediate the majority of fast synaptic inhibition in the central nervous system (CNS). GABAARs belong to the Cys-loop superfamily of pentameric ligand-gated ion channels (pLGIC) and are assembled from 19 different subunits. As dysfunctional GABAergic neurotransmission manifests itself in neurodevelopmental disorders including epilepsy and anxiety, GABAARs are key drug targets. The majority of synaptic GABAARs are anchored at the inhibitory postsynaptic membrane by the principal scaffolding protein gephyrin, which acts as the central organizer in maintaining the architecture of the inhibitory postsynaptic density (iPSD). This interaction is mediated by the long intracellular loop located in between transmembrane helices 3 and 4 (M3–M4 loop) of the receptors and a universal receptor-binding pocket residing in the C-terminal domain of gephyrin. In 2014, the crystal structure of the β3-homopentameric GABAAR provided crucial information regarding the architecture of the receptor; however, an understanding of the structure and assembly of heteropentameric receptors at the atomic level was lacking. This review article will highlight recent advances in understanding the structure of heteropentameric synaptic GABAARs and how these structures have provided fundamental insights into the assembly of these multi-subunit receptors as well as their modulation by diverse ligands including the physiological agonist GABA. We will further discuss the role of gephyrin in the anchoring of synaptic GABAARs and glycine receptors (GlyRs), which are crucial for maintaining the architecture of the iPSD. Finally, we will also summarize how anti-malarial artemisinin drugs modulate gephyrin-mediated inhibitory neurotransmission. KW - GABAA KW - gephyrin KW - diazepam KW - GABA KW - PIP2 KW - artemisinin KW - Cryo-EM KW - inhibitory neurotransmission Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189308 SN - 1662-5099 VL - 12 ER - TY - JOUR A1 - Kasaragod, Vikram Babu A1 - Schindelin, Hermann T1 - Structure of heteropentameric GABA\(_A\) receptors and receptor-anchoring properties of gephyrin JF - Frontiers in Molecular Neuroscience N2 - γ-Aminobutyric acid type A receptors (GABA\(_A\)Rs) mediate the majority of fast synaptic inhibition in the central nervous system (CNS). GABA\(_A\)Rs belong to the Cys-loop superfamily of pentameric ligand-gated ion channels (pLGIC) and are assembled from 19 different subunits. As dysfunctional GABAergic neurotransmission manifests itself in neurodevelopmental disorders including epilepsy and anxiety, GABA\(_A\)Rs are key drug targets. The majority of synaptic GABA\(_A\)Rs are anchored at the inhibitory postsynaptic membrane by the principal scaffolding protein gephyrin, which acts as the central organizer in maintaining the architecture of the inhibitory postsynaptic density (iPSD). This interaction is mediated by the long intracellular loop located in between transmembrane helices 3 and 4 (M3–M4 loop) of the receptors and a universal receptor-binding pocket residing in the C-terminal domain of gephyrin. In 2014, the crystal structure of the β3-homopentameric GABA\(_A\)R provided crucial information regarding the architecture of the receptor; however, an understanding of the structure and assembly of heteropentameric receptors at the atomic level was lacking. This review article will highlight recent advances in understanding the structure of heteropentameric synaptic GABA\(_A\)Rs and how these structures have provided fundamental insights into the assembly of these multi-subunit receptors as well as their modulation by diverse ligands including the physiological agonist GABA. We will further discuss the role of gephyrin in the anchoring of synaptic GABA\(_A\)Rs and glycine receptors (GlyRs), which are crucial for maintaining the architecture of the iPSD. Finally, we will also summarize how anti-malarial artemisinin drugs modulate gephyrin-mediated inhibitory neurotransmission. KW - GABAA receptors KW - gephyrin KW - diazepam KW - GABA KW - PIP2 KW - artemisinin KW - Cryo-EM KW - inhibitory neurotransmission Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201886 VL - 12 IS - 191 ER - TY - JOUR A1 - Wutzler, Alexander A1 - Krogias, Christos A1 - Grau, Anna A1 - Veltkamp, Roland A1 - Heuschmann, Peter U. A1 - Haeusler, Karl Georg T1 - Stroke prevention in patients with acute ischemic stroke and atrial fibrillation in Germany - a cross sectional survey JF - BMC Neurology N2 - Background Atrial fibrillation (AF) is present in 15–20% of patients with acute ischemic stroke. Oral anticoagulation reduces