TY - JOUR A1 - Welker, Armin A1 - Kersten, Christian A1 - Müller, Christin A1 - Madhugiri, Ramakanth A1 - Zimmer, Collin A1 - Müller, Patrick A1 - Zimmermann, Robert A1 - Hammerschmidt, Stefan A1 - Maus, Hannah A1 - Ziebuhr, John A1 - Sotriffer, Christoph A1 - Schirmeister, Tanja T1 - Structure‐Activity Relationships of Benzamides and Isoindolines Designed as SARS‐CoV Protease Inhibitors Effective against SARS‐CoV‐2 JF - ChemMedChem N2 - Inhibition of coronavirus (CoV)‐encoded papain‐like cysteine proteases (PL\(^{pro}\)) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure‐activity relationships (SAR) of the noncovalent active‐site directed inhibitor (R)‐5‐amino‐2‐methyl‐N‐(1‐(naphthalen‐1‐yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS‐CoV PL\(^{pro}\). Moreover, we report the discovery of isoindolines as a new class of potent PL\(^{pro}\) inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS‐CoV‐2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS‐CoV PL\(^{pro}\) are valuable starting points for the development of new pan‐coronaviral inhibitors. KW - antiviral agents KW - computational chemistry KW - drug design KW - protease inhibitors KW - structure-activity relationships Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225700 VL - 16 IS - 2 SP - 340 EP - 354 ER - TY - JOUR A1 - Spinelli, Simona A1 - Müller, Tanja A1 - Friedel, Miriam A1 - Sigrist, Hannes A1 - Lesch, Klaus-Peter A1 - Henkelman, Mark A1 - Rudin, Markus A1 - Seifritz, Erich A1 - Pryce, Christopher R. T1 - Effects of repeated adolescent stress and serotonin transporter gene partial knockout in mice on behaviors and brain structures relevant to major depression JF - Frontiers in Behavioral Neuroscience N2 - In humans, exposure to stress during development is associated with structural and functional alterations of the prefrontal cortex (PFC), amygdala (AMY), and hippocampus (HC) and their circuits of connectivity, and with an increased risk for developing major depressive disorder particularly in carriers of the short (s) variant of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR). Although changes in these regions are found in carriers of the s allele and/or in depressed patients, evidence for a specific genotype x developmental stress effect on brain structure and function is limited. Here, we investigated the effect of repeated stress exposure during adolescence in mice with partial knockout of the 5-HIT gene (HET) vs. wildtype (WT) on early-adulthood behavioral measures and brain structure [using magnetic resonance imaging (MRI)] relevant to human major depression. Behaviorally, adolescent stress (AS) increased anxiety and decreased activity and did so to a similar degree in HET and WT. In a probabilistic reversal learning task, HET-AS mice achieved fewer reversals than did HET-No-AS mice. 5-HIT genotype and AS were without effect on corticosterone stress response. In terms of structural brain differences, AS reduced the volume of two long-range white matter tracts, the optic tract (OT) and the cerebral peduncle (CP), in WT mice specifically. In a region-of-interest analysis, AS was associated with increased HC volume and HET genotype with a decreased frontal lobe volume. In conclusion, we found that 5-HIT and AS genotype exerted long-term effects on behavior and development of brain regions relevant to human depression. KW - mouse-brain KW - white-matter integrity KW - linked polymorphic region KW - C57BL/6 mice KW - lerned helplessness KW - 5-HTTLPR polymorphism KW - childhood maltreatment KW - rhesus macaques KW - 3-dimensional MRI KW - life stress Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122240 VL - 7 ER - TY - JOUR A1 - Hennings, Johannes M. A1 - Kohli, Martin A. A1 - Czamara, Darina A1 - Giese, Maria A1 - Eckert, Anne A1 - Wolf, Christiane A1 - Heck, Angela A1 - Domschke, Katharina A1 - Arolt, Volker A1 - Baune, Bernhard T. A1 - Horstmann, Sonja A1 - Brückl, Tanja A1 - Klengel, Torsten A1 - Menke, Andreas A1 - Müller-Myhsok, Bertram A1 - Ising, Marcus A1 - Uhr, Manfred A1 - Lucae, Susanne T1 - Possible Associations of NTRK2 Polymorphisms with Antidepressant Treatment Outcome: Findings from an Extended Tag SNP Approach JF - PLoS ONE N2 - Background: Data from clinical studies and results from animal models suggest an involvement of the neurotrophin system in the pathology of depression and antidepressant treatment response. Genetic variations within the genes coding for the brain-derived neurotrophic factor (BDNF) and its key receptor Trkb (NTRK2) may therefore influence the response to antidepressant treatment. Methods: We performed a single and multi-marker association study with antidepressant treatment outcome in 398 depressed Caucasian inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Two Caucasian replication samples (N = 249 and N = 247) were investigated, resulting in a total number of 894 patients. 