TY - JOUR A1 - Spinaci, Andrea A1 - Lambertucci, Catia A1 - Buccioni, Michela A1 - Dal Ben, Diego A1 - Graiff, Claudia A1 - Barbalace, Maria Cristina A1 - Hrelia, Silvana A1 - Angeloni, Cristina A1 - Tayebati, Seyed Khosrow A1 - Ubaldi, Massimo A1 - Masi, Alessio A1 - Klotz, Karl-Norbert A1 - Volpini, Rosaria A1 - Marucci, Gabriella T1 - A\(_{2A}\) adenosine receptor antagonists: are triazolotriazine and purine scaffolds interchangeable? JF - Molecules N2 - The A\(_{2A}\) adenosine receptor (A\(_{2A}\)AR) is one of the four subtypes activated by nucleoside adenosine, and the molecules able to selectively counteract its action are attractive tools for neurodegenerative disorders. In order to find novel A\(_{2A}\)AR ligands, two series of compounds based on purine and triazolotriazine scaffolds were synthesized and tested at ARs. Compound 13 was also tested in an in vitro model of neuroinflammation. Some compounds were found to possess high affinity for A\(_{2A}\)AR, and it was observed that compound 13 exerted anti-inflammatory properties in microglial cells. Molecular modeling studies results were in good agreement with the binding affinity data and underlined that triazolotriazine and purine scaffolds are interchangeable only when 5- and 2-positions of the triazolotriazine moiety (corresponding to the purine 2- and 8-positions) are substituted. KW - A\(_{2A}\) adenosine receptor antagonist KW - purine derivatives KW - triazolotriazine derivatives KW - anti-Parkinson agents KW - anti-inflammatory agents KW - molecular modeling Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270618 SN - 1420-3049 VL - 27 IS - 8 ER - TY - JOUR A1 - Kunzmann, Steffen A1 - Hütten, Matthias A1 - Ottensmeier, Barbara A1 - Kramer, Boris W. A1 - Fehrholz, Markus T1 - A20 is increased in fetal lung in a sheep LPS model of chorioamnionitis JF - Oxidative Medicine and Cellular Longevity N2 - Chorioamnionitis is associated with an increased risk of preterm birth and aggravates adverse outcomes such as BPD. Development of BPD is associated with chronic inflammatory reactions and oxidative stress in the airways which may be antenatally initiated by chorioamnionitis. A20 is an immunomodulatory protein involved in the negative feedback regulation of inflammatory reactions and is a possible regulator protein in oxidative stress reactions. The influence of chorioamnionitis on A20 gene regulation in the fetal lung is unknown. We characterized the influence of LPS and proinflammatory cytokines on A20 expression in human lung endothelial (HPMEC-ST1.6R) and epithelial (A549) cells in vitro by real-time PCR and/or western blotting and used a sheep model of LPS-induced chorioamnionitis for in vivo studies. To study the functional role of A20, endogenous A20 was overexpressed in HPMEC-ST1.6R and A549 cells. LPS induced proinflammatory cytokines in HPMEC-ST1.6R and A549 cells. Both LPS and/or proinflammatory cytokines elevated A20 at transcriptional and translational levels. Intra-amniotic LPS transiently increased IL-1β, IL-6, IL-8, and TNF-α mRNA levels in fetal lamb lungs, associated with an increase in A20 mRNA and protein levels. Overexpression of A20 reduced proinflammatory cytokines in vitro. Repeated LPS exposure induced LPS tolerance for proinflammatory cytokines and A20 in vitro and in vivo. Antenatal inflammation induced a transient increase in proinflammatory cytokines in the preterm fetal lung. The expression of proinflammatory cytokines increased expression of A20. Elevated A20 may have a protective role by downregulating chorioamnionitis-triggered fetal lung inflammation. A20 may be a novel target for pharmacological interventions to prevent chorioamnionitis-induced airway inflammation and lung damage, which can result in BPD later in life. KW - Chorioamnionitis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265869 VL - 2022 ER - TY - JOUR A1 - Mayr, Eva-Maria A1 - Ramírez-Zavala, Bernardo A1 - Krüger, Ines A1 - Morschhäuser, Joachim T1 - A Zinc Cluster Transcription Factor Contributes to the Intrinsic Fluconazole Resistance of Candida auris JF - mSphere N2 - ABSTRACT The recently emerged pathogenic yeast Candida auris is a major concern for human health, because it is easily transmissible, difficult to eradicate from hospitals, and highly drug resistant. Most C. auris isolates are resistant to the widely used antifungal drug fluconazole due to mutations in the target enzyme Erg11 and high activity of efflux pumps, such as Cdr1. In the well-studied, distantly related