the risk of AF-related recurrent stroke but clinical guideline recommendations are rather vague regarding its use in the acute phase of stroke. We aimed to assess the current clinical practice of medical stroke prevention in AF patients during the acute phase of ischemic stroke. Methods In April 2017, a standardized anonymous questionnaire was sent to clinical leads of all 298 certified stroke units in Germany. Results Overall, 154 stroke unit leads participated (response rate 52%). Anticoagulation in the acute phase of stroke is considered feasible in more than 90% of AF patients with ischemic stroke. Clinicians assume that about two thirds of all AF patients (range 20–100%) are discharged on oral anticoagulation. According to local preferences, acetylsalicylic acid is given orally in the majority of patients with delayed initiation of oral anticoagulation. A non-vitamin K-dependent oral anticoagulant (NOAC) is more often prescribed than a vitamin K-dependent oral anticoagulant (VKA). VKA is more often chosen in patients with previous VKA intake than in VKA naive patients. In the minority of patients, stroke unit leads discuss the prescription of a specific oral anticoagulant with the treating general practitioner. Adherence to medical stroke prevention after hospital discharge is not assessed on a regular basis in any patient by the majority of participating stroke centers. Conclusions Early secondary stroke prevention in AF patients in German stroke units is based on OAC use but prescription modalities vary in clinical practice. KW - Ischemic stroke KW - Secondary stroke prevention KW - Atrial fibrillation KW - Survey KW - Oral anticoagulation KW - Stroke unit Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201078 VL - 19 ER - TY - JOUR A1 - Kim, Brandon J. A1 - McDonagh, Maura A. A1 - Deng, Liwen A1 - Gastfriend, Benjamin D. A1 - Schubert-Unkmeir, Alexandra A1 - Doran, Kelly S. A1 - Shusta, Eric V. T1 - Streptococcus agalactiae disrupts P-glycoprotein function in brain endothelial cells JF - Fluids and Barriers of the CNS N2 - Bacterial meningitis is a serious life threatening infection of the CNS. To cause meningitis, blood–borne bacteria need to interact with and penetrate brain endothelial cells (BECs) that comprise the blood–brain barrier. BECs help maintain brain homeostasis and they possess an array of efflux transporters, such as P-glycoprotein (P-gp), that function to efflux potentially harmful compounds from the CNS back into the circulation. Oftentimes, efflux also serves to limit the brain uptake of therapeutic drugs, representing a major hurdle for CNS drug delivery. During meningitis, BEC barrier integrity is compromised; however, little is known about efflux transport perturbations during infection. Thus, understanding the impact of bacterial infection on P-gp function would be important for potential routes of therapeutic intervention. To this end, the meningeal bacterial pathogen, Streptococcus agalactiae, was found to inhibit P-gp activity in human induced pluripotent stem cell-derived BECs, and live bacteria were required for the observed inhibition. This observation was correlated to decreased P-gp expression both in vitro and during infection in vivo using a mouse model of bacterial meningitis. Given the impact of bacterial interactions on P-gp function, it will be important to incorporate these findings into analyses of drug delivery paradigms for bacterial infections of the CNS. KW - Group B Streptococcus KW - Streptococcus agalactiae KW - Brain endothelial cells KW - P-glycoprotein KW - Efflux transport KW - Meningitis KW - Stem cells KW - P-gp Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201895 VL - 16 ER - TY - JOUR A1 - Schlottmann, Elisabeth A1 - Schicke, David A1 - Krüger, Felix A1 - Lingnau, Benjamin A1 - Schneider, Christian A1 - Höfling, Sven A1 - Lüdge, Kathy A1 - Porte, Xavier A1 - Reitzenstein, Stephan T1 - Stochastic polarization switching induced by optical injection in bimodal quantum-dot micropillar lasers JF - Optics Express N2 - Mutual coupling and injection locking of semiconductor lasers is of great interest in non-linear dynamics and its applications for instance in secure data communication and photonic reservoir computing. Despite its importance, it has hardly been studied in microlasers operating at mu W light levels. In this context, vertically emitting quantum dot micropillar lasers are of high interest. Usually, their light emission is bimodal, and the gain competition of the associated linearly polarized fundamental emission modes results