18 tagging SNPs in the BDNF gene region and 64 tagging SNPs in the NTRK2 gene region were genotyped in the discovery sample; 16 nominally associated SNPs were tested in two replication samples. Results: In the discovery analysis, 7 BDNF SNPs and 9 NTRK2 SNPs were nominally associated with treatment response. Three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) also showed associations in at least one replication sample and in the combined sample with the same direction of effects (\(P_{corr}\) = .018, \(P_{corr}\) = .015 and \(P_{corr}\) = .004, respectively). We observed an across-gene BDNF-NTRK2 SNP interaction for rs4923468 and rs1387926. No robust interaction of associated SNPs was found in an analysis of BDNF serum protein levels as a predictor for treatment outcome in a subset of 93 patients. Conclusions/Limitations: Although not all associations in the discovery analysis could be unambiguously replicated, the findings of the present study identified single nucleotide variations in the BDNF and NTRK2 genes that might be involved in antidepressant treatment outcome and that have not been previously reported in this context. These new variants need further validation in future association studies. KW - brain KW - bipolar disorder KW - mood disorder KW - treatment response KW - genome-wide association KW - major depressive disorder KW - neurotrophic factor gene KW - VAL66MET polymorphism KW - sequence variations KW - messenger RNA Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130924 VL - 8 IS - 6 ER - TY - JOUR A1 - Chatterjee, Manik A1 - Andrulis, Mindaugas A1 - Stühmer, Thorsten A1 - Müller, Elisabeth A1 - Hofmann, Claudia A1 - Steinbrunn, Torsten A1 - Heimberger, Tanja A1 - Schraud, Heike A1 - Kressmann, Stefanie A1 - Einsele, Hermann A1 - Bargou, Ralf C. T1 - The PI3K/Akt signaling pathway regulates the expression of Hsp70, which critically contributes to Hsp90-chaperone function and tumor cell survival in multiple myeloma JF - Haematologica N2 - Despite therapeutic advances multiple myeloma remains largely incurable, and novel therapeutic concepts are needed. The Hsp90-chaperone is a reasonable therapeutic target, because it maintains oncogenic signaling of multiple deregulated pathways. However, in contrast to promising pre-clinical results, only limited clinical efficacy has been achieved through pharmacological Hsp90 inhibition. Because Hsp70 has been described to interact functionally with the Hsp90-complex, we analyzed the suitability of Hsp72 and Hsp73 as potential additional target sites. Expression of Hsp72 and Hsp73 in myeloma cells was analyzed by immunohistochemical staining and western blotting. Short interfering RNA-mediated knockdown or pharmacological inhibition of Hsp72 and Hsp73 was performed to evaluate the role of these proteins in myeloma cell survival and for Hsp90-chaperone function. Furthermore, the role of PI3K-dependent signaling in constitutive and inducible Hsp70 expression was investigated using short interfering RNA-mediated and pharmacological PI3K inhibition. Hsp72 and Hsp73 were frequently overexpressed in multiple myeloma. Knockdown of Hsp72 and/or Hsp73 or treatment with VER-155008 induced apoptosis of myeloma cells. Hsp72/Hsp73 inhibition decreased protein levels of Hsp90-chaperone clients affecting multiple oncogenic signaling pathways, and acted synergistically with the Hsp90 inhibitor NVP-AUY922 in the induction of death of myeloma cells. Inhibition of the PI3K/Akt/GSK3b pathway with short interfering RNA or PI103 decreased expression of the heat shock transcription factor 1 and down-regulated constitutive and inducible Hsp70 expression. Treatment of myeloma cells with a combination of NVP-AUY922 and PI103 resulted in additive to synergistic cytotoxicity. In conclusion, Hsp72 and Hsp73 sustain Hsp90-haperone function