yeast Candida albicans, overexpression of drug efflux pumps also is a major mechanism of acquired fluconazole resistance and caused by gain-of-function mutations in the zinc cluster transcription factors Mrr1 and Tac1. In this study, we investigated a possible involvement of related transcription factors in efflux pump expression and fluconazole resistance of C. auris. The C. auris genome contains three genes encoding Mrr1 homologs and two genes encoding Tac1 homologs, and we generated deletion mutants lacking these genes in two fluconazole-resistant strains from clade III and clade IV. Deletion of TAC1b decreased the resistance to fluconazole and voriconazole in both strain backgrounds, demonstrating that the encoded transcription factor contributes to azole resistance in C. auris strains from different clades. CDR1 expression was not or only minimally affected in the mutants, indicating that Tac1b can confer increased azole resistance by a CDR1-independent mechanism. IMPORTANCE Candida auris is a recently emerged pathogenic yeast that within a few years after its initial description has spread all over the globe. C. auris is a major concern for human health, because it can cause life-threatening systemic infections, is easily transmissible, and is difficult to eradicate from hospital environments. Furthermore, C. auris is highly drug resistant, especially against the widely used antifungal drug fluconazole. Mutations in the drug target and high activity of efflux pumps are associated with azole resistance, but it is not known how drug resistance genes are regulated in C. auris. We have investigated the potential role of several candidate transcriptional regulators in the intrinsic fluconazole resistance of C. auris and identified a transcription factor that contributes to the high resistance to fluconazole and voriconazole of two C. auris strains from different genetic clades, thereby providing insight into the molecular basis of drug resistance of this medically important yeast." KW - Candida auris KW - fluconazole resistance KW - transcription factor Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229937 VL - 5 IS - 2 ER - TY - JOUR A1 - Baader, Anna A1 - Kiani, Behnaz A1 - Brunkhorst-Kanaan, Nathalie A1 - Kittel-Schneider, Sarah A1 - Reif, Andreas A1 - Grimm, Oliver T1 - A within-sample comparison of two innovative neuropsychological tests for assessing ADHD JF - Brain Sciences N2 - New innovative neuropsychological tests in attention deficit hyperactivity disorder ADHD have been proposed as objective measures for diagnosis and therapy. The current study aims to investigate two different commercial continuous performance tests (CPT) in a head-to-head comparison regarding their comparability and their link with clinical parameters. The CPTs were evaluated in a clinical sample of 29 adult patients presenting in an ADHD outpatient clinic. Correlational analyses were performed between neuropsychological data, clinical rating scales, and a personality-based measure. Though inattention was found to positively correlate between the two tests (r = 0.49, p = 0.01), no association with clinical measures and inattention was found for both tests. While hyperactivity did not correlate between both tests, current ADHD symptoms were positively associated with Nesplora Aquarium's motor activity (r = 0.52 to 0.61, p < 0.05) and the Qb-Test's hyperactivity (r = 0.52 to 0.71, p < 0.05). Conclusively, the overall comparability of the tests was limited and correlation with clinical parameters was low. While our study shows some interesting correlation between clinical symptoms and sub-scales of these tests, usage in clinical practice is not recommended. KW - ADHD KW - neuropsychology KW - continuous performance test KW - Qb-Test KW - Nesplora Aquarium KW - attention KW - hyperactivity KW - GHQ-28 KW - UPPS KW - impulsivity Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220089 SN - 2076-3425 VL - 11 IS - 1 ER - TY - JOUR A1 - von Bohl, Andreas A1 - Kuehn, Andrea A1 - Simon, Nina A1 - Nkwouano Ngongang, Vanesa A1 - Spehr, Marc A1 - Baumeister, Stefan A1 - Przyborski, Jude M. A1 - Fischer, Rainer A1 - Pradel, Gabriele T1 - A WD40-repeat protein unique to malaria parasites associates with adhesion protein complexes and is crucial for blood stage progeny JF - Malaria Journal N2 - Background During development in human erythrocytes, Plasmodium falciparum parasites display a remarkable number of adhesive proteins on their plasma membrane. In the invasive