in complex switching dynamics. We report on selective optical injection into either one of the two fundamental mode components of a bimodal micropillar laser. Both modes can lock to the master laser and influence the non-injected mode by reducing the available gain. We demonstrate that the switching dynamics can be tailored externally via optical injection in very good agreement with our theory based on semi-classical rate equations. (C) 2019 Optical Society of America under the terms of the OSA Open Access Publishing Agreement KW - Nonlinear Dynamics KW - Bistability KW - Generation KW - Subject KW - Regimes KW - Physics KW - Vcsels Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228603 VL - 27 IS - 20 ER - TY - JOUR A1 - Lenczyk, Carsten A1 - Roy, Dipak Kumar A1 - Nitsch, Jörn A1 - Radacki, Krzysztof A1 - Rauch, Florian A1 - Dewhurst, Rian D. A1 - Bickelhaupt, F. Matthias A1 - Marder, Todd B. A1 - Braunschweig, Holger T1 - Steric Effects Dictate the Formation of Terminal Arylborylene Complexes of Ruthenium from Dihydroboranes JF - Chemistry - A European Journal N2 - The steric and electronic properties of aryl substituents in monoaryl borohydrides (Li[ArBH\(_3\)]) and dihydroboranes were systematically varied and their reactions with [Ru(PCy\(_3\))\(_2\)HCl(H\(_2\))] (Cy: cyclohexyl) were studied, resulting in bis(σ)‐borane or terminal borylene complexes of ruthenium. These variations allowed for the investigation of the factors involved in the activation of dihydroboranes in the synthesis of terminal borylene complexes. The complexes were studied by multinuclear NMR spectroscopy, mass spectrometry, X‐ray diffraction analysis, and density functional theory (DFT) calculations. The experimental and computational results suggest that the ortho‐substitution of the aryl groups is necessary for the formation of terminal borylene complexes. KW - Arylborylene Complexes KW - Ruthenium KW - Dihydroboranes KW - boranes KW - borohydrides KW - borylenes KW - steric effects KW - sigma boranes Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219537 SN - 1521-3765 VL - 25 IS - 59 ER - TY - JOUR A1 - Zhang, Fangyuan A1 - Michail, Evripidis A1 - Saal, Fridolin A1 - Krause, Ana-Maria A1 - Ravat, Prince T1 - Stereospecific Synthesis and Photophysical Properties of Propeller-Shaped C\(_{90}\)H\(_{48}\) PAH JF - Chemistry - A European Journal N2 - Herein, we have synthesized an enantiomerically pure propeller‐shaped PAH, C\(_{90}\)H\(_{48}\), possessing three [7]helicene and three [5]helicene subunits. This compound can be obtained in gram quantities in a straightforward manner. The photophysical and chiroptical properties were investigated using UV/Vis absorption and emission, optical rotation and circular dichroism spectroscopy, supported by DFT calculations. The nonlinear optical properties were investigated by two‐photon absorption measurements using linearly and circularly polarized light. The extremely twisted structure and packing of the homochiral compound were investigated by single‐crystal X‐ray diffraction analysis. KW - chirality KW - enantiomers KW - helicenes KW - polycyclic aromatic hydrocarbons KW - stereospecific sythesis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-208682 VL - 25 IS - 71 ER - TY - JOUR A1 - Elhfnawy, Ahmed Mohamed A1 - Heuschmann, Peter U. A1 - Pham, Mirko A1 - Volkmann, Jens A1 - Fluri, Felix T1 - Stenosis length and degree interact with the risk of cerebrovascular events related to internal carotid artery stenosis JF - Frontiers in Neurology N2 - Background and Purpose: Internal carotid artery stenosis (ICAS)≥70% is a leading cause of ischemic cerebrovascular events (ICVEs). However, a considerable percentage of stroke survivors with symptomatic ICAS (sICAS) have <70% stenosis with a vulnerable plaque. Whether the length of ICAS is associated with high risk of ICVEs is poorly investigated. Our main aim was to investigate the relation between the length of ICAS and the development of ICVEs. Methods: In a retrospective cross-sectional study, we identified 95 arteries with sICAS and another 64 with asymptomatic internal carotid artery stenosis (aICAS) among 121 patients with ICVEs. The degree and length of ICAS as well as plaque echolucency were assessed on ultrasound scans. Results: A statistically significant inverse correlation between the ultrasound-measured length and degree of ICAS was detected for sICAS≥70% (Spearman correlation coefficient ρ = –0.57, p < 0.001, n = 51) but neither for sICAS<70% (ρ = 0.15, p = 0.45, n = 27) nor for aICAS (ρ = 0.07, p = 0.64, n = 54). The