and critically contribute to the survival of myeloma cells. Translation of Hsp70 inhibition into the clinic is therefore highly desirable. Treatment with PI3K inhibitors might represent an alternative therapeutic strategy to target Hsp70. KW - Haematology Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130574 VL - 98 IS - 7 ER - TY - JOUR A1 - Morris, E. Kathryn A1 - Caruso, Tancredi A1 - Buscot, Francois A1 - Fischer, Markus A1 - Hancock, Christine A1 - Maier, Tanja S. A1 - Meiners, Torsten A1 - Müller, Caroline A1 - Obermaier, Elisabeth A1 - Prati, Daniel A1 - Socher, Stephanie A. A1 - Sonnemann, Ilja A1 - Wäschke, Nicola A1 - Wubet, Tesfaye A1 - Wurst, Susanne A1 - Rillig, Matthias C. T1 - Choosing and using diversity indices: insights for ecological applications from the German Biodiversity Exploratories JF - Ecology and Evolution N2 - Biodiversity, a multidimensional property of natural systems, is difficult to quantify partly because of the multitude of indices proposed for this purpose. Indices aim to describe general properties of communities that allow us to compare different regions, taxa, and trophic levels. Therefore, they are of fundamental importance for environmental monitoring and conservation, although there is no consensus about which indices are more appropriate and informative. We tested several common diversity indices in a range of simple to complex statistical analyses in order to determine whether some were better suited for certain analyses than others. We used data collected around the focal plant Plantago lanceolata on 60 temperate grassland plots embedded in an agricultural landscape to explore relationships between the common diversity indices of species richness (S), Shannon's diversity (H'), Simpson's diversity (D-1), Simpson's dominance (D-2), Simpson's evenness (E), and Berger-Parker dominance (BP). We calculated each of these indices for herbaceous plants, arbuscular mycorrhizal fungi, aboveground arthropods, belowground insect larvae, and P.lanceolata molecular and chemical diversity. Including these trait-based measures of diversity allowed us to test whether or not they behaved similarly to the better studied species diversity. We used path analysis to determine whether compound indices detected more relationships between diversities of different organisms and traits than more basic indices. In the path models, more paths were significant when using H', even though all models except that with E were equally reliable. This demonstrates that while common diversity indices may appear interchangeable in simple analyses, when considering complex interactions, the choice of index can profoundly alter the interpretation of results. Data mining in order to identify the index producing the most significant results should be avoided, but simultaneously considering analyses using multiple indices can provide greater insight into the interactions in a system. KW - molecular diversity KW - plant diversity KW - plantago lanceolata KW - shannon index KW - simpson's index KW - arbuscular mycorrhizal fungi KW - Hill's powers KW - chemical diversity KW - Berger-Parker KW - arthropods Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115462 SN - 2045-7758 VL - 4 IS - 18 ER - TY - JOUR A1 - Bartmann, Catharina A1 - Fischer, Leah-Maria A1 - Hübner, Theresa A1 - Müller-Reiter, Max A1 - Wöckel, Achim A1 - McNeill, Rhiannon V. A1 - Schlaiss, Tanja A1 - Kittel-Schneider, Sarah A1 - Kämmerer, Ulrike A1 - Diessner, Joachim T1 - The effects of the COVID-19 pandemic on psychological stress in breast cancer patients JF - BMC Cancer N2 - Background: The majority of breast cancer patients are severely psychologically affected by breast cancer diagnosis and subsequent therapeutic procedures. The COVID-19 pandemic and associated restrictions on public life have additionally caused significant psychological distress for much of the population. It is therefore plausible that breast cancer patients might be particularly susceptible to the additional psychological stress caused by the pandemic, increasing suffering. In this study we therefore aimed to assess the level of psychological distress currently experienced by a defined group of breast cancer patients in our breast cancer centre, compared to distress levels preCOVID-19 pandemic. Methods: Female breast cancer patients of all ages receiving