merozoites, these include members of the PfMSP1 and PfAMA1/RON complexes, which facilitate contact between merozoites and red blood cells. In gametocytes, sexual precursor cells mediating parasite transmission to the mosquito vector, plasma membrane-associated proteins primarily belong to the PfCCp and 6-cys families with roles in fertilization. This study describes a newly identified WD40-repeat protein unique to Plasmodium species that associates with adhesion protein complexes of both merozoites and gametocytes. Methods The WD40-repeat protein-like protein PfWLP1 was identified via co-immunoprecipitation assays followed by mass spectrometry and characterized using biochemical and immunohistochemistry methods. Reverse genetics were employed for functional analysis. Results PfWLP1 is expressed both in schizonts and gametocytes. In mature schizonts, the protein localizes underneath the merozoite micronemes and interacts with PfAMA1, while in gametocytes PfWLP1 primarily accumulates underneath the plasma membrane and associates with PfCCp1 and Pfs230. Reverse genetics failed to disrupt the pfwlp1 gene, while haemagglutinin-tagging was feasible, suggesting a crucial function for PfWLP1 during blood stage replication. Conclusions This is the first report on a plasmodial WD40-repeat protein associating with cell adhesion proteins. Since WD40 domains are known to mediate protein–protein contact by serving as a rigid scaffold for protein interactions, the presented data suggest that PfWLP1 supports the stability of adhesion protein complexes of the plasmodial blood stages. KW - PfCCp protein KW - Pfs230 KW - PfAMA1 KW - WD40 KW - gametocyte KW - microneme KW - merozoite KW - plasmodium falciparum KW - malaria Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-139728 VL - 14 IS - 435 ER - TY - JOUR A1 - Kirchner, Philipp H. A1 - Schramm, Louis A1 - Ivanova, Svetlana A1 - Shoyama, Kazutaka A1 - Würthner, Frank A1 - Beuerle, Florian T1 - A water-stable boronate ester cage JF - Journal of the American Chemical Society N2 - The reversible condensation of catechols and boronic acids to boronate esters is a paradigm reaction in dynamic covalent chemistry. However, facile backward hydrolysis is detrimental for stability and has so far prevented applications for boronate-based materials. Here, we introduce cubic boronate ester cages 6 derived from hexahydroxy tribenzotriquinacenes and phenylene diboronic acids with ortho-t-butyl substituents. Due to steric shielding, dynamic exchange at the Lewis acidic boron sites is feasible only under acid or base catalysis but fully prevented at neutral conditions. For the first time, boronate ester cages 6 tolerate substantial amounts of water or alcohols both in solution and solid state. The unprecedented applicability of these materials under ambient and aqueous conditions is showcased by efficient encapsulation and on-demand release of β-carotene dyes and heterogeneous water oxidation catalysis after the encapsulation of ruthenium catalysts. KW - absorption KW - hydrocarbons KW - materials KW - organic compounds KW - stability KW - boronate esters Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-361245 SN - 0002-7863 VL - 146 IS - 8 ER - TY - JOUR A1 - Schwartz, Faina A1 - Neve, Rachel A1 - Eisenman, Robert A1 - Gessler, Manfred A1 - Bruns, Gail T1 - A WAGR region gene between PAX-6 and FSHB expressed in fetal brain N2 - Developmental delay or mental retardation is a frequent component of multi-system anomaly syndromes associated with chromosomal deletions. Isolation of genes involved in the mental dysfunction in these disorders should define loci important in brain formation or function. We have identified a highly conserved locus in the distal part of 11 p 13 that is prominently expressed in fetal brain. Minimal expression is observed in a number of other fetal tissues. The gene maps distal to PAX-6 but proximal to the loci for brain-derived neurotrophic factor (BDNF) and the beta subunit of follicle stimulating hormone (FSHB), within a region previously implicated in the mental retardation component of some WAGR syndrome patients. Within fetal brain, the corresponding transcript is prominent in frontal, motor and primary visual cortex as weil as in the caudate-putamen. The characteristics of this gene, including the striking evolutionary conservation at the locus, suggest that the encoded protein may function in brain development. KW - Biochemie Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59125 ER - TY - JOUR A1 - Dindas, Julian A1 - Dreyer, Ingo A1 - Huang, Shouguang A1 - Hedrich, Rainer A1 - Roelfsema, M. Rob G. T1 - A voltage-dependent Ca\(^{2+}\) homeostat operates in the plant vacuolar membrane JF - New Phytologist N2 - Cytosolic calcium signals are evoked by a large variety of biotic and abiotic stimuli and play an important role in cellular and long distance signalling in plants. While the function of the plasma membrane in cytosolic Ca\(^{2+}\) signalling has been intensively studied, the role of the vacuolar membrane remains elusive. A newly developed vacuolar voltage clamp technique was used in combination with live-cell imaging, to study the role of the vacuolar membrane in Ca\(^{2+}\) and pH homeostasis of bulging root hair cells of Arabidopsis. Depolarisation of the vacuolar membrane caused a rapid increase in the Ca\(^{2+}\) concentration and alkalised the cytosol, while hyperpolarisation led to the opposite responses. The relationship between the vacuolar membrane potential, the cytosolic pH and Ca2+ concentration suggests that a vacuolar H\(^{+}\)/Ca\(^{2+}\) exchange mechanism plays a central role in cytosolic Ca2+ homeostasis. Mathematical modelling further suggests that the voltage-dependent vacuolar Ca\(^{2+}\) homeostat could contribute to calcium signalling when coupled to a recently discovered K\(^{+}\) channel-dependent module for electrical excitability of the vacuolar membrane. KW - voltage clamp KW - Arabidopsis thaliana KW - calcium signalling KW - computational cell biology KW - cpYFP cytosolic pH reporter KW - R-GECO1 cytosolic Ca\(^{2+}\) reporter KW - TPC1 channel KW - vacuolar membrane Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259627 VL - 230 IS - 4 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Andree, Christian A1 - Javadi, Mehrbod S. A1 - Lapa, Constantin A1 - Buck, Andreas K. A1 - Higuchi, Takahiro A1 - Pomper, Martin G. A1 - Gorin, Michael A. A1 - Rowe, Steven P. A1 - Pienta, Kenneth J. T1 - A Voice From the Past: Re-Discovering the Virchow Node with PSMA-targeted \(^{18}\)F-DCFPyL PET Imaging JF - Urology - The Gold Journal N2 - No abstract available. KW - 18F-DCFPyL KW - PET KW - PSMA-PET KW - Positron Emission Tomography KW - Prostate Cancer KW - Virchow Node Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164632 SN - 0090-4295 VL - 117 ER - TY - JOUR A1 - Kiser, Dominik P. A1 - Gromer, Daniel A1 - Pauli, Paul A1 - Hilger, Kirsten T1 - A virtual reality social conditioned place preference paradigm for humans: Does trait social anxiety affect approach and avoidance of virtual agents? JF - Frontiers in Virtual Reality N2 - Approach and avoidance of positive and negative social cues are fundamental to prevent isolation and ensure survival. High trait social anxiety is characterized by an avoidance of social situations and extensive avoidance is a risk factor for the development of social anxiety disorder (SAD). Therefore, experimental methods to assess social avoidance behavior in humans are essential. The social conditioned place preference (SCPP) paradigm is a well-established experimental paradigm in animal research that is used to objectively investigate social approach–avoidance mechanisms. We retranslated this paradigm for human research using virtual reality. To this end, 58 healthy adults were exposed to either a happy- or angry-looking virtual agent in a specific room, and the effects of this encounter on dwell time as well as evaluation of this room in a later test without an agent were examined. We did not observe a general SCPP effect on dwell time or ratings but discovered a moderation by trait social anxiety, in which participants with higher trait social anxiety spent less time in the room in which the angry agent was present before, suggesting that higher levels of trait social anxiety foster conditioned social avoidance. However, further studies are needed to verify this observation and substantiate an association with social anxiety disorder. We discussed the strengths, limitations, and technical implications of our paradigm for future investigations to more comprehensively understand the mechanisms involved in social anxiety and facilitate the development of new personalized treatment approaches by using virtual reality. KW - retranslational research KW - conditioned place preference KW - approach–avoidance KW - social anxiety KW - virtual reality KW - personality traits KW - individual differences Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-293564 SN - 2673-4192 VL - 3 ER -