median (IQR) length for sICAS<70% and ≥70% was 17 (15–20) and 15 (12–19) mm (p = 0.06), respectively, while that for sICAS<90% and sICAS 90% was 18 (15–21) and 13 (10–16) mm, respectively (p < 0.001). Among patients with ICAS <70%, a cut-off length of ≥16 mm was found for sICAS rather than aICAS with a sensitivity and specificity of 74.1% and 51.1%, respectively. Irrespective of the stenotic degree, plaques of the sICAS compared to aICAS were significantly more often echolucent (43.2 vs. 24.6%, p = 0.02). Conclusion: We found a statistically insignificant tendency for the ultrasound-measured length of sICAS<70% to be longer than that of sICAS≥70%. Moreover, the ultrasound-measured length of sICAS<90% was significantly longer than that of sICAS 90%. Among patients with sICAS≥70%, the degree and length of stenosis were inversely correlated. Larger studies are needed before a clinical implication can be drawn from these results. KW - ischemic stroke KW - carotid stenosis KW - carotid atherosclerosis KW - length of stenosis KW - degree of stenosis KW - carotid ultrasound KW - outcome Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196225 SN - 1664-2295 VL - 10 IS - 317 ER - TY - JOUR A1 - Bratengeier, Klaus A1 - Holubyev, Kostyantyn A1 - Wegener, Sonja T1 - Steeper dose gradients resulting from reduced source to target distance—a planning system independent study JF - Journal of Applied Clinical Medical Physics N2 - Purpose: To quantify the contribution of penumbra in the improvement of healthy tissue sparing at reduced source‐to‐axis distance (SAD) for simple spherical target and different prescription isodoses (PI). Method: A TPS‐independent method was used to estimate three‐dimensional (3D) dose distribution for stereotactic treatment of spherical targets of 0.5 cm radius based on single beam two‐dimensional (2D) film dosimetry measurements. 1 cm target constitutes the worst case for the conformation with standard Multi‐Leaf Collimator (MLC) with 0.5 cm leaf width. The measured 2D transverse dose cross‐sections and the profiles in leaf and jaw directions were used to calculate radial dose distribution from isotropic beam arrangement, for both quadratic and circular beam openings, respectively. The results were compared for standard (100 cm) and reduced SAD 70 and 55 cm for different PI. Results: For practical reduction of SAD using quadratic openings, the improvement of healthy tissue sparing (HTS) at distances up to 3 times the PTV radius was at least 6%–12%; gradient indices (GI) were reduced by 3–39% for PI between 40% and 90%. Except for PI of 80% and 90%, quadratic apertures at SAD 70 cm improved the HTS by up to 20% compared to circular openings at 100 cm or were at least equivalent; GI were 3%–33% lower for reduced SAD in the PI range 40%–70%. For PI = 80% and 90% the results depend on the circular collimator model. Conclusion: Stereotactic treatments of spherical targets delivered at reduced SAD of 70 or 55 cm using MLC spare healthy tissue around the target at least as good as treatments at SAD 100 cm using circular collimators. The steeper beam penumbra at reduced SAD seems to be as important as perfect target conformity. The authors argue therefore that the beam penumbra width should be addressed in the stereotactic studies. KW - radiotherapy KW - stereotactic irradiation KW - penumbra KW - leaf width KW - virtual isocenter Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177424 VL - 20 IS - 1 ER - TY - JOUR A1 - Wick, Christoph A1 - Hartelt, Alexander A1 - Puppe, Frank T1 - Staff, symbol and melody detection of Medieval manuscripts written in square notation using deep Fully Convolutional Networks JF - Applied Sciences N2 - Even today, the automatic digitisation of scanned documents in general, but especially the automatic optical music recognition (OMR) of historical manuscripts, still remains an enormous challenge, since both handwritten musical symbols and text have to be identified. This paper focuses on the Medieval so-called square notation developed in the 11th–12th century, which is already composed of staff lines, staves, clefs, accidentals, and neumes that are roughly spoken connected single notes. The aim is to develop an algorithm that captures both the neumes, and in particular its melody, which can be used to reconstruct the original writing. Our pipeline is similar to the standard OMR approach and comprises a novel staff line and symbol detection algorithm based on deep Fully Convolutional Networks (FCN), which perform pixel-based predictions for either staff lines or symbols