either adjuvant, neoadjuvant, or palliative therapies were recruited for the study. All patients were screened for current or previous COVID-19 infection. The participants completed a self-designed COVID-19 pandemic questionnaire, the Stress and Coping Inventory (SCI), the National Comprehensive Cancer Network (R) (NCCN (R)) Distress Thermometer (DT), the European Organization for Research and Treatment of Cancer (EORTC) QLQ C30, and the BR23. Results: Eighty-two breast cancer patients were included. Therapy status and social demographic factors did not have a significant effect on the distress caused by the COVID-19 pandemic. The results of the DT pre and during COVID-19 pandemic did not differ significantly. Using the self-designed COVID-19 pandemic questionnaire, we detected three distinct subgroups demonstrating different levels of concerns in relation to SARS-CoV-2. The subgroup with the highest levels of concern reported significantly decreased life quality, related parameters and symptoms. Conclusions: This monocentric study demonstrated that the COVID-19 pandemic significantly affected psychological health in a subpopulation of breast cancer patients. The application of a self-created "COVID-19 pandemic questionnaire"could potentially be used to help identify breast cancer patients who are susceptible to increased psychological distress due to the COVID-19 pandemic, and therefore may need additional intensive psychological support. KW - COVID-19 KW - breast cancer KW - psychological distress Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265802 VL - 21 ER - TY - JOUR A1 - Maass, Anne A1 - Düzel, Sandra A1 - Brigadski, Tanja A1 - Goerke, Monique A1 - Becke, Andreas A1 - Sobieray, Uwe A1 - Neumann, Katja A1 - Lövdén, Martin A1 - Lindenberger, Ulman A1 - Bäckman, Lars A1 - Braun-Dullaeus, Rüdiger A1 - Ahrens, Dörte A1 - Heinze, Hans-Jochen A1 - Müller, Notger G. A1 - Lessmann, Volkmar A1 - Sendtner, Michael A1 - Düzel, Emrah T1 - Relationships of peripheral IGF-1, VEGF and BDNF levels to exercise-related changes in memory, hippocampal perfusion and volumes in older adults JF - NeuroImage N2 - Animal models point towards a key role of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in mediating exercise-induced structural and functional changes in the hippocampus. Recently, also platelet derived growth factor-C (PDGF-C) has been shown to promote blood vessel growth and neuronal survival. Moreover, reductions of these neurotrophic and angiogenic factors in old age have been related to hippocampal atrophy, decreased vascularization and cognitive decline. In a 3-month aerobic exercise study, forty healthy older humans (60 to 77 years) were pseudo-randomly assigned to either an aerobic exercise group (indoor treadmill, n = 21) or to a control group (indoor progressive-muscle relaxation/stretching, n = 19). As reported recently, we found evidence for fitness-related perfusion changes of the aged human hippocampus that were closely linked to changes in episodic memory function. Here, we test whether peripheral levels of BDNF, IGF-I, VEGF or PDGF-C are related to changes in hippocampal blood flow, volume and memory performance. Growth factor levels were not significantly affected by exercise, and their changes were not related to changes in fitness or perfusion. However, changes in IGF-I levels were positively correlated with hippocampal volume changes (derived by manual volumetry and voxel-based morphometry) and late verbal recall performance, a relationship that seemed to be independent of fitness, perfusion or their changes over time. These preliminary findings link IGF-I levels to hippocampal volume changes and putatively hippocampus-dependent memory changes that seem to occur over time independently of exercise. We discuss methodological shortcomings of our study and potential differences in the temporal dynamics of how IGF-1, VEGF and BDNF may be affected by exercise and to what extent these differences may have led to the negative findings reported here. KW - Exercise KW - Neurotrophic factors KW - Hippocampus KW - Vascular plasticity KW - Aging Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189219 VL - 131 ER - TY - JOUR A1 - Hanke, Kathrin A1 - Rausch, Tanja K. A1 - Sosnowski, Runa A1 - Paul, Pia A1 - Spiegler, Juliane A1 - Müller, Mirja A1 - König, Inke R. A1 - Göpel, Wolfgang A1 - Herting, Egbert A1 - Härtel, Christoph T1 - Early skin-to-skin contact does not affect cerebral tissue oxygenation in preterm infants <32 weeks of gestation JF - Children N2 - Aim: It was the aim of our study to determine the regional cerebral tissue oxygenation saturation (rcSO\(_2\)) as an additional monitoring parameter during early skin-to-skin contact (SSC) in preterm infants with a gestational age of <32 gestational weeks. Methods: We conducted two observational convenience sample studies using additional monitoring with near-infrared spectroscopy (NIRS) in the first 120 h of life: (a) NIRS 1 (gestational age of 26 0/7 to 31 6/7 weeks) and (b) NIRS 2 (gestational age of 24 0/7 to 28 6/7 weeks). The rcSO\(_2\) values were compared between resting time in the incubator (period I), SSC (period II) and handling nursing care (period III). For the comparison, we separated the sequential effects by including a “wash-out phase” of 1 h between each period. Results: During the first 120 h of life 38/53 infants in NIRS 1 and 15/23 infants in NIRS 2 received SSC, respectively. We found no remarkable differences for rcSO\(_2\) values of NIRS 1 patients between SSC time and period I (95% confidence interval (CI) for the difference in %: SSC vs. period I [1; 3]). In NIRS 2, rcSO\(_2\) values during SSC were only 2% lower compared with period I [median [1. quartile; 3. quartile] in %; 78 [73; 82] vs. 80 [74; 85]] but were similar to period III [78 [72; 83]]. In a combined analysis, a small difference in rcSO\(_2\) values between SSC and resting times was found using a generalized linear mixed model that included gender and gestational age (OR 95% CI; 1.178 [1.103; 1.253], p < 0.0001). Episodes below the cut-off for “hypoxia”; e.g., <55%, were comparable during SSC and periods I and III (0.3–2.1%). No FiO\(_2\) adjustment was required in the vast majority of SSC episodes. Conclusions: Our observational data indicate that rcSO\(_2\) values of infants during SSC were comparable to rcSO\(_2\) values during incubator care and resting time. This additional monitoring supports a safe implementation of early SSC in extremely preterm infants in NICUs. KW - regional cerebral oxygenation saturation KW - near infrared spectroscopy KW - skin-to-skin contact KW - preterm infants Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262290 SN - 2227-9067 VL - 9 IS - 2 ER - TY - JOUR A1 - Müller, Patrick A1 - Meta, Mergim A1 - Meidner, Jan Laurenz A1 - Schwickert, Marvin A1 - Meyr, Jessica A1 - Schwickert, Kevin A1 - Kersten, Christian A1 - Zimmer, Collin A1 - Hammerschmidt, Stefan Josef A1 - Frey, Ariane A1 - Lahu, Albin A1 - de la Hoz-Rodríguez, Sergio A1 - Agost-Beltrán, Laura A1 - Rodríguez, Santiago A1 - Diemer, Kira A1 - Neumann, Wilhelm A1 - Gonzàlez, Florenci V. A1 - Engels, Bernd A1 - Schirmeister, Tanja T1 - Investigation of the compatibility between warheads and peptidomimetic sequences of protease inhibitors — a comprehensive reactivity and selectivity study JF - International Journal of Molecular Sciences N2 - Covalent peptidomimetic protease inhibitors have gained a lot of attention in drug development in recent years. They are designed to covalently bind the catalytically active amino acids through electrophilic groups called warheads. Covalent inhibition has an advantage in terms of pharmacodynamic properties but can also bear toxicity risks due to non-selective off-target protein binding. Therefore, the right combination of a reactive warhead with a well-suited peptidomimetic sequence is of great importance. Herein, the selectivities of well-known warheads combined with peptidomimetic sequences suited for five different proteases were investigated, highlighting the impact of both structure parts (warhead and peptidomimetic sequence) for affinity and selectivity. Molecular docking gave insights into the predicted binding modes of the inhibitors inside the binding pockets of the different enzymes. Moreover, the warheads were investigated by NMR and LC-MS reactivity assays against serine/threonine and cysteine nucleophile models, as well as by quantum mechanics simulations. KW - covalent inhibitors KW - in vitro study KW - protease inhibitors KW - peptidomimetic sequence KW - warhead KW - reactivity and selectivity study Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313596 SN - 1422-0067 VL - 24 IS - 8 ER -