and their respective types. Then, the staff line detection combines the extracted lines to staves and yields an F\(_1\) -score of over 99% for both detecting lines and complete staves. For the music symbol detection, we choose a novel approach that skips the step to identify neumes and instead directly predicts note components (NCs) and their respective affiliation to a neume. Furthermore, the algorithm detects clefs and accidentals. Our algorithm predicts the symbol sequence of a staff with a diplomatic symbol accuracy rate (dSAR) of about 87%, which includes symbol type and location. If only the NCs without their respective connection to a neume, all clefs and accidentals are of interest, the algorithm reaches an harmonic symbol accuracy rate (hSAR) of approximately 90%. In general, the algorithm recognises a symbol in the manuscript with an F\(_1\) -score of over 96%. KW - optical music recognition KW - historical document analysis KW - medieval manuscripts KW - neume notation KW - fully convolutional neural networks Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197248 SN - 2076-3417 VL - 9 IS - 13 ER - TY - JOUR A1 - Radeva, Mariya Y. A1 - Walter, Elias A1 - Stach, Ramona Alexandra A1 - Yazdi, Amir S. A1 - Schlegel, Nicolas A1 - Sarig, Ofer A1 - Sprecher, Eli A1 - Waschke, Jens T1 - ST18 Enhances PV-IgG-Induced Loss of Keratinocyte Cohesion in Parallel to Increased ERK Activation JF - Frontiers in Immunology N2 - Pemphigus is an autoimmune blistering disease targeting the desmosomal proteins desmoglein (Dsg) 1 and Dsg3. Recently, a genetic variant of the Suppression of tumorigenicity 18 (ST18) promoter was reported to cause ST18 up-regulation, associated with pemphigus vulgaris (PV)-IgG-mediated increase in cytokine secretion and more prominent loss of keratinocyte cohesion. Here we tested the effects of PV-IgG and the pathogenic pemphigus mouse anti-Dsg3 antibody AK23 on cytokine secretion and ERK activity in human keratinocytes dependent on ST18 expression. Without ST18 overexpression, both PV-IgG and AK23 induced loss of keratinocyte cohesion which was accompanied by prominent fragmentation of Dsg3 immunostaining along cell borders. In contrast, release of pro-inflammatory cytokines such as IL-1 alpha, IL-6, TNF alpha, and IFN-gamma was not altered significantly in both HaCaT and primary NHEK cells. These experiments indicate that cytokine expression is not strictly required for loss of keratinocyte cohesion. Upon ST18 overexpression, fragmentation of cell monolayers increased significantly in response to autoantibody incubation. Furthermore, production of IL-1 alpha and IL-6 was enhanced in some experiments but not in others whereas release of TNF-alpha dropped significantly upon PV-IgG application in both EV- and ST18-transfected HaCaT cells. Additionally, in NHEK, application of PV-IgG but not of AK23 significantly increased ERK activity. In contrast, ST18 overexpression in HaCaT cells augmented ERK activation in response to both c-IgG and AK23 but not PV-IgG. Because inhibition of ERK by U0126 abolished PV-IgG- and AK23-induced loss of cell cohesion in ST18-expressing cells, we conclude that autoantibody-induced ERK activation was relevant in this scenario. In summary, similar to the situation in PV patients carrying ST18 polymorphism, overexpression of ST18 enhanced keratinocyte susceptibility to autoantibody-induced loss of cell adhesion, which may be caused in part by enhanced ERK signaling. KW - pemphigus KW - desmosome KW - desmoglein KW - ST18 KW - ERK KW - cytokines Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224910 VL - 10 ER - TY - JOUR A1 - Streng, Andrea A1 - Goettler, David A1 - Haerlein, Miriam A1 - Lehmann, Lisa A1 - Ulrich, Kristina A1 - Prifert, Christiane A1 - Krempl, Christine A1 - Weißbrich, Benedikt A1 - Liese, Johannes G. T1 - Spread and clinical severity of respiratory syncytial virus A genotype ON1 in Germany, 2011–2017 JF - BMC Infectious Diseases N2 - Background The Respiratory Syncytial Virus (RSV) A genotype ON1, which was first detected in Ontario (Canada) in 2010/11, appeared in Germany in 2011/12. Preliminary observations suggested a higher clinical severity in children infected with this new genotype. We investigated spread and disease severity of RSV-A ON1 in pediatric in- and outpatient settings. Methods During 2010/11 to 2016/17, clinical characteristics and respiratory samples from children with acute respiratory tract infections (RTI) were obtained from ongoing surveillance studies in 33 pediatric practices (PP), one pediatric hospital ward (PW) and 23 pediatric intensive care units (PICU) in Germany. RSV was detected in the respiratory samples by PCR; genotypes were identified by sequencing. Within each setting, clinical severity markers were compared between RSV-A ON1 and RSV-A non-ON1 genotypes. Results A total of 603 children with RSV-RTI were included (132 children in PP, 288 in PW, and 183 in PICU). Of these children, 341 (56.6%) were infected with RSV-A, 235 (39.0%) with RSV-B, and one child (0.2%) with both RSV-A and RSV-B; in 26 (4.3%) children, the subtype could not be identified. In the 341 RSV-A positive samples, genotype ON1 was detected in 247 (72.4%), NA1 in 92 (26.9%), and GA5 in 2 children (0.6%). RSV-A ON1, rarely observed in 2011/12, was the predominant RSV-A genotype in all settings by 2012/13 and remained predominant until 2016/17. Children in PP or PW infected with RSV-A ON1 did not show a more severe clinical course of disease compared with RSV-A non-ON1 infections. In the PICU group, hospital stay was one day longer (median 8 days, inter-quartile range (IQR) 7–12 vs. 7 days, IQR 5–9; p = 0.02) and duration of oxygen treatment two days longer (median 6 days, IQR 4–9 vs. 4 days, IQR 2–6; p = 0.03) for children infected with RSV-A ON1. Conclusions In children, RSV-A ON1 largely replaced RSV-A non-ON1 genotypes within two seasons and remained the predominant RSV-A genotype in Germany during subsequent seasons. A higher clinical severity of RSV-A ON1 was observed within the group of children receiving PICU treatment, whereas in other settings clinical severity of RSV-A ON1 and non-ON1 genotypes was largely similar. KW - Children KW - Respiratory tract infection KW - RSV-A ON1 KW - Epidemiology KW - Disease severity Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201516 VL - 19 ER - TY - JOUR A1 - Sierra, Miguel A. A1 - Sánchez, David A1 - Gutierrez, Rafael A1 - Cuniberti, Gianaurelio A1 - Domínguez-Adame, Francisco A1 - Díaz, Elena T1 - Spin-polarized electron transmission in DNA-like systems JF - Biomolecules N2 - The helical distribution of the electronic density in chiral molecules, such as DNA and bacteriorhodopsin, has been suggested to induce a spin–orbit coupling interaction that may lead to the so-called chirality-induced spin selectivity (CISS) effect. Key ingredients for the theoretical modelling are, in this context, the helically shaped potential of the molecule and, concomitantly, a Rashba-like spin–orbit coupling due to the appearance of a magnetic field in the electron reference frame. Symmetries of these models clearly play a crucial role in explaining the observed effect, but a thorough analysis has been largely ignored in the literature. In this work, we present a study of these symmetries and how they can be exploited to enhance chiral-induced spin selectivity in helical molecular systems. KW - chirality-induced spin selectivity KW - helical molecules KW - spin transport KW - spin polarization KW - DNA electronic transport Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193813 SN - 2218-273X VL - 10 IS - 1 ER - TY - JOUR A1 - Lohr, David A1 - Terekhov, Maxim A1 - Weng, Andreas Max A1 - Schroeder, Anja A1 - Walles, Heike A1 - Schreiber, Laura Maria T1 - Spin echo based cardiac diffusion imaging at 7T: An ex vivo study of the porcine heart at 7T and 3T JF - PLoS ONE N2 - Purpose of this work was to assess feasibility of cardiac diffusion tensor imaging (cDTI) at 7 T in a set of healthy, unfixed, porcine hearts using various parallel imaging acceleration factors and to compare SNR and derived cDTI metrics to a reference measured at 3 T. Magnetic resonance imaging was performed on 7T and 3T whole body systems using a spin echo diffusion encoding sequence with echo planar imaging readout. Five reference (b = 0 s/mm\(^2\)) images and 30 diffusion directions (b = 700 s/mm\(^2\)) were acquired at both 7 T and 3 T using a GRAPPA acceleration factor R = 1. Scans at 7 T were repeated using R = 2, R = 3, and R = 4. SNR evaluation was based on 30 reference (b = 0 s/mm\(^2\)) images of 30 slices of the left ventricle and cardiac DTI metrics were compared within AHA segmentation. The number of hearts scanned at 7 T and 3 T was n = 11. No statistically significant differences were found for evaluated helix angle, secondary eigenvector angle, fractional anisotropy and apparent diffusion coefficient at the different field strengths, given sufficiently high SNR and geometrically undistorted images. R≥3 was needed to reduce susceptibility induced geometric distortions to an acceptable amount. On average SNR in myocardium of the left ventricle was increased from 29±3 to 44±6 in the reference image (b = 0 s/mm\(^2\)) when switching from 3 T to 7 T. Our study demonstrates that high resolution, ex vivo cDTI is feasible at 7 T using commercial hardware. KW - Heart KW - Diffusion tensor imaging KW - Eigenvectors KW - Cardiac ventricles KW - Tractography KW - Magnetic resonance imaging KW - Data acquisition KW - Swine Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201376 VL - 14 IS - 3 ER - TY - JOUR A1 - Avota, Elita A1 - de Lira, Maria Nathalia A1 - Schneider-Schaulies, Sibylle T1 - Sphingomyelin breakdown in T cells: role of membrane compartmentalization in T cell signaling and interference by a pathogen JF - Frontiers in Cell and Developmental Biology N2 - Sphingolipids are major components of cellular membranes, and at steady-state level, their metabolic fluxes are tightly controlled. On challenge by external signals, they undergo rapid turnover, which substantially affects the biophysical properties of membrane lipid and protein compartments and, consequently, signaling and morphodynamics. In T cells, external cues translate into formation of membrane microdomains where proximal signaling platforms essential for metabolic reprograming and cytoskeletal reorganization are organized. This review will focus on sphingomyelinases, which mediate sphingomyelin breakdown and ensuing ceramide release that have been implicated in T-cell viability and function. Acting at the sphingomyelin pool at the extrafacial or cytosolic leaflet of cellular membranes, acid and neutral sphingomyelinases organize ceramide-enriched membrane microdomains that regulate T-cell homeostatic activity and, upon stimulation, compartmentalize receptors, membrane proximal signaling complexes, and cytoskeletal dynamics as essential for initiating T-cell motility and interaction with endothelia and antigen-presenting cells. Prominent examples to be discussed in this review include death receptor family members, integrins, CD3, and CD28 and their associated signalosomes. Progress made with regard to experimental tools has greatly aided our understanding of the role of bioactive sphingolipids in T-cell biology at a molecular level and of targets explored by a model pathogen (measles virus) to specifically interfere with their physiological activity. KW - T cell KW - sphingomyelinase KW - activation KW - motility KW - measles virus Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199168 SN - 2296-634X VL - 7 IS - 152 ER - TY - JOUR A1 - Gräb, Patrick A1 - Geidel, Ekkehard T1 - Spectroscopic studies of food colorings JF - World Journal of Chemical Education N2 - In chemical education, it is often a challenge to understand the basic principles of spectroscopic techniques due to missing connections to the real world. Therefore, the present contribution offers context-based applications of UV/Vis spectroscopy for analytics of food colorings with which learners can improve their skills regarding this method. The spectroscopic determination of food colorings seems to be a promising approach due to the long tradition and omnipresence of dyes in supermarket products. The therefor-required spectral data for commonly used dyes are provided for educational usage. Qualitative and quantitative analytics of food colorings in four different lemonades and chocolate beans have been used to introduce learners to important analytical techniques like sample preparation or elimination of confounding factors. These analytics also display the limitations of the method in the visible range of light in the case of tartrazine and curcumin. By applying Lambert-Beer-Bouguer’s Law in different variations, typical calculations of concentrations can be studied in quantitative analyses. The studied food samples demonstrate the different usage of food colorings depending on the country of sale. Finally, a 3D-printable low-cost photometer suitable for the discussed quantitative analytics in educational contexts is presented. KW - UV/Vis spectroscopy KW - quantitative analysis KW - food colorings KW - context-based teaching KW - low-cost photometer Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201908 VL - 7 IS - 2 ER - TY - JOUR A1 - Nickel, Joachim A1 - Mueller, Thomas D. T1 - Specification of BMP signaling JF - Cells N2 - Bone Morphogenetic Proteins (BMPs) together with the Growth and Differentiation Factors (GDFs) form the largest subgroup of the Transforming Growth Factor (TGF)β family and represent secreted growth factors, which play an essential role in many aspects of cell communication in higher organisms. As morphogens they exert crucial functions during embryonal development, but are also involved in tissue homeostasis and regeneration in the adult organism. Their involvement in maintenance and repair processes of various tissues and organs made these growth factors highly interesting targets for novel pharmaceutical applications in regenerative medicine. A hallmark of the TGFβ protein family is that all of the more than 30 growth factors identified to date signal by binding and hetero-oligomerization of a very limited set of transmembrane serine-threonine kinase receptors, which can be classified into two subgroups termed type I and type II. Only seven type I and five type II receptors exist for all 30plus TGFβ members suggesting a pronounced ligand-receptor promiscuity. Indeed, many TGFβ ligands can bind the same type I or type II receptor and a particular receptor of either subtype can usually interact with and bind various TGFβ ligands. The possible consequence of this ligand-receptor promiscuity is further aggravated by the finding that canonical TGFβ signaling of all family members seemingly results in the activation of just two distinct signaling pathways, that is either SMAD2/3 or SMAD1/5/8 activation. While this would implicate that different ligands can assemble seemingly identical receptor complexes that activate just either one of two distinct pathways, in vitro and in vivo analyses show that the different TGFβ members exert quite distinct biological functions with high specificity. This discrepancy indicates that our current view of TGFβ signaling initiation just by hetero-oligomerization of two receptor subtypes and transduction via two main pathways in an on-off switch manner is too simplified. Hence, the signals generated by the various TGFβ members are either quantitatively interpreted using the subtle differences in their receptor-binding properties leading to ligand-specific modulation of the downstream signaling cascade or additional components participating in the signaling activation complex allow diversification of the encoded signal in a ligand-dependent manner at all cellular levels. In this review we focus on signal specification of TGFβ members, particularly of BMPs and GDFs addressing the role of binding affinities, specificities, and kinetics of individual ligand-receptor interactions for the assembly of specific receptor complexes with potentially distinct signaling properties. KW - TGFβ/BMP signaling KW - ligand-receptor promiscuity KW - signal specification Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193869 SN - 2073-4409 VL - 8 IS - 12 ER - TY - JOUR A1 - Streinzer, Martin A1 - Chakravorty, Jharna A1 - Neumayer, Johann A1 - Megu, Karsing A1 - Narah, Jaya A1 - Schmitt, Thomas A1 - Bharti, Himender A1 - Spaethe, Johannes A1 - Brockmann, Axel T1 - Species composition and elevational distribution of bumble bees (Hymenoptera, Apidae, Bombus Latreille) in the East Himalaya, Arunachal Pradesh, India JF - ZooKeys N2 - The East Himalaya is one of the world’s most biodiverse ecosystems. However, very little is known about the abundance and distribution of many plant and animal taxa in this region. Bumble bees are a group of cold-adapted and high elevation insects that fulfil an important ecological and economical function as pollinators of wild and agricultural flowering plants and crops. The Himalayan mountain range provides ample suitable habitats for bumble bees. Systematic study of Himalayan bumble bees began a few decades ago and the main focus has centred on the western region, while the eastern part of the mountain range has received little attention and only a few species have been verified. During a three-year survey, more than 700 bumble bee specimens of 21 species were collected in Arunachal Pradesh, the largest of the north-eastern states of India. The material included a range of species that were previously known from a limited number of collected specimens, which highlights the unique character of the East Himalayan ecosystem. Our results are an important first step towards a future assessment of species distribution, threat, and conservation. Clear elevation patterns of species diversity were observed, which raise important questions about the functional adaptations that allow bumble bees to thrive in this particularly moist region in the East Himalaya. KW - Alpine habitats KW - Apidae KW - conservation KW - global change KW - insect collection KW - pollination Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201937 VL - 851 ER -